Long Term Follow Up After Hematopoietic Stem Cell Transplant General Guidelines for Referring Physician

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1 FRED HUTCHINSON CANCER RESEARCH CENTER/ SEATTLE CANCER CARE ALLIANCE Version March 08, 2019 LONG-TERM FOLLOW-UP AFTER HEMATO POIETIC STEM CELL TRANSPLANT GENERAL GUIDELINES FOR REFERRING PHYSICIANS These guidelines and the information they contai n are copyrighted material of Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance (“FHCRC / SCCA”), all rights reserved. They are intended sole ly for the use of referring physic ians who are involved in the care of patients who have had an hematopoietic at FHCRC / SCCA. They stem cell transplant may not be used for any other purpose, and FHCRC bility for the use of / SCCA disclaims all lia these guidelines except as expressly permitted by FHCRC / SCCA. No portion of these guidelines may be copied, displayed for redistribu commercial purposes or tion to third parties for for any non-permitted use without the prior written permission of FHCRC / SCCA. These guidelines describe generally accepted prac tices for medical care after hematopoietic stem cell transplantation. Care has be en taken to assure that the info rmation in these guidelines is rature and the experience of physicians and current and accurate based on the available lite patients at FHCRC / SCCA. R must be implemented in a ecommendations in these guidelines medically reasonable way that accounts for the specific situation of th e individual patient. Recommendations for patients who are enrolled in specific protocols may differ from the recommendations in these guidelines and will be communicated separately. Questions s or their application to particular patients concerning the recommendations in these guideline should be directed to the LTFU office. See Sec tion I of the guidelines for information on how to contact the LTFU office. Contributions to these updated guidelines were made by Mary E. D. Flowers, M.D.; George McDonald, M.D.; Paul Carpenter, M.D.; Mich ael Boeckh, M.D.; Jean Sanders, M.D.; Joachim Deeg, M.D.; Guang-Shing Cheng, MD; Jean Stern, M.S.R.D.; Leona Holmberg, M.D., P.H.D.; Mark Schubert, D.D.S., M.S.D. and Paul J. Martin, M.D. 1

2 TABLE OF CONTENTS Page I. FHCRC / SCCA 5 How to Contact the LTFU Office at II. Frequency of Office Visits 6 III. Laboratory Tests 7-9 A. Complete Blood cell counts B. Liver function tests C. Renal function tests D. Drug levels E. Fasting Lipids Profile F. Thyroid Function in Blood G. Blood cultures CMV monitoring H. CMV, EBV and Adenovirus monitoring af I. ter treatment with ATG (ATGAM or Thymoglobulin) J. Disease monitoring of Blood and Bone marrow IV. Infections Prophylaxis, Pre-emptive Ther apy, and Intravenous Immunoglobulin 10-22 A. Pneumocystis carinii Varicella zoster B. C. Encapsulated bacteria D. Cytomegalovirus E. Fungal organisms Intravenous immunoglobulin (IVIG and CMV IG) F. V. Fever of Unknown Etiology 23 VI. Evaluation of Respiratory Problems and Lung Infiltrates 24-26 A. Diagnostic evaluation (Tests recommended for BAL and transbronchial biopsy specimens) Bronchoalveolar lavage B. C. Thoracoscopic lung biopsy rsistent infiltrates with negative BAL) (Evaluation of pulmonary nodules or pe Evaluation of Diarrhea and Other GI Problems 27-29 VII. A. Diagnostic evaluation and initial management B. Procedures for gastrointe stinal endoscopic biopsy C. Algorithm for Evaluation of Acute Onset Diarrhea in Transplant VIII. Treatment of Specific Infections 30-31 A. Cytomegalovirus Varicella zoster B. Pneumocystis carinii C. 2

3 IX. Vaccinations 32-40 X. Chronic Graft-Versus-Host Disease (GVHD) 41-51 Categories of acute and chronic GVHD (Table 1) A. B. Signs and symptoms of chronic GVHD (Table 2) C. How to diagnosis chronic GVHD D. How to score each organ/site aff ected by chronic GVHD (Appendix D) E. How to assess overall severity of chronic GVHD – Global assessment of chronic GVHD severity (Table 3) F. Other Laboratory testing and diagnostic indicators used in chronic GVHD G. Monitoring and other chronic GVHD information H. Guidelines for treatment of chronic GVHD I. Monitoring and Management of Bronchi olitis Obliterans Syndrome after HCT General Guidelines for Prevention of Oste oporosis including during treatment with XI. corticosteroids 52-57 A. Patient monitoring B. Elemental Calcium requirements C. Vitamin D requirements D. Magnesium Exercise E. F. Gonadal hormone replacement G. Bisphosphonates (Adults Only) Calcitonin as secondary therapy for osteoporosis H. I. Low Sodium Diet J. Endocrinology XII. Hyperlipidemia 58-62 Hypertension 63-66 XIII. XIV. Recurrent Malignancy 67 XV. Secondary Malignancies 68 XVI. Other Complications 69-79 A. Gonadal hormone insufficiency B. Endocrine abnormalities plications C. Ocular com D. Oral complications and gui delines for dental care E. Renal insufficiency F. Neurological complications G. Bone complications H. Chronic Pulmonary complications Hepatobiliary complications I. Gastrointestinal complications J. 3

4 XVII. Blood Product Transfusion 80 XVIII. Viral Hepatitis 81-84 A. Hepatitis B B. Hepatitis C XIX. Iron Overload 85-89 A. Evaluation of iron overload after HSC Transplant B. Phlebotomy after transplant Chelation therapy C. Vitamins, Mineral Supplements 90 XX. Calcium and Vitamin D A. B. Magnesium 91-93 XXI. Diets and Other Nutritional Guidelines A. Diet for immunosupp ressive patients B. Additional dietary recommendations 1. Diet for patients receiving treatment with corticosteroids 2. Diet for patients with GVHD of gastrointestinal tract XXII. Naturopathic (Herbal and Nu trient supplement preparations) 94 Return to Seattle for Long-Term Follow-Up Evaluation 95 XXIII. XXIV. How to Send Specimens for Testing at FHCRC / SCCA 96 XXV. References 97-100 APPENDICES A. FAX Consult Request 101 B. LTFU Alert 102 C. Skin Assessment Form 103 D. Chronic GVHD Scoring Form 104-106 E. Skin Thickness Assessment (patients with scleroderma) 107 F. Flexibility 108 4

5 I. HOW TO CONTACT THE LONG-TERM FO LLOW-UP OFFICE AT THE FRED HUTCHINSON CANCER RESEARCH CENTER AND SEATTLE CANCER CARE ALLIANCE We offer telephone consultation to all physicians caring for patients who have been Research Center (FHCRC) and Seattle Cancer transplanted at the Fred Hutchinson Cancer oped a Consultation FAX form (Appendix A) in Care Alliance (SCCA). We have devel order to facilitate communication between your office and the LTFU office. This form can be filed in your medical records and sent to 1-800-376-8197 (toll-free, USA and Canada) whenever you need assistance. All efforts will be made to respond within 48 hours on regular workdays. For urgent questions from 8:00 a.m. to 4:00pm Pacific Time on workdays, you can call (206) 667-4415. For urgent questions after hours and on weekend and holidays, please call (206) 606-7600 and ask fo r the transplant charge nurse . The nurse will triage the call and page the appropriate physician to assi st you. For non-urgent in quiries, you may also contact our LTFU Office at [email protected] g. Please include the patient identification and your phone number to contact you back. Information about LTFU services can be accessed on our website at; http://www.fhcrc.org/science/ clinical/ltfu/contact.html . by typing "Information , then clicking in the FHCRC.LTFU You can also find us on Google for Physician" in the left hand navigation column. We also request that you notify us immediatel y after certain types of events. We have developed an LTFU Alert FAX form in order to facilitate the notifica tion from your office to the LTFU office (Appendix B). This form can be filed in your medical records and sent to 1-800-376-8197 (toll-free, USA and Cana da) to report the following events : 1. Death of the patient 2. Diagnosis or change in therapy of chronic GVHD 3. Recurrent malignancy 4. Diagnosis of myelodysplasia or secondary malignancy 5. Surgery or biopsy planned for evaluati on of suspected secondary malignancy 6. Change of M.D. 7. Change of M.D. office address 8. Change of patient name or address refrain from contacting them Requests from patients that we 9. 5

6 II. FREQUENCY OF OFFICE VISITS transplant patients should be followed with weekly office After returning home, hematopoietic visits for one month. The interval time between visits can be extended to 2 weeks for 2 months and then monthly for 6-12 months if the patien t's medical condition remains stable. Vital signs and body weight should be monitored at each clinic visit. Weight and height should be recorded nd development in pediatric patients. Patients at monthly intervals for assessment of growth a who have had an allogeneic hematopoietic st em cell transplant should be monitored for development of chronic graft-ve rsus-host disease (GVHD). Help ful tips on how to assess and score chronic GVHD can be found at http://www. fhcrc.org/ltfu by clicking on "Information for n. Then click on the right blue “GVHD Tips & Physicians" in the left hand navigation colum c GVHD Assessment and Scoring form (Appendix Forms" button. Here you will find the Chroni D), Range of Motion Assessment form (Appendi x F), Skin Thickness Assessment form/ Rodnan Score for patients with sclerosis or fasciitis (A ppendix E) and other helpful information. More detailed information about chronic GVHD is outlined in Section X. worsen, please contact the LTFU office If manifestations of chronic GVHD develop or (Appendix A). 6

7 III. LABORATORY TESTS A. Complete blood cell counts (CBC), differential and platelet counts should be measured ganciclovir (or ValGANCiclovir), daily at each office visit. Patients receiving Trimethoprim/Sulfamethoxazole (TMP/SMX), Cellcept (mycophenolate mofetil), and a CBC at weekly intervals or more often other myelosuppressive medication should have when counts are low. B. Liver function tests (LFT's) (alkaline phosphatase, ALT, AST, LDH and total bilirubin) should be measured at each office visit. Patients receiving immunosuppressive medications or other hepatotoxic drugs such as itraconazole, voriconazole, INH, should have LFT's measured at two-week interv als or more often when abnormalities are present. If drug toxicity suspected, blood levels should be checked if available. C. Renal function tests (serum creatinine, BUN, and magnesium) should be measured at each office visit. Patients receiving cyclospor ine, tacrolimus (formerly known as FK506), amphotericin or other nephrotoxic drugs should have renal function monitored at weekly intervals or more often when abnormalities are present. Dose adjustment may be needed for medications such as cyclosporine, tacrolimus, ganciclovir, valacyclovir, acyclovir, among others. : D. Drug levels vels should be monito red at least twice Cyclosporine or tacrolimus (FK506) blood le monthly until levels remain stable within th e therapeutic range. Sirolimus (rapamycin) should be monitored weekly until levels remain stable within levels maintained no higher than 10 ng/dL). Sirolimus, cyclosporine or tacrolimus (FK506) levels should be checked more frequently when toxicity is suspect ed (i.e., new onset of thrombocytopenia, worsening anemia, abnormal renal function, abnormal LFT's, development of tremors or other neurological symptoms), when blood leve ls are outside the therapeutic range or when manifestations of GVHD is not under control. ls should be monitored at monthly intervals until levels remain Itraconazole blood leve stable within the therapeutic range. Itra conazole levels should be checked more frequently when results are outside the ther apeutic range and when results of LFT's are Voriconazole, posaconazole and the oth er azoles should be used with caution abnormal. during treatment with sirolimus. If treatment with azoles is warranted please contact the LTFU office to discuss sirolimus dose adjustment. E due to increased risk of . Fasting lipids profile is recommended periodically cardiovascular disease and increa sed risk of metabolic syndrome in transplant survivors. In patients receiving sirolimus, tacrolimus or cyclosporine, monthly fasting lipids profile is recommended until acceptable values are achieved, thereafter, monitoring may be re often if clinically indicated. decreased to every 3 to 6 months, or mo 7

8 . Thyroid function in blood F should be monitored yearly due to increased thyroid disease radiolabeled iodine antibody therapy, thyroid after transplant. For patients who received function should be checked sooner at 3 and 6 mo year after transplant, nths within the first and other times as clinically indicated. should be drawn whenever clinically G. Blood cultures indicated. For high risk patients (i.e., treatment with prednisone mg/kg/day), weekly surveillance at a dose of more than 1 blood cultures may be beneficial. H. CMV monitoring ll patients who are at risk of CMV in blood should be instituted for a disease after transplant. CMV seropositive recipients of non-cord blood allogeneic transplants or CD34 selected autologous transplants s hould have CMV monitored in blood weekly until day 100 . CMV seropositive cord blood recipients after transplant twice weekly until day 100 after transplant. CMV should have CMV monitored seronegative recipients of cord blood should have CMV monitored weekly until day 100 days after transplant. CMV seronegative non-cord bloo d transplant recipients should be monitored weekly until day 60 after transplant. until weekly, itoring in blood continued, initially After day 100 posttransplant, CMV mon recipients at risk of late CMV disease which allogeneic 1 year after transplant for include:  CMV-seropositive recipients rece iving steroids for chronic GVHD Patients who were treated for CMV early after transplant.   Cord blood transplant recipients The frequency of CMV blood surveillance afte r day 100 posttransplant may be decreased for non-cord transplant recipien ts. In patients receiving treatment with <1mg/kg/day of llance tests after day corticosteroids and who have had three consecu tive negative survei CMV monitoring may be sufficient. If treatment with every other weekly 100, corticosteroid is increased or additiona l systemic immunosuppressive treatment for chronic GVHD is added, weekly CMV monitoring should be resumed as long as clinically indicated. eased risk of CMV inf ections and thus are Cord blood transplant recipients have incr ent in addition to CMV blood surveillance recommended to receive prophylactic treatm (see section IV, D). CMV surveillance tests: CMV monitoring can be performed using CMV DNA by PCR or hybrid capture, pp67 mRNA, or pp65 antigenem ia (culture based assays are not mmended over pp65 antigenemia for patients appropriate for monitoring.) PCR is reco who have samples shipped to the FHCRC or to other laboratories requiring overnight shipping. 8

9 I. CMV, EBV and Adenovirus Monitoring A fter Treatment with Anti-Human Thymocyte Globulin (ATG) (ATGAM or Thymoglobulin) Un Differently per Protocol less Specified Weekly blood monitoring by PCR for EBV, adenovi rus, and CMV is recommended for at least 6 3 months after last dose of ATG or absolute lymphocyte count >300 cells/mm , whichever is later for recipients at increase risk for viral disease which include:  Patients receiving ATG for the treatment of steroids refractory GVHD  Haplo identical, cord blood or CD 34+ select ed transplants recipients who received ATG as part of conditioning J. Disease Monitoring of Blood and Bone marrow. Bone Marrow: Bone marrow should be evaluated at one year after transplant. Testing should include evaluation of morphology and immunophenotypi molecular testing ng, cytogenetics and as applicable. Subsequent bone marrow ev aluations should be done as clinically indicated such as: The CBC or platelet coun t shows any abnormalities   If the most recent marrow evaluation or other testing showed any evidence of persistent malignancy  If the patient has a disease for which main tenance treatment would be indicated if r a previous evaluation with no evidence of malignant disease were discovered afte cells. Blood: Patients transplanted for chronic myeloid leukemia (CML) or Philadelphia chromosome- positive acute lymphocytic leukemia (Ph-positive ALL) should have blood tested for BCR/abl transcripts at 6 month intervals for the splant and then at first 2 years after tran yearly intervals. When BCR/ abl transcripts are detected in the blood, a marrow aspirate should be evaluated by cytogenetic tes ting, morphology and molecular testing. rs, please contact the LTFU If recurrent malignancy occu office for consultation for specific treatment and follow- up recommendations (Appendix A). 9

10 IV. INFECTIONS PROPHYLAXIS, PREEM PTIVE THERAPY AND INTRAVENOUS IMMUNOGLOBULIN some degree of immunodeficienc y, especially during the first All transplant recipients have Bacterial, fungal a nd viral infections occur most frequently 6-12 months after the transplant. GVHD, most patients ha ve adequate immune during this time interval. In the absence of reconstitution by one year af ter the transplant. Patients with chronic GVHD remain immunodeficient and have a hi gh risk of infections. A. Pneumocystis jiroveci pneumonia (PCP) All patients should receive prophylaxis agai nst PCP for at least 6 months after the transplant or until all immunosuppressive medi cations have been discontinued, whichever occur later. The preferred drug is trimet hoprim-sulfamethoxazole administered according to the following regimen:  Adults: 1 double strength tablet p.o. b.i.d. on 2 consecutive days weekly  Children > 20 kg: 1 single strength tabl et p.o. b.i.d. on 2 consecutive days weekly  ethoprim component in two divided doses on Children < 20 kg: and 5 mg/kg/day of trim 2 consecutive days weekly. Patients who are allergic to sulfa should be desensitized whenever possible. If desensitization is not feasible, Dapsone s hould be administered at a dose of 50 mg p.o. b.i.d. daily for adults and 1 mg/kg/day in two divided doses (up to 100 mg/day) for children. Before starting treatment with Dapsone , patients must be tested to rule out G-6- PD deficiency. For patients who cannot to lerate Bactrim or dapsone, atovaquone or pentamidine IV may be given. Atovaquone: Dosing Adults and pediatric patients > 50 kg: 1500 mg oral suspension, once daily, to be taken with a meal. Pediatric patients less than or equal to 50 kg : to be taken with a meal. 30 mg/kg, once daily, Pentamidine Dosing Pediatric: Children < 24 months: 4 mg/kg/dose (max 300 mg) IV ove r 90 minutes every two weeks. Children > 2 years: 90 minutes every four weeks. 4 mg/kg/dose (max 300 mg) IV over Adult: 300 mg IV over 90 minutes, every four weeks. 10

11 B. Varicella-zoster virus All VZV-seropositive patients (via vaccine or via disease) should receive prophylaxis ter the transplant or until 8 with acyclovir or valacyclovi r throughout the first year af months after systemic immunosuppressi on ends, whichever is longer. Acyclovir should be administered accord ing to the following regimen (assuming adequate renal function):  Weight > 40 kg, receiving < 0.5 mg/kg/day of corticosteroids: 800 mg P.O. B.I.D.* 2 y of corticosteroids: 600 mg/ m P.O. B.I.D.  Weight < 40kg, receiving < 0.5 mg/kg/da stered according to the following regimen: Alternatively, valacyclovir should be admini Weight > 40 kg, receiving > 0.5 mg/kg/day of  corticosteroids: 500 mg P.O. B.I.D*. corticosteroids: 250 mg P.O. B.I.D.  Weight < 40 kg, receiving > 0.5 mg/kg/day of *Note: In VZV seropositive/HSV seronegative , patients > 40 kg, lower doses of prophylaxis mg/day of valacyclovir. For patients < 40 kg, are sufficient, 800 mg/day of acyclovir or 500 2 the dose of acyclovir should be 300 mg/m (maximum 400 mg) P.O. B.I.D. It is difficult to prevent VZV transmission to susceptible patients because infected r 24-48 hours before the rash appears. The incubation period individuals are contagious fo ingles) remain contagious ls with VZV (chickenpox or sh of VZV is 10-21 days. Individua until all skin lesions have crusted. All patients exposed to chickenpox or zoster dur ing the first year afte r the transplant or dications should be evaluated. VZV- during treatment with immunosuppressive me seronegative patients and thos e not receiving prophylactic acyclovir should be treated with valacyclovir from days 3 to 22 after exposure unless treatment with ganciclovir, foscarnet or cidofovir is being given for another reason. Vala cyclovir should be given at a dose of 1gm p.o. t.i.d. for patients > 40 kg and at a dose of 500 mg p.o. t.i.d. for patients < 40 kg. In adults and children without ad equate oral intake, acyclovir can be 2 l function is normal. In IV every 8 hours if rena administered at a dose of 500mg/m seronegative recipients, admini stration of VZIG within 96 ho urs of exposure should also be used, if available, in addition to valcyc lovir as outlined above. Patients exposed to chickenpox or zoster during prophylaxis with ac yclovir or valacyclovir must be followed closely for the development of VZV infection. Vaccination against VZV should be delayed (See vaccination Section IX for details). C. Encapsulated bacteria Patients with chronic GvHD are highly suscep tible to recurrent bacterial infections, especially with encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. Susceptibility to these organisms may be due to persistent low levels of opsonizing antibodies , low CD4 counts, poor reticuloendothelial function, and long-term use of immunosuppressive therapy, es pecially corticosteroids, ytosis. Long-term chemoprophylaxis is with their suppressive effects on phagoc ng due to unpredictable prot recommended in this setti ection provided by vaccination, 11

12 which is also recommended after transplant. Due to the emergence of penicillin resistance axis in these patients), trimethoprim- (and the concomitant need for PCP prophyl sulfamethoxazole (TMP-SMX) is recommende d as first-line dr ug for chemoprophylaxis for infections with encapsulated bacteria. If TMP-SMX is not tolerated, the traditional penicillin-based prophylaxis should be substi tuted for encapsulated bacteria and dapsone also should be prescribed to provide PCP prophylaxis. Other patient groups who should be consider ed for encapsulated organism prophylaxis include those who are:  Without GVHD but are receiving glucocor ticoid or other immunosuppressive medications. With persistent or recurrent manifesta  tions of chronic GVHD without ongoing use of immunosuppressive medications Being treated for relapsed or progr essive malignancy after transplant   Surgically and/or functionally asplenic (see below for more details).  Patients who are age> 65 years old post- allogeneic stem cell transplantation. Patients receiving systemic immunosuppr essive therapy for chronic GVHD should receive antibiotic prophylaxis ag ainst infection with encapsulated bacteria for at least 6 months after discontinuati on of all immunosuppressive me dications. Double-strength g sulfamethoxazole) given as a single dose (DS) trimethoprim-sulfamethoxazole (800m and encapsulated bacteria in daily is adequate for preventi on of infection with both PCP adults. cillin VK (Pen-Vee-K) should be given for In patients with sulfa allergies, Peni encapsulated bacteria prophylaxis (see Ta ble below). Children < 30 kg who do not (TMP/SMX) should re ceive Penicillin VK tolerate daily trimethoprim-sulfamethoxazole (See Table below). Additional medication is required fo r PCP prophylaxis in patients who receive penicillin instead of daily trimet hoprim-sulfamethoxazole (TMP/SMX). (See Section IV.A) Table - Penicillin VK dosing for enca psulated bacterial prophylaxis: g 750 m g ) PO BID Adults and Children ( > 60 k PO BID g Adults ( < 60 k 500 m g ) and Children (40 to 60 k g ) g ) 250 m g PO BID Children (20 to 40 k 125 mg PO BID or Children (< 20 kg) (50m ) g /k g /da y For more information, see the Standard ction “Antibiotic Practice Guideline se Allogeneic Patients with Chronic GVHD Prophylaxis for Encapsulated Bacteria in Requiring Immunosuppressive Therapy” 12

13 Antimicrobial prophylaxis for asplenic patients Patient education is paramount to prevent fata l infections in asplenic patients. Studies have shown that 11% to 50% of postsplen ectomy patients remain unaware of their increased risk for serious infection or the a ppropriate health precautions that should be undertaken. Important education points include the following:  Persons without a functioning spleen are mo re susceptible to certain infections.  The risk of infection is life-long, but it is highest in the first y ear or two after the surgery. ), patients should seek  fever associated with rigors If unwell (particularly in case of prompt medical attention pidly progressive and life- . Infections can be ra threatening in a matter of hours. The us e of prophylactic or preemptive measures should never be allowed to engende r a false sense of security.  Travel-related infections (such as babesiosis and malaria) are particularly important; adherence to antimalarial prophylaxis cannot be overemphasized.  All physicians caring for the patient should be informed of the condition, no matter how long after the splenectomy. Antimicrobial regimens are the same as for pr evention of encapsulated bacteria in patients with chronic GVHD, and include daily Tr imethoprim/Sulfamethoxazole (TMP/SMX) or VK provides no protection against PCP; thus twice-daily Penicillin VK therapy. Penicillin dapsone or other PCP prophylaxis must be added. The duration of antibiotic prophylaxi s in the asplenic patient afte r transplant is dependent of the presence of chronic GVHD (See Table below). Table - Duration of propylaxis for encapsualt ed organism in asplenic patients according to chronic GVHD HCT recipients with chronic GVHD Until 6 months after immunosuppression d/c’d OR until age 6 OR 2 years after splenectomy (whichever occurs later) 1 year after BMT OR until age 6 OR 2 years after All HCT receipients without chronic splenectom GVHD (allo, auto, s y n g enic) (whichever occurs later) y Antimicrobial prophylaxis should also be c onsidered for patients AT ANY TIME post- splenectomy during travel to sites where me dical care will not be rapidly accessible. Preemptive therapy for the post-splenectomy patient with fever and rigors Another strategy that has been advocated is the provision of "standby" antipneumococcal antibiotics; this strategy may be particularly relevant for patients who are not receiving prophylaxis. Under this strategy, the patient re tains a personal supply of antibiotics to be taken at the first sign of respirat ory illness, fever, or rigors, particularly if there is likely to be a delay in medical evaluation. There is currently no evidence that such early self- th post splenectomy sepsis (PSS). In fact, treatment will lower the mortality associated wi the literature series with the lowest mort ality reported to date emphasized patient 13

14 education, close follow-up, and prompt physicia earliest sign of even n intervention at the their own supply of antibiotics, medical help minor infection. Thus, even if patients have should be sought immediately , at which time a physician should decide whether to continue antibiotic therapy. Recommended antibiotics and doses that may be useful in preemptive approaches include the following:  Adults: Amoxicillin 500 mg tablets; take 4 tablets (2 grams) and report immediately for medical attention Levofloxacin 500 mg tablets; take 1 tablet and report immediately for medical attention  Children 20-40 kg: Amoxicillin 250 mg tablets; take 4 tablets (1 gram) and immediately for medical attention report Children < 20 kg: Amoxicillin 50 mg /kg administered as chewable tablets  and report immediately for medical attention For penicillin-allergic children, consider Bactrim or other drugs as clinically indicated. Empiric therapy for post-splenectomy seps is (PSS) or other serious infections the cornerstone of essive intervention is Early recognition of infection followed by aggr PSS management. Initial empiric antimicrobial therapy for the splenectomized patient should always include a with unexplained fever, rigors, and other systemic symptoms N. broad-spectrum antibiotic active against S. pneumoniae, H. influenzae , and ith high-level penicillin-resistant meningitidis such as ceftriaxone. In areas w lly, particularly in cases with suspected pneumococci, vancomycin may be added empirica or proven meningitis 14

15 D. Cytomegalovirus (Section III H and I for monitoring frequency). 1. Who Should Receive Pre-emptive Therapy for CMV Recipients of non-cord blood allogeneic transplants after day 100, ganciclovir  should be given preemptively when CMV DNA is detected in the blood by PCR tests with > 250 IU per mL (equivalent to >1000 numbers of copies per mL), or rising DNA levels (> 5x baseline within one month) or by an antigenemia test with any numbers of positive cells per slide. See Table 1  Recipients of CD34 select ed autologous transplants, ganciclovir should be given preemptively when CMV DNA is dete cted in the blood by PCR tests with > 25 IU per mL (equivalent to >100 numb ers of copies per mL) or by any level of antigenemia test before 100 days post transplant. See Table 1 Table 1. Pre-emptive Regimen for CMV Reacti vation Among NON-Cord Blood Recipients with Adequate Renal Function After 100 days to 1 year After Transplant INDUCTION MAINTENANCE Alternative Preferred Alternative Preferred Ganciclovir Ganciclovir Foscarnet Foscarnet 5 mg/kg IV Q 12hrs 90 mg/kg 5 mg/kg IV Q DAY 90 mg/kg IV Q 12hrs IV Q DAY OR OR ValGANCiclovir (ONLY for patients with ValGANCiclovir (ONLY for no good oral intake, no active gut GVHD, patients with good oral significant liver disease and no severe intake, no active gut GVHD, diarrhea): no significant liver disease and no severe diarrhea): Adults and Peds > 50 kg: Adults and peds > 50 kg: 900 mg PO Q 12 hrs 900 mg PO Q Day ≥ 40 to < 50kg: Peds Peds 40 to < 50 kg: ≥ 675 mg PO Q 12 hrs 30 to < 40kg: Peds ≥ 675 mg PO Q Day Peds ≥ 30 to < 40 kg: 450 mg PO Q 12 hrs 20 to <30 kg: ≥ Peds 450 mg PO Q Day ≥ Peds 20 to <30 kg: or 450 mg PO Q 12 hrs Liquid 14 mg/kg Q 12 hrs 450 mg PO Q Day or Liquid 14 mg/kg QD Peds 15 to <20 kg: ≥ Peds 15 to <20 kg: ≥ or 225 mg PO Q12 hrs (= ½ pill) Liquid 14 mg/kg Q12 hrs 225 mg PO QD (= ½ pill) or Liquid 14 mg/kg QD Peds ≥ 10 to < 15 kg: Peds ≥ 10 to < 15kg: Liquid 14 mg/kg Q12 hrs Liquid 14 mg/kg QD Duration: Maintenance therapy should be Duration: Induction therapy should be given for 1 week or until a decrease of PCR or antigenemia levels have been given for at least 2 weeks after induction documented, whichever is later. therapy has been completed. Preemptive therapy may be discontinued when the surveillance test is negative after a minimum of 3 weeks of therapy. Shorter courses may be appropriate for subsequent episodes of CMV reactivation. Please consult the LTFU office for questions (206-667-4415)  Recipients of cord blood transplant af ter day 100, ganciclovir should be given preemptively when CMV by PCR DNA testing is detected in > 250 IU per mL (equivalent to > 1000 copies per mL) or rising DNA levels (> 5x baseline within one . See additional information for Cord Blood Transplant recipients month) 15

16 including CMV prophylaxis after day 100 below. See Table 2 Table 2. Pre-emptive Regimen for CMV Reacti vation Among Cord Blood Recipients with Days to 1 Year After Transplant Adequate Renal Function After 100 INDUCTION MAINTENANCE Preferred Alternative Preferred Alternative Ganciclovir 5 mg/kg IV Q DAY Ganciclovir 5 mg/kg IV Q 12hrs Foscarnet Foscarnet 90 mg/kg IV Q DAY 90 mg/kg IV OR OR Q 12hrs * ValGANCiclovir (ONLY for ValGANCiclovir *( ONLY for patients with good oral intake, no patients with good oral intake, no active gut GVHD, active gut GVHD, no significant no significant liver disease and no severe liver disease and no severe diarrhea): diarrhea): Adults and Peds > 50 kg: Adults and Peds > 50 kg: 900 mg PO Q Day 900 mg PO Q 12 hrs ≥ Peds Peds ≥ 40 to < 50kg: 40 to < 50 kg: 675 mg PO Q 12 hrs 675 mg PO Q Day ≥ Peds 30 to < 40 kg: Peds ≥ 30 to < 40kg: 450 mg PO Q 12 hrs 450 mg PO Q Day Peds 20 to <30 kg: Peds ≥ 20 to <30 kg: ≥ 450 mg PO Q 12 hrs 450 mg PO Q Day or or Liquid 14 mg/kg Q 12 hrs Liquid 14 mg/kg QD Peds 15 to <20 kg: ≥ Peds ≥ 15 to <20 kg: 225 mg PO Q12 hrs (= ½ pill) or or 225 mg PO QD (= ½ pill) Liquid 14 mg/kg Q12 hrs Liquid 14 mg/kg QD Peds 10 to < 15 kg ≥ 10 to < 15kg: ≥ Peds Liquid 14 mg/kg QD Liquid 14 mg/kg Q12 hrs Duration: Maintenance therapy sh ould be given for at least Duration: 1 week or until a decrease of PCR or antigenemia levels have been documented, 2 weeks after induction therapy has been completed. whichever is later. Preemptive therapy may be discontinue d when the surveillance test is nega tive after a minimum of 3 weeks of therapy. Shorter courses may be appropriate fo r subsequent episodes of CMV reactivation. Please consult the LTFU office for questions (206-667-4415) Upon discontinuing pre-emptive therapy, resume prophylaxis for CMV (see Table 3) * Consider evaluation for CMV resistance in pa tients who develop CMV viremia on ValGANCiclovir maintenance, particularly in those w ith poor response to ganciclovir induction. 16

17 Monitoring during treatment:  CBC and differential must be measured with in 24 hours before initiating treatment.  CBC and differential must be measured 2- 3 times weekly during treatment with ganciclovir. 3  . neutrophil count (ANC) is <1,500/mm Daily CBC is mandatory if the absolute 3 iclovir is started, alternative If ANC <1,000/mm before ganciclovir or ValGANC  therapy is foscarnet.  Renal function tests must be measured at least weekly. Dose adjustment and other precautions during treatment : 3  STOP ganciclovir or ValGANCicl ovir if the ANC is below 1,000/mm and consider foscarnet.  AVOID using ganciclovir, ValGANCiclovir and fo scarnet concurrently with acyclovir. Please contact the LTFU office (Appendix A) for consultation. Ganciclovir, ValGANCiclovir and foscarnet MUST be adjusted for renal dysfunction.  If quantitative CMV by PCR or antigenemia levels rises for more than 3 weeks on lovir or foscarnet treatment, antiviral drug resistance continuous ganciclovir/ValGANCic should be considered.. Testing for antiviral se nsitivity or molecular screening for UL97 and UL54 mutations should be considered as we ll as changing to other drugs. Clinical Research Center Infectious Disease Service management with the Fred Hutchinson Cancer t the LTFU office (Appendix A). may be considered. Please contac 17

18 ve Cord Blood Transplant Recipients 2. CMV Prophylaxis After Day 100 in Seropositi CMV seropositive cord blood transpla nt recipients remain at signifi cantly increased risk for CMV reactivation after day 100 after tran splant. Therefore, antiviral prophylaxis and continued close monitoring after day 100 (see Table 3 below) are recommended for all CMV seropositive cord blood transplant recipients. Table 3: CMV 1 Year for CMV-seropositive Cord Blood Prophylaxis and Monitoring after Day 100 to Recipients with Prior Posttransplant CMV Reactivation PREFERRED ALTERNATIVE Unable to MONITORING Able to tolerate PO Able to tolerate PO tolerate PO BLOOD DOSING † Weekly: ≥ ValGANCiclovir 50 kg Adult or Pediatric Valacyclovir* Ganciclovir 2 grams PO TID 5 mg/kg IV 900mg PO QD CMV PCR, Q DAY Creatinine, † CBC with ValGANCiclovir 40 to <50 kg ≥ Pediatric Valacyclovir* Differential. 2 grams PO TID 675 mg PO QD(=1½ pills) † ≥ ValGANCiclovir 30 to <40 kg Pediatric Valacyclovir* 1 gram PO TID 450 mg PO QD † ValGANCiclovir Pediatric ≥ 20 to < 30 kg Valacyclovir* 1 gram PO TID 450 mg PO QD) or Liquid 14 mg/kg QD † ValGANCiclovir Pediatric ≥ 15 to < 20 kg Acyclovir* 2 600 mg/m 225 mg PO QD(= ½ pill) PO QID or Liquid 14 mg/kg QD † ValGANCiclovir Pediatric ≥ 10 to < 15 kg Acyclovir* 2 600 mg/m Liquid 14 mg/kg QD PO QID should be instructed to † Absorption of ValGANCiclovir is significantly enhanced when taken with food; thus patients take ValGANCiclovir with food. Patients with poor or al intake, severe diarrhea/gut GVHD are NOT good candidates for ValGANCiclovir and should receive IV ganciclovir daily. * Valacyclovir tablets should NOT be crushed. Oral acycl ovir suspension has poor bioavailability and is not a preferred choice. 18

19 Prophylaxis and Monitoring after Day 100 for CMV-seropositive Cord Blood Table 4: CMV Recipients without Prior Posttransplant CMV Reactivation MONITORING PREFERRED ALTERNATIVE BLOOD Unable to Able to tolerate tolerate PO DOSING PO intake intake ‡ Ganciclovir 50 kg Valacyclovir* Adult or Pediatric Acyclovir ≥ 2 5 mg/kg 500 mg/m 2 grams PO TID IV Q DAY IV Q 8 hr 40 to <50 kg Valacyclovir* ≥ Pediatric 2 grams PO TID Weekly: ≥ Pediatric 30 to <40 kg Valacyclovir* CMV by PCR 1 gram PO TID Creatinine and CBC with ≥ Pediatric Valacyclovir* 20 to < 30 kg Differential 1 gram PO TID ≥ 15 to < 20 kg Acyclovir Pediatric 2 600 mg/m PO QID Pediatric ≥ 10 to < 15 kg Acyclovir 2 600 mg/m PO QID * Oral Valacyclovir is the preferred agent and is av ailable in tablets or compounded liquid formulation for children. Crushing tablets is NOT recommended. ‡ If patients cannot tolerate oral tablets or liquid formulation, they should receive IV Acyclovir (adjusted to ideal body weight). Oral acyclovir suspension has poor bioavailability, thus not a preferred choice. Dose adjustment and other precautions during treatment : 3 and consider  ovir if the ANC is below 1,000/mm STOP ganciclovir or ValGANCicl acyclovir, valacyclovir or foscarne t, as clinically indicated. foscarnet and valacyclovir concurrently  AVOID using ganciclovir, ValGANCiclovir, with acyclovir. Please contact the LT FU office (Appendix A) for consultation. GANCiclovir, valacyclovir and acyclovir MUST be adjusted Ganciclovir, foscarnet, Val  for renal dysfunction. E. Fungal organisms The current standard practice for antifungal pr ophylaxis is to administer fluconazole (400 mg/day) until day 75 after an allogeneic or CD34 selected autologous transplant or until engraftment and resolution of mucositis after an unselected autologous transplant. This strategy has been shown to reduce the incidence of candi demia and candidiasis-related mortality. Fluconazole does not prevent infection with Aspergillus and other mold species. 19

20 F. Intravenous immunoglobulin (IVI G) replacement and adjunctive therapy A) Use of IVIG after hematopoietic ce ll transplantation (HCT) from day 100 through 1 year. [1-9] Reported IVIG studies are listed in th e end of the LTFU general guidelines . For information regarding IVIG administrati on before100 days after transplant see Standard Practice Committee guidelines. 1. Dosing and administration of prophylactic IVIG: a. For allogeneic patients transplanted fo r myeloma, low grade lymphoma or CLL, monthly intervals to maintain serum IgG levels above Administer IVIG 400 mg/kg at 400 mg/dL for 10 months after transplant prior to start of vaccinations. b. For primary immune deficiency disease (PID): 1,2 1 Pre-infusion IgG serum level IVIG dosing regimen (mg/dL) Begin at 200 mg/kg/every 2 weeks and 600 – 1000 wean to 400 mg/kg/every 4 weeks if g hs remain satisfactor y trou 300 mg/kg/every 2weeks up to 500 mg/kg < 600 2 y k ever wee 400 mg/kg/every 4 weeks until B cell >1000 function full y restored 1 When low levels are attributable to increased losses (e.g. chronic diarrhea) both IVIG dose and frequency should be increased. 2 For pediatric patients the maximum dose of IVIG is 40 grams. For pediatric patients whose central line is only being used for IVIG prophylaxis, transition to subcutane ous human immunoglobulin preparation (Hizentra  ) may be considered under the approval and guidance of Pediatric Service. I mmunolo gy c. for allogeneic patients with haploidentical donors Other than above diseases, or cord blood transplant, pediatric pa tients with unrelated donors or for patients with ongoing infections or chronic GVHD with severe hypogammaglobulinemia: Continue to check IVIG levels monthly and administer IVIG 400 mg/kg at monthly intervals to maintain serum IgG levels a bove 400 mg/dL. Continue for 10 months after transplant prior to anticipat ed start of routine vaccinations. d. IVIG should be held two months before the annual posttransplant evaluation to assess immune reconstitution. (e.g. serum immunoglob ulins levels and other immunological panel). e. Select immunoglobulin product according to pr ecautions to decrease adverse effects as applicable (see cautionary note below). 20

21 B) Use of IVIG after hematopoietic ce ll transplantation (HCT) > 1 year Dosing and administration of prophylactic IVIG beyond 1 year For allogeneic patients with Chro nic GVHD beyond 1 year with recurrent sinopulmonary infections and p ersistent hypogammaglobulinemia Recommend to check IgG level monthl y and administer IVIG 400mg/kg at monthly intervals to maintain serum IgG levels > 400mg/dl C) IVIG for treatment of CMV pneumonia: There is no convincing efficacy data to add standard IVIG to antiviral therapy for CMV pneumonia after HCT. The overall benefit of CMV IgG combined with antiviral for treatment of CMV pneumonia by some but not all has been reported investigators. Due to high mortality asso ciated with CMV pneumonia, some experts recommends antiviral therapy combine with CMV IgG as follows:  CMV-IVIG may be administ ered at 150mg/kg every ot her day for 2 weeks (7 doses) followed by weekly administration for 4 additional weeks in combination with anti-CMV medication.  When high titer CMV-IVIG product (CytoGam) is not available, some experts has recommended using standard IVIG at 500mg/kg given at the same schedule as described above for CMV IgG. Premedications before IVIG administration: D) IVIG infusion (i.e., fever, chills, nausea, Given the high incidence of side effects of emesis, headache, myalgias, rash a anaphylaxis), nd hypotension without premedication with acetoaminophen and anti -histaminices (i.e., diphenhydramine) is recommended. Contraindication for IVIG: E) 1. Antibodies to IgA present 2. Anaphylaxis or severe prior reaction to immunoglobulin or serum therapy. F) Cautionary note about IVIG: ed a contraindication IgA deficiency: IgA deficiency is consider for IVIG use because ich increases their risk of anaphylaxis patients may develop IgE antibodies to IgA wh if exposed to a product containing significan t quantities of IgA. IVIG formulation products with the lowest IgA content availa ble should be given to patients known to be deficient in IgA who require IVIG and who do not have detect able antibodies to IgA. All patients with absent pre-transplant serum IgA levels should be evaluated for the presence of anti-IgA antibodies. (see table below) Renal insufficiency (creatinine clearan ce less than 60 ml/min): Sucrose-free containing IVIG products shoul d ONLY be used in the setting of renal insufficiency. (see table below) 21

22 Continued F: Cautionary note about IVIG, Renal insufficiency: IVIG Preparations Preparation Sugar Content IgA Content CMV IVIG y to g a m C ? 5% Sucrose IVIG Carimune 5% Sucrose 720mc g /ml Pano g lobulin 5% Sucrose 720mc g /ml Gamma 5% Sucrose ? r Sando g lobulin 5% Sucrose ? Octa g a m 10% Maltose <200 mc g /ml Veno g lobulin 5% Sorbitol 15-50mc g /ml Flebo /ml g <50mc 5% Sorbitol g amma 5% Glucose <25 mc g /ml r Gamma g a Ivee m 5% Glucose <10mc g /ml Low IgA containing IVIG 2% Glucose /ml g Pol yg a m <3.7mc g ard SD (powder) 2% Glucose <1 mc g Gamma Sugar Free IVIG g Gamunex 45mc /ml Gamma g ard 10% (liquid) 37 mc g /ml g /ml en <25mc Privi g Gammaplex ? 22

23 V. FEVER OF UNKNOWN ETIOLOGY Fever should be considered a sign of infection until proven otherwise. The following evaluation should be instituted promptly in all patients with fever. 1. nd rectal area. Complete physical examination includi ng the perineal a 2. Blood culture Urine culture 3. 4. Cultures from any site suspicious for infection 5. Chest X-ray. CT of the chest should be obtai ned if respiratory symptoms are present even if the chest x-ray is negative. Sinus CT scan should be obtained if re spiratory symptoms are present. 6. ve been obtained. Empiric treatment with antibiotics may be indi cated after cultures ha Sudden, overwhelming sepsis syndrome with Pneumococcu s or other encapsulated s who have poor compliance with antibiotic organisms can occur, especially in patient antibiotic susceptibility. Please contact the prophylaxis. Organisms should be tested for ultation or assistance regarding specific treatment and LTFU office (Appendix A) for cons other evaluation as needed. 23

24 VI. EVALUATION OF RESPIRATORY PROBLEMS AND LUNG INFILTRATES If the patient develops respiratory problems r initial diagnostic that do not resolve afte act the LTFU office (Appendix A) to discuss evaluation and treatment, we urge you to cont further evaluation and management. A. Diagnostic Evaluation 1. Chest x-ray PA and lateral 2. Lung CT scan if respiratory symptoms persist 3. Sinus CT scan if symptomatic or suspected sinus infection 4. Blood culture (always) 5. Nasopharynx culture for pertus sis if clinical ly indicated 6. ended for patients with pulmonary Bronchoalveolar Lavage (BAL) is recomm symptoms or pulmonary infiltrates to rule out infectious complication. 7. Transbronchial or thoracoscopic biopsy if BAL is negativ e with persistent pulmonary infiltrates Tests Recommended for BAL and Transbronchial Biopsy Specimens B. See algorithm on the end of this section for overview. 1. Bacterial, fungal, mycobacter ial, and Legionella cultures 2. Stains specific for viral inclusions an d general morphology to rule out malignancy (Papanicolaou, Wright-Giemsa, Hematoxylin & Eosin) 3. Methenamine silver, Kinyoun AFB, modi fied Gimenez and Gram stains, KOH 4. for BAL Aspergillus Galactomannan Enzyme Immunoassay (GM EIA) (fluid only) or aspergillus by PCR CMV shell vial test 5. 6. tibody) staining for herpes viruses (HSV, VZV), DFA (direct fluorescent an PCR for respiratory viruses (RSV, influen 7. zae A and B, parainfluenzae, adenovirus) 8. DFA (direct fluorescent antibody) for Legionella or P CR for Legionella 9. If clinically indicated, PCR or IHC for EBV. Evaluation of Pulmonary Nodules or Persis tent Infiltrates with a Negative BAL C. 1. Thoracoscopic biopsy or open lung biopsy is recommended for pa tients with nodular infiltrates to rule out fungal, malignancy, bronchiolitis obliterans syndrome (BOS), cryptogenic organizing pneumonia (COP)or other processes. Thoracoscopic lung biopsy generally causes less morbidity than open lung biopsy. Fresh tissue should be submitted for microbiologic and pathologic evaluation. 2. Tests recommended for lung tissue a) A and culture or PCR for Legionella. Fresh samples should be obtained for DF ent section should be made and evaluated b) Imprints of the frozen section and perman inclusions and possible malignancy by for morphology and assessment of viral using Papanicolaou, Wright-Giemsa, hema toxylin and eosin stains. Specimens should be evaluated for Pneumocystis, f ungi, mycobacteria, Legionella and other bacteria by using methenamine silver , Kinyoun AFB, modified Gimenez and tissue Gram stains. Warthin-Starry st ain should be done if needed. When available, immunohistochemistry stai ning and in situ hybridization are recommended for detection of viral infection. c) Samples should be submitted for microbi ologic evaluation to detect fungi, mycobacteria, and other bacterial organisms. Aspergillus by PCR d) viral cultures, in addition: e) Samples should be submitted for 24

25 -DFA staining for herpes viruses (HSV, VZV) -PCR for respiratory viruses (RSV, influenzae A and B, parainfluenzae, adenovirus) -Shell vial testing for CMV or PCR te sting for CMV, VZV, HSV, EBV, HHV-6, depending on the level of clinical suspicion. 3. ider BOS After Allogeneic Transplant If Infections Ruled Out, Then Cons See section X, I for work up and treatment 25

26 veolar Lavage Fluid or Tests Recommended for Bronchoal Lung Biopsy Specimens STRONGLY RECOMMENDED: Legionella (culture & DFA or PCR)  ALWAYS:  AFB (culture & stain) Bacteria & fungal cultures   Modified Gimenez stain  Gram Stains, KOH  Viral cultures Histology / cytology   by PCR Aspergillus , silver stain ) ( H & E Galactomannan Enzyme Aspergillus  Immunoassay (GM EIA) (fluid only) If patient or donor are CMV seropositive:  Shell vial cultures for CMV During respiratory season: RSV and others respiratory virus  (for example influenzae A & B, parainfluenzae, adenovirus) by PCR SPECIFIC SITUATIONS If VZV is suspected (skin lesions, hepatitis):  DFA or PCR If HSV is suspected: or PCR DFA  If EBV is suspected: EBV by PCR or immuno-histo-  chemistry, IHC  nitive diagnosis is made. gerator / freezer until a defi Keep material in the refri not available locally, please cont If any of the tests above is  act the LTFU office (Appendix A). 26

27 EVALUATION OF DIARRHEA AND OTHER GI COMPLICATIONS VII. If the patient develops diarrhea or other gast rointestinal complications that do not resolve after initial diagnostic evaluati on and treatment (see al gorithm on the end of this section), we office (Appendix A) to discuss further evaluation and urge you to contact the LTFU management. A. Diagnostic Evaluation and Initial Management 1. Diarrhea caused by oral magnesium suppl ementation should be ruled out. If necessary, patients should receiv e IV replacement of magnesium. 2. The clinical evaluation of diarrhea depends on its duration and volume, the presence of blood, and the occurrence of fever and other constitutional symptoms. Normal stool volume is <200 ml/day. Volumes >1000 ml/day indicate a small intestinal source (GVHD, magnesium effect, enteric virus, osporidiosis). Bloody giardiasis or crypt diarrhea suggests a bacterial enteric pathogen, GVHD or CMV enteritis. A more directed approach can be taken if there is a history of foreign tr avel or history of exposure to children from day-care setting. An algorithm for evaluation of diarrhea is summarized on the following page. 3. Patients should remain NPO for 24-48 hours an d IV fluids should be given to prevent volume depletion. Special diets are recommende d for patients with diarrhea caused by GVHD (Section XX). 4. Immunosuppressive medications should be given IV if th e volume of diarrhea exceeds 1.5 liter/day in adults of if diarrhea persists for more than 3 days. Contact the LTFU office (Appendix A) for IV doses of immunosuppressive medications. 5. closporine or tacrolimus (FK506) level Monitor creatinine closely, and check the cy weekly. Avoid treatment with anti-diarrhea agen ts containing atropine-like drugs (e.g. 6. Loperimide). If the diarrhea does not resolve with these measur es or recurs after th e patient resumes oral 7. medications, a search for enteric pathogens in cluding, for example, norovirus, c. difficile, adenovirus and for children, rotavirus a nd endoscopy with biopsies is recommend. Adequate platelet count and coagulation pa rameters should exist to do biopsy safely. B. Procedures for Gastrointestinal Endoscopic Biopsies ter the procedure. 1. Maintain platelet counts >50,000 before a nd for 3 - 4 days af 2. with multiple biopsies. Biopsy Esophagogastroduodenoscopy should be carried out d. If there are no macroscopic abnormalities of any erosion or ulcerations is indicate found, we suggest 6-8 biopsies of the gastric antrum. To minimize the risk of bleeding, avoid biopsies of the duodenum unless this is the only site of abnormalities. 3. When diarrhea is the major GI symptom in a patient without othe r manifestations of ay be indicated to rule out CMV GVHD, either upper endoscopy or colonosc opy m infection or occult GVHD. All infections other than CMV can be identified from stool samples. Biopsies obtained from the gastric antrum are usually sufficient to diagnose GVHD, even in cases where the major symptom is diarrhea. 4. Biopsies samples (n = 4) should be placed in fresh buffered formalin. 5. Fresh biopsy samples (gastric, rectal or co lon) should be placed in viral transport medium and sent to a virology lab to perf orm rapid testing (shell vial) for CMV and e esophageal lesions. The last stomach Varicella zoster as well as HSV if there ar media to test for H. Pylori. sample should be placed in CLO 27

28 6. Please send slides and biopsy blocks to the address below if you wish our pathologists to review the specimen. Because GVHD may be found in one but not all sites, it is important to send as many slides or blocks as possible. Please label the material with the patien 7. t’s name, the date obtained and sites. 8. Send the material to the fo llowing address: Hutchinson Cancer Research Center Seattle Cancer Care Alliance / Fred 825 Eastlake Ave. E. / Attn: LTFU G-1500 PO Box 19023 Seattle, WA 98109-1023 en to expect the arrival of shipments. Please call (206) 667-4415 to notify our office wh 9. 28

29 t Diarrhea in Transplant Survivors* C. Algorithm for Evaluation of Acute Onse Severity of illness Asymptomatic or other symptoms limited Fever, rigors or to anorexia, nausea or vomiting bloody diarrhea Chronic GVHD Test stool for in other organs?  enteric bacterial pathogens: Salmonella Shigella C. fetus jejuni No Yes H7:0157 E. coli Yersinia Other family Aeromonas members ill with  C. difficile similar symptoms?  viral culture-including adenovirus and norovirus  E. histolytica Yes No  Rotavirus EIA Watchful Test stool for C. waiting Ne g Pos difficile, giardia anti g en O&P , Endoscopic biopsies Treat and cultures Pos g Ne GVHD CMV Another Dx Consider need to Treat document intestinal GVHD and to R/O CMV by biopsy Treat Treat Treat ++ ea, oral administration of Mg In all patients with diarrh * should be discontinued, and IV administration should be substituted. 29

30 TREATMENT OF SPECIFIC INFECTIONS VIII. Please contact the LTFU office (Appendix A) to discuss the most appropriate therapy in patients developing any of the in fections described below. A. Cytomegalovirus (CMV) Late onset CMV infections have become an increasingly difficult problem for patients who have had a hematopoietic stem cell transp lant. Reconstitution of the T cells that respond to CMV is slow and may be delaye d by prophylactic use of ganciclovir during the first 3 months after the tr ansplant. Patients at risk of CMV infection should be tic antiviral treatment to prevent CMV monitored closely and should receive prophylac disease. Note that some patients pr nd vomiting as initial esent with nausea a manifestations of CMV infection, in th e absence of CMV viremia. To obtain recommendations for treatment of patie nts who develop CMV pneumonia or other diseases caused by this virus, we urge you to contact the LTFU office (Appendix A). B. Varicella zoster Varicella zoster virus (VZV) in fection occurs in 40-50% of patients during the first year after the transplant (peak risk 2-8 months) when prophylactic acyclovir is not given. In approximately 10% of patients, VZV infecti on presents with abdominal distension or pain in the abdomen or back, often accomp anied by increased serum ALT, before the frequently fatal if tr eatment is delayed. development of any skin lesions. Visceral VZV is If prodromal zoster or documented VZV inf ection occurs during the first year after the transplant or at any time during continued treatment with immunosuppressive started immediately with high dose acyclovir, medications, parenteral treatment should be and blood should be sent to confir m the diagnosis by a VZV PCR test. Patients should be treated according to the following recommendations. Fluids should be administered at twice th vel during treatment e daily maintenance le 1. with high dose acyclovir. 2. Prophylactic treatment with acyclovir should be resume d after high–dose treatment has been completed. closely during treatment with high dose 3. Renal function tests must be followed acyclovir. in patients with renal impairment. Doses of acyclovir must be decreased 4. Disseminated zoster: 2 IV acyclovir 500 mg/m administered as a one hour IV infusion q 8 hr until there is no evidence of new lesions for 72 hours. Tr eatment may then be continued with valacyclovir 1 gm t.i.d. p.o. for patients > 40 kg and 500 mg t.i.d. p.o. for patients < 40 kg to complete the course of treatment (generally 10-14 days). Localized zoster: 2 IV acyclovir 500 mg/m administered as a one hour IV infusion q 8 hr for three doses, then change to oral valacyclovir as outlined above to complete the course of treatment. tients with impaired renal function. Dose adjustment is necessary in pa Pneumocystis Carinii Pneumonia (PCP) C. All patients should receive trimethoprim-sulfamethoxazole prophylaxis (Section IV A). 30

31 C. Pneumocystis Carinii Pneumonia (PCP) All patients should receive trimethoprim-sulfamethoxazole prophylaxis (Section IV A). gimen may develop Patients who do not comply with the reco mmended prophylactic re PCP and will require appropriate treatment. Trimethoprim-sulfamethoxazole should be given at a dose of 15-20 mg/ ponent in divided doses every kg/day of the trimethoprim com tment of PCP pneumonia. 6-8 hr for 14-21 days for trea 31

32 IX. VACCINATIONS Antibody titers to vaccine-preventab le diseases (e.g. tetanus, poli o, measles, mumps, rubella, and encapsulated organisms) decline between 1 and 4 y ears after allogeneic or autologous HCT if the e diseases is recipient is not revaccinated. The clinical relevance of reduced an tibody titers to thes not readily apparent because only a limited number of vaccine-preventable diseases have been reported among HCT recipients. No netheless, vaccine-preventable diseases continue to pose risks to the population. Additiona lly, there is evidence that infections with encapsulated organisms, measles, varicella and influenzae can pose risk to HCT recipients. Therefore, HCT recipients should be routinely vaccinated after HC T so that they can experience immunity to the same vaccine-preventable diseases as others. cations Among Hematopoietic Cell Transplant “Guidelines for Preventing Infectious Compli been updated by organi Recipients: A Global Perspective” have recently zations that include: ntation (ASBMT), Center for International American Society for Blood and Marrow Transpla Blood and Marrow Transplant Research (CIBMT R), National Marrow Donor Program (NMDP), the European Group of Blood and Marrow Transplant ation (EBMT), Infectious Diseases Society or America (IDSA), and the Centers for Disease Control and Prevention (CDC). The vaccination recommendations shown in the following schema were formulated based on review of the tions is 6 months post approaches taken by these organizations. The earlie st time to start vaccina transplant in Non-Primary Imm une Deficiency patients and shoul d be considered in conjunction delay immune reconstitution. with factors that significantly See tables for recommendation for vaccina tions for adult and pediatric patients: Vaccines: Vaccination before 12 months (if IX.A1 Adult Vaccination Schema- Inactivated eligible) IX.A2 Adult Vaccination Schema- Inactivated Va ccines: If patient not vaccinated before 12 months IX.A3 - Adult Vaccination Schema- For Live and Non-Live Adjuvant Vaccines IX.P1 Pediatric Vaccination Schema: Vacci nation before 12 months (if eligible) IX.P2 Pediatric Vaccination Schema: If pa tient not vaccinated before 12 months 32

33 33 dose Interval 6 month 2 month Between 1-2 month 1-2 month 1-2 month accinations alysis patients. 2 m after 1st; 4 m after 2nd V Minimal Time 1, 6 >60m 5 3 2a promised or hemodi titers titers titers >24m observing patients for     titers dose to ensure protection. Patients who rd 2b V V HP HA >18m PCV13 or Pneumovax rs should strongly consider re 12 months (if eligible) HBV ttransplant Vaccination of Primary Immunodeficiency Disorders”.) 18 y) ≥ >16m mmended 1-2 months after the 3 V vaccination is recommended in immunocom Td Td IPV IPV HP HBV >14m ® 2a = HBV/HAV (age hepatitis B V V V titers IPV titers HP HB HA Tdap >12m   Twinrix Bexsero rders see following section, “Pos ® HiB >10m Vaccines: Vaccination befo PCV13 Bexsero body to hepatitis B surface antigen is reco , do it at 24 months. = Tdap (age > 10 y), post last dose of IVIG. on (i.e. chronic GVHD) or increased environmental risk. HiB >8m it is preferable to administer a 4th dose of Prevnar (PCV13) Boostrix MCV4 PCV13 ican Academy of Pediatrics (AAP) recommend that vaccine provide Inactivated lanted for immunodeficiency diso 1 Flu patients should be observed until the symptoms resolve. HiB MCV4 er not done at 12 months PCV13 receive a second 3 dose series. High dose (40mcg/dose) ) hould be at least 2 months 2b = Tdap (age > 11 y), functional asplenia conditi ) 4 Adacel months. Post-vaccination testing for anti 7 ) Pneumovax ( Prevnar 13™ ( ears Bexsero® (Sept –March) y ( ate g accine >6m u saccharide V j y ) Group B ACWY (Menactra, Menveo, MCV4) pe B , 9 to 45 y ) 4 4, 5 A ococcal ococcal inactivated g g Gardasil ( ( 15 minutes after they are vaccinated. If syncope develops, Advisory Committee on Immunization Practices (ACIP) and the Amer In patients with CGVHD who are unlikely to respond to Pneumovax Check titers for S. Pneumonia (IgG, 23 serotypes). If tit Titer at 24 month visit if not done at 20 Check Anti-tetanus toxoid titer Recommended for patients with anatomic or do not respond to the primary vaccine series should For patients not markedly immunosuppressed (For adults transp Combination vaccines may be available: For inactivated “dead” virus vaccine, vaccination s 2a 3 2b 5 4 1 7 Table IX.A1: Adult Vaccination Schema- 6 cellular Pertussis-Tetanus-Diphtheria Pneumococcal-con Pneumococcal-pol H. Influenzae t Polio Menin Hepatitis Influenzae (inactivated) Hepatitis B Menin HPV A

34 34 1, 6 6 month 2 month 2nd dose 1-2 month 1-2 month 1 -2 month 2 m after 1st; 4 m after Minimal Time Interval Between Vaccinations observing patients for dose to ensure protection. Patients who rd >60m mmunocompromised or hemodialysis 18 y) ≥ 2 2 3 5 titers titers titers titers >24m     PCV13 or Pneumovax rs should strongly consider = HBV/HAV (age ttransplant Vaccination of Primary Immunodeficiency Disorders”.) V HP mmended 1-2 months after the 3 Twinrix >22m CGVHD who are unlikely to respond to Pneumovax it is preferable to vaccination is recommended in i V V V 2 hepatitis B HP HB HA : If patient not vaccinated before 12 months >18m In patients with Bexsero® titers rface antigen is reco = Tdap (age > 10 y),  rders see following section, “Pos ® Boostrix Td IPV HiB >16m PCV13 do it at 24 months. Bexsero body to hepatitis B su post last dose of IVIG V V Td IPV HiB HP HB >14m MCV4 PCV13 on (i.e. chronic GVHD) or increased environmental risk. = Tdap (age > 11 y), Inactivated Vaccines - ican Academy of Pediatrics (AAP) recommend that vaccine provide Adacel lanted for immunodeficiency diso V V Flu IPV HiB HB HA Tdap patients should be observed until the symptoms resolve. MCV4 PCV13 receive a second 3 dose series. High dose (40mcg/dose) hould be at least 2 months pes). If titer not done at 18 months then functional asplenia conditi ) 4 7 months. Post-vaccination testing for anti ) Prevnar 13™ ( ears Bexsero® (Sept –March) y ( ate g accine >12m u V j ) ACWY (Menactra, Menveo, MCV4) Group B pe B , 9 to 45 y ) 4 4, 5 A 2 ococcal ococcal inactivated g g Gardasil ( ( 15 minutes after they are vaccinated. If syncope develops, Advisory Committee on Immunization Practices (ACIP) and the Amer Titer at 24 month visit if not done at 20 patients. do not respond to the primary vaccine series should administer a 4th dose of Prevnar (PCV13) Recommended for patients with anatomic or Check titers for S. Pneumonia (IgG, 23 seroty Combination vaccines may be available for certain age groups: Check anti-tetanus toxoid titer. For inactivated “dead” virus vaccine, vaccination s For patients not markedly immunosuppressed (For adults transp 2 3 4 7 cellular Pertussis-Tetanus-Diphtheria Table IX.A2: Adult Vaccination Schema 1 5 6 Polio HPV H. Influenzae t Menin Hepatitis B Hepatitis See note Menin Pneumococcal-polysaccharide (Pneumovax) Influenzae (inactivated) A Pneumococcal-con

35 35 3 1 2-6 months later accinations accinations Second dose given Second dose given 1 month later Minimal Time Interval Between V V Minimal Time Interval Between 2 accinations 2 tients regarding risks/benefits Minimal Time Interval Between V Second dose 1-2 months later observing patients for VZV >24m >24m MMR vaccine) adjuvant (non-live, Vaccines SHINGRIX ++ , + ZIG or most recent plasma transfusion. vaccine) prophylaxis (i.e. acyclovir or valacyclovir) until 1 SHINGRIX > day + 50 (non-live, adjuvant rs should strongly consider rapy is completed. Counsel pa ient. onths since last dose of IVIG/V Live and Non-Live Adjuvant <24m <24m flare-up of GVHD. Recommend continue VZV use on case by case basis after immunothe < day 50 seroconversion of the VZV seronegative pat Do not give therapy (IST) and at least 5 m st dose of IVIG. ght be variable for patients younger than 50 years of age. ican Academy of Pediatrics (AAP) recommend that vaccine provide column* only when certain other criteria are met as outlined in the left-hand No Adjuvant Vaccines are given until at least 2 yr post-HCT and then column when certain other criteria are met as outlined in the left-hand No Live Vaccines are given until at least 2 yr post-HCT and then only patients should be observed until the symptoms resolve. ir) based on drug being used for maintenance therapy. inhibitors) for maintenance, consider east 5 months post la 2 off immunosuppressive therapy (IST) and no hs after second dose of Varivax to ensure : Adult Vaccination Schema: For 3 Adults > 50 yr* "2-1-5 Rule" and ation should be at l and on. Counsel patients regarding risks and benefits, iven with MMR g Table IX.A # be y Not until 2 years post HCT and > 1 year off all immunosuppressive 2 For patients receiving immunotherapy (e.g. PD-1 Continue VZV prophylaxis (i.e. acyclovir or valacyclov This indication is not yet FDA approved and insurance coverage mi 2-1-5 Rule = Check varicella serology at least 1-2 mont For live virus vaccine, vaccin > 18 Years old 2 Seronegative ONLY Varicella-Zoster (Varivax) VZV Seropositive ONLY FOR ALLOGENEIC PATIENTS, ONLY: "2-1-5 Rule Measles/Mumps/Rubella (MMR) *Not until 2 years post HCT and > 8 months + 3 ++ B) Non-Live Adjuvant Vaccines 1 A) Live Vaccines month after first vaccinati # VZV Seropositive patients ONLY and FOR AUTOLOGOUS PATIENTS ONLY: First dose ma Advisory Committee on Immunization Practices (ACIP) and the Amer 15 minutes after they are vaccinated. If syncope develops,

36 36 4 = Twinrix 2 month 6 month 1 month 2nd dose 1-2 month 1-2 month 1-2 month 1-2 month 1-2 months 2 m after 1st; 4 m after Minimal Time Interval accine series should receive a Between Vaccinations = Tdap (age > 10 y), 1-2 months observing patients for 7 4, 7 Boostrix 1, 8 >25m MMR 3 6 VZV 7 2a 7 do not respond to the primary v titers titers titers VZV  >24m titers MMR   = Tdap (age > 11 y),  uss with parents as optional recommendation. rs should strongly consider Adacel 2b ion. Patients who V V V HP HB HA >18m PCV13 or months post last dose of IVIG. Pneumovax dose to ensure protect rd = DTaP/HiB/IPV (age < 4 y), Td IPV 0. DTaP >16m or other patients 16-18 years of age, disc Pentacel isk. F ZIG or most recent plasma transfusion V V Td IPV HP HB DTaP >14m vaccination should be at least 2 osttransplant Vaccination of Primary Immunodeficiency Disorders”.) ient 2a 9 V V V mmended 1-2 months after the 3 titers IPV ” virus vaccine, HP HA titers Tdap HB DTaP >12m   Bexsero® Vaccination before 12 months (if eligible) = DTaP/HBV/IPV (age < 7 y), mmended giving Tdap to patients ages 7-1 the left-hand column Pediarix ican Academy of Pediatrics (AAP) recommend that vaccine provide r inactivated “dead HiB >10m PCV13 Bexsero® patients should be observed until the symptoms resolve. = DTaP (age < 7 y), >8m therapy (IST) and at least 5 months since last dose of IVIG/V ibody to hepatitis B surface antigen is reco nal asplenia condition (i.e. GVHD) or increased environmental r 1 then only when certain other criteria are met as outlined in post last dose of IVIG. Fo No Live Vaccines are given until at least 2 yr post-HCT and x it is preferable to administer a 4th dose of Prevnar (PCV13) Flu Flu Flu HiB HiB >6m nization Practices (ACIP) has recently reco MCV4 MCV4 Varivax to ensure seroconversion of the VZV seronegative pat PCV13 PCV13 Infanrix, Daptacel ) 5 7 10, 11 "2-1-5 Rule" months. Post-vaccination testing for ant Bexsero®) < 9 years ailable for certain age groups: > 7 years (Tdap) and 5 < 7 years (DTaP 5 accine V 7 2b 6, 9 18 y) Also, the Advisory Committee for Immu 5, 5 ≥ Advisory Committee on Immunization Practices (ACIP) and the Amer 15 minutes after they are vaccinated. If syncope develops, Not until 2 years post HCT and > 1 year off all immunosuppressive Recommended for patients > 10 years old with anatomic or functio If Bexsero® is not given, Trumenba® can be substituted in patients > 10 years old as 3 doses (0, 2, 6 months apart) If using Hepatietis B vaccine Recombivax HBR, dosing schedule is 0, 1 and 6 months if patient is 0 to 19 years of age. For live virus vaccine, vaccination should be at least 5 months 9 11 10 8 Table IX.P1: Pediatric Vaccination Schema: "2-1-5 Rule (September –March) > 9 years Influenzae (inactivated) Meningococcal ACWY (Menactra, Menveo, MCV4) H. Influenzae type B Measles/Mumps/Rubella (MMR) Meningococcal Group B ( Pneumococcal-polysaccharide HPV (Gardasil), 9 to 45 years Hepatitis B Pneumococcal-conjugate (Prevnar 13™) Varicella-Zoster (Varivax) Acellular Pertussis-Tetanus-Diphtheria Seronegative ONLY (Pneumovax) Hepatitis A Polio (inactivated) First dose may be given with MMR second 3 dose series. HBV/HAV (age In patients with CGVHD who are unlikely to respond to Pneumova Check titers for S. Pneumonia (IgG, 23 serotypes). If titer not done at 12 months, do it at 24 months. Titer at 24 month visit if not done at 20 Check anti-tetanus toxoid titers. For patients not markedly immunosuppressed (For children transplanted for immunodeficiency disorders see following section, “P 2-1-5 Rule = Check varicella serology at least 1-2 months after second dose of Combination vaccines may be av 6 1 4 7 3 2a 2b 5

37 37 4 . = Tdap (age > 11 2 month 1 month 6 month 2nd dose 1-2 month 1-2 month 1-2 month 1-2 month 1-2 months Adacel 2 m after 1st; 4 m after Minimal Time Interval Between Vaccinations . 1-2 months 1, 8 7 4, 7 >25m MMR VZV 2 months post last dose of IVIG dose to ensure protection. Patients who do not respond 6 7 rd 7 = DTaP/HiB/IPV (age < 4 y), 2 3 titers rs should strongly consider observing patients for titers VZV >24m MMR   titers PCV13 or Pentacel titers   Penumovax ZIG or most recent plasma transfusion or other patients 16-18 years of age, discuss with parents as optional V HP >22m isk. F P) has recently recommended giving Tdap to patients ages 7-10 “Posttransplant Vaccination of Primary Immunodeficiency Disorders”.) ient who are unlikely to respond to Pneumovax it is preferable to administer a 4th dose vaccination should be at least 2 mmended 1-2 months after the 3 2 V V V HP HA HB >18m titers Bexsero®  = DTaP/HBV/IPV (age < 7 y), Pediarix Td IPV HiB DTaP >16m PCV13 Bexsero® V V If patient not vaccinated before 12 months Td Flu IPV HiB HP HB DTaP >14m MCV4 PCV13 IG. For inactivated “dead” virus vaccine, = DTaP (age < 7 y), therapy (IST) and at least 5 months since last dose of IVIG/V ican Academy of Pediatrics (AAP) recommend that vaccine provide 9 V V least 2 yr post-HCT and then only when certain other criteria are met No Live Vaccines are given until at as outlined in the left-hand column Flu Flu IPV HiB HA Tdap HB DTaP >12m MCV4 PCV13 nted for immunodeficiency disorders see following section, patients should be observed until the symptoms resolve. 0, 1 and 6 months if patient is 0 to 19 years of age. onal asplenia condition (i.e. GVHD) or increased environmental r ) ) ) 5 Infanrix, Daptacel done at 18 months, do it at 24 months. In patients with CGVHD 18 y) Also, the Advisory Committee for Immunization Practices (ACI patients > 10 years old as 3 doses (0, 2, 6 months apart) ≥ ) Tdap 2 ( DTaP accination testing for antibody to hepatitis B surface antigen is reco ( ) 7 ears y ears y at least 5 months post last dose of IV 10, 11 13™ hs after second dose of Varivax to ensure seroconversion of the VZV seronegative pat Pneumovax ( = HBV/HAV (age > 7 < 7 Prevnar "2-1-5 Rule" ( ears Twinrix Bexsero®) < 9 years y ( Menactra, Menveo, MCV4 accine ( umenba® can be substituted in ate and g V 5 iven with MMR u saccharide j y g 5 ) ACWY Group B pe B , 9 to 45 7 be y ) y 5 5, 6, 9 Not until 2 years post HCT and > 1 year off all immunosuppressive (September –March) > 9 years A = Tdap (age > 10 y), ococcal ococcal inactivated Advisory Committee on Immunization Practices (ACIP) and the Amer 15 minutes after they are vaccinated. If syncope develops, g g Gardasil ( ( "2-1-5 Rule Table IX.P2: Pediatric Vaccination Schema: Boostrix For live virus vaccine, vaccination should be Recommended for patients > 10 years old with anatomic or functi If Bexsero® is not given, Tr Seronegative ONLY Varicella-Zoster (Varivax) Pneumococcal-pol Menin Menin HPV Measles/Mumps/Rubella (MMR) Pneumococcal-con Polio Acellular Pertussis-Tetanus-Diphtheria Influenzae (inactivated) Hepatitis H. Influenzae t Hepatitis B First dose ma to the primary vaccine series should receive a second 3 dose series. Titer at 24 month visit if not done at 20 months. Post-v Check anti-tetanus toxoid titer If using Hepatietis B vaccine Recombivax HBR, dosing schedule is Check varicella serology at least 1-2 mont Combination vaccines may be available for certain age groups: 2-1-5 Rule = Check titers for S. Pneumonia (IgG, 23 serotypes). If titer not For patients not profoundly immunosuppressed (For children transpla 6 5 3 4 11 10 7 8 y), 2 9 1 recommendation. of Prevnar (PCV13)

38 Please keep records of all vacc all vaccines) given to the  inations (dates and types of port any toxicity to the LTFU. patient after the transplant and re Posttransplant Vaccination of Primar y Immunodeficiency Disorders (PID): From a practical standpoint, pa tients with primary immunodefici ency disorders (PID) are not  tice early vaccination policy that begins at 6 months after candidates for the Standard Prac transplant. Bacteriophage testing will be offered to all PID patients when they have discontinued all  immunosuppressive therapy with few exceptions (e.g. history of anti-CD20 antibody therapy or PID with poor donor B cell engraftment) but will not be the main arbiter to determine when a PID patient is eligible to receive vaccines.  s for vaccination at 1 year after transplant if PID patients will first be considered as candidate they satisfy the following criteria: A. It is reasonable to attempt a 3 month trial off IVIG replacement therapy based on a negative history of patient in fections in the past 6 months and The prevalence of community infections B. V, metapneumovirus, with influenza, RS or parainfluenza during the planne and d trial off IVIG therapy is low C. All of the following laboratory criteria: Criteria Comment Suggests numeric IgG reconstitution Trough IgG > 600 mg/dL 1. on standard IVIG dosin g Detectable serum IgA (> 6 2. A detectable IgA level indicates potential ability to “class m switch” g /dL) a Donor B cell count 3. Arbitrarily set at 1-log higher than our standard practice for > 200 per microlite nanc y those transplanted for mali g r b 4. Donor CD4 T cell count Same as our standard practice for those transplanted for > 200 per microlite r mali g nanc y a as determined by donor B cell chimerism times total absolute B cell count b as determined by donor CD4 cell chimerism times total absolute CD4 T cell count Standard Protocol for Re-vaccination wi th Killed Vaccines after HCT for PID: 1. If patient satisfies criteria A a nd B above, then obtain results of trough IgG, IgA and IgM levels, CD19 or CD20 B cell count per microliter and B cell chimerism (% donor), CD4 T cell count per microliter. If patient visit is not timed with the expected trough following last dose of IVIG, then defe r quantitative immunoglobulin te sting until trough levels are expected. 2. If the results of (1) indicate that the patient now satisfies criteria A, B and C then: o Plan to hold IVIG therapy for the next 12 weeks o Week 0 : Give one dose each of: Prevnar, HiB, DTaP (or Tdap) and HBV (combination vaccines are prefer red to limit the number of shots). o Wks 6-8 : Repeat the series given at Week 0 : Check antibody respons e titers including : o Week 12 Hib, 23-pneumococcal serotypes, tetanus toxoid, and hepatitis B surface antibody 38

39 Pediatric LTFU Attendings will decide whether patient’s responses to tetanus, HiB and 3. remain off immunoglobulin therapy and to Prevnar are sufficient for the patient to proceed with vaccination against pneumococcu s, hemophilus influenza Type B, tetanus, diphtheria, pertussis, and hepatitis B, as well as to begin a standard series of conjugated meningococcal vaccines. Alternatively, if vaccine , hepatitis A and inactivated polio me IVIG therapy and response is inadequate then patient will resu further vaccination will be deferred. th Live Vaccines after HCT for PID: Standard Protocol for Re-vaccination wi If patient has responded adequately to killed 1. vaccines the patient may be considered for the live attenuated measles, mumps and rubell a vaccine, and the varicella-zoster vaccine (in VZV seronegative patients only) assuming the following additional criteria are met: At least 2 years posttransplant a. At least 1 year off all syst b. emic immunosuppressive therapy c. At least 5 months after last dose of gammaglobulin therapy Posttranslant Vaccination of All Other Patients (NON-PID) Clinically relevant, 2-4 fold rises in specifi c antibody levels, or a rise from undetectable lease partial reconstitution of adaptive (T and to a level considered protective, require at B cell) immunity. Therefore, f actors that might influence a de cision to delay a series of vaccinations include: Table IX.1 Delay of B cell recovery Delay of T cell recovery /    CD4 T cells < 200 CD19 or CD20 B cells < 20 /  L L y Anti-CD20 antibod  Active GVHD  < 6 months   y < 2 m onths a g o IVIG therap Moderate to severe GVHD  Receiving chemotherapy or Receiving chemotherapy or  ical therapeutic a g ents b iolo g b iolo g ical therapeutic a g ents General Recommendations:  If patient is on disease-associat ed maintenance therapy that can affect T or B cell numbers, then before beginning vaccination:   L Check CD 19 or CD 20 B cells to determine > 20/ and Check CD4 T cells to determine > 200/  L.   Vaccination for S. pneumoniae and H. influenzae is recommended for all transplant recipients, but does not supplant chemoprophylaxis rologic responses. due to variable se  Inactivated vaccine inje ctions should be used for family members who need vaccinations against polio. Isolation is necessary if live (o ral) polio vaccine is administered to family members or other persons in close contact with the patient during the first year after the transplant or at any time during treatment with immunosuppressive medications. The virus can be shed for 8 to 12 weeks after vaccination. vaccination: Live attenuated infl Influenzae uenzae vaccine is not recommended.  39

40  Smallpox vaccine Smallpox vaccination is is comprised of live vaccinia virus. contraindicated in HSCT recipients because it may result in de velopment of generalized vaccinia or inadvertent inoculation at other si tes such as the face, eyelid, nose, mouth, genitalia, and rectum. Smallpox vaccine should not be administered to any family members or other persons who share living space with the patient during the first year after transplant and beyond one year if the patient contin ues on treatment with immunosuppressive medications. If smallpox vaccination is admini stered to these close contacts, then these individuals should be preven ted from having close contact with the immunocompromised for further detailed information HSCT recipient. See the CDC website . http://www.bt.cdc.gov  Other live vaccines (i.e., BCG, or al polio, yellow fever, typhoid) should not be administered in patients with active manifest ation of GVHD or receiv ing immunosuppressive therapy.  .g., no dead or live bacteria in Anthrax vaccine is an inactivated, cell-fr ee filtrate vaccine (e the preparation). Currently, anthrax vaccina tion is not routinely recommended for anyone except certain high-risk groups such as persons working directly with the organism in the laboratory or certain military personnel. Recommendations for HSCT recipients would be the information is available at the CDC website same as for other at-risk individuals. Detailed http://www.bt.cdc.gov . 40

41 CHRONIC GRAFT-VERSUS-H OST DISEASE (GVHD) X. Chronic GVHD is a major complication of alloge neic hematopoietic cell transplantation. The incidence of chronic GVHD varies between 20 to 85% and depends on many factors such as the transplant source (blood stem cell vs. marrow vs. umbilical cord), donor type and other characteristics (previous pregna nt female versus male donor), age (older vs. younger) and others factors. Chronic GVHD syndrome has features resembling autoimmune and other immunologic disorders such as scleroderma, Sjogren’s syndrome, primary biliary cirrhosis, wasting syndrome, bronchiolitis obliterans, immune cytopenias, and chronic imm unodeficiency. Symptoms usually present within three years after allogeneic HC T and are often preceded by a history of acute lop chronic GVHD are di agnosed by 6 months GVHD. Approximately 50% of patients who deve after transplant. n before day 100 after the transp lant and manifestations that Features of chronic GVHD can begi are typical or “classical” of acute GVHD can de velop or persist long after day 100. Moreover, [1,2] chronic and acute GVHD features may present simultaneously . For this reason, the differential c GVHD cannot be made solely a diagnosis between acute and chroni ccording to the time interval [3,4] from transplant . Criteria to categorize acute and chronic GVHD by the chronic GVHD NIH [4] . Helpful tips on how to assess and score chronic consensus working group is outlined in Table 1 GVHD can be found at http://www.fhcrc.org/ltfu by clicking on " Information for Physicians " in GVHD Tips & Forms " button. Here the left hand navigation column. Then click on the right blue “ you will find the Chronic GVHD Assessment and Sc oring form (Appendix D), Range of Motion ssessment form/ Rodnan Score for patients with Assessment form (Appendix F), Skin Thickness A sclerosis or fasciitis (Appendix E) and other helpful information. [4] A. Table 1. Categories of acute and chronic GVHD Presence Presence of Time of of Acute Chronic symptoms GVHD GVHD after HCT Category † Features Features* or DLI Acute GVHD Classic acute GVHD 100 days  No Yes Persistent, recurrent or late onset No > 100 days Yes acute GVHD Chronic GVHD No time limit No Yes Classic chronic GVHD Overlap syndrome No time limit Yes Yes † DLI (donor lymphocyte infusion) See Table 2 below * 41

42 [4] B. Table 2. Signs and Symptoms of chronic GVHD ORGAN DIAGNOSTIC DISTINCTIVE OTHER COMMON (Sufficient to establish (Seen in chronic GVHD, but (Seen with both OR SITE FEATURES* the diagnosis of chronic insufficient alone to establish a acute and GVHD) diagnosis of chronic GVHD) chronic GVHD) Poikiloderma Erythema ● ● ● Sweat impairment ● Depigmentation Skin ● Maculopapular Lichen planus-like ● Ichthyosis ● ● Keratosis pilaris features rash ● ● Hypopigmentation Pruritus Sclerotic features ● Hyperpigmentation ● Morphea-like ● features ● Lichen sclerosus- like features ● Dystrophy Nails Longitudinal ridging, ● splitting or brittle features ● Onycholysis Pterygium unguis ● Nail loss** (usually ● symmetric, affects most nails) ● Thinning scalp ● New onset of scarring or non- Scalp and scarring scalp al opecia, (after hair, typically Body recovery from patchy, coarse or Hair dull (not explained chemoradiotherapy) Scaling, papulosquamous ● by endocrine or lesions other causes), ● Premature gray hair ● Lichen-type features Gingivitis Xerostomia ● ● Mouth ● Mucositis Mucocele ● Hyperkeratotic ● ● Erythema Mucosal Atrophy ● plaques ● Pain Pseudomembranes** Restriction of mouth ● ● ● Ulcers** opening from sclerosis ‡ ● ● New onset dry, gritty, or Photophobia Eyes † Periorbital ● painful eyes Cicatricial conjunctivitis ● hyperpigmentation † Keratoconjunctivitis sicca ● ● Blepharitis (erythema of the Confluent areas of punctate  eye lids with keratopathy edema) ● Lichen planus-like Erosions**  Genitalia features Fissures**  Vaginal scarring or ●  Ulcers** stenosis  Esophageal web Exocrine   Anorexia GI Tract Strictures or stenosis in  pancreatic Nausea  the upper to mid third of insufficiency Vomiting  the esophagus** Diarrhea  Weight loss  Failure to  thrive (infants and children 42

43 [4] (continued) Table 2 - Signs and Symptoms of chronic GVHD ORGAN DIAGNOSTIC DISTINCTIVE OTHER COMMON (Sufficient to establish (Seen in chronic GVHD, but (Seen with both OR SITE FEATURES* the diagnosis of chronic insufficient alone to establish a acute and GVHD) diagnosis of chronic GVHD) chronic GVHD)  Total bilirubin, Liver alkaline phosphatase > 2 x upper limit † of normal ● ALT or AST > 2x upper limit † of normal ● Bronchiolitis Bronchiolitis obliterans   BOOP Lung obliterans diagnosed diagnosed with PFTs and † with lung biopsy radiology  Fasciitis Edema   Myositis or Muscles, † polymyositis Muscle cramps Joint stiffness or   Fascia, contractures  Arthralgia or Joints secondary to sclerosis arthritis  Thrombocytopenia Hematopoietic  Eosinophilia and Immune Lymphopenia   Hypo- or hyper- gammaglobulinemia Autoantibodies  (AIHA, ITP)  Pericardial or pleural Other effusions  Ascites Peripheral neuropathy   Nephrotic syndrome  Myasthenia gravis  Cardiac conduction abnormality or cardiomyopathy * Can be acknowledged as part of the chronic GVHD symptomatology if diagnosis is confirmed ** In all cases, infection, drug effect, mali gnancy or other causes must be excluded. † y confirmation (or Ophthalmology exam for eyes). Diagnosis of chronic GVHD requires biopsy or radiolog ‡ Schirmer’s test with a mean value < 5 mm (average of both eyes) at 5 minutes, or values of 6-10 mm in patients who have sicca symptoms, or keratitis detected by slit lamp examination are used for the diagnosis of chronic GVHD or the eyes (again other causes of dry eyes need to be ruled out (e.g., drug effect). Abbreviations: GVHD (graft versus host disease); A LT (alanine aminotransferase); AST (aspartate aminotransferase); BOOP (bronchiol itis obliterans organizing pneumonia) ; PFTs (pulmonary function tests); AIHA (autoimmune hemolytic anemia); ITP (idiopathic thrombocytopenic purpura). 43

44 C. How to diagnosis chronic GVHD Signs and symptoms of chronic GVHD have been reviewed and reported by the NIH consensus sis and classification of chronic GVHD for the Working Group to standardize criteria for diagno [4] purpose of clinical trials (Table 2) . The diagnosis of chronic GVHD has no time limit and requires the presence of at least one diagnostic clinical sign of chronic GVHD (e.g. poikiloderma presence of at least one or esophageal web) or the manifestation (e.g. distinctive keratoconjunctivitis sicca) confirme levant tests in the same or d by pertinent biopsy or other re another organ (Table 2) The criteria for the diagnos is of chronic GVHD include: i. Distinction from acute GVHD (Table 1) tion OR at least one distinct one diagnostic clinical manifesta ii. Presence of at least manifestation confirmed by relevant tests (Table 2) pertinent biopsy or other iii. Exclusion of other possible diagnosis for the clinical manifestation (e.g., infection, drug effect, others) D. How to score each organ/site severity with chronic GVHD (Appendix D) has been developed to describe The new scoring system (0-3) the severity of chronic GVHD for [4] each organ or site taking functional impact into account . Appendix D is a modified chronic GVHD Scoring and Assessment form to help physicians to evaluate their patients with chronic GVHD. Appendix E is another tool developed to help physicians to assess skin thickness in patients with sclerotic features or fasciitis related to chronic GVHD. chronic GVHD - Global Assessment E. How to assess overall severity of may be restricted to a single organ or tissue or may be Manifestations of chronic GVHD widespread. Historically, chroni c GVHD was classified as “limited” or “extensive” based on a [5] . Because of inadequacies of the small cohort patients reported more than two decades ago original classification (e.g., difficu a in patients transplanted with lty to apply the historical criteri newer HCT approaches and progr ess in our understanding of chronic GVHD), overtime, this [3,4] cation has proved to have limitation . The widely adopted chronic GVHD classifi new global assessment of chronic GVHD severity is based on numbers of (mild, moderate or severe) [4] gree of involvement in affected organs/sites (Table 3) . This new organs/sites involved and the de global assessment of chronic GVHD severity has been developed to replace the historical “extensive/limited” classification. Table 3. Global assessment of chronic GVHD severity Global severity No. organs/site Maximum score in all affected organ/site* s affected ‡ ‡ Mild ) 1 One or two (except lungs ‡ Moderate Three or more 1 or ‡‡ One or more 2 Severe Any 3 * See Appendix D. ‡ A lung score of 1 is considered moderate. ‡‡ is considered severe. lung score of 2 or greater A 44

45 F. Other laboratory testing and diagn ostic indicators used in chronic GVHD Biopsy (Skin, lip and other tissues). Histol ogical confirmation is necessary in the absence of diagnostic clinical features or distinctive features confirmed by other pertinent test (Table 2). Nonetheless, di agnostic histological features of chronic GVHD are uncommon. represent GVHD lung involvement if: Lung New obstructive lung defect may infectious process, asthma or recurren t aspiration from the sinuses or from gastroesophageal reflux have been ruled out (Table 2 and Appendix D). In the absence of prior history of chroni c GVHD or concomitant GVHD in any other organ, the diagnosis of bronchiolitis obliterans (BO) requires specific spirometric criteria with negative workup for infection and evidence of signs of bronchiolitis by high resoluti on end-expiratory and end- inspiratory CT scan of the lungs, or confirmation by lung biopsy. For information on monitoring of lung function post transplant and treatment of ans syndrome (BOS), see section I. bronchiolitis obliter Esophagus e or dysmotility demonstrated by barium Esophageal web formation, strictur swallow, endoscopy or manometry. Muscle Elevated CPK or al dolase, EMG findings consistent with myositis with biopsy revealing no othe r etiologica l process. Blood Thrombocytopenia (usually 20,000- 100,000/microliter), eosinophilia (> 500/microliter), hypogammaglobulin emia. Hypergammaglobulinemia and autoantibodies occur in some cases. G. Monitoring and other chronic GVHD information Karnofsky or Lansky Clinical Performance scor es <60%, >15% weight loss, and recurrent . infections are usually signs of poorly controlled chronic GVHD Chronic GVHD can lead to debilitating consequences, e.g., jo int contractures, loss of sight, end-stage lung disease, or mortality resulting from profound chronic immune suppression l eading to recurrent or life- recommended after all ogeneic HCT or donor threatening infections. Close monitoring is lymphocyte infusion so that appropriate treatmen t and supportive care can be instituted promptly to prevent serious outcome. 45

46 H. Guidelines for treatment of chronic GVHD We strongly recommend that you consult the LTFU offi ce (Appendix A) before beginning treatment and before making changes in immunosuppressive tr eatment for patients with chronic GVHD. Clinical trials should always be considered because current standar d therapies are associated with high morbidity and decreased survival for patients with high risk chronic GVHD (Section X.A. 2). Appendix D is a modified chronic GVHD Scoring and A ssessment form to help physicians to evaluate patients for chronic GVHD. Appendix E is another tool developed to help physicians to assess skin thickness in patients with sclerotic features or f asciitis related to chronic GVHD. Appendix C provides a ng the percentage of skin involved by GVHD. cartoon with body area surface to help calculati Table 4 outlines the criteria curren tly used for indication of systemic therapy in patients diagnosed with chronic GVHD according to global seve rity (Table 3) and risk factors. Table 4. Indication for systemic treatment for chronic GVHD ‡ High risk* Prolonged systemic therapy Global severity No No Mild ‡‡ Mild Yes Yes ‡‡ Yes or No Yes Moderate Severe Yes or No Yes ‡ See Table 3 * Patients with either thrombocyt openia (<100,000/microliter) or recei ving glucocorticoids at time of diagnosis of chronic GVHD. ‡‡ e risk of chronic GVHD require careful consideration The benefits of graft-versus-tumor effect and th especially in patients transplanted for ma lignancy with high risk of relapse. Standard treatment of chronic GVHD usually begi ns with administration of glucocorticoids (1mg/kg/day) followed by taper to eventually reach an alternate-day regimen, with or without daily cyclosporine or tacrolimus (FK 506). For information on other medications used for glucocorticoid-resis tant or dependent chronic GVHD or in combination, telephone consultation with the LTFU medical team is av ailable to you, seven days a week, to discuss appropriate treatment and provide other follow up reco mmendations (Appendix A). The duration of systemic immunosuppressive tr eatment of chronic GVHD varies but requires at patients require systemic immunosuppressive for least one year of therapy. Approximately 80% of 2 years and 40% of them requires therapy for at least 4 years. 46

47 chiolitis Obliterans Syndrome after HCT I. Monitoring and Management of Bron Introduction te non-infectious pulmonary complication that Bronchiolitis obliterans syndrome (BOS) is a la  affects 5.5% of allogeneic HCT recipien ts and 14% of those with chronic GVHD (7). BOS is the clinical correlate of obliterative br onchiolitis which is c onsidered a pulmonary  manifestation of chronic GVHD.  Lung function impairment is ge nerally irreversible but may stabilize with treatment (8).  ter HCT (8, 9) and 6 months after diagnosis of The median time to BOS diagnosis is 1.5 years af chronic GHVD (10). Definition of BOS after allogeneic HCT idelines (adapted from Reference 11) A. Definition of BOS by NIH Consensus Gu 1. Significant new obstructive change on spirometry: Decrease of the absolute FEV a. (mL) by  10% in comparison in prior 2 years or 1 pre-transplant baseline b. FEV is <75% predicted 1 1 FEV c. /VC ratio < 0.7 or FEV /FVC 120%, or RV/TLC > 20% of predicted value Air-trapping or other features of bronchiolitis including centrilobular nodules, b. airway thickening, or bronchiectasis noted on high resolution computed tomography (HRCT). B. Lung biopsy showing obliterative bronchiolitis may be required to make the diagnosis of lung GVHD in patients with no prior history of chr onic GVHD or other organ manifestations of chronic GVHD for the purposes of enro llment into a clinical trial. C. Diagnostic considerations for BOS: 1. Alternative spirometric phenotype (12) a. Reduced FVC and FEV 1 /FVC ratio b. Normal FEV 1 Normal TLC c. Patients with baseline pretransplant supranormal FEV 2. : 1 FEV a. decline >10 % (meets criteria 1a) 1 /VC <0.7 (meets criteria 1c) b. FEV 1 c. FEV >75% predicted (does not meet criteria 1b) 1 Monitoring of lung function after day +100 after allogeneic transplant cluding spirometry, lung volumes, and DLCO. A. Pulmonary function test (PFT) monitoring in 1. PFTs for asymptomatic allo-HCT recipients: a. At 6 months At 1 year b. 1 Slow VC, which is always greater than or equal to FVC, should be used for this calculation if available as per ATS/ERS guidelines (13). Otherwise FVC is used. 47

48 c. Yearly thereafter until 5 years as clinically indicated d. At diagnosis of chronic GVHD (14) i. Full PFT testing including: spirometry, lung volumes, and DLCO ii. Q3 months after diagnosis of chronic GVHD for at least one year. (spirometry alone may be adequate) Thereafter, at Q6 months for 1 year iii. (spirometry alone may be adequate) iv. With at least yearly full PFT testi ng including: spirometry, lung volumes, and DLCO until year 5 post HCT Evaluation and monitoring of new airflow decline detected by PFTs A. Pulmonary consult should be initiated. B. New lung function decline: Airflow obstruction is defined as decline in absolute FEV /VC <0.7. Lung >/=10%, with FEV 1 1 function decline may be due to obstructi ve, restrictive, or mixed processes. a. Evaluate for upper respiratory infection or other etiologies of airflow decline i. Nasal swab for respiratory virus PCR if indicated by symptoms ii. Perform high resolution chest CT (HRCT) o If there are infiltrates, consider bronchoscopy to evaluate for infection b. If diagnostic criteria for BOS are met  Start treatment promptly c. If alternative diagnosis is made, repeat sp irometry monthly for at least 3 months i. If % FEV stabilizes at 3 months, monitor PFTs every 3 months for one year 1 ii. If stable at 1 year, q6 month intervals for one year Thereafter, if stable, yearly. iii. C. High Resolution CT (HRCT): 1. changes and/or suspicion for BOS Indication: Unexplained lung function 2. Order with inspiratory and expiratory phases Radiographic findings consistent with BOS (15, 16): 3. a. Mosaic attenuation (indicative of air-trapping) b. Peripheral ground glass opacities or cen trilobular ground glass opacities/nodules c. Airway thickening or bronchiectasis (usually a late finding) 4. Patient may still have diagnosis of BOS with normal chest CT D. Bronchoscopy is indicated when there are si gns and symptoms of potential infection. 1. Clinical symptoms Productive cough, fever, runny nose, sore throat 2. Imaging findings Pulmonary infiltrate including ground glass opacities and/or new pulmonary nodules Treatment of suspected or confirmed BOS (Figure 1) Prior to specific BOS treatment, all confounding etiologies of airflow obstruction should be A. r BOS should not be delayed if suspicion is investigated and treated. However, treatment fo strong. 1. Infection: Diagnostic evaluation as directed by clinical symptoms include the following: a. Sinus CT, nasal washes for respiratory virus PCR panel, sinus aspiration, CXR, CT chest, sputum culture, bronchoalveolar lavage, and/or surgical lung biopsy. 2. Gastroesophageal reflux a. Consider treating with proton pump inhibitor if not already on one b. Lifestyle modifications including elevation of the head of bed 3. Post-nasal drip/sinus symptoms Evaluate for URI a. b. Evaluate for environmental allergies/triggers 48

49 Nasal saline, antihistamine, or steroid as needed c. Consider ENT evaluation if chronic sinusitis is suspected d. 2 B. Initial Treatment Initiate F luticasone, a zithromycin and m 1. ontelukast (Singulair) (FAM) + Long-Acting Beta-Agonist (LABA) (9,17,18) F luticasone (Flovent) 440 mcg BID + a zithromycin 250mg po MWF + a. FAM = ontelukast (Singulair) 10mg po QD m LABA = long-acting beta2-agonist (such as salmeterol) b. c. For FAM + LABA, inhaled corticostero id (ICS)/LABA combination may be prescribed in lieu of separate inhaled medications. d. Inhaled corticosteroid combinations: i. First choice: Symbicort HFA 160/80 2 inh BID ii. Alternatives: o Advair HFA 230/21mcg 2 inh BID Advair Diskus 500/50 mcg 1 inh BID o Dulera 200/5 mcg 2 inh BID o o Breo Ellipta 200/5 mcg 1 inh QD e. Treatment should continue without exacerbation after resolution of active chronic GVHD, which is at least 6 months after discontinuation of all systemic immunosuppressive treatments for other organ manifestations of chronic GVHD. 2. Prednisone a. Asymptomatic with mild FEV decline (FEV >70% predicted): no new or 1 1 increase in prednisone b. Symptomatic, or with moderate to severe FEV <70% predicted): decline (FEV 1 1 Start or increase prednisone to 1mg/kg/day x 2 weeks then taper (see below) Other immunosuppressive treatments as indicated to control GVHD in other c. organs. d. After 2 weeks of therapy, begin taper over next 3 weeks to get down to a total dose of 0.25mg/kg/day or to pre BOS therapy dose by week 5, as tolerated by stability of FEV and/or other organ manifestations of chronic GVHD. 1 If prednisone is not required, taper pred nisone off within 6-8 weeks as tolerated e. (including adrenal insufficiency issues). PFT Monitoring during treatment of BOS C. 1. After initial diagnosis: Q4-6 weeks x 6 months (Qmonthly) while on prednisone taper. 2. If % FEV stabilizes after 3 months, space out to q2-3 months. 1 If % FEV 3. continues to decrease, see D below. 1 4. If % FEV normalizes, see E below 1 D. Persistent FEV decline despite initiation of above treatment (FEV decline of >/= 10%): 1 1 1. Rule out infection or other confounding etiologies 2. Consider enrollment in a clinical trial 3. Consider extracorporeal photopheresis (ECP) or other immunosuppression therapies with LTFU attending If FEV 4. 1mg/kg/day x 2 weeks and follow taper has stabilized, taper prednisone to 1 schedule in section B.#2. E. FEV to patient’s pre-HCT baseline) normalizes on treatment (FEV % predicted >80% or returns 1 1 1. Consider alternative diagnosis for airflow obstruction 2. Taper prednisone as soon as possible (unless th ere is another indication for prednisone) 3. If BOS remains most likely diagnosis, continue FAM + LABA for 6 months 4. Consider tapering off inhale d corticosteroid by reducing dose in a stepwise fashion monthly. Recommend Pulmonary consultation. 5. Azithromycin and montelukast can be stopped one at a time over period of 1-2 months 2 Dosages provided are for adult patients. For pediat lt pharmacist for dosing. ric patients, please consu 49

50 hs, 6 months, and 1 year after cessation of 6. Continue to monitor PFTs at 1 month, 3 mont treatment (assuming stability of lung function) F. Supportive treatment 1. Vaccinations 2. Prophylactic antibiotics Treat infections 3. Pulmonary rehabilitation 4. 5. Supplemental oxygen if resting or ambulatory O2 sat 2 years after HCT without evidence of malignancy b. Life expectancy <2 years from respiratory failure No other end-organ damage c. d. No significant requirement for immunosuppression (prednisone < 20mg/qd e. BMI >/= 18 Appropriate social support and compliance f. 3 criteria for lung transplant eligibility. There is no specific FEV 1 50

51 Figure 1. Schema for Treatment of Bronchiolitis Obliterans Syndrome (BOS) A. B. 51

52 XI. GENERAL GUIDELINES FOR PREVEN TION OF OSTEOPOROSIS AND GLUCOCORTICOSTEROID I NDUCED OSTEOPOROSIS Treatment with high-dose glucocor ticoids has been recognized as the primary risk factor for development of osteoporosis after stem cell tr ansplantation. Areas of loss include the femoral neck, vertebrae, ribs. Glucocor ticoid myopathy and muscle weakness may contribute to osteoporosis by removing the normal forces on bone that are produced by muscle contraction. In hematopoietic transplant recipients, other factor s that may contribute to osteoporosis include electrolyte imbalances, inactivity, significant weight loss, and endocrine deficiencies. Two degrees of bone loss can be described. Os teopenia is defined as bone mineral density less than -1 standard deviation but above –2.5 st andard deviations below the peak mean of young normal controls [T-score]. A T-scor e of < -2.5 is defined as osteoporosis. A. Patient monitoring Women : Baseline and annual measurement of FSH a nd estradiol for ages > 10 and < 61 years Men : Baseline and annual measurement of LH, FSH and free testosterone for ages < 60 years, Free testosterone and FSH for ages > 60 years Baseline and followup prostate exam, meas urements of PSA and lipid profile in d with testosterone men who are being treate All patients:  Height: twice yearly Weight: monthly.   DEXA SCANS: a) for allogeneic patients on steroid thera py, Dexa scan annually during steroid therapy b) for all other allogeneic patients > 40 years of age, Dexa scan at one year post transplant c) for all autologous lymphoma and myeloma transplant patients, Dexa scan at one year post transplant. d) for all pediatric patients not on steroid therapy, Dexa scan at one year post transplant from SCCA system was abnormal only if Dexa scan at Discharge three months from starting treatment with  Urinary N-telopeptide (NTx): baseline and at bisphosphonates, or as clinica lly indicated. NTx test (Ost eomark) is used to assess treatment response of bisphosphonate. It measur es urinary excretion of the cross-linked marker of bone resorption. A decrease of 30% N-telopeptide of type I collagen which is a or greater in urinary NTx is et al.: Biological variability clinically significant (Eastell R of serum and urinary N-telopeptides of type I collagen in postmenopausal women. J Bone 2000; 15: 594-8. Miner Res. 52

53  Vitamin D blood level Vitamin D (25 Hydroxy) blood level shoul – d be checked between 80-100 days post transplant for all patients. – Vitamin D (25 Hydroxy) levels are ge nerally rechecked 2-3 months after beginning therapy and th e target level is ≥ 30 ng/mL. Patients treated with bisphosphonate: liver function tests, calcium, magnesium,  d be measured at baseline an d at least monthly thereafter creatinine and electrolytes shoul B. Elemental Calcium requirement between diet and supplement following amounts of The Medical Nutrition Therapy staff educates pa tients to consume the calcium during steroid therapy: Age 7-12 months 600 mg/day Age 1-3 years: 1000 mg/day Age 4-8 years: 1200 mg/day Age > 9 years: 1500 mg/day The nutritionist recommends appropriate leve ls of calcium supplementation for patients the preferred formulation. unable to meet daily requirements with diet. Calcium citrate is Calcium requirement for patients not on steroid therapy: Daily Minimal Calcium requirements (milligrams) Age Children 7-12 months 250 Children 1-3 years 700 Children 4-8 years 1000 Children 9-18 years 1300 Adult Males 1000-1200 Adult Females On hormone therapy 1000-1200 1500 Not on hormone therapy 53

54 C. Vitamin D requirement Currently there is not substa ntive benefit by choosing Vitami n D2 or vitamin D3 over the other with regard to correcting Vitamin D (25 Hydroxy) levels. The more important ncy appears to be less important than decision is prescribing enough. Dose freque 50 days is approximately equivalent to cumulative amount so that 2000 IU daily for giving 50,000 IU monthly for 2 months. Table 1: Vitamin D3 (or D2) Supplementation Adults Children (>18 yrs) (<18 yrs) 2 Prevention of Deficiency / Treatment of Insufficiency [ ] Vitamin D (25 Hydroxy) levels 20-30 ng/mL  Routine  1000 IU per day  Age < 1 yr: ─ 400 IU daily (800 IU in dark skinned) Age 1-8 yr:  ─ 600 IU daily  Age 9-18 yr: ─ 800 IU daily 1 50,000 IU per week    Age < 1 yr: Malabsorption syndromes ─ Consult Endocrinology  Age 1-18 yr: ─ 50,000 IU per week or ─ 5000 IU daily  Chronic Renal Disease  Consult Nephrology  Consult Nephrology 2 [Vitamin D (25 Hydroxy) level <20 ng/mL] Treatment of Deficiency 50,000 IU per wk x 8  Uncomplicated   Age 1-12 months: (Repeat if Vitamin D (25 ─ 1000-2000 IU daily x 8 wks level < 30 ng/mL Hydroxy)  Age 1-18 yr: otherwise treat as for ─ 1000-5000 IU daily x 8 wks insufficiency above) or 50,000 IU weekly x 8 ─ (Repeat if Vitamin D (25 Hydroxy) level < 30 ng/mL otherwise treat as for insufficiency above) 1 Malabsorption syndromes  10,000-50,000 IU daily or  Age < 1 yr:  every other day Consult Endocrinology ─ UVB irradiation in patients  Age 1-18 yr:  also with skin GVHD ─ 50,000 IU per week  Chronic Renal Disease  Consult Nephrology  Consult Nephrology 1 Patients who remain deficient or insufficient after adequate therapy are generally treated with hydroxylated vitamin D metabolites which are more readily absorbed or , if feasible, with sun or sunlamp exposure. While 25-OH vitamin D (Calcidiol) is the most logical choice of activated vitamin D for patients with liver disease, calcidiol is not readily available in the U.S. The 1,25-OH activated formul ation of vitamin D (Calcitriol) is used most commonly in chronic renal disease when th ere is secondary hyperparathyroidism. Calcitriol can also be used in patients with liver disease or severe malabsorption when there is a lack of the 25-OH vitamin D substrate to be converted to 1,25-OH vitamin D by the kidney. 2 levels are generally rechecked 2-3 months Vitamin D (25 Hydroxy) after beginning therapy and the target level 30 ng/mL. ≥ is 54

55 D. Magnesium Hypomagnesemia may result in hypocalcemia , peripheral vitamin D resistance and serum magnesium levels are necessary to resistance to parathyroid hormone. Normal prevent osteopenia and bone fr agility. Patients taking cyclos porine or tacrolimus should receive adequate magnesium supplementation to maintain normal concentrations of serum magnesium (see Section XX) E. Exercise A combination of weight bear ing and resistive exercise is recommended for 30-60 minutes daily to promote cardiovascular function, mini mize bone loss, strengthen skeletal muscles and improve balance, helping to prevent falls. Appropriate forms of exercise include swi mming, biking (on a stati onary bike if the rdic tracking, rowing, low impact aerobic dancing. Duration patient has poor balance), No should be gradually increased to 30-60 minutes daily. Excessive stress to joints caused by high impact exercise (running, jumping, etc.) should be avoided. F. Gonadal hormone replacement with estrogen can be treated with Females: Women who are not on hormonal therapy biphosphonates. Free testosterone, FSH and LH seru m levels should be evaluated as follows: Males: LH, FSH and free testosterone for ages < 60 years, Free testosterone and FSH for ages > 60 years Testosterone replacement should be prescribed as appropriate. Testosterone replacement should be given to men if the serum testoste rone level is low, unl ess contraindicated. G. Bisphosphonates Therapy with anti-resorptive agents to prevent bone loss may be considered for T-score less than -1 for HCT recipients with a prior sign ificant history of corticosteroid exposure and those with GVHD anticipated to remain on long te rm corticosteroids. In low risk patients with a T-score between -1 and -2.5 (osteopeni a), we encourage assessment of fracture risk ). Anti-resorptive therapy can be (eg, using the FRAX score)( www.shef.ac.uk/FRAX/ considered in patients who are at high risk for subsequent fractures. All patients with osteoporosis (T-score < -2.5) es should be offered therapy. or bone loss-associated fractur McClune, Navneet S Majhail, and Mary E.D. Flowers Bone Loss and Avascular Necrosis of Bone After ( Hematopoietic Cell Transplantation. Semin Hematol 49:59-65, January 2012 ) Bisphosphonates are effective for prevention and treatment of post-menopausal and glucocorticoid-induced osteoporosis. Because the risks and benefits of bisphosphonates lear, consideration of during the early posttransplant period are unc bisphosphonate therapy is not recommended for osteoporosis until at approximately 3 months posttransplant. 55

56 Bisphosphonates (Continued) Adults with hip or vertebral fractures, or documented osteoporosis (DEXA T score < -2.5) may receive either oral or intrav enous bisphosphonate ther apy. Therapy is also advised for posttransplant patients with osto epenia (T-score -1.0 to -2.5) who are not receiving hormone replacement therapy and who are to receive prolonged glucocorticoid therapy. For postmenopausal women, and men age 50 and over, the widely used FRAX® WHO Fracture Risk Assessment Tool ( www.shef.ac.uk/FRAX/ ) can be used to help guide it from bisphosphonate therapy based on their which patients with osteopenia might benef estimated 10-year hip fracture probability being 3% or their 10-year major osteoporosis ≥ related fracture probability being ≥ 20%. Therapy is usually continued unt il glucocorticoid therapy ha s been discontinued and the T- score enters the normal range (-1.0 to +1.0) or the risk for fractures based on the FRAX® tool is no longer increased. In patients taking alendronate for 5 years or more, post-marketing reports have recently highlighted the occurrence of atypical hip fractu res. (Watts NB and Diab DL. Long-term use of bisphosphonates in osteoporosis. J C lin Endocrinol Metab 95: 1555-1565, 2010.) e randomized bisphosphonate trials showed that Secondary analyses of the results from 3 larg rates of subtrochanteric or diaphyseal femoral fractures were very low (1 to 6 cases per 10,000 patient years). While these analyses did not demonstrate an increase in risk associated with bisphosphonate use, the study was underpowered for definitive conclusions. (Black DM et al. Bisphosphonates and fractur es of the subtronchanteric or diaphyseal femur. N Engl J Med 362: 1761-1771, 2010.) One approach to consider for patients at m ild risk for fracture is to stop bisphosphonate therapy after 5 years and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients may be treated for 10 years, and then consider having a bisphosphonate holiday for 1-2 years, with nonbisphosphonate thera py during that time. (Watts NB and Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 95: 1555-1565, 2010. Children score, or at risk for reduced BMD may with documented osteoporosis based on Z- discussion with the Pedi atrician. If it is be considered for bisphosphonate therapy after determined that bisophosphonate therapy is a ppropriate, the specifi c bisphosphonate regimen will be decided by the Pediatrician, often in collaboration with a consulting Pediatric Endocrinologist. Cautionary Notes about Bisphosphonates:  Intravenous bisphosphonates are not recommende d for patients with creatinine clearance <35 ml/minute. Oral bisphosphonates can cause esophageal ulceration (pill esophagitis). Oral administration  should be discontinued if patient s develop esophageal symptoms. 56

57 Drugs:  ) i. Alendronate (Fosamax Osteoporosis treatment: Administer alendronate as a single dose of 70 mg weekly (or 35 mg twice weekly).  ii. Risedronate (Actonel ) Osteoporosis treatment: Administer risedronate as a single dose of 35 mg weekly (or 150 mg monthly). Zoledronate (Reclast®) iii. Zoledronate may be given as a single 5 mg intravenous dose once a year. iv. Forteo and Prolia are newer drugs but to date there has not been much experience in their use in the posttransplant setting. H. Calcitonin as secondary therapy for osteoporosis y daily) may be given to adults if the Calcitonin (100-200 International Units nasal spra measures described above are not adequate. I. Low Sodium Diet reduced sodium diet (<4 grams daily) is Sodium increases urinary calcium loss. A encouraged during steroid therapy. Endocrinology J. if clinically indicated. Refer for endocrinology consult 57

58 XII. HYPERLIPIDEMIA Hyperlipidemia, especially chronic elevation of serum low-density lipoprotein cholesterol (LDL- C), is an established risk fact or for premature (<55 years) cor onary heart disease (CHD) in the important to recognize that su rvivors of hematopoietic cell general population. It is also rience increased cardiovascular death compared transplantation (HCT) have been shown to expe 1 to a randomly selected matched control population. Increased cumulative incidence of CHD, cardiomyopathy, heart failure, stroke, vascular diseases, rhythm disorders, hypertension, dyslipidemia and diabetes was also shown am ong these HCT survivors. The latter three conditions are also relevant because together with abdominal obesity, insulin resistance and prothrombotic/inflammatory states, they constitute a cluster of risk factors for premature CHD known as the . Recipients of allogeneic HCT did not differ from their metabolic syndrome autologous counterparts aside from having a high er rate of hypertension. A 49% prevalence rate een noted among long-term survivors of HCT, (95% CI: 38%-60%) for metabolic syndrome has b ared with controls in one cross-sectional or a 2.2-fold increase (95% CI, 1.3–3.6, P = 0.002) comp 2 study. Taking all these observations together it follows that effective management of hyperlipidemia be considered for patients who have undergone HCT. A. Principles and special considerations for lipid lowering therapy after HCT The approach outlined here follows the guidance of the National Heart Lung and Blood Institute therapeutic rventions with and includes inte (NHLBI) Adult Treatment Panel III (ATP III) lifestyle changes imarily to LDL goals as determined by and drug therapy that are calibrated pr http://www.nhlbi.nih.gov/guidel ines/cholesterol/index.htm ): CHD risk category (see  Therapeutic lifestyle changes (TLC) include:  Dietary saturated fat < 7% of calories, transfat < 1% of cal ories, cholesterol < 200 mg/day  Dietary increased soluble fiber 10-25 g/day ove triglyceride and LDL-C levels but  Omega-3-fatty acid supplements may impr ontent. Therefore, cons uming a diet rich in most are not regulated and are of variable c method of supplementation (major sources omege-3-fatty acids is the preferable include flaxseed oil, canola oil, walnut oil, wheat germ , soybeans, mackerel, herring, salmon, sardines in oil, and swordfish).  Weight management  Increased physical activity on a regular basis/ regular exercise regimen  Management of hyperlipidemia in the general population begins and always includes TLC. However, after hematopoietic cell transplant ation TLC are not alwa ys possible due to transplant-related complications or concerns. ATPIII drug therapy first focuses on achieving goal LDL levels using HMG-CoA reductase  inhibitors (statins) because they protect ag ainst premature CHD and improve survival among levels in the general population. those with elevated cholesterol 58

59  Statins also protect against pr emature CHD and improve survival in solid organ transplant 4-12 Additional roles for statins in media ting improved renal function, control of recipients. 14-20 hypertension, osteopenia, avascular necros is, and even GVHD have been suggested.  While statins may offer sim ilar benefits for Blood or Bone Marrow Transplant (BMT) survivors with hyperlipidemia the safety of sta lished in this group and tins has not been estab extra caution is advised due to the potentia l for important drug interactions in the BMT setting. nt of Hyperlipidemia in BMT Survivors B. Algorithm for Evaluation and Manageme Step 1: ndrome and obstruc tive liver disease. Exclude untreated hypothyroidism, nephrotic sy Step 2: Identify presence of clinical atherosclerotic disease (CHD or “CHD risk equivalents” which include symptomatic carotid artery disease, peri pheral vascular disease and abdominal aortic aneurysm) and if present the 10-year risk is > 20% (“High-risk”) and then skip to Step 4. Step 3: Consider major risk factors other than LDL, CHD or CHD risk equiva lents (ie. Cigarette st smoking, hypertension, low HDL, premature CHD in a 1 degree relative, age) and categorize as “Moderate” or “Low” 10-year risk using the Framingham tables or online risk calculator available at: http://hp2010.nhlbihin.net/atpiii /calculator.asp?usertype=prof . Step 4: rmine the need for TLC and drug therapy: Establish the LDL goal of therapy and dete for BMT patients adapted from ATPIII Simplified Fasting Level Target Goals LDL level to consider LDL level to LDL Goal Risk Category (mg/dL) begin TLC drug therapy (mg/dL) (mg/dL) High 130 10-yr risk > 20%: <100 ≥ ≥ 100 CHD or CHD risk equivalents ≥ 130 if 10-yr risk 10-20% 130 ≥ <130 Moderate 2+ risk factors or ≥ 160 if 10-yr risk <10% Low ≥ ≥ 160 <160 190 ≤ 10-yr risk 10% 0-1 risk factors If clinically feasible in a te TLC if LDL is above goal. post-transplant survivor initia Step 5: Consider adding drug therapy with TLC for Hi Step 6: gh-risk (CHD/CHD-equivale nts). For other risk month trial of TLC before adding drug therapy categories, if clinically feasible allow a 3- 59

60 Suggested Medication Options for High LDL-C in Adults* after BMT a Daily Dose Class Effects mg Drug Precautions and Monitoring Statins (HMG-CoA Contraindicated in liver disease  Start at lowest reductase inhibitors)  Counsel patient to report muscle pain, doses and rarely 18-55% LDL  weakness, dark or cola-colored urine, exceed middle of especially when accompanied by fever HDL  5-15% the dose range and malaise. 7-30%  TG when taking  Routinely monitor liver functions at concomitantly baseline, 2 & 4 weeks and then calcineurin monthly on therapy. inhibitors .  If myopathy or rhabdomyolysis is suspected, or if AST/ALT are significantly elevated stop therapy and check CK and creatinine.  Atorvastatin Toxicities may occur weeks to many  10-80 (Lipitor) months after starting therapy.  Toxicities are potentially enhanced by b 20-80 like cyclosporine, CYP3A4 inhibitors Fluvastatin (Lescol)  tacrolimus, macrolide antibiotics, sirolimus and triazole antifungals, Lovastatin  10-80 non-dihydropyridine calcium channel (Mevacor) blockers (verapamil, diltiazem).  Consider reduction of statin dose  Pravastatin when adding a calcineurin inhibitor 10-40 (Pravachol) or other drug that can increase toxicities  Simvastatin (Zocor) c) 5-40 (80 Rosuvastatin (Crestor) 5-40 a Consult Pharmacy for pediatric dosing of statins . b Adverse interactions with CYP3A4 inhibitors may be less for statins metabolized by other pathways: d rosuvostatin (CYP2C9 & CYP2C19), however, pravastatin (non-CYP), fluvastatin (CYP2C9) an toxicities have been reported for all statins. c Patients on 80 mg for more than 1 year can continue (Check manufacturer black box warning) gement of hyperlipidemia should always be Risk benefit ratio of drug therapy for mana Step 7: considered and medical intervention individualized in BMT recipients. 60

61 Step 8: Identify metabolic syndrome based on presence of any three of the following: Waist circumference: Abdominal obesity: Men >102 cm (>40 inches) – Women >88 cm (>35 inches) – Hypertriglyceridemia  150 mg/dL Low HDL cholesterol – Men <40 mg/dL Women - <50 mg/dL Hypertension http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf Per JNC7 Fasting hyperglycemia  150 mg/dL Treat any underlying causes:  Intensify weight management  Increase physical activity on a regul ar basis/ regular exercise regimen  Treat lipid and non-lipid risk factors if they persist despite TLC:  Treat hypertension (See hypertensi on section of LTFU guidelines)  reduce prothrombotic state if not Consider aspirin for CHD patients to contraindicated Treat elevated triglyceride s and/or low HDL (Step 9)  Treat elevated triglycerides: Step 9: Primary aim of therapy is to reach LDL goal   Intensify weight management  Increase physical activity on a regul ar basis/ regular exercise regimen  If triglycerides are 200 mg/dL after LDL goal is reached, set secondary goal for r than LDL goal (see Table below): non-HDL-C (total – HDL) 30 mg/dL highe Non-HDL goals for HCT survivors Non-HDL Goal (mg/dL) Risk Category High”: 10-yr risk > 20%: <130 CHD or CHD risk equivalents 20% Moderate : 10-yr risk ≤ <160 2+ risk factors Low: 10-yr risk ≤ 20% <190 0-1 risk factors 61

62 Therapies for Hyperlipidemia for Adult Patients Precautions and Monitoring Drug Daily Dose Class mg Effects Generally minimal side  effects, eructation, Omega-3-Acid  LDL may a dyspepsia Ethyl Esters HDL  9%  May potentiate INR if on warfarin 45% TG  2000 BID Avoid if fish/shellfish allergic  Lovaza   VLDL 40%   Monitor AST/ALT periodically Has been combined with simvastatin for mixed  hyperlipidemia Contraindicated in severe  liver or renal disease Fibric Acids  May cause myopathy especially when combined LDL 5-20%  Start at lowest with statins, and in setting of impaired renal  HDL 10-20% doses and function in patients receiving cyclosporine or  TG 20-50% rarely exceed other drugs that interact with statins middle of the  May cause cholelithiasis and GI symptoms dose range  May cause reversible increase in serum creatinine when taking  Fenofibrate-statin combination may be better that gemofribrozil-statin therapy because gemfibrozil concomitantly can increase statin levels by 2-6 fold calcineurin  Counsel patient to report muscle pain, weakness, . inhibitors dark or cola-colored urine, especially when accompanied by fever and malaise. Routinely monitor liver functions (including  AST/ALT) at baseline, 2 & 4 weeks and then monthly on therapy. 48-145 If myopathy or rhabdomyolysis is suspected, or if  Fenofibrate  AST/ALT are significantly elevated stop therapy and check CK and creatinine. (Tricor)  Toxicities may occur weeks to many months after 600-1200 starting therapy. Gemfibrozil  Toxicities are potentially enhanced by CYP3A4  b (Lopid) like cyclosporine, tacrolimus, inhibitors macrolide antibiotics, sirolimus and triazole antifungals, non-dihydropyri dine calcium channel blockers (verapamil, diltiazem). a e generally insufficient to significantly lower Note over the counter omega-3-acid ethyl esters ar triglycerides and VLDLs. Only Lovaza® has been approved for this indication. Consult Pharmacy for pediatric dosing of Lovaza® or fibric acids.  If triglycerides 200-499 mg/dL after LD L goal is reached consider intensifying therapy with LDL-lowering drug, or add fibrate or Lovaza® to further lower VLDL. If statin fails to lower both LDL and TG it is very reasonable to consider referral to consultant cardiologist, endocrinologist, or ot her expert on high risk patients with mixed hyperlipidemia.  If triglycerides > 500 mg/dL, first lowe r triglycerides to prevent pancreatitis:  Add fibrate unless counterindicated Or Lovaza® if patient is unable to take fibrates  Very low-fat diet  Weight management and physical activity 62

63 XIII. HYPERTENSION New onset or aggravation of hypertension o ccurs frequently after hematopoietic cell transplantation (HCT) w ith the most common cause of hypert ension after allogeneic HCT being due to treatment with glucorticoids and tacrolimus or cyclosporine. It is important to recognize also that HCT survivors have a high prevalence metabolic syndrom e which represents a cluster 1 of risk conditions associated with pr emature coronary heart disease (CHD). Components of the ccurred with higher emia, and diabetes o metabolic syndrome including hypertension, dyslipid 2 cumulative incidence among HCT survivors compar ed to a randomly selected matched control. Thus, adequate control of hypertension is strongl y recommended in HCT r ecipients to minimize target organ damage and most importa ntly in the brain, heart and kidneys. A. Key Points about Hyperten sion and its treatment  In uncomplicated hypertension, without di abetes mellitus, renal dysfunction or cardiac dysfunction the blood pr essure (BP) goals are indicated in the table below Female Male Age (y) 18 140/90 140/90 ≥ 17 132/82 125/80 16 130/80 124/80 15 127/79 123/79 14 125/78 122/78 13 122/77 121/77 12 120/76 119/76 11 117/76 117/75 10 115/75 115/74 9 114/75 113/73 8 112/73 111/72 7 111/72 109/71 6 110/70 108/70 5 108/68 106/68 4 107/65 104/66 3 105/61 103/63 2 102/57 101/59 1 99/52 100/54 th Pediatric data based on 90 percentile limits for blood pressure at th percentile for height (1999-2000 NHANES) The 50 If an adult patient has a diagnosis of diabetes and/or renal dysfunction, the BP goal is  < 130/80 mm HG. If an adult patient has more than 1 gm of proteinuria, the BP goal is < 125/75 mm HG. B. Other key points about control of hypertension and treatment :  Reductions in myocardial in farctions, stroke incidence and heart failure with BP lowering below 140/90 mm HG are approximate ly 25%, 35%, and 50%, respectively. mm HG and/or DBP > 100 mm HG tend to need two  Patients with SBP > 160 two agents are begun at the same time. different agents and it is recommended that 63

64  Caffeine intake and nicotine use an hour before blood pressure monitoring may give falsely elevated readings.  Referral to a hypertension specialist is adv ised for patients with poorly controlled blood pressure.  In the general population, thiazide diuretics s hould be used in drug treatment for most e or combined with drugs from other patients with uncomplicated hypertension, alon e-renal azotemia and other thiazides to aggravate pr classes but the potential of electrolyte abnormalities ofte n limit their use in HCT. the standard of care for management of  No single class of drugs has emerged as hypertension in patients receiving calcineuri n inhibitors (CNI). Other agents may be indicated for patients with other co-morbidities (s ee Table 1). Table 1 - Antihypertensive Medicati ons According to Clinical Setting Monitoring Clinical Setting Anti-Hypertensive Therapy Uncomplicated Options include CCB, beta-  If not on a CNI or at risk for volume depletion, blockers, thiazide diuretics, Hypertension thiazide diuretics are the treatment of choice . If used ACE-I or ARBs with CNI, limit dose to 12.5-25 mg per day to limit most metabolic side effects.  Calcium Channel Blockers ( CCB) can affect CNI levels (cyclosporine and tacrolimus). Check CNI levels with K and Cr 7-10 days after starting CCB.  Non-dihydropyridine CCBs (e.g. verapamil, diltiazem) may potentiate the toxicity of CNI, statins and fibrates  CCB may worsen proteinuria  Beta-blockers may diminish sympathetic activity including CNI induced headaches/migraines and tachyarrhythmias. Chronic kidney  ACE-I/ARB,  Possibly in combination with CCB if still on CNI. disease*, history of  Avoid CCB alone due to further increase in proteinuria presence of AKI, Consider holding during persistent diarrhea, vomiting  proteinuria or or poor fluid intake microalbuminuria  Check serum K and Cr 7- 10 days after adding (see Table 2) Diabetes Angiotensin converting  No known interactions with CNI. With or without enzyme inhibitors (ACE-I) or and prerenal azotemia; May aggravate hyperkalemia  proteinuria angiotensin II receptor avoid in patients with or at risk for volume depletion. blockers (ARBs) Consider holding during persistent diarrhea, vomiting or poor fluid intake Check serum K and Cr 7- 10 days after adding  Heart Failure Careful to avoid pre-renal azotemia with potent loop  Diuretics  diuretics. ACE-I or ARBs  one or eplerenone if no  Consider adding spironolact  Beta-blockers monitor for subsequent hyperkalemia . hyperkalemia but  Carvedilol and metoprolol are beta-blockers of choice For those unable to tolerate ACE-I and ARB’s, therapy  with hydralazine plus isosorbide may be beneficial, particularly in African Americans 64

65 Table 1 - Antihypertensive Medications According to Clinical Setting (continued) Clinical Setting Anti-Hypertensive Therapy Monitoring High-risk for Diuretic may also be indicated based on risk/benefits  ACE-I, ARBs, calcium  Coronary Artery profile channel blockers and Disease beta-blockers. CCB) can affect CNI levels Calcium Channel Blockers (  (cyclosporine and tacrolimus). Check CNI levels with K and Cr 7-10 days after starting CCB. Ischemic Heart  Carvedilol and metoprolol are the beta-blockers of  Beta blockers Disease choice History of   ACE-I, aldosterone actone or eplerenone if Consider adding spironol Myocardial hyperkalemia is not present antagonists and the beta- Infarction blockers carvedilol or metoprolol are indicated. History of Strokes  CCB) can affect CNI levels  Calcium channel Calcium Channel Blockers ( blockers, thiazides or (cyclosporine and tacrolimus). Check CNI levels with ARB. K and Cr 7-10 days after starting CCB. Hypertensive  Clonidine  Clonidine has rapid onset of action, can cause dry mouth Urgency not and somnolence; avoid for general use Labetatlol  requiring  Hydralazine can cause edema and tachycardia Hydralazine  hospitalization Evaluate patient every 1-3 days to assess response to  Preferred option is to  therapy consult a hypertension expert CCB; calcium channel blockers, * Definition of chronic kidne y disease (CKD) criteria 1. Kidney damage for > 3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifest by either:  Pathological abnormalities; or  Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests 2 for > 3 months, with or without kidney damage 2. GFR < 60 mL/min/1.73 m and additional recommendations C. Evaluation for microalbuminuria Screening for microalbuminuria before and after transplant is helpful for early diagnosis of ment. Microalbuminuria is determined by measuring the proteinuria and to guide treat albumin and creatinine ratio in an urine sample. 65

66 min/creatinine ratio and hypertension Table 2. Recommendations based on albu Spot Urine Albumin/creatinine ratio ) Interpretation Recommendations (U ACR Less 30 mg/g in 1 year – Repeat U ACR Normal 30-300 mg/g without hypertension and Abnormal – Repeat U in 3-6 months ACR not on hypertensive medications 30-300 mg/g – If not already on, c onsider change to ACE-I or ARB therapy Abnormal with hypertension and on – hypertensive medications Repeat U in 3-6 months ACR If not already on, consider treating – Greater than 300 mg/g with ACE-I or ARB therapy on hypertensive Quantify 24-hr total urine protein – medications Abnormal – If proteinuria (>1 gram) confirmed, refer to nephrologist in 3 months Monitor spot U – ACR 66

67 RECURRENT MALIGNANCY XIV. In most cases recurrent malignancy occurs within the first 2 years after the transplant, with few occurring more than 5 years after the transplant. logical malignancies, For patients who had leukemia or other hemato peripheral blood counts should be monitored at least monthly for the first year. Monitoring for minimal residual disease and recurrent malignancy will vary acco rding to the specific disease and enrollment blood or bone marrow may be needed to help in specific protocols. Chimerism testing in establish the diagnosis of recurrent malignancy and to assess options for treatment (adoptive immunotherapy, biologic res ponse modifiers, gene th erapy among others). spected or confirmed, please co ntact the LTFU office (Appendix If recurrent malignancy is su agnostic tests and treatment options. A) promptly to discuss additional di 67

68 XV. SECONDARY MALIGNANCIES Recipients of hematopoietic st em cell transplant have an increased risk of developing secondary malignancies, including skin cance rs, solid tumors, myelodysplastic syndromes, leukemias and post-transplant lymphoproliferative disorder (PTLD). Solid tumors that occur at increased frequency include skin cancers (squamous cell, basal cell, malignant melanoma) and cancers of the buccal cavity, followed by liver, central nervous system, thyroid, bone, and connective tissue. PTLD generally occurs within the first year after the transplant, predominantly in patients who received T cell-depl eted grafts and in patients treated with intensive immunosuppressive regimens to control GVHD. All transplant recipients s hould have oncologic screening ev aluations at annual intervals throughout life. We recomme nd the following general guidelines for oncologic screening. 1. te physical and history Skin exam with the comple Pap smears & mammogram (women > 35 years) & education to reinforce self breast 2. exams 3. Prostate exam and PSA (men > 45 years) Occult blood in stool (> 40 years) 4. Colonoscopy (baseline at age 50 years and as clinically indicated thereafter) 5. Oral exam by the dentist at 6 month intervals 6. Complete blood counts, thyroid functi 7. on, and other tests as applicable All patients should use sunblocking creams (> 30 SPF – sun protection factor) when outdoors ent activation of chronic GVHD. to prevent skin cancers and to prev Please contact the LTFU office (Appendix A) if you are planning surgery or a biopsy for y or if secondary malignancy has been evaluation of suspected secondary malignanc diagnosed. 68

69 XVI. OTHER COMPLICATIONS A. G ONADAL H ORMONE I NSUFFICIENCY Gonadal hormone insufficiency is related to th e age of the patient a nd the intensity of the transplant preparative regimen. M ALES : Prepubertal boys may require treatment with gradually escalated doses of testosterone to promote sexual maturation. (Hormonal replacement in prepubertal boys should be done in collaboration with a pedi Men who were past atric endocrinologist.) puberty at the time of transplant may devel op primary gonadal failure. Testosterone replacement should also be considered in men who are receiving corticosteroids for long- term treatment of chronic GVHD (see Secti on XI). Men who receive testosterone replacement therapy should have a baseline pr ostate exam and measurement of prostate specific antigen (PSA), liver enzymes and serum lipids. Follow-up monitoring of these parameters may be appropriate. F EMALES : Women often develop primary ovarian failu re and have symptoms of premature lopment of osteoporosis. Permanent ovarian menopause. They are also at risk for deve failure invariably occurs in all female patients who receive busulfan and cyclophosphamide been observed after transplant in 54% of (BU/CY). Recovery of ovarian function has younger patients (less than 26 years) condi tioned with cyclophosphamide alone. The recovery after fractionated TB I is at least 10% by 6 years probability of ovarian function after transplant. Premature (<40 years) or early (40 – 50 y ears) onset of menopausal symptoms and antly affect the quality of life of osteoporosis can signific women after a hematopoietic cell transplant (HCT). During the past 30 years, replacement therapy with estrogen alone (for patients without a uterus) or combined with prog estin (for patients wi th a uterus) has been used to prevent or treat menopausal symptoms and to prevent bone loss. In children, hormonal replacement therapy (HRT) is needed after transplant to promote the development of secondary sexual characteristics. Estrogen can treat hot flashes, vaginal and vulvar symptoms, prevent bone loss and improve the quality of life for HCT recipients who are postmenopausal or who have premature ognitive function claime d by many women taking ovarian failure. The positive effect on c estrogen remains to be confirmed. In young gi rls, estrogen replacement therapy is often critical for the development of secondary sexua l characteristics and for the attainment of peak bone mass in early adulthood. Special Considerations: a)  It is unclear if estrogen alone or combined with progesterone replacement will add to the already increased risk of secondary breast can cer in posttransplan t women (Friedman et al.Blood;2008;111:939-944). Among patients w ho survived for more than 10 years posttransplant the observed/expected risk ratio is 3.2 for breast cancer (Rizzo et al, Blood entified as the primary risk factor 2009; 113: 1175-1193). Radiation has been id associated generally with the development of solid tumors after a stem cell transplant. 69

70 b) Hormonal Replacement Guidelines for Girls: In young girls, estrogen replacement therapy is often critical for the development of secondary sexual characteristics during the tran sitional from adolesce nce to adulthood and for the attainment of peak bone mass in early adulthood. Hormonal replacement in prepubertal girls should be done in collaboration with a pediatric endocrinologist . c) Hormonal Replacement Guidelines for Women: Temporary relief of menopausal symptoms: Unless medically contraindicated, a finite course of estrogen al one (women without uterous) or combined with progesterone (wom en with uterous) may be prescribed for nts are frequently ms, provided that patie the temporary relief of menopausal sympto reassessed by their physician to determin e the appropriate duration of therapy. General considerations for po sttransplant Gonadal Hormonal Therapy (HRT) include: Management of ovarian failure should be ta  ilored according to a patient’s particular clinical manifestations a nd individual risks for side effects of HRT such as: a) history (or family history) of breast cancer , stroke or hypercoaguable state b) history of deep venous thrombosis c) history (or family history of colorectal cancer severe osteoporosis with vertebral crush fractures d) e) presence of absence of a uterus Overall benefits and risks of long-term HRT should be discussed  with each patient.  Information about non-hormonal alternatives for management of ovarian failure manifestations should be discussed with all patients. clearly state the indica  A patient and her physician should be able to tion (s) for which the patient is to start (or cont inue) posttransplant HRT. HRT should be prescribed at the lowest effective dose.   Annual gynecological follow-up evaluati on is recommended for all women.  Monthly self-breast examination is recommended for all women.  Baseline mammography is recommended for a ll women from 35-40 years of age. Annual follow-up is also recommended. failure management plan is recommended to Yearly re-evaluation of a patient’s ovarian  determine if it remains the most appropriate plan for that patient. 70

71 Specific Contraindications to HRT: Systemic estrogen alone or combined with proge sterone should not be prescribed for patients  with a history of thromboembolic diseases (i.e., venous thrombosis, pulmonary embolism, on disorders, breast cancer strokes, etc.), hypercoagulati or active liver disease. Alternatives to HRT:  Diet, exercise and other non-hormo nal strategies are available fo r management of hot flashes, insomnia and mood disturbances. Topical estrogen alone may relieve local  vaginal/vulva symptoms caused by gonadal insufficiency.  Osteoporosis can alternatively be treated with bisphosphonates in combination with adequate calcium and vitamin D intake (See St andard Practice Osteoporosis document).  libido and/or dyspareunia may be Difficulties such as decreased multifactorial in etiology and may often be managed without the use of systemic conjugated equine estrogen and medroxyprogesterone. B. Endocrine Abnormalities d neoplasms may develop in dism, thyroiditis and thyroi Compensated or overt hypothyroi dence of compensated hypothyroidism after patients who received radiation. The inci fractionated total body irradia tion (TBI) before transplant ranges between 15-25%. ical examination and t hyroid function tests. Patients should be evaluated yearly with phys Growth hormone (GH) deficiency and growth failure (decreased growth rate/year) occurs  in 70-80% of children who rece ived total body irradiation or 1800 cGy cranial irradiation. The onset of GH de ficiency and growth failure varies with the age of the child at the time of irradiation. The onset of these problems appears to occur later in younger children than in peri-pubertal childr en. All children should have height monitored at least annually, and those <14 years of age should have annual GH testing until they either develop GH deficiency or are >1 4 years of age, whichever occurs first. Among pre-pubertal children, treatment with total body irradiation, busulfan or >2400 ation may delay subsequent pubert al development. Children who cGy testicular irradi received busulfan appear to have the highest risk of delayed or absent pubertal development. Approximately half of th e very young children tr eated with total body irradiation progress through pube rtal development at an a ppropriate age, while older children treated with total body irradiation have a higher risk of delayed pubertal development. Treatment with cyclophos phamide alone does not delay pubertal development. Tanner development scores determined as Beginning at age 10, all children should have ren who are Tanner Stage I or II by age 12 part of an annual physical examination. Child aluate the need for hormonal years should be referred to a pediatric endocrinologist to ev supplementation. 71

72 Ocular complications C. An annual eye exam with slit lamp examination is recommended for all patients who have had an allogeneic transpla nt and for those who are at risk of cataracts. The risk of cataracts after transplant is high for patient s who received fractionated TBI (30 – 50%) and for patients treated with corticosteroids af ter the transplant (45%). In patients who received neither TBI or prior cranial i rradiation, the incidence for cataract is rticosteroids. The median time to develop approximately 15% and, is primarily due to co cataracts after transplant ranges from 2 to 5 y ears. Cataract extraction can be performed safely even when ocular sicca is present. Unanticipated complicati ons after placement of an intraocular lens have not been reported. Other late complications involving the eyes scribed in Section X A and B. are related to chronic GVHD as de 72

73 D. Oral complications and guidelines for dental care The new development of oral pain or dryness beyond day 100 after the transplant suggests the development of chronic GVHD involving salivary glands or the mucosal surface. Cultures for candida albicans and DFA or rapid cultures for herpes simplex virus should always be obtained to rule out concomitant infections. A dental/oral medicine consultation should be strongly c onsidered in all patients with oral complications. General guidelines for dental care in he matopoietic transplant recipients include: Routine (non-urgent/non-emergency) dental care especially in patients with chronic  GVHD should be delayed for at least the first year after transplant due to increase risk of bacteremia because patients are still immunocompromised.  Routine dental health examinations (w ith radiographs as needed) are recommended to monitor for tooth decay and oral hygiene effectiveness/gingivitis/periodontitis. Patients should be encouraged to carry out focused and effective oral hygiene (brushing, flossing, etc.).  on a regimen of daily brush-on fluoride gel Patients with dry mouth should be placed of dental decay. to reduce the risk unt should be checked  Complete blood cell counts with differen tial and platelet co before any dental procedure to assess the risk of bleeding and infection.  When urgent or emergency dental treatme nt is required efforts should be taken to antibiotics and reduce the risk of minimize bacteremia including prophylactic aspiration of aerosolized bacteria and debris (i.e., perform proce dures under a rubber ray during procedures, etc.). For short dam, use high volume suction, reduce air sp non-surgical/non invasive surgical pr ocedures, we recommend following the American Heart Association (AHA) c recommendations. prophylactic antibioti Antibiotic administration should be extended if there is significant local dental infection and risk of subsequent spread of infection (local or disseminated). ophylactic antibiotics (AHA guidelines for low- In lieu of evidence based guidelines, pr  r all dental procedures in patients who moderate endocarditis risk) should be used fo al venous catheters. have indwelling centr 73

74 Renal insufficiency E. Nephrotoxic drugs are the most common cause of impaired renal function after a stem cell transplant. Monitoring renal function and drug levels is recommended for all patients who are at risk of renal insufficiency (Section III C & D). Neurological Complications F. Peripheral neuropathy and central nervous system complications may develop after transplantation. may be caused by drugs used to Central nervous system dysfunction sirolimus, tacrolimus) (Section X), electrolyte control GVHD (cyclosporine, abnormalities, infection (HHV-6, HSV, VZV, fungal organisms, toxoplasma, among others), prior cranial irradiation, intrathecal chemotherapy, GVHD and malignancy. The following recommended: evaluation is Central Nervous System Dysfunction Evaluation CNS Dysfunction 1) Perform neurological examination including mini mental state exam . Consider 2) potential etiologies: - Medications (CSA, FK506, opioids, benzodiazepines, high - dose steroids, sirolimus, voriconazole, 506) cefepime, intrathecal chemotherapy, etc) and check cyclosporine (CSA)/Tacrolimus (FK levels/Voriconazole levels - Metabolic abnormalities (hypo/hypernatremia, hypercalcemia, hypercapnia, hyperosmolarity, renal or hepatic failure, hypothyr oidism, adrenal insufficiency, hypoglycemia, etc.) Non - CNS infection such as bacteremia, urinary tract infection (UTI ), pneumonia, etc. - - Unremitting pain or insomnia - Intracranial hemorrhage due to bleeding or other cause – Hypovolemia - - Head trauma CNS malignancy - - CNS infection - Prior cranial radiation When available, refer to institutional policies on the management of patients with delirium. If medication/metabolic/endocrine/pain effect/sleep deprivation are felt to be unlikely etiologies, the patient develops focal neurologic or infectious symptoms, OR if symptoms persist for >24 - 48 hours despite efforts to correct what’s felt to be underlying cause strongly consider: 1) Brain Imaging (MRI preferred) Lumbar puncture 2) r standard testing including: cell count/differential, total protein, glucose, CSF sent to laboratory fo cytology, gram stain, bacterial/fungal cultures, HHV - 6 PCR (viremia should not be assumed to be a marker be saved for future studies. for HHV - 6 CNS disease); please note on order that additional CSF should Additional testing for malignancy or infection (see table below) may be considered as clinically indicated. 3) Consider ID consult for evaluation of infectious etiologies of delirium 4) Consider Neurology consult for evaluation of n eurological etiologies of delirium 5) Consider psychiatry consult for evaluation and treatment of delirium Depending on the clinical scenario, the following additional tests for infectious etiologies may be considered on the next table 74

75 Relat ive Clinical Setting Recommended Initial Evaluation Pathogen Frequency Viruses - 6 Frequent - HHV CSF: HHV 6 PCR  Early after transplant  Temporal lobe contrast - enhancing lesions  Memory loss characterizing delirium HSV Occasional CSF: HSV PCR - enhancin g lesions  Temporal lobe contrast and not on ACV/GCV Seropositive  VZV Occasional CSF: VZV PCR  Seropositive or following significant not on ACV/GCV exposure and CMV Rare CSF: CMV PCR Donor or recipient seropositive and late  after transplant EBV Occasional CSF: EBV PCR cell depleted, including CD 34+ T  - selected - T cell antibodies  Receipt of anti Occasional Enterovirus CSF: Enterovirus PCR  Child Summer/fall  Occasional West Nile Virus* CSF: WNV PCR (low sensitivity), Donor is from endemic state  ELISA) IgM (MAC - Significant mosquito exposure  ELISA) Serum: IgM (MAC - Neuromusc ular weakness as component  Contact Public Health of meningoencephalitis CSF: JCV PCR Rare JC virus  enhancing white Brain imaging: non - Brain biopsy matter lesions other work - up negative  virus Very Rare Zika ID Consult  Donor or Recipient from endemic area Parasites Toxoplasma CSF: PCR (low sensitivity) Occasional  Ring - enhancing lesions Plasma: PCR Seropositive pretransplant and not on  prophylaxis TMP/SMX Fungi Asperg illus and other CSF: PCR and galactomannan Frequent Enhancing brain lesion (s) consistent with  (unknown sensitivity/specificity), molds abscess fungal culture  Concurrent pulmonary lesions (nodules) alactomannan Plasma: g High degree of immunosuppression, or  neutropenia Rare CSF: cryptococcal antigen, fungal Cryptococcus  High degree of immunosuppression, or culture neutropenia Serum: cryptococcal antigen  enhancing meningitis or nodule or - +/ hydrocephalus Bacteria Usual bacterial No additional testing Frequent Meningitis  pathogens: S. recommended as these pathogens  Enhancing brain lesion (s) consistent with iae , pneumon should be identified by standard abscess bacterial culture. Listeria, GNR, Nocardia, etc. Syphilis Rare CSF: VDRL, FTA, or TPPA; IgM - transplant se rology Positive pre  immunoblotting: intrathecal T. Significant exposure  pallium antibody (ITPA) index, PCR, CSF: AFB stain and culture, PCR Rare Tuberculosis**  Meningitis (basilar or diffuse) or ring - (both, low sensitivity) enhancing lesion(s) Recipient from endemic area  Positive PPD pretranspl ant   Significant exposure * If concerned about other arboviruses, please discuss with Infectious Diseases. ** If concerned about non-tuberculous mycobacteria, please discuss with Infectious Diseases. 75

76 If the appropriate test is not locally availa ble, arrangements should be made to send the specimen to another laboratory. Please c ontact the LTFU office (see Appendix A) Some children, especially those given cranial irradiation before the transplant, may have learning disabilities (particularly in math ematics and abstract thinking). These abnormalities typically begin to appear 24-42 months after the transplant. When recognized as a problem, refer for psychologica l testing. Special e ducational instruction should be considered for these children. Short-term memory deficit ca n occur in adults, performed as clinically indicated. and psychometric testing should be y the onset of developmental landmarks in very young Total body irradiation can dela children. These effects are most severe thr oughout the first year after transplant, and affected children benefit from occupational therapy to assist their normal development. After they have achieved appropriate deve lopmental landmarks, further development appears to proceed normally. IQ and ability to succeed in school do not appear to be affected by total body irradiation. G. Bone Complications (see Section XI) is (AVN) are common complications after Osteoporosis, fractures and avascular necros ment with corticosteroids is transplantation. Long-term treat the primary risk factor for trolyte imbalances, physical inactivity and these complications, while gonadal failure, elec treatment with cyclosporine play an additiona l contributory role. Approximately 50% of patients receiving long-term corticosteroid therapy will eventually develop bone fractures. Increased osteoclast-mediate d bone resorption and decreased osteoblast- loss. In allogeneic HCT recipients, mediated bone formation cause trabecular bone evaluation for bone loss and osteoporosis includ es a careful assessment of risk factors ( www.shef.ac.uk/FRAX/ ) and exposures in addition to BMD measurement. (see References, section XXV, Other Co mplications, Bone Complications) Bone loss can be minimized by minimizing gl ucocorticoid dose, optimizing calcium and earing exercise, and by hormone replacement vitamin D intake, participating in weight-b therapy. Section XI provides detailed guidelines for preventing and monitoring osteoporosis in patients who ar e being treated with corticosteroids. Section XX describes vitamins and other minerals requirements. S ection XXI outlines diet for patients treated with corticosteroids. Section XI outlines hormone replacement therapy. Chronic Pulmonary Complications H. /FVC is less than 70% in 15% of patients by one Some reports have shown that the FEV 1 year after the transplant a nd in 30% of patients by thr ee years after an allogeneic develop severe obstructive ith chronic GVHD, 5-10% will transplant. Among patients w airway disease that resembles obliterative bronchiolitis. 76

77 Monitoring of lung function after day +100 after allogeneic transplant. Pulmonary function test (PFT) monitoring incl uding: spirometry, lung volumes, and DLCO. PFTs for asymptomatic allo-HCT recipients: a. At 6 months b. At 1 year c. Yearly thereafter until 5 year s as clinically indicated d. At diagnosis of chronic GVHD i. Full PFT testing including: spirometry, lung volumes, and DLCO ii. Q3 months after diagnosis of ch ronic GVHD for at least one year. (spirometry alone may be adequate) iii. Thereafter, at Q6 months for 1 year (spirometry alone may be adequate) iv. sting including: spirometry, lung With at least yearly full PFT te volumes, and DLCO until year 5 post HCT. (Section X B). If new abnormalities are noted in PFT s please contact the LTFU office to discuss further recommendations (Appendix A). Children who received total body irradiation are at risk of delayed onset pulmonary nt. All patients who were in the pediatric restrictive disease 5-20 years after the transpla age group at the time of transplant shoul d have annual pulmonary function tests. Hepatobiliary Complications I. (see References, section XXV, Liver) line phosphatase or bilirubin may occur after day 100, even Elevations of serum ALT, alka in patients who had no indication of liver pr oblems earlier. The presentations fall into four clinical categories.  Acute hepatitis. Elevations of serum ALT after day 100 are most commonly caused by drug-induced liver injury (a n azole antifungal or trimethoprim- s of Drug Induced Liver Injury (DILI) sulfamethoxazole are the most common cause in this setting), chronic GVH B or C, or a herpesvirus D, an exacerbation of hepatitis hepatitis (VZV, HSV). Four clinical situations demand im mediate diagnosis and treatment. Rapidly rising ALT accompanied by anorexia 1) , abdominal distension or pain in the abdomen or back can be signs of visceral VZV infection (Section VIII B). 2) Patients who have indications of hepatitis B before transplant (HBsAg-positive or anti-HBc-positive) or who had a donor who was infected with hepatitis B are at risk of fulminant hepatitis B after the transplant if they did not receive antiviral prophylaxis.. after tapering or hepatitis, usually Chronic GHVD can present as an acute 3) discontinuation of immunosuppr essive medications, particularly cyclosporine or tacrolimus, or after DLI. 77

78 4) In Hepatitis C infected patients, a diagnosis of fulminant immune-rebound hepatitis should be considered, es pecially if patient is tapering cated, treatment with Direct Acting immunosuppression, and, if clinically indi Antiviral (DAA) drugs. Patients with a rapidly rising ALT and thos e with ALT values >500 u/L should be given IV acyclovir until VZV hepatitis is ruled out. An urgent PCR for VZV DNA in serum is needed to establish the di agnosis. Contact the LTFU office (Appendix A) for guidance in difficult cases. Chronic hepatitis. Chronic fluctuations in seru m ALT levels without a discrete  episode of acute hepatitis may represent DILI, hepatitis B or C virus infection (Section XVII), iron overload (Secti on XVIII) or cGVHD (Section X).  Jaundice or signs of cholestasis. Elevated serum bilirubin and elevated alkaline phosphatase can be caused by chronic GVHD (Section X), drug-induced cholestasis, acute hepatitis (see above), or biliary obstr uction. An ultrasound should be obtained to evaluate whether the co mmon bile duct is dilated. Liver biopsy might not be needed in patients who ha ve cholestasis with biopsy-documented tients have liver involvement as the chronic GVHD in other organs. Some pa dominant manifestation of chronic GVHD, and liver biopsy might be needed in ations of chronic GVHD are gnosis when other manifest order to establish the dia absent. The sudden onset of  Hepatomegaly or right upper quadrant pain. hepatomegaly suggests acute hepatitis, Epstein-Barr virus-induced lymphoproliferative disorder involving the li ver, or rarely, Budd-Chiari syndrome. More indolent hepatomegaly can occur with metastatic tumor, leukemia infiltration or rarely, constrictive pericarditis or mycobacterial infection. Right upper quadrant pain can be caused by acute cholecystitis , biliary obstruction with cholangitis, aging with helical biliary sludge syndrome, or rarely, fungal li ver abscess. Liver im CT X-ray or ultrasound is needed to resolve the diagnosis. Suggestions for liver biopsy and handling of liver tissue. The technique of liver biopsy depends on the clinical situation (diffuse process vs. focal lesion) and the platelet 3 count. A percutaneous biopsy is pref erred if platelet counts are >100,000/mm and the risk of bleeding is small (including norm al PT/PTT) but transvenous biopsy through either the femoral or jugular route is satisfact ory for diagnosis of a ny diffuse hepatitis or GVHD. Tissue should be cultured for viruses and fungi and should be fixed in freshly- prepared neutral buffered formalin. J. Gastrointestinal Complications: (see References, section XXV, Liver) 78

79 ia, nausea, vomiting and diarrhea after an GVHD is the most common cause of anorex allogeneic transplant. However, each of these symptoms has a narrow differential diagnosis that requires carefu l evaluation before concluding th at GVHD is the sole cause. Anorexia, nausea and vomiting can be caused by HSV, VZV, and CMV infections and by certain medications such as trimethoprim-s ulfamethoxazole, voriconazole, itraconazole, imus. Abdominal pain can be caused by mycophenolate mofetil, cyclosporine or tacrol visceral VZV infection, biliary sludge syndrom e, acute cholecystitis, or rarely, Epstein- Barr virus-induced lymphoprolifer ative disease. Diarrhea o ccurring more than 3 months after transplant is commonly caused by magne sium – containing medications, unresolved iasis, cryptosporidiosis, C. difficile, or GVHD, or less commonly by an infection (giard for evaluation of di CMV). Section VII provides guidelines arrhea and endoscopy. 79

80 BLOOD PRODUCT TRANSFUSIONS XVII. All Red Blood Cells and Platelets be irradiated (2,500 cGy) to prevent transfusion related ced to prevent HLA GVHD. Red blood cells an d platelets will also be leukocyte redu alloimmunization and reduce the risk of CMV transmission. Leukocyte reduced blood components are accepted as “CMV safe” for CMV seronegative patients. Granulocytes are never leukoreduced. If the donor and recipient had ABO blood group incompatibility, low-grade hemolysis can . Hemagglutinin titers and delay erythroid recovery for ma ny months after the transplant itor the change from recipient to donor ABO reticulocyte counts should be followed to mon type. Type O red cells should be used for pa tients who have isoagglut inins against donor red blood cell antigens until the donor blood group type is fully established in the recipient. Treatment with erythropoietin can be benefici al in some patients. Donor-type platelets should be used for transfusions. 80

81 erm transplant survivors XVIII. VIRAL HEPATITIS in long t (see References, section XXV, Liver) Compared to hepatitis C, hepatitis B is more lik ely to result in severe clinical hepatitis and hough these outcomes occu death from post-transplant liver disease, alt r only in the minority of HBV-infected patients. One exception: patients infected by HCV who are receiving MMF for GVHD prophylaxis may develop a more severe, potentially fatal form of liver disease called fibrosing cholestati c hepatitis C. In this sett ing, it should be assessed whether MMF may be discontinued. Antiviral treatmen t should be considered for HBV-and HCV- infected transplant recipients esent. Liver test abnormalities unless contraindications are pr HBV, HCV, a herpes virus infection post-transplant may be caused by hepatic GVHD, (VZV, CMV, HSV), adenovirus, or drug-induced injury (Secti ons I, X and XV). In this situation, liver biopsy should be performed to determine the dominant pathologic process. A. Hepatitis B Even in patients with very low levels of viral replication before transp lantation and relatively normal liver function and histol ogy, impaired cellular immunity can permit reactivation of HBV. Serological patterns of HBV infection may be atypical in transplant survivors, likely as a consequence of immunosuppression. Pa tients with HBV requiring systemic chronic GVHD remain at risk for acute immunosuppressive medications for control of ssion is tapered or ceased. Such flares exacerbation of hepatitis whenever immunosuppre may result in hepatic failure and death. Cirrhos is due to chronic HBV has not emerged as a major problem after transplantation. The risk of fatal HBV liver disease among pa tients who are persistently HBsAg-positive after transplant and who are not receiving entecavir is approx imately 12%. In hematopoietic cell transplant recipients who are anti-HBc and anti-HBs-positive, but HBsAg-negative, reactivation of latent infection can occur and may lead to fulminant hepatic failure, particularly if nucleotide substitutions in th e precore region of the genome interfere with production of HBcAg. Because these patients rema in HBcAg-negative despite high levels of viral replication, monitoring of HBV DNA levels is necessa ry in these HBsAg-positive patients. Posttransplant HBV infection may result from  Active HBV infection before transplant Reactivation of latent HBV infection   New infection during the transplantation process Infected hematopoietic cell pr o oduct from an infected donor o Infected blood products (risk estimated in U.S. to be 1 in 500, 000 units). 1) Monitoring of Patients at Risk for HBV Infection For allogeneic transplant patients who had a donor who was either HBsAg or  antiHepB core positive: Serum ALT and HBV DNA monthly to six months post transplant 81

82  For allogeneic transplant patients where patient is HBsAg positive and on entecavir: Serum ALT monthly post transplant wh ile on immunosuppressive therapy. If increase in serum ALT, then check HBV DNA by PCR .  For allogeneic transplant patients where patient is antiHepB core positive: while on immunosuppressive therapy. Serum ALT and HBV DNA monthly  For autologous transplant patients who is either HBsAg or antiHepB core positive: one year post transplant and continue o if on entecavir, serum ALT monthly to while on maintenance therapy. if not on entecavir, serum ALT a nd HBV DNA monthly to one year post o ile on maintenance therapy. transplant and continue wh 2) Treatment For patients at risk for HBV infection afte r transplant who are NOT receiving antiviral prophylaxis, we recommend initiation of antivir al treatment with entecavir when HBV DNA is first detected after transplant. For patients already on entecavir and not appropriately responding, consid er alternative antiviral ther apy. The aim of antiviral replication completely, thereby minimizing the risk of viral treatment is to suppress viral hs or 6 months after discontinuation of mutation. Patients should be treated for 12 mont ent, whichever is longer. systemic immunosuppressive treatm 3) Other considerations erved and is particul arly likely if the -Clearance of antigenemia is commonly obs hematopoietic cell donor was anti-HBs-positive. - Based on CDC guidelines, vaccination with H AV is considered particularly important and is strongly recommended for any patient with evidence of infection with HBV to prevent the development of fulminant liver fa ilure secondary to he patitis A infection. (See section IX Vaccinations) B. Hepatitis C Infection with HCV virus is more frequent in patients who received blood product transfusions than with transfusions given after 1991. before 1991 when HCV testing was unavailable The prevalence of chronic hepatitis C in long-term HCT survivors ranges from 5% to 70%, depending on the endemic prevalence. Long-te rm survivors with HC V infection commonly have fluctuating levels of AST and ALT. During the first 10 y ears after infection, hepatitis C has little impact in morbidity or mortalit y—with the exception possibly of HCV-infected patients who are receiving MMF. The frequency of cirrhosis and end-stage liver disease caused by Hepatitis C in 40-year survivors of hema topoietic cell transplant is about 33%. Regardless of whether HCV infection occurred be fore or after the tran splant, clinical or biochemical evidence of hepatitis usually coincides with the return of cellular immunity and the tapering of immunosuppressive drugs used for GVHD prophylaxis. During this time, it ant of GVHD of the liver from an exacerbation is difficult to differentiate the hepatitic vari of HCV. The presence of hepatitis C viremia, ev sufficient to make the en in high titer, is in 82

83 disorders. The absence of hepatitis C viremia, however, distinction between these two ions. Unless there is evidence of active GVHD means that HCV is not a cause of ALT elevat in other organs, a liver biopsy may be require d before a therapeutic decision is made. Pathologic distinction between hepatitis C a nd GVHD may be difficult, since both processes ration and bile duct inju ry. Marked bile duct may be associated with portal lymphoid infilt interlobular bile ducts is more typical of injury with epithelial cell dropout and loss of GVHD. A flare of hepatitis C and hepatic GVHD may occur simultaneously. If the liver biopsy suggests both processes, immunosuppressive therapy s hould be administered, since ongoing lymphocytic attack leading to loss of in terlobular bile ducts may result in severe and progressive cholestasis. reported only rarely af ter withdrawal of Fulminant immune-rebound hepatitis C has been immunosuppression. Patients infected by HCV w ho are receiving MMF may be at risk to develop fatal fibrosing cholestati c hepatitis C. After the initial flare of hepatitis during immune reconstitution, the serum ALT levels ma y again return to normal, but laboratory abnormalities often settle into the pattern of ch ronic hepatitis seen in other patients with HCV infection. Anti-viral therapy for chronic HC V infection should be considered after the patient has discontinued all i mmunosuppressive drugs and has no evidence of active GVHD. Monitoring:  Liver function tests at le ast weekly to day 100, then bimonthly until 1 year HCV RNA should be checked around day 50 post e rare patients who transplant in thos  gative pretransplant or whose donor was were HCV antibody positive but HCV RNA ne HCV RNA positive.  Repeated testing for HCV RNA is not necessary once the diagnosis of HCV infection has been established. Patients known to have HCV should be referred  to a hepatologist to assess three major issues: 1) Has the virus infection caused any da mage to the liver yet? 2) Are there other causes of liver damage (i.e., alcohol, medications, chroni c GVHD, hemosiderosis or the dications for HCV be instituted? hepatitis B virus? 3) Should me All HCV-infected long-term HC T survivors should be evalua  ted for progression of liver c function panel, complete blood count, and disease every 6 to 12 months with a hepati evaluation of prothrombin time/international norma lized ratio. If fibrosis is suspected in long-term HCT survivors, noninvasive tests such as serologic panels and transient elastography can be used to evaluate for the presence of advanced fibrosis (Scoring System for Histological Stage Metavir score > F3) and cirrhosis (Metavir score F4).  For HCV-infected HCT long-term survivors with advanced fibrosis (Metavir score > F3), surveillance for hepatocellula r carcinoma with ultrasonography every 6 months is recommended. For patients with cirrhosis, endo scopic surveillance for esophageal varices is recommended. Therapy any long-term HCT survivor with chronic Antiviral therapy should be considered in active against HCV are now available. hepatitis C infection. Newer antiviral drugs 83

84 Combination antiviral drug therapy is more effective in clearing HCV than older interferon/ribavirin regimens. (see References, section XXV, Liver)` In patients with concomitant iron overloa d, phlebotomy or chelation therapy may be ection XVIII) before Direct Acting Antiviral indicated to reduce hepatic iron stores (S (DAA) therapies. The mobilization of iron af ter transplant largely depends on the iron burden, especially cardiac ir on. A review of this topi c has been published. (see References, section XXV, Liver) lead to fibrosis should be In all HCT survivors with active HCV infection, cofactors that can addressed. Patients should be counseled to ght gain, ethanol and avoid excessive wei medications or herbal supplements that are he patotoxic, as well as on treatment of other causes of liver diseas e (nonalcoholic fatty liv er disease, hepatitis B virus, HIV, and extrahepatic obstruction), and mobilization of excess iron. stage liver disease can be considered for liver transplant; HCT recipients who develop end- al hematopoietic cell donor may er transplant from the origin in rare cases, a living donor liv be feasible. Other Considerations: against HAV and HBV are considered - Based on CDC guidelines, vaccination mmended for any patient with evidence of particularly important and are strongly reco infection with HCV to prevent the developmen t of fulminant liver failure secondary to infection with other hepatitis viruses. (See section IX Vaccinations) 84

85 XIX. IRON OVERLOAD Iron overload occurs frequently after th e transplant, often caused by ineffective erythropoiesis with associated intestinal hypera bsorption, in addition to red cell transfusions and, in some patients, genetic hemochromatosis. Relatively little is known about the effects her than those with hemoglobinopathies. Other of iron overload in HSC transplant patients ot oad in the range of 3200 to 7000  g/g dry weight have patients with hepatic iron overl normal life expectancy. Extrem e tissue iron overload (> 15,000  g/g dry weight) has been associated with extensive organ toxicity in the posttransplant survivors of thalassemia. the heart, liver, pancreas a Principal organs at risk include nd pituitary gland, resulting in is and cirrhosis, insuli n-dependent diabetes dysrhythmias and cardiac failure, portal fibros mellitus and other endocrine insufficiencies. In patients with chronic hepatitis C, iron overload may accelerate the development of cirr hosis. Once transplant has restored normal hematopoieses and red cell transfusions are no longer required, body iron stores decline over several years [Angelucci, Lancet 1993]. Mobilization of iron in heavily overloaded patients improves cardiac function, normalizes serum AL T levels, and results in improved liver histology [Angelucci, Blood 1997; Mariotti, BJH, 1998]. Liver or marrow iron content correlates poorly with number of transfused red blood cell units. Marrow and hepatic iron content has b een determined by spectrophotometry among 10 consecutive autopsied patients who were tran splanted for hematological malignancy. The  g/g dry median hepatic iron content (HIC) at 50 to 100 days posttransplant was 4307 nd the median marrow iron content was 1999 weight (range 1832-13120; normal 530-900) a  /g dry weight (range 932-3942). Marrow ir on content can also be measured by morphometry based on digital phot omicrographs of a Prussian blue-stained marrow biopsy. Because of correlation between morphometric and spectrophotometric analyses of marrow iron content (r = 0.8, P= 0.006) and hepatic ir on index (r = 0.82, P = 0.004) morphometric ng tissue iron stores analysis of marrow iron content is an acceptable alternative for quantifyi demonstated a close relationship between [Strasser, BMT 1998]. Earlier work also ing of marrow iron [Gal e et al 1963] although biochemical concentration and histologic grad on between and within observers [Cavill 1982]. histological grading is subject to variati Because the carrier frequency for homozygous HF E gene mutations is relatively high (0.3 to 0.5%) among individuals of northern and wester n European extraction, the possibility of genetic hemochromatosis contributing to posttrans plant iron overload needs to be considered in relevant individuals. Two point mutati ons, C282Y (Cys282Tyr) and H63D (His63Asp), Homozygosity for C282Y is associated with have been described within the HFE gene. haemochromatosis; the effect of compound he terozygosity (C282Y/H63D)) on iron status in HCT recipients is variable [Grigg et al, 2001]. Individuals Particularly at risk for Iron Overload  Hemoglobinopathies (Sickle Cell Disease, Thalassemia major)  Congenital Anemia (e.g., Diamond-Blackfan)  Hereditary Hemochromatosis Chronic Anemia with transfusional ove  rload and ineffective erythropoiesis  Hepatitis C may accelerate siderosis-induced hepatic damage 85

86 A. Evaluation of Iron Overload after HSC Transplant Bone Marrow 1.  Measurement of marrow iron by morphometry or spectrophotometry is appropriate to assess iron stores in most cases. 2. Serum Iron Studies and Liver function tests if > 2 in grade in B one Marrow, at 80-100 days post transplant, 1 year post transplant or at increased ri sk for iron overload.  Transferrin Saturation (TS)  Serum ALT and AST ng Capacity (TIBC) Serum Iron, Total Iron-bindi   Serum Ferritin  HFE genotype should be considered in patients with a family member with HC and in patients with Transferrin Saturati on (TS) > 45% in patients of Northern or Western European ethnicity. 3. Assessment of Iron Stores in Tissues  Indications Assessment of Iron Stores is indicated in patients with Transferrin Saturation (TS) C282y/H63D C282y/C282y or HFE with either a ferritin level > 1000 or > 45% and HFE wild type with either ferritin abnormal ALT and in patients with TS > 45% with HFE levels > 2500 or abnormal ALT. tometry of liver biopsy is the gold Measurement of hepatic iron by spectropho  patients with markedly elevated serum standard for testing and is preferred for ferritin and ALT (especially if HFE homozygous or com pound heterozygous). In ewed for liver pathology (e.g., portal addition, these samples should be revi fibrosis, cirrhosis, or hepatitis).  While measurement of liver iron concentr ation is the gold standard, an iron- specific magnetic resonance imaging test (Ferriscan) is highly accurate in measuring liver iron and is an alternative to liver biopsy for the measurement of hepatic iron content. 4. Indication for Iron Mobilization Therapy A ccording to Tissue Iron Content Hepatic Iron Content Mobilization of Iron Marrow Iron Content g/g dry weight)  ( >15000 Very high Phlebotomy + Desferoxamine ++++ t s 7000 – 15000 Moderately high 1 choice: Phlebotomy nd ++ to +++ 2 choice: Desferoxamine or Desferasirox (especially if HCV+) type ild w 1) HFE : <7000 Not increased or mildly observe increased C282Y/C282Y or C282Y/H63D : 2) HFE + Phlebotomy 86

87 B. Phlebotomy after Transplant  If indicated, phlebotomy is lik ely to be the safest and most cost-effective approach for the mobilization of tissue iron. Regular phlebotomy requires normal hematopoi  esis or hematopoiesis that can respond satisfactorily to weekly or every-other-w eek erythropoietic stimulating agents.  Phlebotomy Regimen: Phlebotomy volume 5 mL/kg as tolerated Frequency every 3-4 weeks as tolerated iron and % iron saturation Monitoring monthly ferritin, Discontinue Phlebotomy n falls below 500-1000 ng/mL ferriti  Erythropoietic Stimulating Agents may be ad ministered subcutaneously to facilitate regular phlebotomy. The smallest number of wh ole vials should be prescribed per dose: 1 2 Darbepoetin Erythropoietin Body Weight (Units weekly) (micrograms every-other-week) (kg) 10-14 6000 to 8000 25 to 60 60 15-20 10000 10000 to 14000 21-24 60 to 100 25-29 14000 100 100 30-39 20000 40-60 40,000 200 Use darpopoetin 200 >60 1 Erythropoeitin (Epogen) vial sizes (2000, 4000, 10000, 20000, 40000 units) 2 Darbepoetin (Aranesp) vial si zes (25, 60, 100, 150, 200, 300 micrograms) C. Chelation Therapy  If phlebotomy cannot be performed despite the use of erythropoietic stimulating agents to mobilize iron stores is within 3 - 6 months after tran splantation, and if treatment mine (Desferal) or deferasirox (Exjade) indicated, iron chelation therapy with desferoxa should be initiated. 1. Desferoxamine (Desferal)  Iron overload increases the susceptibility of pa tients to Yersinia enterocolic and Yersinia pseudotubera infections. In rare cases, treatm ent with desferoxamine has enhanced this susceptibility, resulting in generalized inf ections by providing this bacteria with a ons with mucormycosis have also been siderophore otherwise missing. Rare infecti reported in association with desferoxamine .  Desferoxamine can be administ ered by continuous subcutane ous or intravenous infusion. Desferoxamine causes less toxicity if administered subcutaneously. The daily dose of deferoxamine (Desferal) should be 20 to 40 mg/kg subcutaneously,  administered at least five days per wee k. The dose should not exceed 50 mg/kg and the kg/hour in order to avoid hypotension. infusion rate should not exceed 15 mg/ 87

88 ed parenterally by continuous Desferoxamine is administer overnight infusion with ambulatory pumps. Plasma concentra tions reach a plateau at 12 hours.  Most of the toxicity caused by desferoxamine occurs when the dose exceeds 50 mg/kg or when the iron burden is not high.  ude ocular and auditory abnormalities, Toxic effects caused by desferoxamine incl sensorimotor, neurotoxicity, re nal insufficiency, pulmonary t oxicity, and failure of linear growth.  Toxicity can be avoided by regular assessment of the body iron stores. Patients receiving desferoxamine should have annual measurem ent of total body iron (liver biopsy or another suitable measure). In general, dir ect assessment of body ir on stores should also follow when desferoxamine toxicity occurs.  If hepatic iron content is <3000 mcg/gm dry liver weight, or marrow iron content is not increased or only mildly increased, treatment with desferoxamine should be discontinued for six months. Thereafter, the dose of desf eroxamine should be adjusted to maintain hepatic iron content between 3000 a nd 7000 mcg/gm dry liver weight. Suggested monitoring of desferoxamine -related toxicity is shown below. Toxicity Tests Frequency Alteration In Rx Stop desferoxamine; Annually; if Audiogram High frequency sensorineural hearing repeat audiogram at 3 symptomatic, check loss month intervals until immediately normal or stable Retinopathy (pigmentairy Eye exam Annually; if Stop desferoxamine if including visual symptomatic, check degenaration); cataracts; retinopathy or hearing corneal opacities; visual acuity, slit-lamp impairment immediately impairment and fundoscopy Metaphyseal/Spinal Plain x-ray of Annually Reduce desferoxamine wrists, knees, to 25 mg/kg/day spine; bone age in children Growth retardation Sitting and Reduce desferoxamine Every 6 months standing height to 25 mg/kg/day; reassess every 6 months 2. Deferasirox (Exjade) Deferasirox is an oral medica tion for iron chelation. It is  available in 125mg, 250mg, and 500mg tablets.  The starting dose of deferasirox is 20mg/kg/day. The dose of deferasirox may be adjusted in 5-10mg/kg/day increments every 3-6 months if necessary depending on serum ferritin trends. Doses of deferasirox should not exceed 30m g/kg/day. Therapy should be temporarily discontinued if the serum ferriti n level falls below 500mcg/L.  Deferasirox should be taken once daily on an empt y stomach (at least 30 min prior to eating). Tablets should be completely disp ersed by stirring in water, ora nge juice, or apple juice until there is a fine suspension. Doses <1 gram should be dispersed in 3.5 ounces of liquid, and liquid. After swallowing, any residue 1 gram should be dispersed in 7 ounces of doses  88

89 should be resuspended in a small volume of liquid and swallowed. Doses should be separated by 2 hours from al uminum containing antacids.  Dosing of deferasirox should be reduced for re nal dysfunction. If the serum creatinine level increases more than 33% over the course of tw o consecutive visits, the dose of deferasirox should be reduced by 10mg/kg. For pediatric patients, the dose should be reduced by 10mg/kg if the serum creatinine is greater th an the upper limit of normal on 2 consecutive visits.  ude GI symptoms (diarrhea, vomiting, nausea, abdominal pain), Toxicities of deferasirox incl headaches, pyrexia, skin rash, increases in serum creatinine, intermittent proteinuria, cytopenias (including agranulocytosis, neut ropenia, and thrombocytopenia), hepatic dysfunction, auditory distur bances, and ophthalmic disturbances. Post marketing surveillance has shown cases of acute renal failure or cytopenias with fatal outcomes in deferasirox in these patients taking deferasirox. The relation to cases is uncertain. d every month while on deferasirox. Serum  Serum ferritin levels should be monitore creatinine, urine protein levels, CBCs, and liver function tests should be checked at baseline s with pre-existing renal dysfunction or other and at least monthly while on therapy. Patient serum creatinine levels for at least the first risk factors should be monitored with weekly line auditory and ophthalmic testing are month, and then monthly thereafter. Base recommended with regular follow up assessments every 12 months. 89

90 XX. VITAMINS AND OTHER MINERAL SUPPLEMENTS It is recommended that all allogeneic patie nts have iron-free multiple vitamin/mineral supplementation for one year or until all immunosuppressive ther apy is discontinued after the transplant. Autologous patients should conti nue supplementation for one year if dietary intake does not meet daily requirements. Iron supplementation should not be used routinely in any patient unless iron deficiency is clearly documented. Most pati ents have iron-overload because of red cell transfusions and increased absorption of iron in th e GI tract (see Section XIX). Calcium and Vitamin D daily intake requirements A. Adequate calcium and vitamin D intake are ne cessary in order to decrease the risk of bone complications after transplant. Wome n with ovarian failure and patients who ith corticosteroids have a hi require long-term treatment w gh risk of osteoporosis, and pediatric patients can have poor bone devel opment after chemothera py and radiation. Avoidance of sunlight and the use of sunscr een to block UV radiat ion can contribute to vitamin D deficiency. Patients who cannot consume adequate calcium or vitamin D from foods should receive supplements to meet their daily requirements . Supplemental calcium should be given in cium citrate. Some "natural" calcium supplements do not divided doses, preferably as cal contain enough bioavailable calcium to prev ent osteopenia. The maximum amount that See Section XI for prevention of osteoporosis can be absorbed with each dose is 500 mg. in patients who are being tr eated with glucocorticoids. Daily requirements ++ Elemental Ca Age (years) Vitamin D 1 - 5 800 mg 400 International Units 6 - 8 1200 mg 400 International Units International Units 9 - 18 1500 mg 400 - 800 >18 800 International Units 1500 mg B. Magnesium supplementation Cyclosporine and tacrolimus (FK-506) incr ease urinary excretion of magnesium, resulting in low serum magnesium levels. Hypomagnesemia has been associated with seizures in patients treated with cyclos porine or tacrolimus (FK506). All patients receiving these immunosuppressive drugs require magnesium supplementation and monitoring serum magnesium levels monthl y, or more often as indicated. Oral magnesium with protein (133 mg/tablet) is better tolerated than magnesium oxide. The re tablets daily for adults and 1 to 9 or magnesium requirements range from 6 to 20 or mo nts may require intravenous supplementation more tablets daily for children. Some patie ministration causes diarrhea. (magnesium sulfate) if oral ad 90

91 XXI. DIETS AND OTHER NUTRI TIONAL GUIDELINES A. Diet for immunosuppressed patients after transplant Patients after hematopoietic tr ansplant or after high dose ch emotherapy are at increased risk of developing food-related infections . It is recommended th at all transplant recipients follow the nutrition guidelines for discharge home, including the Diet for Immunosuppressed Patients. Thes e guidelines can be found at www.seattlecca.org patientsandfamilies/nutrition/ under nutritionDietsguidelines/ The duration of immunosuppressed patient diet osteoporosisNutritionguidelines. depends on the immunocompromised status of th e patient and the type of transplant, as described below: transplant recipients should fo Allogeneic  llow the immunosuppressed patient diet guidelines until all immunosuppressive treatments are discontinued. llow the immunosuppressed patient diet  Autologous transplant recipients should fo guidelines until one month after discontinuation of corticosteroids or three months after chemotherapy or transplant (whichever as long as there are occurs later) and no GI symptoms. B. Additional dietary recommendations: 1. Diet for patients receiving treatment with corticosteroids: In addition to the Diet for Immunosuppre ssed Patients, nutritional recommendations These nutritional to minimize the risk of osteoporosis are n eeded (see Section XI). guidelines can also be found at www.seattle cca.org/ patientsandf amilies/nutrition/ nutritionDietsguidelines/ost eoporosisNutritionguidelines . 2. Diet for patients with graft-versus- host disease of gastrointestinal tract : nt Diet, specific diets are recommended In addition to the Immunosuppressed Patie for patients with GVHD of the GI tract to help alleviate th e gastrointestinal symptoms. Two different gastrointestinal diets (GI1 and GI2) have been developed by the dietitians at the FHCRC and the S CCA. These GI1 and GI2 diets have limited amounts of fats, fiber, lactose, acidic items and GI irritants. The diets can be found at www.seattlecca.org under patientsandfamilies/nutrition/ nutritionDietsguidelines/. For patients with severe diarrhea (ex ceeds 8-10 ml/kg/day) or significant crampy abdominal pain, bowel rest (NPO) is r ecommended. TPN at 1.5 x basal energy needs or higher, 1.5-2.0 g protein/kg with suppl emental zinc is also usually needed. Replacement of stool losses on a mL/mL basis with half-normal saline hydration is se to oral feeding is recommended. As diarrhea subsides, the respon highly variable. 91

92 otonic beverage in When oral intake is appropriate, we reco mmend beginning with is e GI1 diet and subsequently to the GI2 small amounts and gradually progressing to th diet as tolerated (see Table next page). GVHD of the upper intestine or stomach ma y present only as anorexia, nausea, and early satiety. High-fat foods are gene rally poorly tolerated. Empiric lactose restriction should be considered. Patie nts may find it easier to meet energy and sipped continuously throughout the day. protein needs with nutritional supplements 92

93 Gastrointestinal GVHD Diet Progression* Phase Diet Diet Intolerance Symptoms Oral: NPO GI cramping 1. Bowel rest Large volume watery diarrhea Depressed serum albumin IV: stress energy and protein Severely reduced transit time Requirements Small bowel obstruction or diminished bowel sounds Nausea and vomiting Increased stool volume Oral: isosmotic, low-residue, Minimal GI cramping 2. Introduction of or Diarrhea less than 500 ml/day low-lactose beverages, oral feeding diarrhea Guaiac-negative stools initially 60 ml every 2-3 Increased emesis Improved transit time (minimum 1.5 hours, for Increased abdominal hours) several days Cramping Infrequent nausea and vomiting IV: as for Phase 1 As in Phase 2 Oral: allow introduction of Minimal or no GI cramping 3. Introduction of solid food, once every 3-4 Formed stool solids a hours: minimal lactose , low fiber, low fat (20-40 b gm/day) , low total acidity, no gastric irritants IV: as for Phase 1 a As in Phase 2 Minimal or no GI cramping , low Oral: minimal lactose 4. Expansion of Formed stool fiber, low total acidity, no diet gastric irrita nts; if stools indicate fat b malabsorption: low fat IV: as needed to meet nutritional requirements As in Phase 2 Oral: progress to regular No GI cramping 5. Resumption of diet by introducing one Normal stool regular diet restricted food per day: Normal transit time acid foods with meals, Normal albumin fiber-containing foods, lactose-containing foods. Order of addition will vary, depending on individual tolerances and preferences. Patients no longer exhibiting steatorrhea should have the fat restriction liberalized slowly IV: discontinue when oral nutritional intake meets estimated needs a R villous atrophy. A commercially-prepared lactose solution (Lact aid Lactose is one of the last disaccharidases to return following ) is used R to reduce the lactose content of milk by >90%. Lactaid milk (100% lactose-free) is also commercially available. b Additional calories may be provided by commercially available medium chain triglycerides which do not exacerbate symptoms. *Adapted from Darbinian J, Schubert MM. Special management problems. In: Lenssen P, Aker SN, eds. N utritional Assessment Seattle, WA: Fred Hutchinson Cancer Research Center; and Management During Marrow Transplantation. A Resource Manual. 1985;63-80. 93

94 XXII. NATUROPATHIC REMEDIES: HERBAL AND NUTRIENT SUPPLEMENT PREPARATIONS  Allogeneic transplant patients: Herbal/botanical preparations should not be given duri ng immunosuppressive therapy or in patients with chronic GVHD. One month after discontinuation of all solution of manifestations of chronic systemic immunosuppressive treatment and re e discretion of the primary aration may be given at th GVHD, herbal/botanical prep physician.  Autologous transplant patients: be given until complete recovery of any Herbal/botanical preparations should not gastrointestinal toxicity a nd until prednisone therapy has been discontinued for one month. Further information regarding guidelines for the use of herbal and nutrient supplement under www.seattlecca.org preparations can be found at patientsandfamilies/nuritionDietsguidelines, Guidelines for herbal & nutrient supplements during . hematopoietic stem cell transplantation and high-dose chemotherapy 94

95 XXIII . RETURN TO SEATTLE FOR LONG -TERM FOLLOW-UP EVALUATION All adults who have had an allogeneic transp lant and all children w ho have had either an to the FHCRC/SCCA for a comprehensive splant should return allogeneic or autologous tran evaluation at one year after the transplant . Depending on clinical indications, follow-up should return for subsequent evaluations at subsequent inte rvals may be arranged. Children evaluations at 2, 3, 5, 10, 15, a nd 20 years after the transplant. These evaluations focus on hematologic and immunologic function, assessmen t of the original disease, and thorough screening for any late transplant complications . The LTFU evaluation requires four to five working days to complete. A detailed summa ry of findings and recommendations will be s must be scheduled at least 4 months in forwarded to the referring physician. Appointment advance by calling the LTFU office assistant at (206) 667-4415 or by sending a FAX to 1-800-376-8197 (toll-free, USA and Canada). TIME TO RETURN FOR TYPE OF TRANSPLANT COMPREHENSIVE EVALUATION Allogeneic (ADULT) One year after the transplant Follow-up evaluations at other times per Autologous (ADULT) One year after the transplant protocol or as clinically based on protocol, patient or indicated physician request Allogeneic & Autologous One year, 2, 3, 5, 10, 15, and 20 (PEDIATRIC) years after the transplant 95

96 HOW TO SEND SPECIMENS XXIV. FOR TESTING AT FHCRC / SCCA Clinical laboratory testing for patients who r eceived treatment at Fred Hutchinson Cancer Research Center / Seattle Cancer Care A lliance (FHCRC / SCCA) is available at the FHCRC/SCCA. The tests most often performed in our laboratories at the request of referring physicians include BCR/abl transcripts by pol ymerase chain reaction (PCR), CMV PCR and chimerism studies by assessment of variable number tandem repeat polymorphisms. We ask that you notify the LTFU office by telephone at (206) 667-4415 or by FAX (Appendix A) to indicate the expect ed date and time of arrival for specimens that are sent for testing at the FHCRC / SCCA. The LTFU office will provide detailed instructions regarding tion for the specific test(s) requested. sample collection and shipment informa If surgery or biopsy is planned for evalua tion of suspected secondary malignancy or recurrence of disease, please contact our LTF U office before the procedure, whenever possible. Guidelines for Sending Clinical Specimens 1. Call the LTFU office at (206) 667-4415 be fore sending the specimen (Appendix A). 2. Do not send fresh / frozen samples to arrive on Fridays, weekends or government holidays. Ship the specimen via an overnight courier 3. service on the day the samples were obtained. Label each tube with 4.  Patient's name  Patient's social security number (i f not available, date of birth)  Date that the sample was obtained marrow, serum, left breast mass, etc.)  Type of specimen (i.e., peripheral blood, bone 5. faxed to you by our office that will be Please complete Test Request Forms S SAMPLE(S) MUST BE ACCOMPANIED BY THE SCCA TEST REQUEST FORM 6. 7. nt or the facility send Shipment charges are the responsibility of the patie ing the sample. ctions to patients who are enrolled in A study coordinator will forward shipment instru sent to the FHCRC / SCCA for research studies. specific protocols that require samples to be 96

97 . REFERENCES XXV Chronic GVHD 1. Sullivan KM. Graft vs. Host Disease. In: Blume KG, Forman SJ, Appelbaum FR eds. Thomas’ Hematopoietic rd Cell Transplantation, 3 . Blackwell Publishing; ; 635-664. 2004 Edition 2003 ; Biol Blood Marrow Transplant 2. Lee SJ, Vogelsang G, Flowers MED. Chronic graft-versus-host disease. 9 : 215-233. 3. Flowers MED, Parker PM, Johnston LJ, et al. Comparison of chronic graft-versus-host disease after bone marrow in allogeneic recipients: long-term follow- transplantation of peripheral blood stem cells versus 2002 up of a randomized trial. ; 100:415-419. Blood 4. Filipovich AH, Weisdorf D, Pavletic S, et al: NIH Consensus Develo pment Project on Criteria for Clinical s and Staging Working Group Report: Biol Blood tVersus-Host Disease: I. Diagnosi Trials in Chronic Graf Marrow Transplant ; 11: 945-955. 2005 5. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic Graft vs. Host syndrome in man. A long-term Am. J. Med. ; 69:204-217. clinicopathologic study of 20 Seattle patients. 1980 6. Stewart BL, Storer B, Storek J, et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. 2004 Blood ; 104:3501-3506. 7. Au BK, Au MA, Chien JW. Bronchiolitis obliterans synd rome epidemiology after allogeneic hematopoietic Biol Blood Marrow Transplant 2011;17:1072-8. doi:10.1016/j.bbmt.2010.11.018 cell transplantation. 8. Cheng GS, Storer B, Chien JW, et al. Lung Function Trajectory in Bronchiolitis Obliterns Syndrome after Allogeneic Hematopoietic Cell Transplant. Ann Am Thorac Soc. 2016 Nov;13(11);1932-1939. 9. Williams KM, Cheng GS, Pusic I, Jagasia M, Burns L, Ho VT, Pidala J, Palmer J, Johnston L, Mayer S, Chien JW, Jacobsohn DA, Pavletic SZ, Martin PJ, Storer BE, Inamoto Y, Chai X, Flowers ME, Lee SJ. Fluticasone, azithromycin, and montelukast treatme ns syndrome after hematopoietic nt for new-onset bronchiolitis oblitera cell transplantation. Biol Blood Marrow Transplant 2016;22:710-6. doi:10.1016/j.bbmt.2015.10.009 Flowers ME and Martin PJ. How we treat chronic graft-versus-host disease. 10. 2015;125:606-615. Blood doi:10.1182/blood-2014-08-551994 Jagasia MH, Greinix HT, Arora M, W illiams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, 11. Cheng GS, Kerr H, Stratton P, Duarte RF, McDonald GB, Inamoto Y, Vigorito A, Arai S, Datiles MB, PJ, Shulman H, Wu RS, Cutler CS, Vogelsang GB, Lee Jacobsohn D, Heller T, Kitko CL, Mitchell SA, Martin ealth consensus development project on criteria for SJ, Pavletic SZ, Flowers ME. National institutes of h clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant 2014;doi:10.1016/j.bbmt.2014.12.001 12. Bergeron A, Godet C, Chevret S, Lorillon G, Peffault de Latour R, de Revel T, Robin M, Ribaud P, Socie G, Tazi A. Bronchiolitis obliterans synd sct: Phenotypes and prognosis. Bone rome after allogeneic hematopoietic Marrow Transplant 2013;48:819-24. doi:10.1038/bmt.2012.241 13. Pelligrini R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CPM, Gustafasson P, Hankinson J, Jensen, R, Johnson DC, MacIntyre N, McKay R Miller MR, Navajas D, Pedersen 2005;26:948-968. Williams KM, OF, Wanger J. Interpretative strategies for lung function tests. Eur Respir J Chien JW, Gladwin MT, Pavletic SZ. Bronchiolitis ob literans after allogeneic hematopoietic stem cell transplantation. 2009;302:306-14. doi:10.1001/jama.2009.1018 JAMA 14. Carpenter PA, Kitko CL, Elad S, Flowers ME, Gea-Ba nacloche JC, Halter JP, H oodin F, Johnston L, Lawitschka A, McDonald GB, Opipari AW, Savani BN , Schultz KR, Smith SR, Sy rjala KL, Treister N, Vogelsang GB, Williams KM, Pavletic SZ, Martin PJ, Lee SJ, Couriel DR. National institutes of health consensus development project on criteria for clinical tria ls in chronic graft-versus-host disease: V. The 2014 e care working group report. ancillary therapy and supportiv Biol Blood Marrow Transplant 2015;21:1167-87. doi:10.1016/j.bbmt.2015.03.024 15. Gunn ML, Godwin, JD, Kanne JP, Flowers ME, Chien JW. High-resolution CT findings of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. J Thorac Imaging 2008 Nov;23(4):244-450. doi:10.1097/RTI.0b013e3181809df0 16. Williams KM, Chien JW, Gladwin MT, Pavletic SZ. Bron chiolitis obliterans after allogeneic hematopoietic JAMA stem cell transplantation. 2009;302:306-14. doi: 10.1001/jama.2009.1018. 97

98 17. Bergeron A, Chevret S, Chagnon K, Godet C, Bergot E, Peffault de Latour R, Dominique S, de Revel T, Juvin K, Maillard N, Reman O, Contentin N, Robin M, Buzyn A, Socie G, Tazi A. Budesonide/formoterol for bronchiolitis obliterans after hematopoi etic stem cell transplantation. Am J Respir Crit Care Med 2015;191:1242-9. doi:10.1164/rccm.201410-1818OC 18. MA, Lee SJ, Moravec CK, Chien JW. Fluticasone, Norman BC, Jacobsohn DA, Williams KM, Au BK, Au azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome Bone Marrow Transplant 2011;46:1369-73. after allogeneic hematopoietic sct: A case series of eight patients. doi:10.1038/bmt.2010.311 19. Cheng GS, Edelman JD, Madtes DK, Martin PJ, Flowers ME Outcomes of lung 2014 . Biol Blood Marrow Transplant. transplantation after allogeneic hematopoietic stem cell transplantation Aug;20(8):1169-75. doi: 10.1016/j.bbmt.2014.04.008. Epub 2014 Apr 13 98

99 IV Immunoglobulin: 1. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled . ;319(14):902-7. clinical trial. N Engl J Med 1988 2. The National Institute of Child Health and Human Developments Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bact erial infections in children with symptomatic human . 1991 ;325(2):73-80. immunodeficiency virus infection. N Engl J Med 3. Magny JF, Bremard-Oury C, Brault D, et al. Intravenous immunoglobulin therapy for prevention of infection in Pediatrics high-risk premature infants: report of a multicenter, double-blind study. 1991 ;88(3):437-43. . 4. Winston DJ, Antin JH, Wolff SN, et al. A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation. . 2001 ;28(2):187-96. Bone Marrow Transplant 5. Cordonnier C, Chevret S, Legrand M, et al. Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, o-controlled, multicenter trial. Ann Intern Med. double-blind, dose effect, placeb 2003 ;139(1):8-18. 6. Sokos DR, Berger M.and Lazarus HM. Intravenous immunoglobulin: appropriate indications and uses in hematopoietic stem cell transplantation [Review]. Biol. Blood and Marrow Transplantation . 2002 .8(3):117-30. 7 Sullivan, KM, Kopecky, KJ, Jocom, J, et al. Imm efficacy of intravenous unomodulatory and antimicrobial N.Engl.J.Med 1990 . immunoglobulin in bone marrow transplantation. . 323:705-712, 8. Sullivan, KM, Storek, J, Kopecky, KJ, et al. A controlled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic graft-vs.-host disease after marrow transplantation: Biol. Blood and Marrow Transplantation 2: 44-53, clinical outcome and effect on subsequent immune recovery. 1996 . 9. Bhella, Sita et al. Choosing Wisely BMT : American Society for Blood and Marrow Transplantation and Canadian Blood and Marrow Transplant Group's List of 5 Tests and Treatments to Question in Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation , Volume 24 , Issue 5 , 909 - 913 Hyperlipidemia: References: 1. Chow et al, Ann Intern Med, 2011 in press 2. Majhail NS et al, High prevalence of metabo lic syndrome after allogeneic hematopoietic cell transpla ntation. Bone Marrow Transp lant 2009;43:49-54. http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm 3. 4. ogeneic bone marrow transplanta tion. Bone Marrow Transplant. 1996; Wang B, Cao LX, Liu HL, et al. Myocardial infarction following all 18: 479-480. 5. O’Rourke B, Barbir M, Mitchell AG. Efficacy and safety of fluvastatin therapy for hy percholesterolemia after heart transplantat ion. Results of a randomized double blind placebo controlled st udy. Int. J. Cardiology. 2004; 94: 235-240. 6. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravas tatin on outcomes after cardiac transplantation. N Engl J Med. 199 5; 333: 621-627. Hyperlipidemia (continued) References: 7. Wenke K, Meiser B, Thiery J, et al. Simvastatin initiated early after heart transplantation: 8-y ear prospective experience. Cir ulation. 2003; 107: 93-97. 8. Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac out comes in renal transplant recipients: a multicen ter, randomized, placebo-controlled tr ial. Lancet. 2003; 361: 2024-2031. 9. Cosio F, Pesavento TE, Pelletier RP, et al. Patient survival after renal transplantation III: the effects of statins. AM J Kidn ey Dis. 2002; 40: 638-643. 10. Del Castillo D, Cruzado JM, Diaz MJ, et al . The effects of hyperlipidemia on graft a nd patient outcome in renal transplantation . Nephrol Dial Transplant. 2004; 19; Suppl 3: 67-71. Chin C, Gamberg P, Miller J, et al. Efficacy and safety of at rovastatin after pediatric heart transplantation. J Heart Transpla nt. 2002; 21: 11. 1213-1217. 12. Mahle WT, Vinvent N, Berg AM. Pravastatin therapy is associated with reduction in co ronary allograft vasc ulopathy in pediatric heart transplantation. J. Heart Lung Transplant. 2005; 24: 63-66. Argent E, Kainer G, Aitken M, et al. Atorvastatin treatment fo r hyperlipidemia in pediatric re nal transplant recipients. Pediat r 13. Transplantation. 2003; 7: 38-42. 14. Borghi C, Dormi A, Veronesi M, et al. Association between different lipid-lowering treatment strategies and blood pressure cont rol in the Brisighella Heart Study. Am Heart J. 2004; 148: 285-292. 15. Tsira S, Elisaf M, Mikhailidis DP. Early vascular benefits of statin therapy. Curr Med Res Opin. 2003; 19: 540-556. 16. Circulation. 2004; 109 (21 Suppl 1): II, 15-17. Mach F. Statins as immunomodulatory agents. 99

100 Fehr T, Kahlert C, Fierz W, et al. Statin-induced immunomodul vivo. Atherosclerosis. 2004; 175 : 83-90. 17. atory effects on human T cells in Prasad GV, Chiu R, Nash MM, et al. Statin use and bone minera l density in renal transplant recipients. Am J Transplant. 2003;3: 1320-1321. 18. 19. of osteonecrosis in patients receiving steroids. Clin Orthop. 2001; 386: 173-178. Pritchett JW. Statin use decreases the risk 20. Wang GJ, Cui Q, Balian G. The pathogenesis and prevention of steroid-induced osteonecrosis Hypertension 1. Chow et al, Ann Intern Med, 2011 in press 2. Majhail NS et al, High prevalence of metabo lic syndrome after allogeneic hematopoietic cell transplantation. Bone Ma rrow Transplant 2009;43:49-54. 3. http://www.nhlbi.nih.gov/guidelin es/hypertension/express.pdf Liver: 1. Strasser SI, McDonald GB. Hepatitis Viruses and Hemato poietic Cell Transplantation: A Guide to Patient and Donor Management. Blood 93 : 1127-1136, 1999. 2. Murakami CS, Louie W, Chan GS, et al. Biliary obstr uction in hematopoietic cell transplant recipients: An uncommon diagnosis with specific causes. Bone Marrow Transplantation 23: 921-927, 1999 . 3. Strasser SI, Sullivan KM, Myerson D, et al. Cirrhosis of the liver in long-term marrow transplant survivors. 1999 93: 3259 – 3266, Blood . C virus infection after bone marrow transplantation: A 4. Strasser SI, Myerson D, Spurgeon CL, et al. Hepatitis cohort study with 10 year follow-up. Hepatology 29: 1893 – 1899, 1999 . 5. Strasser SI, Shulman HM, McDonald GB. Cholestasis after hematopoietic cell transplantation. Clinics in Liver 1999 Disease 3: 651 – 668, . 6. Strasser SI, Shulman HM, Flowers MED, et al. Chronic graft-vs-host disease of the liver: Presentation as an acute hepatitis. Hepatology 32: 1265 – 1271, 2000 . 7. Strasser SI, McDonald GB. Chapter 56, Gastrointestinal and hepatic complications, in Hematopoietic Cell Transplantation, Second Edition , edited by Thomas ED, Blume KG, Forman SJ. Cambridge, MA., Blackwell , pp.627 – 658. 1999 Scientific Publications, 8. Strasser SI, McDonald GB. Chapter 67, Hepatobiliary co mplications of hematopoietic cell transplantation, in , edited by Schiff ER, Sorrell MF, Maddrey WC. Philadelphia, PA., Schiff’s Diseases of the Liver, Ninth Edition J.B. Lippincott Company, 2002. 9. McDonald GB. Hepatobiliary complicat ions of hematopoietic cell transplanta tion, 40 years on. Hepatology 51: 1450 – 1460, 2010. nald GB. Chapter 96, Gastrointestinal and hepatic complications, in 10. Hockenbery DM, Strasser SI, McDo Thomas’ Hematopoietic Cell Transplantation, Fifth Editi on, edited by Appelbaum FR, Forman SJ, Negrin RS, Antin JH. Oxford, UK, Wiley-Bl ackwell Publishing, in press. 11. Kida A, McDonald GB. Gastrointestinal, hepatobiliary , pancreatic, and iron-related diseases in long term ation. Seminars in Hematology 49:43-58, 2012). survivors of allogeneic hematopoietic cell transplant 12. AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES (AASLD) AND Infectious Diseases Society of America (IDSA) Recommendations for Testing, Managing, and Treating Hepatitis C. Accessed on February 20, 2014. http://hcvgu idelines.org Other Complications, Bone Complications: 1. McClune, Navneet S Majhail, and Mary E.D. Flowers Bone Loss and Avascular Necrosis of Bone After Hematopoietic Cell Transplantation. Semin Hematol 49:59-65, January 2012 100

101 APPENDIX A FAX LTFU CONSULT Date: __________ To: FRED HUTCHINSON CANCER RESEARCH CENTER From: ______________________________ Long Term Follow Up Fax: 1-800-376-8197 (toll-free, USA & Canada) Fax: ________________________________ Phone: (206) 667-4415 Phone: ______________________________ Patient name: _______________________________ Date of birth: ______________________ (check all the apply): Current GVHD Treatments  Corticosteroids:  daily  alternate day (dose: _________)  Trimethoprim-sulfamethoxazole  Cyclosporine (Neoral, Sandimmune) (or equivalents)  Penicillin  Tacrolimus (FK506)  Dapsone Acyclovir or valacyclovir   Mycophenolate Mofetil (MMF) (Cellcept)  Thalidomide (Thalomid) Ganciclovir, ValGANCiclovir  Rapamycin (Sirolimus) Fluconazole or itraconazole    Rituximab  Extracorporeal photopheresis (ECP) Other:  No immunosuppressive medications  Current problems(s): What questions would you like the consultant to address? Laboratory and other reports are being sent with this FAX:  YES  NO Reply to (if other than sender listed above): ______________________________________________ Phone (_____) ___________________ Fax (____ ) ___________________ 101

102 APPENDIX B FAX LTFU ALERT Date: ____________ To: FRED HUTCHINSON CANCER RESEARCH CENTER From: ____________________________ Long Term Follow Up Fax: 1-800-376-8197 (toll-free, USA & Canada) Fax: ______________________________ Phone: (206) 667-4415 Phone: ___________________________ Date of birth: _________________ Patient name: ______________________________ ❑ This patient expired on _____/_____/_____ due to ___________________________________. This patient was newly diagnosed with clinical extensive chronic GVHD. ❑ (Please send copies of any reco rds regarding this diagnosis.) ❑ Check here if you would like a consultation regarding the management of GVHD in this case. ❑ This patient has now started immunosuppressive therapy. This patient has now stopped all immunosuppressive therapy. ❑ ❑ The immunosuppressive thera py for this patient has been changed. The ❑ original disease (see above) has recurred. This patient was diagnosed with a secondary malignancy of (primary site)_________________. ❑ ❑ Surgery or biopsy has been planned for evaluation of suspect ed secondary malignancy. (We are interested in obtaining fresh tissue specimens.) ❑ This patient has been diagnosed with myelodysplasia. to: patient’s name and/or ❑ This address has changed ❑ This patient is now being seen by (practitioner, address, phone number): office has moved/ changed it’s phone number to: ❑ This patient requests discontinuation of further contact from the FHCRC ❑ This due to (reason, if stated): Reply to (if other than sender listed above): ____________________________________ Fax (_______) ___________________ Phone (________) _________________ 102

103 APPENDIX C FORM FOR DESCRIPTION OF SKIN INVOLVEMENT Date of Birth: NAME: DATE OF ASSESSMENT:___________________ % Area % Area Region Region Involved Involved Head (9%) Right leg (8%) Neck (1%) Right foot (1%) Left arm (4%) Chest (9%) Left forearm (4%) Abdomen (9%) Back (18%) Left hand (1%) Left thigh (8%) Right arm (4%) Right forearm (4%) Left leg (8%) Right hand (1%) Left foot (1%) Right thigh (8%) 103

104 APPENDIX –D (Pages 1-3 of the CHRONIC GVHD ASSESSMENT AND SCORING FORM) 104

105 APPENDIX –D (Pages 1-3 of the CHRONIC GVHD ASSESSMENT AND SCORING FORM) 105

106 APPENDIX –D (Pages 1-3 of the CHRONIC GVHD ASSESSMENT AND SCORING FORM) 106

107 APPENDIX E ASSESSMENT OF SKIN THICKNESS Modified Rodnan Score* Patient Name: ___________________________________Date of Birth: ____________ summing the scores from all evaluated anatomic areas. Calculate skin score by A. Evaluate skin thickness by clinical palpation: 0 = normal skin thickness 1 = mildly increased skin thickness 2 = moderately increased skin thickness 3 = severely increased skin thickness (inability to pinch skin into a fold) B. Surface of anatomic areas evaluated (N = 17) Dates: Area of Body Range Score Score Score Score Score Face 0-3 Anterior chest 0-3 Abdomen 0-3 Fingers R 0-3 L 0-3 Dorsum of hands R 0-3 L 0-3 Forearms R 0-3 0-3 L Upper arms R 0-3 L 0-3 Thighs R 0-3 L 0-3 Lower legs R 0-3 L 0-3 Dorsum of feet R 0-3 L 0-3 0-51 TOTAL “Skin Thickness Score in Systemic Sclerosi s: An Assessment of Inter-observer Variability in 3 Independent Studies,” Clements et al, The Journal of Rheumatology 1993, 20:11, 1892-1896 C-GVHDassessment&scori ngform.medf.2.28.2006 107

108 108 APPENDIX F

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