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1 From www.bloodjournal.org by guest on May 5, 2019. For personal use only. CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study Luciana Annino, Maria Luce Vegna, Andrea Camera, Giorgina Specchia, Giuseppe Visani, Giuseppe Fioritoni, Felicetto Ferrara, Antonio Peta, Stefania Ciolli, Wilma Deplano, Francesco Fabbiano, Simona Sica, Francesco Di Raimondo, Nicola Cascavilla, Antonio Tabilio, Pietro Leoni, Rosangela Invernizzi, Michele Baccarani, Bruno Rotoli, Sergio Amadori, and Franco Mandelli, for the GIMEMA Group The GIMEMA ALL 0288 trial was designed 18% showed associated myeloid mark- respectively. PDN pretreatment response resulted the main independent factor influ- to evaluate the impact of a 7-day pred- ers; 47 of 216 analyzed patients (22%) had encing CR achievement, OS, CCR, and Philadelphia chromosome–positive ALL. nisone (PDN) pretreatment on complete remission (CR) achievement and length, DFS; the addition of cyclophosphamide Response to PDN pretreatment was ob- the influence of the addition of cyclophos- served in 65% of cases. CR was achieved in induction significantly influenced CR achievement in a multivariate analysis. in 627 patients (82%). Resistant patients phamide (random I) to a conventional and induction death rates were 11% and Neither induction intensification nor early 4-drug induction on CR rate and duration, and whether an early post-CR intensifica- 7%, respectively. Random II was applied consolidation appeared to influence CCR tion (random II) by an 8-drug consolida- to 388 patients with CR; 201 had mainte- and DFS duration. For the first time PDN tion could improve CR duration. Median nance alone and 187 had consolidation pretreatment response proved to be a follow-up of this study was 7.3 years. followed by maintenance. The relapse powerful factor predicting disease out- rate was 60%; isolated central nervous From January 1988 to April 1994, among come in adult ALL patients. (Blood. 2002; 60 years) patients < 12 but > 794 adult ( system relapses were 8% of all CRs and 99:863-871) 13% of all relapses. Median survival (over- registered, 778 were eligible. Their me- dian age was 27.5 years; 73% had B- all survival [OS]), continuous complete lineage acute lymphoblastic leukemia remission (CCR), and disease-free sur- vival (DFS) were 2.2, 2.4, and 2 years, (ALL) and 22% had T-lineage disease; © 2002 by The American Society of Hematology Introduction In adult acute lymphoblastic leukemia (ALL), unlike in child- by an 8-drug consolidation phase could influence the percentage of long-term remitters and survivors. hood ALL, the percentage of long-term remitters and survivors After a median potential follow-up of 7.3 years (range, 3.9-10.4 has not improved significantly during recent decades, although years; all surviving patients were followed until June 1999), we several trials have attempted to intensify the induction and are now able to determine the real proportion of adult patients postremission strategy, including early bone marrow transplan- 1-12 with ALL who become long-term disease-free survivors and tation (BMT). In the previous GIMEMA trial ALL 0183, we investigate the prognostic factors that significantly influenced the demonstrated that a mild 4-drug induction led to an excellent disease outcome. complete remission (CR) rate (79.3%), and that a short intensive post-CR therapy did not prevent recurrence of leukemia, leaving only 25% of remitter patients as more than 10-year 13 long-term survivors. Patients, materials, and methods Some recent studies have focused on the hypothesis that an intense initial cytoreduction followed by multidrug intensification Treatment program could increase the likelihood of long-term disease-free survival 6,14 The general plan of therapy is drawn in Figure 1 and drug doses are listed (DFS) in adults with ALL. in Table 1. The GIMEMA ALL 0288 trial was started in 1988 with the aim Pretreatment with PDN was given over 7 days (day 7today  1) in  of testing whether (1) a 7-day prednisone (PDN) pretreatment 2 2 2 day  6, 40 mg/m day 7, 30 mg/m  5, day  escalating doses: 20 mg/m response could have a prognostic significance on CR achievement 2 4today  1. Response to PDN, as defined by from day  and 60 mg/m and duration, as demonstrated in childhood ALL; (2) the random- L, was evaluated at day 0. peripheral blast cell count of at least 1000/  ized addition of cyclophosphamide (Cy) in induction could im- Induction phase I (random I) was given over 4 weeks either as a 5-drug regimen (arm A) with Cy, vincristine (VCR), daunorubicin (DNR), prove CR rate and length; and (3) an early post-CR intensification From the GIMEMA Group, Rome, Italy. A list of the participating institutions and Hematology, Via Benevento, 6-00161, Rome, Italy; e-mail: [email protected] responsible individuals appears in the Appendix. med.uniroma1.it. Submitted June 29, 2001; accepted September 27, 2001. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby Supported by grants progetto finalizzato CNR no. 92.02240.PF39, no. marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734. 93.02217.PF39, no. 94.01182.PF39. © 2002 by The American Society of Hematology Franco Mandelli, Department of Cellular Biotechnology and Reprints: 863 BLOOD, 1 FEBRUARY 2002 VOLUME 99, NUMBER 3 

2 From by guest on May 5, 2019. For personal use only. www.bloodjournal.org 864 BLOOD, 1 FEBRUARY 2002 ANNINO et al VOLUME 99, NUMBER 3  9 9 - 10  1.5  10 g/dL; platelets  /L; hemoglobin  10  100 /L; no circu lating blast cells) and fewer than 5% blast cells with normal cellularity at bone marrow examination. Patients who exhibited more than 5% blasts in bone marrow were given salvage chemotherapy; if they did not obtain CR after the salvage course, they were considered resistant. Patients Patients aged 12 to 60 years, with previously untreated ALL of French- American-British (FAB) classi cation subtypes L1 and L2 or undifferentiated fi Table 1. Chemotherapy courses and drug doses in the GIMEMA ALL 0288 randomized trial Route Dosage Days Course Prephase 2 1 Day  7to  PO 20 to 60 mg/m Prednisone Induction phase I 2 Day 1, 2 IV 800 mg/m Cyclophosphamide 2 Day 1, 8, 15, 22 IV 40 mg/m Daunorubicin 2 Day 1, 8, 15, 22 IV 2 mg/m Vincristine 2 Day 1-14 PO Prednisone 60 mg/m 2 Day 15-31 40 mg/m 2 Day 22-31 SC L-asparaginase 6000 U/m Salvage 2 Day 33-36 Cytosine arabinoside 1000 mg/m CI 2 Day 33-36 Mitoxantrone 6 mg/m IV 2 Day 32-39 40 mg/m PO Prednisone Induction phase II 2 Day 32 IV 2 mg/m Vincristine 2 Day 32-34 10 mg/m IV Mitoxantrone 2 Day 32-39 Prednisone PO 40 mg/m fi Intensi cation Figure 1. GIMEMA ALL 0288 treatment plan. The trial includes 2 randomizations.  3 courses L-VAMP Total post-CR treatment duration is 30 months. 2 Day 1 1.5 mg/m IV Vincristine 2 Day 1 1000 mg/m CI Methotrexate 2 asparaginase (ASP), and prednisone (PDN), or as a 4-drug regimen (arm B) Day 1 100 mg/m Cytosine arabinoside IV 2 with VCR, DNR, ASP, and PDN. Day 1 Cytosine arabinoside CI 400 mg/m 2 32. Patients not in CR received a salvage CR was evaluated on day  Day 1-5 10 mg/m Dexamethasone IV regimen that included high-dose cytosine-arabinoside (HDARA-C) in  VM-26 CA 4 doses  2 continuous infusion and mitoxantrone (MITOX). Patients in CR after Day 1, 5, 9, 13 165 mg/m VM-26 IV 2 induction phase I or after salvage chemotherapy were given induction phase Day 1, 5, 9, 13 300 mg/m IV Cytosine arabinoside II (VCR, MITOX, and PDN) followed by intensi fi cation, which consisted 3 Consolidation: every course  of 3 courses of L-VAMP followed by 4 doses of teniposide (VM-26) plus A 2 ARA-C. L-VAMP is a combination of VCR, methotrexate (MTX), ARA-C, Day 1 800 mg/m IV Cyclophosphamide 2 and dexamethasone (Dexa). A rescue with folinic acid was provided Day 3-10 75 mg/m SC Cytosine arabinoside thereafter. L-VAMP courses were given at 15-day intervals. B 2 cation therapy (random II) consisted of consolidation plus fi Postintensi Day 1 IV Vincristine 1.5 mg/m 2 M) or maintenance alone (M). Consolidation therapy  maintenance (C Day 1 IV Daunorubicin 40 mg/m 2 included 8 drugs in 5 courses (A, B, C, D, E) that were repeated 3 times Day 1-7 PO Prednisone 40 mg/m each (Figure 1). The expected consolidation time was 6 months. C 2 Maintenance chemotherapy was based on daily oral 6 mercaptopurine Day 8 1.5 mg/m IV Vincristine 2 (6-MP) plus intramuscular MTX weekly for 3 weeks, followed by VCR and Day 8-10 Mitoxantrone IV 10 mg/m 2 fi cation therapy (C  MorM PDN pulses. Total duration of postintensi Day 8-15 40 mg/m PO Prednisone alone) was 24 months. D 2 Central nervous system (CNS) prophylaxis was based on intrathecal Day 1, 5 VM-26 IV 165 mg/m 2 MTX plus PDN weekly, times 4 during induction (day 0, 8, 15, 22), Day 1, 5 IV 300 mg/m Cytosine arabinoside fi fi cation and postintensi cation for a total of 16 monthly during intensi E doses, associated with the systemic high-dose MTX given during the 3 L-VAMP courses of L-VAMP. 2y  Maintenance 5-wk courses 2 All patients were given low-dose trimethoprim (80 mg/d), sulfamethox- Day 1, 8, 15 30 mg/m Methotrexate IM 2 azole (400 mg/d) for 3 days a week as prophylaxis against Pneumocystis Day 1-21 70 mg/m PO 6-Mercaptopurine 2 carinii pneumonia. The use of prophylactic oral antibiotic therapy and the Day 22, 29 IV Vincristine 1.5 mg/m 2 management of febrile episodes were carried out according to GIMEMA Day 22-36 Prednisone PO 40 mg/m 15 infection program guidelines. 16 doses  CNS prophylaxis 12 mg Methotrexate IT Criteria for response 40 mg IT Methylprednisolone After induction phase I, patients were considered to be in CR if they had PO indicates orally; IV, intravenously, SC, subcutaneously; CI, continuous infusion; normal peripheral blood count (polymorphonuclear cells [PMNs] IM, intramuscularly; IT, intrathecally. A, B, C, D, and E are abbreviations of each course.

3 For personal use only. From by guest on May 5, 2019. www.bloodjournal.org VOLUME 99, NUMBER 3 BLOOD, 1 FEBRUARY 2002 865 GIMEMA ALL 0288 TRIAL  leukemia (AUL) were considered eligible for this study. Patients with B .05 as indicating a statistically P All tests were 2-sided, accepting  signi fi cant difference. S(Ig) ALL were excluded. All patients were registered by telephone at the GIMEMA Data Center Median follow-up time was estimated by reversing the codes for the before treatment; at registration cytology, cytochemistry, and immunophe- censoring indicator in a Kaplan-Meier analysis. 22,23 notype, performed at the local institution, were required. Diagnosis of ALL Logistic regression and Cox proportional hazards regression models was con fi ’ s review of blood smears and rmed by the Central Committee were performed to examine and check for treatment results and the risk bone marrow specimens for cytologic and cytochemical characteristics, factors affecting CR rate and time to event. These were performed using the 24 16 according to FAB criteria. SAS procedures LOGISTIC and PHREG, respectively. Central review of immunophenotype data were 17 also required and done. Analysis of the full trial population was followed by analysis of rele- vant subgroups. Pretreatment cytogenetics was recommended to be performed at the local center level; however, it was not mandatory, and a centralized karyotype review was not planned. At the beginning of this study, pretreatment molecular analysis for bcr/abl rearrangement was not included; then, from May 1990, Results when in the context of this trial a pilot study for patients positive for  Philadelphia chromosome (Ph rearrangements (or both) was bcr/abl )or Patient accrual 18 planned, rst framework for centralized fi the GIMEMA group activated the fusion gene was analyzed in 3 centers, bcr/abl molecular analysis. The From January 1988 to April 1996, 794 adult patients with ALL Rome (F. Lo Coco), Turin (G. Saglio), and Naples (F. Pane). were registered in the GIMEMA ALL 0288 study from 41 centers No therapeutical lumbar puncture for cerebrospinal fl uid examination throughout Italy. At central reviewing of the initial data, 16 patients was mandatory at diagnosis for all patients; 3 patients with CNS involve-  7), age were considered ineligible because of misdiagnosis (n fi nable blast cells in cytospin sample) were considered not ment ( 3de   3), B S(Ig)  over 60 years (n  2), CNS involvement (n ALL eligible for the randomized study and excluded from this analysis.  2).  (n 2), and severe organ failure (n Statistical methods Patient characteristics The primary goals of the trial were to conduct a multicenter, randomized Of the 778 eligible patients, 459 were men; median age was 27.5 controlled clinical trial to evaluate the effect of addition of Cy during fi ed cacy of intensi fi induction in increasing the CR rate and the ef years (range, 12-59.9 years); 231 (30%) were aged 20 years or postremission therapy in reducing relapse risk. younger, 188 (24%) were 21 to 30 years old, 121 (16%) were aged 31 to 40 years, 113 (14%) were aged 41 to 50 years, and 125 (16%) Allocation to study groups were older than 50 years. 9 Initial median WBC count was 13.6  10 /L (range, 0.5-527  Randomization was performed using randomly permuted blocks. For the 9 9 10 /L); 575 (74%) had an initial WBC count of 50 10 /L or less,  fi rst random, the only stratifying variable was white blood cell (WBC) 9 12% had WBC counts of 50 to 100  10 /L; and 14% had WBC count at entry; for the second random, the type of allocated induction group 9 was considered. A central repository of randomization schedules was kept  10 counts more than 100 /L. by the Trial Secretariat at the GIMEMA Data Center. After obtaining At diagnosis, performance status (PS) according to World written informed consent, the hospital investigator had to call the Data Health Organization (WHO) criteria was available for 740 patients. Center to obtain the allocation for that patient. Allocation was granted only Only 58 patients (8%) were classi fi ed as having WHO PS more after the data on eligibility had been verbally transferred, recorded, than 3. Fever was present in 90 cases (11.6%); infection was and checked. documented in 34 patients. Splenomegaly more than 3 cm and adenomegaly more than 3 Sample size cm were documented (by physical examination) in 304 patients We assumed a percentage of CR of 80% in the conventional chemotherapy (38%) and in 121 patients (16%), respectively, among 778 eligible group (no Cy) with an increase in this frequency to 90% with Cy addition, patients. A mediastinal mass was detected in 74 of 764 patients (10%). and a reduction of 33% of relapse risk in patients treated with C M versus  A centralized review of immunophenotype data was undertaken M only. To have an 80% chance of detecting these differences required a in 706 of 778 cases; the remaining 72 could not be reviewed. Of the fi rst randomization and 152 events after sample size of 390 patients in the reviewed cases, 513 (73%) were classi fi ed as having B-lineage the second randomization (  0.05, 2-sided test). The follow-up period ALL, 154 (22%) as T-lineage ALL, and 39 (5%) were considered was established at 5 years. fi able. In 122 cases (102 B lineage, 20 T lineage) myeloid not classi (My) markers (CD13 or CD33 or both) were found, and they were Analysis  ed as My classi fi ALL. All primary analyses were conducted using the intention-to-treat rule; that is, the outcome for each patient was counted against the trial group to which Response to induction therapy he/she was originally allocated, regardless of whether he/she later deviated PDN pretreatment. In vivo response to PDN pretreatment (de- from the protocol. We compared the prevalence of risk factors and the incidence of end 1000/  ned as circulating blasts at day 0 fi L) was evaluable in  2  points in randomized groups using . 657 of the 778 eligible patients, whereas in the remaining 121 cases ned as the time from randomization to death or date of fi Survival was de response to PDN pretreatment could not be assessed because the last follow-up. Continuous complete remission (CCR) was calculated from patients were already taking PDN before enrollment in the study. At the time of achieving CR to relapse or date of last follow-up; DFS was diagnosis, of 657 evaluable patients 154 had at least 1000 blasts de ned as the time from achieving CR to relapse, death, or date of last fi and 503 had more than 1000 blasts; 429 (65%) were considered follow-up. responders (143 and 286 among patients with initial peripheral The probability of survival, CCR, and DFS were estimated using the 1000 and  1000, respectively) and 228 were nonre- blasts  19 Kaplan-Meier method. 20 sponders. Response to PDN was not related to age, whereas it was The log-rank test was used to compare treatment effect and risk factor associated with initial WBC count (Table 2). A signi fi cantly higher categories. The 95% con fi dence intervals (CIs) for these probabilities and 21 percentage of PDN responder patients was recorded in B-lineage the median survival times were obtained using the Simon and Lee method.

4 From www.bloodjournal.org on May 5, 2019. For personal use only. by guest BLOOD, 1 FEBRUARY 2002 ANNINO et al VOLUME 99, NUMBER 3 866  Table 2. Response to PDN pretreatment according to WBC count at diagnosis Table 4. Postinduction hematologic recovery and grade III to IV toxicity (WHO) % patients responding to PDN Arm A Arm B   pretreatment* Initial WBC count (Cy (Cy ) ) n 366 P  n 371  9  10 10 84 /L 9 Days to PMN count greater than or equal to 60   10 10 and 20 /L 9 1 000/ 20.7 (0-50) 18.1 (0-61) .002  L 61 10  20 and 30  /L 9 Days to platelet count greater than or equal 52  30 and 50 10  /L 9 14.2 (0-58) to 100 000/  L 16 (0-58) .04 44   10 50 and 100 /L 9 47 Patients with severe infection NS 35 39 100   10 /L 52 Patients with liver toxicity NS 64 *  .0001. P Patients with neurologic toxicity 40 38 NS Patients with cardiac toxicity 9 1 .01  NS indicates not signi fi cant. ALL cases (71%) as compared to T-lineage ALL (56%) and My ALL (56%) (  .002). In T-lineage ALL the lower PDN response P Postremission treatment and outcome 9 rate did not show a relationship to higher ( 100  10  /L) WBC 9 100  10  count, because even among patients with lower ( /L) Of 627 patients showing a CR, 239 did not undergo the second WBC count, fewer were PDN responders (62%) as compared to 37), death in CR  randomization because of treatment toxicity (n 44),   24), early relapse (n 83), early transplantation (n  (n P .02).  those with B-lineage ALL (74%) ( and protocol violation or treatment refusal or lost to follow-up Response to induction and toxicity. Of the 778 eligible pa-  51). Thus, 388 patients (62%) were randomized for postinten- (n  tients, 391 were randomized in arm A (Cy ) and 387 in arm B  M and 201 M alone.  cation therapy; 187 received C si fi (Cy ). Five patients died before starting treatment and 4 responses Of the 187 patients allocated to receive C  M, 79 completed the could not be evaluated; thus, 769 patients, 387 in arm A and 382 in assigned treatment regularly, whereas 108 (58%) went off the study arm B, were evaluable for response. Among those, 627 (82%)  because of early relapse (n 76), chemotherapy-related toxicity patients achieved a CR, 87 (11%) were resistant, and 55 (7%) died  (n  11), treatment refusal (n 17), or BMT (3 allogeneic, 1 during induction. No difference between the 2 randomized induc- autologous). Only 28 patients (35%) completed consolidation in tion arms was found concerning CR rate (81% in arm A, 83% in the expected 6 months; the median time to complete consolidation arm B), resistant patients, and induction deaths (Table 3). was 10 months. Hematologic toxicity, mainly during or after Of 87 resistant patients, 62 were given the salvage regimen; 33 courses A and D (which did not include prednisone), was the main (53%) obtained a CR, 22 remained resistant, and 7 died during cause of treatment delay or interruption. The median duration of treatment. Thus, after the salvage regimen overall CR rate in- 1000/  L) and thrombocytopenia (plate-  neutropenia (PMN count creased to 86%. 100 000/  L) during these 2 courses was 21 days (range, lets  Hematologic recovery and toxicity after induction are summa- 0-98 days) and 10.2 days (range, 0-67 days), respectively. fi rized in Table 4. There was a signi cantly faster neutrophil Of 201 patients receiving M only, 113 completed the assigned recovery in arm B, with fewer severe infections and less cardiac treatment regularly, whereas 88 (44%) went off the study because toxicity. All patients were hospitalized during induction phase I. 68), chemotherapy-related toxicity (n  of early relapse (n 6),  The main cause of induction death was infection (27 patients); 12 treatment refusal (n 4), or BMT (5 allogeneic, 5 autologous).  patients died or went off the study because of hemorrhage or Of the 627 CR patients, 375 (60%) had a relapse in a median ASP. Escherichia coli a thromboembolic event mainly due to  time of 10 months (range, 1 month to 6.6 years); late relapse ( 24 The induction response rate was related to age ( .001) and  P months from CR) occurred in 101 patients (27%). Relapses were  .004), even if in the subgroup of patients with WBC count ( P mainly hematologic; there were 50 isolated CNS relapses, represent- 9 100 10   hyperleukocytosis ( /L) the CR rate was 83%. The CR ing 8% of all CRs and 13% of all relapses; this type of relapse rate according to revised immunophenotype was 83% in B-lineage occurred in a median time of 14 months (range, 1 month to 6.5  ALL, 85% in T-ALL, and 71% in My ). ALL ( P  .001; Table 5 years) from CR achievement. In 17 cases, isolated CNS relapse In vivo response to PDN pretreatment appeared to in fl uence occurred after more than 2 years (median CCR time was 2.3 years) signi fi cantly CR achievement; 374 of 429 PDN responders (87%) when patients were still on treatment (n 8). 9) or off therapy (n   obtained CR as compared to 159 of 228 PDN nonresponders (70%) Prognostic factors for overall survival, CCR, and DFS .001; Table 5).  P ( No association was found between CR rate and sex, WHO The median overall survival (OS) of the 778 eligible patients was PS status, the presence or absence of fever or infection, or 2.2 years; at 9 years, 27% (95% CI, 23%-30%) are projected to organomegaly. fi be long-term survivors (Figure 2). OS appeared to be signi - In multivariate analysis, the CR rate proved to be strongly P uenced by age ( fl cantly in .0001;  P .0001) and WBC count (   in fl uenced by age ( P .0001), PDN pretreatment response Table 5). ( P P  .0001), and by the addition of Cy (  .0441). fi cant The PDN pretreatment response proved to have a signi impact on survival. At 8 years 33% (95% CI, 28%-38%) of PDN responder patients are survivors compared to 17% (95% CI, Table 3. Induction results by treatment arm fi ed as nonresponders ( P 12%-23%) of those classi  .0001).   Cy Percent Total Cy Percent Percent uence survival. At 8 years 28% fl The type of induction did not in Patients evaluable 769 387 382 of patients treated with Cy were survivors compared to 27% of 312 627 315 81 83 82 CR .9261).  those treated without Cy ( P 43 Resistant 87 11 44 11 11 Median survival from the second randomization in the 388 Induction death 55 7 31 8 24 6 patients involved was 4 years; at 8 years, 38% (95% CI, 32%-44%)

5 From www.bloodjournal.org by guest on May 5, 2019. For personal use only. BLOOD, 1 FEBRUARY 2002 867 GIMEMA ALL 0288 TRIAL VOLUME 99, NUMBER 3  Table 5. Univariate analysis of prognostic factors on CR rate, OS, and DFS Variable P % OS at 8 years P % DFS at 8 years P % CR No. patients 20 288 87 34 38 Age (y) 20 and 30 187  36 32 83  30 and 40 120 86 .001 20 .0001 15 .0164  40 and 50 113 75 21 29 15  50 and 60 121 19 68 9 33 32 568 50 83 10  WBC ( /L)  50 and 93 100 .0001 19 .0001 15 .004 78  108 83 18 19 100 Immunophenotype B lineage 411 83 30 30 .001 T lineage 134 85 NS 27 24 .0204  122 71 26 32 My 32 Yes 429 87 33 PDN response .0003 .0001 17 No 228 70 .001 22 Median DFS was 2 years; at 9 years, 29% (95% CI, 24%-33%) of these are projected to survive. The type of post-CR treatment fi uence on fl cant in (C M or M only) did not reveal any signi  fi cation of induc- of patients are disease-free survivors. The intensi survival from randomization. At 8 years, 38% (95% CI, 31%-46%) fl uence DFS probability and tion by the addition of Cy did not in of patients in arm C M were survivors versus 37% (95% CI,  length. At 8 years, 31% of patients are disease-free survivors in arm P .1710). 28%-46%) of patients in arm M only (  A and 28% in arm B; median DFS in the 2 groups was 2.3 and 1.9 After a median potential follow-up of 7.3 years (range, 3.9-10.4 .8055). P years, respectively (  years), median CR duration was 2.4 years; at 9 years, 33% (95% rst induction course strongly fi Failure to achieve CR after the CI, 28%-37%) of all responders are in CCR (Figure 3). uenced DFS. In the group of 33 patients who achieved CR after fl in fi cation of induction by the addition of Cy did not The intensi salvage therapy, median DFS was 7 months; at 3 years, only 12% of uence percentage and length of CCR. At 8 years, 34% of fl in these were disease-free survivors. patients in arm A and 31% in arm B had CCR; median CCR length ed post-CR treatment (C fi M) did not prove to More intensi  P  .7946; in the 2 groups was 2.5 and 2.2 years, respectively ( in fl uence DFS. At 8 years, 34% of patients are disease-free Figure 4).  survivors in the C M group and 35% in the M group; median DFS fi M) did not show any  cation of post-CR treatment (C Intensi .3811).  P was 2.4 and 2.9 years, respectively ( in uence on CCR. At 8 years, 36% (95% CI, 28%-44%) of patients fl uenced by the entire more Disease-free survival was not in fl in the C  M group and 37% (95% CI, 29%-45%) in the M group  ed treatment, that is, Cy fi intensi Min  in induction and C showed CCR. The median CCR was 2.9 and 3.5 years in the 2 post-CR. At 8 years, 37% of patients, who were given the more groups, respectively ( P  .4439; Figure 5). fi intensi ed approach, were disease-free survivors compared to 34% Patient age did not signi fi cantly associate with CCR. The  and M of those who received the less intense treatment (Cy 20 years) probability of CCR at 8 years is 39% for young (  alone); median DFS was 2.2 and 2.9 years, respectively ( .7337).  P patients, 33% for those 21 to 30, 18% for those 31 to 40, 33% for uenced by age, Disease-free survival appeared signi fi cantly in fl .4540).  P those 41 to 50, and 25% for those 51 to 60 years old ( initial WBC count, immunophenotype, and response to PDN rmed to have a fi The PDN pretreatment response was con cant impact on CCR. At 8 years, 36% (95% CI, 30%-42%) of signi fi pretreatment (Table 5). PDN responders had CCR versus 24% (95% CI, 16%-32%) of The results of multivariate analysis are shown in Table 6. PDN .0004; Figure 6). those considered nonresponders ( P  pretreatment was a powerful independent prognostic factor in fl uenc- cantly longer CCR B-lineage ALL appeared to have a signi fi cantly ing OS, DFS, and CCR. Age at diagnosis in fl uenced signi fi compared to T-lineage ALL. At 8 years, 34% (95% CI, 28%-40%) uence fl OS and DFS, whereas initial WBC count appeared to in of B-lineage ALL cases showed CCR compared to 27% (95% CI, DFS and CCR only. 17%-37%) of the T-ALL cases ( .0059).  P Both randomized additions of Cy (during induction as well as in fl Initial WBC count also appeared to have a signi fi uence cant in consolidation) failed to show any in fl uence on OS, DFS, and CCR. on CCR probability at 8 years: 36%, 22%, and 21% for patients with no more than 50, more than 50 or less than 100, and more than 9 100  10 .0001).  P /L, respectively ( Patients who achieved CR after salvage therapy Figure 3. CCR duration. Figure 2. Overall survival. are excluded.

6 From www.bloodjournal.org by guest on May 5, 2019. For personal use only. BLOOD, 1 FEBRUARY 2002 ANNINO et al 868 VOLUME 99, NUMBER 3  Figure 6. CCR by response to PDN pretreatment. PDN pretreatment response Figure 4. CCR by induction arm. The addition of Cy in induction did not predicted longer CR duration. in fl uence CCR. 5), or be-  15), chemotherapy-related toxicity (n  relapse (n Transplantation cause when they were diagnosed the program of early transplanta-  tion for Ph  ALL had not been activated yet (n 5). In this study, 61 patients underwent a transplantation procedure, 41  Overall CHR duration was 9 months in the whole group of allogeneic and 20 autologous. Of these, 14 were Ph ALL and will  patients with Ph ALL and 18 months in patients undergoing BMT. be discussed later. Of the 47 remaining patients, 34 underwent allotransplantation and 13 autotransplantation; 37 (79%) were younger than 40 years and 10 (21%) had an initial WBC count 9  10 more than 50 /L. Posttransplantation median CR duration Discussion was 50 and 29 months in patients undergoing autotransplantation This study represents one of the largest adult ALL series reported in and allotransplantation, respectively; 18 patients had relapse (7 ed therapy, which fi literature. Patients were treated with an intensi autotransplantation and 11 allotransplantation) and 8 deaths related compares well with the intensive approaches designed and applied to the allotransplantation were recorded. 1-13 during the past 10 years.  Ph rearranged patients bcr/abl or In childhood leukemia, PDN pretreatment (plus intrathecal MTX) response was recognized as a new, independent, powerful Cytogenetic analysis at diagnosis was performed in 216 patients; in es 10% of all fi prognostic factor. Poor response to PDN identi 158 there was a suf fi cient number of evaluable metaphases. The Ph pediatric ALL with a dismal prognosis, whose estimated event-free fi chromosome was identi ed in 30 patients (19%). Molecular 25 survival is less than 50%. In this study the in fl uence of PDN analysis for gene rearrangement from blood or marrow was BCR rst time tested in adult ALL and fi pretreatment alone was for the performed in 200 cases; 38 (19%) were rearranged. When the revealed to be an independent prognostic factor for CR achieve- results of cytogenetic and molecular tests were combined, 47 ment as well as for OS, CCR, and DFS. Response to PDN patients were positive for one or both techniques (Table 7). pretreatment correlated directly with initial WBC count and In this subset, the median age was 35.7 years (range, 13.4-58.3 immunophenotype, but not with age and the presence of cytoge- 9 years) and initial median WBC count was 20.9  10 /L (range, netic or molecular abnormalities. 9 1.4-190  10 ed as having B-lineage ALL, 2 as /L); 38 were classi fi One of the main aims of this study was to test whether the  T-lineage ALL, 5 with My ALL, and 2 were not classi fi ed. intensi cation of a conventional 4-drug induction by adding Cy fi Thirty-six of these 47 patients were evaluable for PDN pretreat- might improve CR rate. Overall CR rate was 82%, which is equal to ment response; 26 (72%) were responders and 10 (28%) nonre- or higher than the one reported in previous, contemporary, and sponders. Thirty-nine patients (83%) achieved complete hemato- successive monocentric and multi-institutional studies of adult logic remission (CHR) and 8 (17%) were resistant; no patient died 1-10 ALL. The addition of Cy did not improve the percentage of CR, during induction.   which was 81% in arm A (Cy ). Thus, at ) and 83% in arm B (Cy For post-CR therapy, 14 of 39 patients with CR (36%) 6 variance with the Cancer and Leukemia Group B experience, underwent BMT, 7 allogeneic and 7 autologous transplantations. reporting an 85% CR rate and a 46% CCR at 3 years with a similar The remaining 25 did not undergo early BMT because of early induction including Cy (although not identical to the present one), Table 6. Signi fi cant factors for predicting OS, DFS, and CCR obtained by multivariate analysis 95% CI Risk ratio P Survival 1.018 .0001 1.011-1.026 Age PDN response (yes, no) 1.632 1.305-2.040 .0001 CCR WBC count 1.000 1.000-1.000 .0007 .0044 1.133-1.972 PDN response (yes, no) 1.495 DFS Age 1.009 1.001-1.018 .0343 1.000 .0029 1.000-1.000 WBC count The addition of intensive Figure 5. CCR according to the second randomization. .0028 PDN response (yes, no) 1.491 1.148-1.938 consolidation (C) to maintenance (M) did not improve CCR duration.

7 From www.bloodjournal.org by guest on May 5, 2019. For personal use only. VOLUME 99, NUMBER 3 BLOOD, 1 FEBRUARY 2002 869 GIMEMA ALL 0288 TRIAL  Table 7. Results of cytogenetic and molecular analysis for t(9;22) 8 years both long-term DFS fraction and median DFS duration rearranged unknown Total bcr not rearranged bcr bcr were similar in the C M and M arms: 34% and 35% and 2.4 and  2.9 years, respectively. In a high percentage of patients consolida-  Ph 30 21 0 9  lled in the expected 6 months, requiring nearly 1 tion was not ful fi 4 117* 7 128 Ph Ph unknown 58 — 13 45 year; we cannot exclude that this delay could have hampered the 216 Total 162 16 38 intensi fi cation, bringing about early relapses, which occurred in 41% of cases randomized in this arm. The present trial did not *Including 6 cases with t(4;11)(q21;q23) and 37 with other abnormalities. include the use of growth factors to overcome myelosuppression during the consolidation phase, because at the time of activation of cant we demonstrate that the addition of Cy does not induce a signi fi the study these recombinant molecules were not readily available increase of cytoreduction translating into CR rate and length in this country. Only a few patients received growth factors during improvement. cacy can consolidation, thus no de fi nitive conclusion about their ef fi Induction failure rates, that is, resistant patients and induction be drawn. However, in childhood high-risk ALL, growth factors deaths, were 11% and 7%, respectively. However, the percentage of during intensive consolidation demonstrated only a moderate true resistant cases was lower, considering that salvage therapy increase of chemotherapy dose intensity, which did not prove to rescued 53% of the cases, thus increasing overall CR rate to 33 fi cant impact on DFS. have a signi 86%. The main cause of induction death was infection, whereas — daily 6-MP and weekly MTX — is Conventional maintenance ASP, E coli hemorrhage and thromboembolic events, due to considered essential to control and to possibly eradicate the 26 disappeared when the drug was substituted by Erwinia ASP. 34-36 minimal residual disease. - Some recent approaches with inten uenced by age, initial WBC count, Achievement of CR was in fl sive post-CR chemotherapy not followed by maintenance failed to and response to PDN pretreatment, but not by immunophenotype demonstrate that this strategy could play a positive role in or cytogenetic or molecular abnormality. The CR rate in T-lineage maintaining durable remission both in adult and in childhood ALL was slightly higher (85%); even in this subset, the impact of 7,37 ALL. In the present study, half the patients with CR, assigned to Cy during induction did not translate into a signi fi cantly better the second randomization, received 24-month conventional mainte- disease outcome. At 8 years, DFS was the same, 20% in arm A   nance only, 35% of them were disease-free survivors at 8 years. As (Cy ) and 22% in arm B (Cy ). The presence of myeloid markers compared to our previous ALL 0183 trial, in patients who received appeared to have an impact on the possibility of achieving CR; in a similar maintenance treatment, DFS percentage (27% versus this subset, CR rate (71%) was signi fi cantly lower than the one 35%) and length (18 versus 35 months) were improved. observed in B- and T-lineage ALL without myeloid markers. However, even in this study the relapse rate (60%) remains ed as fi In this study, 47 (22%) patients of 216 tested were identi  intolerably high; relapses were mainly hematologic (52% of Ph rearrangement (or both); 72% of them were or with bcr/abl patients) and the majority occurred early, with a median time from responders to PDN pretreatment and 83% achieved CR. This CR  CR to relapse of 10 months. Isolated CNS relapse occurred in 8% rate is higher than the one reported in other adult Ph ALL 1-3,6,10 of all CRs and 13% of all relapses. In this trial CNS prophylaxis multi-institutional studies using a similar induction regimen. fi ed by systemic intermediate doses of MTX and Dexa; was intensi This suggests that for these patients a more intensive induction may  nevertheless, isolated CNS relapse rate was the same as recorded in not be necessary. Because in this series of adult Ph patients the 13 our previous GIMEMA ALL 0183 study. One may thus infer that response rate to PDN pretreatment was the same (72%) as observed  27 intermediate-dose MTX, combined with a standard dose of Dexa, in childhood Ph cases, it can be argued that, as in children, even fi cient to eradicate CNS given for 3 courses only, is not suf in adult patients, response to PDN pretreatment could be useful in leukemia. Because Dexa penetrates into CNS better than pred- identifying those with a relatively better prognosis. In fact, among 38  nisolone, thus showing a higher antileukemic activity, a larger use our Ph cases, 7 patients with low initial WBC count (median 9 of Dexa at high dose might improve CNS prophylaxis in adult  10 12.8 /L), who were PDN responders and did not undergo a patients as well as in children. In the successive GIMEMA ALL transplantation procedure, had a prolonged ( rst 24 months) fi  2 0394 study, in which systemic high-dose (20 mg/m ) Dexa was CHR (one of them is still in rst CHR, off therapy for 12 years). fi 27-29 used during induction and subsequently during systemic CNS Thus, as in children, low initial WBC count and PDN prophylaxis, the incidence of isolated CNS relapse dropped to 2% pretreatment response could be taken into account in designing  (unpublished data, May 2001), similar to that reported both in M. therapeutic approaches for Ph adult patients ineligible for a 39 D. Anderson Center (Houston, TX) adult series and in a pediatric transplantation procedure. In view of the use of new agents, such as 40 one. The role of cranial irradiation in adult ALL still remains a tyrosine kinase inhibitors, this information may acquire importance 8 debated issue; in some monocentric experiences it proved to be a because chemotherapy combined with tyrosine kinase inhibitors 30,31 successful approach, whereas in larger studies radiotherapy did not could be an innovative approach for selected patient categories. 6 completely prevent CNS leukemia recurrence. The question is Of 6 patients recognized to have t(4;11)(q21;q23), 5 achieved whether in adult patients, as in children, CNS cranial radiotherapy CR and 4 of them were PDN pretreatment responders; 2 of the should be reserved for patients with CNS-3 status (5 or more patients with CHR achieved molecular remission during post-CR 32 leucocytes/  L with de fi nable blast cells or the presence of cranial chemotherapy and became long-term remitters and survivors. 39 nerve palsies) fi only and whether a cyclic intensi cation with Because in our previous GIMEMA ALL 0183 study we ascribed systemic high dose of MTX plus Dexa could help in eradicating the high percentage (64%) of early leukemia recurrence to the short 13 CNS leukemia. duration of post-CR therapy, in the present study post-CR therapy In multivariate analysis, so-called conventional factors such as ed and prolonged for 24 months. Nevertheless, in the was intensi fi fi age and initial WBC count con fi cant role in rmed their signi present group of patients the median CCR duration was 2.4 years, fl in uencing DFS (Table 6). Response to PDN pretreatment arose as uenced by a more intensive post-CR treatment. fl only marginally in an important independent factor predicting disease outcome; in The randomized addition of intensive consolidation to a conven- PDN responder patients, a high CR rate (87%) translated into a cant impact on CCR. At fi tional maintenance failed to show a signi

8 From by guest on May 5, 2019. For personal use only. www.bloodjournal.org VOLUME 99, NUMBER 3 870 BLOOD, 1 FEBRUARY 2002 ANNINO et al  heterogeneous disease as well as that in our population more cantly higher percentage of long-term CCRs (Figure 6). fi signi aggressive forms were predominant. Initial rapid cytoreduction is considered a basic step in the Bone marrow transplantation in the fi rst CR is retained as the treatment of adult ALL; it directly correlates with prolonged 1,2 best approach for high-risk ALL patients, especially for those with remission and survival. This goal can be achieved by intensifying 10-12,36,42-44 genetic abnormalities ; for the remaining patients it the induction regimen or by applying a preinduction chemotherapy 6,9 remains a controversial issue, because long-term follow-up analy- not including PDN. However, unlike the PDN pretreatment, sis did not show a signi cant impact of bone marrow transplanta- fi neither of these approaches can be used to allocate patients into 2 45 tion on leukemia-free survival with respect to chemotherapy. In different risk categories. only our study, in which early BMT was planned from 1990 onward 13 In this study, as in our previous ALL 0183 trial, we were not 18  for Ph patients, fewer than 10% of those with CR underwent early able to demonstrate an independent prognostic role for the immuno- BMT, half of them coming from high-risk categories. The median CR fi phenotype. B-lineage ALL was con rmed to show a marginally duration in the whole transplantation series was 30 months and 50% better outcome. Compared to B-lineage, T-lineage ALL was less were CCR at 5 years. Considering the low number of patients - fi responsive to PDN pretreatment without reaching statistical signi undergoing transplantation, we cannot draw any factual conclusion cance; nevertheless CR rate was slightly higher (83% versus 85%). about the role of this procedure. However, this excellent induction result did not translate into a In conclusion, the present long-term follow-up analysis shows, higher percentage of long-term CCR and DFS. The addition of Cy compared to our previous GIMEMA study, that the percentage of during induction as well as during the consolidation phase did not long-term survivors and those with DFS improved with this cantly in fl uence the outcome of T-ALL. Other multi- signi fi protocol. However, the relapse rate remained disappointingly high, institutional studies suggested that Cy plus intermediate-dose even using a more intensive schedule in induction and in consolida- ARA-C may be the most appropriate consolidation approach for tion. The reasons for the persistently high relapse rate may include 1,6,41 this patient subset. In the present study, both drugs were used at the following: (1) no speci fi c strategy was applied for high-risk standard dose after a double randomization; as a consequence, 48 patient subsets and (2) treatment delay, mainly in the consolidation of our T-ALL cases received these drugs in induction or consolida- arm, may have hampered an optimal dose intensity of the drugs tion or both and 35% of them resulted in DFS at 3 years, compared used. It may also be that long-term follow-up analysis shows the to 39% of the remaining 23 T-ALL patients who received neither true outcome of adult ALL, for which, regardless of different  Cy induction nor consolidation. However, due to the small intensive approaches, leukemia recurrence represents a constant number of patients in each subgroup, we do not think that these phenomenon. The observation that response to PDN pretreatment results are suf fi cient to argue against the data obtained from larger is one of the main prognostic factors even in adults indicates that series of homogeneously treated T-ALL patients. the evaluation of this early therapeutic phase should not be omitted fi nitively explain the prognosis of T Nevertheless, we cannot de in the future trials for adult ALL and may be useful to stratify patients for different postremission approaches. ALL in our series; it may be speculated both that T ALL is a References 1. Hoelzer D, Thiel E, Lof fl er B, et al. Prognostic fac- 9. Daenen S, van Imhoff GW, van den Berg E, et al. 16. Bennett JM, Catowsky D, Daniel MT, et al. The tors in a multicenter study for treatment of acute Improved outcome of adult acute lymphoblastic French-American-British (FAB) Cooperative lymphoblastic leukemia in adults. Blood. 1989;71: fi leukaemia by moderately intensi ed chemo- fi Group. 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Rowe JM, Richards S, Wiernick PH, et al. Alloge- fi tensi ed treatment for acute lymphoblastic leuke- rosine kinase in the blast crisis of chronic myeloid neic bone marrow transplantation (BMT) for mia of childhood. J Clin Oncol. 2000;18:1508- leukemia and acute lymphoblastic leukemia with adults with acute lymphoblastic leukemia (ALL) in 1516. the Philadelphia chromosome. N Engl J Med. rst complete remission (CR): early results from fi 38. Kamps WA, Bokkering JPM, Hahlen K, et al. In- 2001;344:1038-1042. international ALL trial (MRC UK ALL/ECOG tensive treatment of children with acute lympho- 31. Kano Y, Akutsu M, Tsunoda S, et al. In vitro cyto- E2993) [abstract]. Blood. 1999;94:732a. blastic leukemia according to ALL-BFM-86 with- toxic effects of a tyrosine kinase inhibitor STI571 out cranial radiotherapy: results of Dutch 45. Zhang MJ, Hoelzer D, Horowitz MM, et al. Long- in combination with commonly used antileukemic Childhood Leukemia Study Group Protocol ALL-7 term follow-up of adults with acute lymphoblastic agents. Blood. 2001;97:1999-2007. 1991). Blood. 1999;4:1226-1236. – (1988 fi rst remission treated with chemo- leukemia in 32. Cimino G, Elia L, Rapanotti MC, et al. A prospec- therapy or bone marrow transplantation. Ann In- Brien S, Smith TL, et al. Results ’ 39. Kantarjian HM, O tive study of residual-disease monitoring of the tern Med. 1995;123:428-431. of treatment with hyper-CVAD, a dose-intensive Appendix A. Gabbas. F. Latte (2); Orbassano: Ospedale S. Luigi Gonzaga, G. Saglio, Participating centers are listed in alphabetical order by city, with the responsible individuals given and the number of cases provided in A. Cajozzo, G. Mariani, M. Musso † F. Vischia (1); Palermo: Policlinico, parentheses. (13); Palermo: Ospedale V. Cervello, F. Caronia, S. Mirto, F. Fabbiano (31); Ancona: Nuovo Ospedale Torrette, P. Leoni, M. Montillo, M. Of fi Palermo: Policlinico, P. Citarrella, S. Miceli (6); Pavia: Policlinico S. dani (21); Avellino: Ospedale Civile, E. Volpe, N. Cantore (17); Aviano: Centro Matteo, E. Ascari, R. Invernizzi (21); Perugia: Policlinico Monteluce, M. Martelli, A. Tabilio (22); Perugia: Policlinico Monteluce, F. Grignani, A.M. di Referimento Oncologico, S. Monfardini, G. Cartei, V. Zagonel (9); Bari: Liberati (1); Pesaro: Ospedale S. Salvatore, G. Lucarelli, G. Sparaventi Policlinico, V. Liso, G. Specchia (70); Bergamo: Ospedali Riuniti, T. Barbui, M. Buelli (8); Bologna: Policlinico S. Orsola, S. Tura, M. (11); Pescara: Ospedale Civile, G. Fioritoni, A. Recchia (34); Potenza: Baccarani, G. Visani (35); Cagliari: Ospedale Oncologico A. Businco, G. Ospedale S. Carlo, F. Ricciuti, M. Pizzuti (11); Reggio Calabria: Azienda E. Cacciola, R. Ospedaliera, F. Nobile, P. Iacopino (15); Roma: Universita` Cattolica del Broccia, † W. Deplano (32); Catania: Ospedale Ferrarotto, † Sacro Cuore B. Bizzi, G. Leone, S. Sica (30); Roma: Universita` degli Studi Giustolisi, F. Di Raimondo (25); Catanzaro: Ospedale Regionale A. F. Mandelli, L. Annino, F. Giona (86); Roma: Ospedale S. ” La Sapienza, “ Pugliese, A. Alberti, A. Peta, F. Iuliano (33); Cremona: Istituti Ospitalieri, Camillo A. De Laurenzi, I. Majolino, L. Pacilli (7); Roma: Ospedale S. A. Porcellini, P. Bodini, S. Morandi (2); Firenze: Policlinico di Careggi, P. Rossi Ferrini, S. Ciolli (33); Foggia: Ospedali Riuniti, M. Monaco, E. Eugenio, † G. Papa, S. Amadori, G. Del Poeta (23); S.G. Rotondo: Ospedale Casa Sollievo della Sofferenza, Capussela (2); Genova: Universita` degli Studi, M. Gobbi, M. Clavio (3); M. Carotenuto, S. Ladogana, N. Cascav- † Latina: Ospedale S. M. Goretti, L. De Riu, A. De Blasio, A. Chierichini illa (23); Sassari: Universita` degli Studi, M. Longinotti, F. Dore (1); (12); Milano: Ospedale Niguarda, De Cataldo, E. Morra, G. Muti (15); Udine: Ospedale S. Maria della Misericordia, M. Baccarani, R. Fanin (15); Vicenza: Ospedale Civile S. Bortolo E. Dini, F. Rodeghiero, R. Napoli: Ospedale A. Cardarelli, R. Cimino, F. Ferrara (31); Napoli: Battista (16); Taranto: Ospedale S.S. Annunziata, P. Mazza, B. Amurri (1); Ospedale Nuovo Pellegrini R. De Biasi, E. Miraglia, D. De Blasi (10); Torino: Ospedale Maggiore S. Giovanni Battista, L. Resegotti, E. Gallo, M. Napoli: Universita` Federico II, B. Rotoli, A. Camera (43); Napoli: Ospedale A. Cardarelli L. De Rosa, V. Mettivier (6); Nuoro: Ospedale S. Francesco, Falda (1).

10 From www.bloodjournal.org by guest on May 5, 2019. For personal use only. 2002 99: 863-871 doi:10.1182/blood.V99.3.863 Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study Luciana Annino, Maria Luce Vegna, Andrea Camera, Giorgina Specchia, Giuseppe Visani, Giuseppe Fioritoni, Felicetto Ferrara, Antonio Peta, Stefania Ciolli, Wilma Deplano, Francesco Fabbiano, Simona Sica, Francesco Di Raimondo, Nicola Cascavilla, Antonio Tabilio, Pietro Leoni, Rosangela Invernizzi, Michele Baccarani, Bruno Rotoli, Sergio Amadori and Franco Mandelli Updated information and services can be found at: http://www.bloodjournal.org/content/99/3/863.full.html Articles on similar topics can be found in the following Blood collections Clinical Trials and Observations (4952 articles) (4182 articles) Neoplasia Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.

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