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Developing optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized, phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m(2) in Philadelphia-negative B- and T-cell disease, respectively. The primary study objective was the comparative assessment of the risk/benefit ratio, combining the analysis of feasibility, toxicity and efficacy. In the liposomal cytarabine arm 17/71 patients (24%) developed grade 3-4 neurotoxicity compared to 2/74 (3%) in the triple therapy arm (P=0.0002), the median number of episodes of neurotoxicity of any grade was one per patient compared to zero, respectively (P=0.0001), and even though no permanent disabilities or deaths were registered, four patients (6%) discontinued intrathecal prophylaxis on account of these toxic side effects (P=0.06). Neurotoxicity worsened with liposomal cytarabine every 14 days (T-cell disease), and was improved by the adjunct of intrathecal dexamethasone. Two patients in the liposomal cytarabine arm suffered from a meningeal relapse (none with T-cell disease, only one after high-dose chemotherapy) compared to four in the triple therapy arm (1 with T-cell disease). While intrathecal liposomal cytarabine could contribute to improved, radiation-free central nervous system prophylaxis, the toxicity reported in this trial does not support its use at 50 mg and prompts the investigation of a lower dosage. (clinicaltrials.gov identifier: NCT-00795756).

We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six to eight rituximab infusions and four to six courses of intensive chemotherapy (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17-78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% had an Eastern Cooperative Oncology Group performance score >1, and 14% were positive for human immunodeficiency virus. The complete response rate and 3-year overall and disease-free survival rates were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted International Prognostic Index scores. In multivariate analysis, only age (≤ versus >60 years) and performance status (0-1 versus >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% and 70.5%, 20% and 28.5% (P=0.0000 and P=0.0001), respectively. The relapse rate was only 7% in patients treated with an intercycle interval ≤ 25 days. This regimen achieved 100% curability in patients with low adapted International Prognostic Index scores (21% of total), and very close to 90% in patients aged ≤ 60 years with performance score 0-1 (48% of total). Rapid diagnosis of Burkitt lymphoma/leukemia with prompt referral of patients to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrials.gov ID, NCT01290120.

Clinical risk classification is inaccurate in predicting relapse in adult patients with acute lymphoblastic leukemia, sometimes resulting in patients receiving inappropriate chemotherapy or stem cell transplantation (SCT). We studied minimal residual disease (MRD) as a predictive factor for recurrence and as a decisional tool for postconsolidation maintenance (in MRDneg) or SCT (in MRDpos). MRD was tested at weeks 10, 16, and 22 using real-time quantitative polymerase chain reaction with 1 or more sensitive probes. Only patients with t(9;22) or t(4;11) were immediately eligible for allogeneic SCT. Of 280 registered patients (236 in remission), 34 underwent an early SCT, 60 suffered from relapse or severe toxicity, and 142 were evaluable for MRD at the end of consolidation. Of these, 58 were MRDneg, 54 MRDpos, and 30 were not assessable. Five-year overall survival/disease-free survival rates were 0.75/0.72 in the MRDneg group compared with 0.33/0.14 in MRDpos (P = .001), regardless of the clinical risk class. MRD was the most significant risk factor for relapse (hazard ratio, 5.22). MRD results at weeks 16 to 22 correlated strongly with the earlier time point (P = .001) using a level of 10−4 or higher to define persistent disease. MRD analysis during early postremission therapy improves risk definitions and bolsters risk-oriented strategies. ClinicalTrials.gov identifier: NCT00358072.

Different molecular levels of post-induction minimal residual disease may predict hematopoietic stem cell transplantation outcome in adult Philadelphia-negative acute lymphoblastic leukemia

Introduction Since the landmark study of Omura et al. (Blood 1980;55:199), validating cranial irradiation as an adjunct to intrathecal (IT) methotrexate, no other randomized trial of CNS prophylaxis was performed in adult ALL. Although the risk of CNS relapse is now only 1-4%, irradiation contributes to cumulative CNS toxicity together with high-dose methotrexate/cytarabine (HD-M/A), or is logistically difficult, so that developing an effective radiation-free CNS prophylaxis remains an important clinical task. IT DepoCyte® (ITD) might be advantageous, the slow release of liposome-associated cytarabine allowing therapeutic concentrations in the cerebrospinal fluid for 14+ days. An open trial reported prohibitive CNS toxicity from ITD in 6/31 patients (Jabbour et al. Blood 2007;109:3214), but ITD to ITD and HD-M/A to ITD intervals were short (14 and 10 days, respectively) and no patient suffered from CNS relapse. Methods In a phase II randomized trial (ClinicalTrials.gov NCT-00795756) we evaluated toxicity and feasibility (as primary study endpoint) of ITD 50 mg in comparison with IT triple therapy (ITT: methotrexate 12,5 mg, cytarabine 50 mg, prednisone 40 mg). Stratification was by cell lineage and risk class. ITT was given on d1 of courses 1,2,4,6,8; d15 of courses 1,2,8; and d1 of maintenance cycles 2-5 (12x). ITD was given on d1 of courses 1,2,4,6,8; d15 of courses 1,8 (T-ALL only); and d1 of maintenance cycle 2 (6-8x). The shortest ITD to ITD interval was 14 days in T-ALL (courses 1-2 [3x] and 8 [2x]), otherwise it was 21 days between ITD and any prior/subsequent ITD and HD course. ALL therapy consisted of eight induction-consolidation courses followed by risk/minimal residual disease-oriented maintenance or stem cell transplantation (SCT). In HD courses 3,7 (M/A) and 5 (M/Asparaginase) M dosage was 2.5 g/m2 (Ph- B-ALL) and 5 g/m2 (T-ALL) up to 55 years, and A 2 g/m2. Imatinib was used with de-intensified chemotherapy in Ph+ ALL; selected high-risk subsets received early SCT. Results Between 2007-12 201 total patients were enrolled and 141 randomized to ITT (n=73) or ITD (n=68). Median age was 42 years (range 18-68) and risk subsets (ITT/ITD) were SR-B 27.4%/29.4%; HR-B Ph- 26%/25%, Ph+ 23.3%/22.1%, SR-T 5.5%/5.9%, HR-T 17.8%/17.7%. Complete remission was 89% (n=65)/89.7% (n=61). Rates of actual v planned IT injections during induction-consolidation cycles 1-8, after removal of study losses (resistance, early death, SCT, toxicity and relapse), were ITT 374/415 (90.1%) v ITD 219/245 (89.3%) (P=0.76). Although toxicity/medical reasons caused 5 ITD patients to discontinue permanently the study v none in ITT arm (P=0.02), toxicity-driven omissions of IT therapy were marginally increased in ITD arm (29/415 [6.9%] v 24/245 [9.8%]; P=0.20). Neurologic toxicity occurred in 20 (27.4%) ITT v 36 (53%) ITD patients, respectively (P=0.002). According to NCI CTC grading (G), neurotoxicity episodes were GI 7 v 10 (P=0.36), GII 13 v 32 (P=0.003), GIII 4 v 12 (P=0.04), GIV 1 v 5 (P=0.12). GIII-IV neurotoxicity developed in 5/73 (6.8%) ITT patients v 10/52 (19.2%) and 5/16 (31.2%) B- and T-ALL ITD patients, respectively (P= 0.01), correlating in T-ALL with the second/third q14d ITD at courses 1,2,8 (4/5 patients, 5/6 episodes). Apart from reversible headache/radicular pain, the most serious toxicity occurred in 3 (4.1%) ITT patients (seizures 1; leukoencephalopathy 1; loss of consciousness 1) v 5 (7.3%) ITD patients (loss of consciousness 4, 1 with seizures; cerebral oedema/pseudotumor cerebri 1) (P=0.48). Four-year overall and disease-free survival were 54% and 52.2% v 58.9% and 47.7% in ITT and ITD arms, respectively, and relapse rate was 32.3% v 24.6% (all P=NS). In ITT arm there were 2 (3%) CNS and 2 (3%) combined CNS/marrow relapses. In ITD arm only one poorly compliant subject not given any HD course had an isolated CNS relapse (1.6%); no other patient had a CNS recurrence. Conclusion A radiation-free CNS prophylaxis with six spaced ITD in conjunction with HD-M/A may be feasible and at least as effective as other regimens. Excluding reversible headache/radiculitis, serious CNS toxicity was not significantly increased compared with ITT regimen, although some patients were forced to discontinue IT prophylaxis. The occasionally severe CNS toxicity prompts the investigation of a lower ITD dosage (25 mg), also to limit GI-II side effects, and the tighter schedule used in T-ALL should be abandoned because too toxic. Disclosures: Bassan: Mundipharma Oncology; Sigma-Tau; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Liposome-encapsulated cytarabine (DepoCyte®) used in a prospective phase II randomized trial of CNS prophylaxis in ALL. Masciulli:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo Osseo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Università degli Studi di Firenze: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding. Gallamini:Millenium: Consultancy. Marfisi:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency: Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore-Roma: Research Funding; Università degli Studi di Firenze: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding. Marchioli:Associazione Italiana Linfomi (AIL): Research Funding; Celgene: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Sigma-Tau: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Genzyme Olanda: Research Funding; AMGEN S.p.A.: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; Ospedali Riuniti di Bergamo: Research Funding; Novartis: Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding; Università degli Studi di Firenze: Research Funding. Rambaldi:Italfarmaco: Honoraria; Sanofi: Honoraria; Novartis: Honoraria.

Abstract 1494 Introduction: Burkitt lymphoma (BL) and B-cell acute lymphoblastic leukemia (B-ALL) are very aggressive malignancies with poor prognosis unless treated with highly specific intensive programs. The German Multicenter Study Group for Adult ALL piloted a short intensive rituximab (R)-chemotherapy program that improved outcome compared to the prior regimen (Hoelzer et al, Blood 110:abstr 518, 2007). The Northern Italy Leukemia Group adopted the same protocol to treat 105 consecutive, unselected adult patients with BL and B-ALL. Aim: To assess long-term outcome and toxicity according to pre-therapy risk factors predominantly identified by higher age and/or performance status (PS) according to the Eastern Cooperative Oncology Group score. Patients and Methods: Between December 2002 and June 2010, 55 BL (stage III-IV 53%, bulky 45%, extranodal involvement 64%) and 50 B-ALL patients were treated. Median age was 47 years (range 17–78), 31% were >55 years, 15% had a PS >2, and 15% were HIV+. Treatment consisted of 6 R-chemotherapy courses (4 in stage I-II disease without mediastinal/extranodal involvement), two additional R doses at completion of chemotherapy and local radiotherapy in case of mediastinal/CNS disease or residual tumor. R-chemotherapy blocks were as follows: A) prednisone-cyclophosphamide prephase (course 1 only), R plus dexamethasone, vincristine, ifosphamide, HD-methotrexate, teniposide [or etoposide], Ara-C, intrathecal therapy [IT]; B) R plus dexamethasone, vincristine, cyclophosphamide, HD-methotrexate, adriamycin, IT; C) R plus dexamethasone, vindesine, HD-methotrexate, etoposide, HD-Ara-C. The A-C sequence was repeated once. Patients aged >55 years received only courses A and B with methotrexate 0.5 g/m2. Results: Eighty-three total patients (79%) achieved CR, 8 were refractory and 14 died of complications. All early deaths occurred in patients older than 40 years, correlated with stage III-IV BL or B-ALL (n=13), PS ≥1 (n=10), and were mainly caused by infections. Among CR patients, 67 (81%) received all planned therapy and 16 did not (toxicity/CR death 11, early relapse 3, other 2). The mean intercycle time (MIT) between chemotherapy courses was 29 days (range 22–52). After a median follow-up of 23.8 months (range 0.7–99), 65 patients (61%) were alive in 1st CR, 19 (18%) died of complications (7 in CR, including 2 late deaths due to secondary AML and cardiovascular accident), and 19 had refractory or recurrent disease. Ten of 67 patients treated with MIT >25 days relapsed within 6 months (15%), compared to one of 15 treated with MIT ≤25 days (7%, P=.34). Projected 3-year overall and disease-free survival and were 67% (OS) and 75% (DFS), respectively. In univariate analysis age, normal LDH, ECOG PS 55 years with PS ≥1 had the worst outcome (n=24; OS 28% and DFS 36%), those with PS=0 fared as well as patients aged ≤55 years with PS=0–1 (n=55; OS 89% and DFS 89%) and the younger patients with PS >1 represented an intermediate-good risk category (n=26; OS 61% and DFS 77%) (P=.0000). The incidence of TRM and relapse varied significantly among the 3 groups, each contributing almost equally to the final outcome. Conclusion: The excellent therapeutic potential of this treatment (89% cure rate) was confirmed in patients with PS=0, regardless of age, and in younger patients with PS=0–1, whereas the results were still good, though significantly inferior, with PS >1 (61% cure rate). Prompt diagnosis and referral of BL and B-ALL patients is essential for exploiting the prognostic advantage associated with a better PS, together with maximized anti-infectious measures and rapid re-cycling of chemo-immunotherapy blocks. Disclosures: No relevant conflicts of interest to declare.

Abstract 2493 MRD is a powerful prognostic tool, increasingly adopted in adult ALL for a risk-oriented application of stem cell transplantation (SCT) in MRD-positive (MRDpos) patients. This policy gives the opportunity to assess the therapeutic value of allogeneic (or autologous) SCT in MRDpos patients, who are very unlikely to be cured by chemotherapy. In this study we reanalyze the long-term results of a prospective Northern Italy Leukemia Group trial (Bassan et al, Blood 2009;113:4153), aiming to determine which MRD levels were predictive of a better SCT outcome in MRDpospatients after induction/consolidation therapy. MRD was evaluated molecularly using one or two patient-specific probe(s) with sensitivity of at least 10−4. In remission patients, bone marrow MRD was assessed after chemotherapy courses no. 3 (week 10), 4 (week 16) and 6 (week 22). In the original risk model, MRDpos was defined by a level of 10−4 or greater at week 16 and/or any positivity at week 22. For this analysis, MRD results from all three time-points were pooled, and the highest value registered in individual patients was used to identify the MRD-negative group (always MRDneg) and three other subsets characterized by increasing levels of residual leukemia (less than 10−4 [MRDpos1], 10−4 and greater but less than 10−3 [MRDpos2], 10−3 and greater [MRDpos3]. Survival, disease-free survival (DFS), and relapse incidence were assessed and compared among these MRD groups, as well as outcome following SCT in MRDpossubsets, and this in accordance with protocol design i.e. in patients having SCT at end of consolidation phase after completion of the MRD study. Three-hundred and four patients with Ph- ALL were treated between 2000–2006 (median age 35 years, range 16–68; male gender 57%), of whom 258 (85%) entered complete remission. One or more sensitive probe(s)were available for 200 responsive patients (77.5%), of whom 141 completed consolidation and 59 did not because of elective early SCT in t(4;11)+ ALL (n=13), relapse (n=41) and toxicity (n=5). Of 141 evaluable patients, 136 completed the MRD study through weeks 10–22 (standard risk: 61 B-lineage and 14 T-lineage; high-risk: 41 B and 17 T; unspecified 3). Altogether, 64 patients were reclassified MRDneg (47%), 21 MRDpos1 (15.5%), 17 MRDpos2 (12.5%) and 34 MRDpos3 (25%). With a minimum observation time of 4 years and a maximum close to 12 years, estimated 6-year survival, DFS and relapse rates were 72.5%, 64% and 36% in MRDneg, 56%, 57% and 32% in MRDpos1, 48.5%, 46% and 50% in MRDpos2 and 23.5%, 15% and 76% in MRDpos3 cohorts, respectively (all P values In this study different MRD levels measured at weeks 10–22 were associated with a progressively worse outcome in the four patient subsets defined by the highest individual value at three study time-points. However, about one half of MRDpos1–2 patients could be salvaged by SCT, and even more with allogeneic rather than autologous SCT. Because of the very poor SCT results in MRDpos3 group, patients with MRD levels of 10−3 and greater should receive further therapy and not proceed to SCT until the MRD signal is below the 10−3 cutoff. Disclosures: No relevant conflicts of interest to declare.

Abstract 662 Introduction: In the last 10 years IM was added to chemotherapy to improve outcome of adult patients (pts.) with Ph+ ALL, with encouraging results. The Northern Italy Leukemia Group (NILG) designed a clinical trial with chemotherapy plus short IM pulses (Bassan et al, JCO 2010; 28:3644–52) aiming to increase the CR rate, limit incidence of early failures and increase the number of patients proceeding to SCT with subsequent improvement of survival. Aim: To analyze the long-term results in Ph+ ALL pts. treated with chemotherapy plus IM, in comparison to a prior cohort treated without IM. Patients and Methods: IM 600 mg/d was given orally for 7 consecutive dd. with each chemotherapy block, starting from day 15 of induction (IDR/VCR/PDN±ASP) and day –3 of consolidation courses (5x IDR/VCR/CY/DEXA; 2x HD-MTX/ARA-C). All pts. received CNS chemo-radioprophylaxis and were eligible to allogeneic SCT, or alternatively to HD therapy with autologous SCT and long-term maintenance with 6MP/MTX and intermittent IM. Between April '00 and November '08, 100 out of 404 pts. enrolled into NILG trial 09/00 had Ph+ ALL (median age 46 years, range 19–66; male 54). The pts. belonged to two subsequent treatment groups: control arm (IM-, n=35) and IM+ arm (n=65), of whom 59 received IM during induction/consolidation and 6 during consolidation only (pts. included in IM- cohort for remission induction analysis and in IM+ cohort afterwards). From March 2005 ASP was omitted during induction due to increased toxicity, so that in the IM+ group 20 pts. received ASP and 39 did not. Results: The complete remission (CR) rate was: 33/41 (80.5%) in IM- vs. 55/59 (93%) in IM+ pts. (p=0.05). With regard to the use of ASP in IM+ group, CR rate was: 16/20 (80%) with ASP vs. 39/39 (100%) without ASP (p=0.004). With a median follow-up of 1,6 years (maximum 11.3), 24/60 (40%) IM+ pts. are alive in 1st CR compared to 5/28 (18%) IM- pts., (p=0.04). Estimated 5-year OS, DFS and early relapse rates were significantly improved and reduced (relapse risk within 6 mos.), respectively, in IM+ vs. IM- group: OS 0.38 vs. 0.23 (p=0.012), DFS 0.40 vs. 0.25 (p=0.015) and relapse risk 0.05 vs. 0.24 (p=0.003). The probability to receive a SCT (autologous or allogeneic) was increased in IM+ pts. (72% vs. 54%), a difference that was statistically significant for allogeneic SCT (63% vs. 39%, p=0.04). In a cumulative analysis, patients receiving a SCT had the best outcome regardless of prior IM use (n=58; 5-years OS 0.49 and DFS 0.50), while in pts. unable to reach SCT outcome was slightly better in those exposed to IM (Figure). Forty CR pts. (28 IM+ and 12 IM-), were evaluable for minimal residual disease (MRD) response at weeks 10–22. PCR-negativity at weeks 10 and 16 was tendentially higher in IM+ group (32% and 37,5%) rather than IM- pts. (25% and 12,5%, p=ns). Conclusion: This long-term update confirms that short IM pulses in combination with chemotherapy increased the rate of CR, reduced incidence of early failures, and allowed to increase the feasibility of SCT, with a marked outcome improvement. An allogeneic SCT appears the best consolidation option for Ph+ ALL. Disclosures: No relevant conflicts of interest to declare.

Abstract 2573 Introduction In adult Ph- ALL two major risk groups are generally identified on account of patient age, presentation white blood cell (WBC) count, disease immunophenotype and genetics/cytogenetics, with 5-year overall and disease-free survival (OS, DFS) rates of approximately 50% in standard-risk (SR) and 30% in high-risk (HR) patients, respectively. Although the difference is significant, this classification reflects a static risk assessment and does not recognize increasingly important factors such as individual response dynamics (complete remission [CR] vs induction failure or early relapse; MRD course) and risk-oriented treatment decisions with or without stem-cell transplantation (SCT). Aim To evaluate dynamic risk factors in association with adherence to risk-oriented therapy as major determinants of outcome. Patients and Methods OS and DFS rates were reanalyzed according to MRD-related risk definitions and risk-oriented treatment steps in a prospective clinical trial (Bassan et al, Blood 2009;113:4153). Different risk and treatment subsets were identified according to (i) achievement of CR vs early failure due to induction death, early relapse or toxicity precluding the application of MRD/risk-oriented therapy according to trial design, and (ii) adherence to planned MRD/risk-oriented chemotherapy or SCT vs non-adherence unrelated to early failure. Outcome results were compared with those obtained using traditional SR and HR definitions. Results Three-hundred and four patients with Ph- ALL were treated (age range 16–68 years, median 35 years; male 57%), of whom 258 (85%) entered CR and 18 and 28 proved refractory or died early, respectively. Among CR patients, 78 did not complete early consolidation and MRD study (50 relapse, 9 toxicity and 19 very HR to early SCT), while 144 did it and were allocated to MRD-oriented therapy and 36 without a sensitive probe for MRD analysis were allocated according to clinical risk class. Six-year OS and DFS were 44% (n=138) and 43% (n=122) in SR vs 28% (n=166) and 28% (n=136) in HR, respectively (P=0.0009). Instead, OS and DFS results according to early treatment response, completion of MRD study for risk re-stratification and adherence to MRD/risk-oriented therapy identified several distinct prognostic categories, in which survival, largely unrelated to age and clinical risk class, ranged from 0% at 2.8 mos. (early deaths) to 73% at 6–10 years (MRD-negative), as detailed in the table and figure. Conclusion In this study, long-term survival rates were about 50% in SR patients (MRD unknown), 70% in MRD-negative ones receiving chemotherapy, and 40%–50% in all those proceeding to allogeneic SCT because very HR, HR MRD unknown or MRD-positive. Therefore, using a risk/MRD-oriented strategy, the adherence to protocol design concurs to identify the patient subsets with the highest probability of cure. Disclosures: No relevant conflicts of interest to declare.

Abstract 2131 Background. Some studies have shown how the use of pediatric-type therapy (PDT) and minimal residual disease (MRD)-oriented programs could improve outcome of adult ALL. Study Design. We included PDT elements in a pilot trial started January, 2008. Protocol 10/07 consisted of standard induction and late reinduction courses plus 3 PDT blocks (modified after BFM therapy) alternating with 3 lineage-targeted Methotrexate (LTM) blocks (B-precursor: 2.5 g/m2; T-precursor: 5 g/m2; Ph+ or age >55 years: 1.5 g/m2). LTM targeted a Methotrexate plasma concentration of ∼35 and ∼65 micromol/L in B- and T-ALL, respectively, in line with a therapeutic concept developed at St. Jude's Hospital (Memphis, TN, USA) in childhood ALL. The program was integrated by (a) a randomised, radiation-free central nervous system (CNS) prophylaxis study comparing intrathecal Methotrexate, Ara-C, and Prednisone (×12) vs. liposomal Ara-C (DepoCyte 50 mg, ×6 [B-ALL]-8 [T-ALL]); (b) the molecular evaluation of MRD at pre-fixed treatment weeks (w), to optimise risk stratification and indications for allogeneic stem cell transplantation (allo-SCT); and (c) by concurrent imatinib in patients with Ph+ ALL. The whole chemotherapy plus MRD study sequence was as follows: prephase (Prednisone, Cyclophosphamide) → induction (Idarubicin, Vincristine, Asparaginase, Dexamethasone) + w4 MRD → PDT1 (Cyclophosphamide, Vincristine, Idarubicin, Dexamethasone, Ara-C, 6-mercaptopurine) → LTM1 (plus high-dose Ara-C) + w10 MRD → PDT2 → LTM2 (plus Asparaginase) + w16 MRD → PDT3 → LTM3 (plus HD Ara-C) + w22 MRD → reinduction (Idarubicin, Vincristine, Cyclophosphamide, Dexamethasone). CNS prophylaxis was administered only during PDT blocks, with a minimum interval >15 days from/to LTM cycles. Risk classes were standard (SR: pre-B and WBC100, or CD1a-negative early or mature T phenotype; and to SR/HR patients with MRD >10-4 after LTM1 (w10) or detectable at any level after LTM3 (w22). Autologous SCT followed by maintenance was a suitable alternative when allo-SCT was not feasible. All patients not eligible to frontline allo-SCT and with low positive ( Results. Seventy-five of 81 evaluable patients (median age 40 years [range 18–65], 54% male, 23% T-ALL, 60% HR, 20% Ph+) achieved CR (92.5%); 55 of them (73.5%) were alive in CR1 at time of interim analysis (April, 2010). Sixteen patients relapsed (21.5%) and four died in CR of therapy-related complications (one after allo-SCT and 3 aged >55 years after a PDT cycle). With a maximum follow-up slightly >2 years (27.5 mos.), projected overall survival (OS) at 1.5 years is 73% (95% CI 57%-83%), and disease-free survival (DFS) 66% (95% CI 52%-77%). The best results were observed in patients aged 55 years and less (n=65, OS 79%) and those with T-ALL (n=20, OS 86%). These findings correlated well with a favourable early MRD response in Ph-negative subsets: 49% of evaluable cases achieved a major MRD response (10-4 (P=0.039). The flexible risk- and MRD-adapted SCT policy resulted in high early transplantability rate in patients with this indication (70% in T-ALL). Finally, the randomised CNS prophylaxis trial preliminarily confirmed the feasibility of intrathecal DepoCyte as planned (total randomised patients = 57). Conclusions. This regimen was highly active, yielding a >90% CR rate in unselected adults aged up to 65 years, with a major early MRD response of 63% in Ph-negative B-ALL and 87% in T-ALL. The toxicity observed after PDT blocks in a first group of patients aged >55 years required a reduction of PDT dose intensity in this age group. LTM therapy proved feasible, up to 5 g/m2 in T-ALL, and remarkable early OS/DFS rates were obtained in T-ALL and in unselected patients aged Disclosures: Bassan: Mundipharma: Consultancy, Research Funding. Off Label Use: Study is devoted to assess feasibility/toxicity/value of intrathecal liposome-encapsulated cytarabine (DepoCyte) vs standard intrathecal therapy as prophylaxis of CNS recurrence in adult ALL.

Background and aims IFIs still pose major challenges in HSCT, and effective prophylaxis remains a matter of debate. The aim of this retrospective study was to evaluate the impact of aerosolized d-AmB on respiratory tract IFIs in a homogeneous cohort of allogeneic HSCT patients, transplanted at our institution. Patients and methods Since 1999, 81 consecutive patients were transplanted from matched related (N=61) or unrelated donor (MUD). Analysis was performed on 74 evaluable patients, in order to monitor the prevalence of respiratory tract IFIs within 40 days after HSCT, according to current guidelines (possible, probable, proven IFIs). Conventional antifungal prophylaxis was based on the association of fluconazole (400 mg/d), plus aerosolized d-AmB (15 mg bid) in 54 out of 74 cases (73%). All the patients were screened before transplant and monitored thereafter with CT or x-rays (paranasal sinuses, thorax), surveillance swabs and galactomannan antigenemia. Chi square test was performed to evaluate correlations between variables. Results Aerosolised d-AmB was administered to 70 patients for a median time of 15 days (range 1–45). Prolonged administration was not associated with increased severe bacterial infections, nor severe adverse events were observed; only a patient developed moderate bronchial spasm. In 13 pts, aerosolized d-AmB was delivered for less than 7 days, due to worsened clinical conditions, or poor compliance. In this group, proven IFIs were diagnosed in 2 patients (1 mucormycosis and 1 fusariosis), possible aspergillosis in one and probable aspergillosis in another one. A shortened administration ( Discussion Despite the low number of patients, prolonged aerosolized d-AmB seems to play a role in preventing respiratory tract IFIs, but a randomised controlled trial is recommended to verify the impact of this prophylaxis in the setting of allogeneic HSCT.

Background The combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy regimens is currently considered the standard of care for newly diagnosed acute promyelocytic leukemia (APL) patients. This combination has greatly contributed to convert APL from a frequently fatal disease to a highly curable one. However, there is lack of data on the impact of such therapies on patients’ health-related quality of life (HRQOL). Objective The main objective of this study was thus to investigate long-term HRQOL of APL patients previously treated with ATRA plus anthracycline-based chemotherapy. The physical and mental HRQOL profile of these patients was compared with that of matched control subjects from the general population to identify specific areas most in need of attention in long-term follow-up care. A secondary objective was to outline symptoms’ burden from the patients’ perspective. Patients and Methods Data were gathered through an ongoing multicenter survivorship study that recruits APL patients previously enrolled in two large GIMEMA trials (i.e., AIDA0493 and AIDA 2000). In both trials, APL patients were treated with ATRA plus Idrarubicin (AIDA). The main inclusion criterion was having survived the initial diagnosis for more than 5 years and being in complete remission (CR). Generic HRQOL was assessed with the SF-36 that consists of 36 items covering eight generic health status/QoL domains: physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE) and mental health (MH). All scales ranged between 0 and 100, with the higher scores representing better outcomes. Clinical significance was evaluated and eight points were considered to be a minimally important difference for the eight SF-36 scales. Mean SF-36 scores were compared to available national general population reference values (i.e., 1997 subjects without cancer) and all analyses were adjusted for age and gender. Symptom burden was assessed according to the M.D. Anderson Symptom Inventory (MDASI). Symptom severity was assessed for the following symptoms: fatigue, pain, sleep disturbance, drowsiness, poor appetite, shortness of breath, nausea, vomiting, dry mouth, numbness, difficulty remembering, distress and sadness. All items were rated on a numeric rating scale from 0 to 10, with the higher scores indicating a higher level of symptoms. These were categorized as “mild” (ratings between 0 and 3) and “moderate to severe” (ratings between 4 to 10). Results Analysis is based on 136 adult APL patients who agreed to participate. At study participation, the mean age of patients was 52 years (55% males and 45% females) and the median time from diagnosis was 13 years (range: 4.5-20). Age and gender adjusted comparisons between APL patients and the general population norms revealed worse outcomes for the following scales: RP (P Conclusions Although ATRA plus anthracycline-based chemotherapy regimens have greatly increased cure rates in APL, the HRQOL of these patients is heavily affected by the consequences of the disease and treatment, that persists many years after diagnosis and treatment. Disclosures: No relevant conflicts of interest to declare.