ALBERT

Description: Key Points INTERIM treatment affects cytogenetic and molecular response, but not the outcome. No patients treated with INTERIM progressed to accelerated or blast phase.

Description: Abstract 2196 Poster Board II-173 BACKGROUND: Imatinib (IM) 400 mg daily is the standard treatment for Chronic Myeloid Leukemia (CML) in early chronic phase (ECP). The European LeukemiaNet (ELN) recommendations were designed to help identify ECP CML patients responding poorly to front-line IM, suggesting, at given time points, when the treatment strategy should be changed (”failure”), or when “the long-term outcome of the treatment would not likely be as favourable” (“suboptimal response”). Suboptimal response is a “grey zone”: the patient may still have substantial benefit from continuing IM, but other therapies should be considered. AIM: To assess the outcome of “failure” and “suboptimal responders” Philadelphia-positive (Ph+) CML patients in a large multicentric, nationwide experience. METHODS: Between January 2004 and April 2007, 559 patients were enrolled in an observational study and in 2 independent intervention studies of the GIMEMA CML WP (Clin Trials Gov. NCT00514488 and NCT00510926). Response monitoring was based on conventional cytogenetic examination of bone marrow cell metaphases every 6 months and RT Q-PCR evaluations of blood cells after 3, 6, 12 months, and every 6 months thereafter. Definitions: major molecular response (MMR): BCR-ABL/ABL ratio 〈 0,1%IS; failure (according to ELN criteria): no hematologic response (HR) at 3 months, no complete HR (CHR) at 6 months, no cytogenetic response (CgR) at 6 months, no partial CgR (PCgR) at 1 year, no complete CgR (CCgR) at 18 months, loss CHR or CCgR, progression or death; suboptimal response (according to ELN criteria): no CHR at 3 months, no PCgR at 6 months, no CCgR at 12 months, no MMR at 18 months ; optimal response: non-suboptimal and non-failure at each time-point; event: failure or treatment discontinuation for any reason. All the calculations have been made according to the intention-to-treat principle. RESULTS: The patients who fitted the ELN criteria for failure had a significantly lower probability of subsequently achieving a CCgR and a MMR, and had a significantly lower overall survival (OS), failure-free survival (FFS) and event-free survival (EFS). The patients who fitted the ELN definitions of suboptimal response at 6 months (data not shown) and at 12 months (figure 1) had a significantly lower probability than “optimal” responders of subsequently achieving a CCgR and a MMR, and a significantly poorer FFS and EFS (figure 1), while the OS was not different in the two groups (90% and 95%, p= 0.35). CONCLUSIONS Our data confirms that suboptimal responders at 6 and at 12 months have a poorer outcome with respect to “optimal” responders, comparable to the outcome of failure patients. Acknowledgments: European LeukemiaNet, COFIN, University of Bologna and BolognAIL. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Imatinib (IM) is the drug of choice for the treatment of CML, where it was shown that a complete cytogenetic response (CCgR) and a major molecular response (MMolR) at 12 months (mos) were the best surrogate markers of progression-free survival (PFS) (O’Brien et al, NEJM, 2003; Hughes et al, NEJM 2003). The issue of the MolR is particularly sensitive, because the degree of the MolR may fluctuate over time and among different labs, also for methodological reasons (Hughes et al, Blood 2006). Aim: To evaluate the prognostic value of the MolR based on a retrospective analysis of the patients (pts) who achieved a CCgR with IM 400 mg daily. Patients and Methods: 130 pts who achieved a CCgR for more than 1 year (confirmed CCgR) and were tested for MolR at least 3 times after achieving the CCgR, were analyzed. Cytogenetic response was assessed every 6 mos by conventional analysis of at least 20 marrow cell metaphases. MolR was assessed every 3 mos by RTQ-PCR (TaqMan) on peripheral blood buffy coat cells and was defined as MMolR when BCR-ABL:ABL

Description: Nilotinib has a higher binding affinity and selectivity for BCR-ABL with respect to imatinib and is an effective treatment of chronic myeloid leukemia (CML) after imatinib failure. In a phase 2 study, 73 early chronic-phase, untreated, Ph+ CML patients, received nilotinib at a dose of 400 mg twice daily. The primary endpoint was the complete cytogenetic response (CCgR) rate at 1 year. With a median follow-up of 15 months, the CCgR rate at 1 year was 96%, and the major molecular response rate 85%. Responses were rapid, with 78% CCgR and 52% major molecular response at 3 months. During the first year, the treatment was interrupted at least once in 38 patients (52%). The mean daily dose ranged between 600 and 800 mg in 74% of patients, 400 and 599 mg in 18% of patients, and was less than 400 mg in 8% of patients. Dose interruptions were mainly due to nonhematologic and biochemical side effects. Myelosuppression was irrelevant. One patient progressed to blastic crisis after 6 months; one went off-treatment for lipase increase grade 4 (no pancreatitis). Nilotinib is safe and very active in early chronic-phase CML. These data support a role for nilotinib for the frontline treatment of CML. This study was registered at ClinicalTrials.gov as NCT00481052.

Description: Abstract 2205 Poster Board II-182 Nilotinib is an effective and registered treatment of chronic myeloid leukemia (CML) after imatinib failure. Its efficacy as frontline treatment has been explored in phase 2 trials from MDACC and Italian GIMEMA , whose results have been presented recently (Cortes ASH Rosti, EHA). Here we present a detailed analysis of the safety profile of nilotinib 800 mg daily in the CML early chronic phase (ECP) setting. Briefly, 73 ECP patients (median age 51 yrs, range 18-83 yrs, 21/73 – 29% - ≥ 65 yrs at enrolment) received nilotinib at a dose of 400 mg BID. With a median follow-up of 15 months (range 12-24 months), the CCgR rate at 1 yr was 96%, and the major molecular response (MMolR) rate 85%. During the first 365 days, the treatment was interrupted at least once in 38 patients (52%; overall, 86 interruptions), with a median cumulative duration of drug interruption of 19 days (5.2% of 365 days) per patient (range 3-169 days); 35 pts (48%) received the full prescribed dose. The proportion of patients with ≥ 1 interruption decreased during the first and second quarter and second half (37%, 25% and 22% respectively). The mean daily dose was 600-800 mg, 400-599 mg, and less than 400 mg in 74%, 18% and 8% of patients, respectively. Four AEs (≥ grade 2) accounted for the great majority of dose interruptions: bilirubin increase (38%, no gr. 4), skin rash and/or pruritus (37%, no gr. 4), asymptomatic amylase and/or lipase increase (16%, gr. 4: 4%) (no pancreatitis), transaminases increase (19%, no gr. 4). Notably, only 3 events of peripheral edema/fluid retention have been recorded so far (2 gr 1, 1 gr. 2). No pleural or pericardial effusion. Only one pt permanently discontinued nilotinib for recurrent amylase and lipase increase gr. 3-4 after 7 months on nilotinib, without pancreatitis (normal ECO scan and MRI): the pt. is on imatinib 400 mg daily from 12 months, maintaining the CCyR but loosing MMolR on imatinib. The transient hyperglicemia (gr. 2 and 3: 6%) did not lead to any treatment discontinuation. The hematopoietic toxicity (grade 3-4) was negligible: only 5 events (3 neutropenias and 2 thrombocytopenias) in 5 pts (7%) (all within 3 months from treatment start: 431/438 q2weeks scheduled blood counts evaluable). Nilotinib 800 mg daily is feasible, safe and very effective in ECP CML (ClinicalTrials Gov.NCT00481052). ACKNOWLEDGEMENTS: The Italian Association Against Leukemia-lymphoma and myeloma (BolognAIL), The Fondazione del Monte di Bologna e Ravenna, The Italian Ministery of Education (PRIN 2005, No. 20050 63732_003, and PRIN 2007, No 2007F7 AE7B_002), The University of Bologna, The European Union (European LeukemiaNet). Disclosures: No relevant conflicts of interest to declare.

Description: Introduction. The application of Pediatric-Type Therapy (PTT) programs to adults with ALL can improve outcome significantly despite higher age-related toxicity. Recent series reported survival rates ≥ 50%, but only few combined PTT with Minimal Residual Disease (MRD) study for risk-oriented Hematopoietic Cell Transplantation (HCT) and/or explored the value of specific PTT element such as higher dose, lineage-targeted MTX up to 5 g/m2. Methods. To improve over prior data, NILG protocol 10/07 (Clinical.Trials.gov NCT-00795756) for unselected adult patients aged 18-65 years combined PTT together with MRD study for risk/MRD-based HCT. The 8-course program consisted of a 5-drug complete remission (CR) induction (cycle no. 1; imatinib added if Ph+) followed by 3 modified BFM blocks (no. 2, 4 and 6), 3 lineage-targeted MTX blocks (no. 3, 5 and 7; MTX 5 g/m2 for T-ALL and 2.5 g/m2 for B-ALL [1.5 g/m2 if age 〉 55 years or Ph+]; no. 3 and 7 with high-dose Ara-C 2 g/m2 x4, no. 5 with L-Asp 10,000 IU/m2 x2) and reinduction (no. 8). CNS prophylaxis was with triple intrathecals or liposomal cytarabine (Haematologica 2015;100:786). MRD was studied molecularly with sensitive probe(s) (sensitivity 10-4 or greater) on marrow samples obtained at end of induction (week 4, w4) and after cycles 3 (w10), 5 (w16), 7 (w22) i.e. after 1st, 2nd and 3rd lineage-targeted MTX block. Patients were risk-stratified at diagnosis and after MRD analysis for the purpose of allocation to HCT or conventional maintenance. The HCT allocation cohort consisted of predefined very high-risk patients (vHR: WBC 〉100, highly adverse cytogenetics, pre-T/mature T-ALL) regardless of MRD, of HR patients without MRD study (HR: late CR; B-ALL with WBC 〉30 or pro-B phenotype), and of HR or standard-risk (SR) patients with MRD ≥ 10-4 at w10/16 or positive at w22. Conversely, the maintenance allocation cohort consisted of SR and HR patients with MRD 〈 10-4 at w10/16 and negative at w22 and of SR patients without MRD study. A family related/unrelated donor search was activated at diagnosis in order to proceed to HCT soon after cycle no. 3 when needed. Results. 205 patients were enrolled, with a median age of 41 years (range 17-67 years, 11% 〉 60 years). 55% were male, 42 had Ph+ ALL, 119 Ph- B-ALL and 44 T-ALL. Of 163 patients with Ph- ALL, 45% were SR, 13% HR and 42% vHR. CR rate was 98% in Ph+ ALL and T-ALL, and 83% in Ph- B-ALL (88% vs 58% in patients ≤ vs 〉 60 years, P .0013). The MRD study was successful in 109/142 CR patients with Ph- ALL (77%), contributing to the final risk classification in 63 patients, of whom 41 were MRD responsive (65%) and 22 MRD resistant (35%). Altogether, 55 CR patients constituted the maintenance allocation group (39%) and 87 the HCT allocation group (61%), which included mainly vHR patients (n=61, 43%) selected for HCT independently of MRD study results. According to intention-to-treat, median OS is not reached (53% at 5 years, figure) and median DFS is 4.8 years (48% at 5 years). In Ph- ALL, 5-year OS/DFS are 74%/61% in T-ALL (medians not reached) and 48% each in B-ALL (medians 3.9 and 4.7 years). Median OS is not reached in both HCT and maintenance allocation groups (58% and 73% at 5 years, respectively, P .078), with a median DFS of 4.7 years (48% at 5 years) versus not reached (59% at 5 years) (P .19). Treatment adherence was good with some exceptions in maintenance allocation group (6 HCT, 11%) and a transplant realization of 68% (53 allogeneic; 6 autologous) in HCT allocation group. With HCT, 5-year incidence of nonrelapse mortality was 17%. The MRD analysis proved that DFS of patients achieving an MRD response 60 years. 5-year OS and DFS of 55% and 52% respectively in Ph- patients aged up to 65 years represent an improvement over prior NILG study (5-year OS and DFS of 36% and 35% respectively). MRD was essential in orientating the HCT choice in SR and HR patients and retained a major prognostic role in all patients. Optimizing the early MRD response with new immunotherapeutics and clarifying the role of HCT in MRD responsive vHR patients are some relevant topics of future research. Figure Figure. Disclosures Ciceri: MolMed SpA: Consultancy. Vitolo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gallamini:Millenium Takeda: Membership on an entity's Board of Directors or advisory committees.

Description: Background: The European LeukemiaNet (ELN) response criteria are widely used to decide, at given time points, when the treatment with tyrosine-kinase inhibitors (TKIs) of CML patients should be continued (optimal response, OR), when a careful monitoring is required (warning, W) or when the therapy should be changed (failure, F). The 2013 ELN response criteria are the same for all chronic phase CML patients, irrespective of the prescribed TKI, but the time to response is influenced by the first-line TKI. Despite faster responses, a clear survival advantage of 2nd generation TKIs over imatinib (IM) has not been demonstrated yet. A validation of the 2013 ELN response definitions and an analysis of their prognostic impact in IM-treated patients may provide important information. Aims: The aim of our study was to assess the significance of 2013 ELN response criteria in CML patients treated frontline with IM, investigating whether or not optimal responders, warnings or failures at 3, at 6 and at 12 months have a different long-term outcome. Methods: 559 patients enrolled within 3 prospective clinical trials (NCT00514488, NCT00510926, observational trial CML/023) were analyzed (ITT population of each study). The 3-month response according to 2013 ELN criteria was not fully evaluable due to missing cytogenetic analysis in 452/559 patients, so we focused on the early molecular response (EMR, BCR-ABL 〈 10% at 3 months), corresponding to OR. The responses at 6 and 12 months were retrospectively defined according to 2013 ELN criteria: F, BCR-ABL 〉 10% and/or Ph+ 〉 35% at 6 months, BCR-ABL 〉 1% and/or Ph+ 〉 0 at 12 months; OR, BCR-ABL 〈 1% and/or Ph+ 0 at 6 months, BCR-ABL 〈 0.1% at 12 months; W: intermediate conditions. As the ELN criteria changed over time, not all the failures switched to alternative treatment. Progression: transformation to advanced phases (2013 ELN definitions) at any time, including after treatment discontinuation. Overall survival (OS): all the deaths at any time (in-study or off-study) were included. Leukemia-unrelated death: known cause of death, no progression, CCyR and/or MMR 〈 6 months prior to death; all other deaths were classified as leukemia-related (LRD). The cumulative incidence of LRD was estimated considering the competing risk of leukemia-unrelated death. Results: The median follow-up was 76 months (66-99 months). The patients with OR at 3 months were 82%; the patients with OR-W-F at 6 months were 76%, 14% and 10%, respectively; the patients with OR-W-F at 12 months were 65%, 20% and 14%, respectively. The OS, the progression-free survival (PFS) and the cumulative incidence of LRD according to the presence-absence of EMR were 87-81% (p=0.015), 85-81% (p=0.035) and 11-5% (p=0.019), respectively. Combining the Sokal score and the EMR, the patients were divided into 4 groups, low and intermediate risk/responders, low and intermediate risk/not responders, high risk/responders, high risk/not responders: the OS and the cumulative incidence of LRD across the 4 groups were 88%, 84%, 86% and 70% (p=0.005, Figure 1) and 3%, 9%, 10% and 20% (p

Description: Introduction Imatinib mesylate (IM) is the first line therapy against Chronic Myeloid Leukemia (CML), effectively prolonging overall survival. Because discontinuation of treatment is associated with molecular relapse, IM is required indefinitely to maintain operational cure. To evaluate the degree of response to therapy and to highlight the persistence of the disease after treatment, patients should be monitored routinely. The gold standard for diagnosing CML is the cytogenetic analysis, a direct not-sensitive method to detect Ph-positive cells. Quantitative real-time RT-PCR (qRT-PCR) provides highly sensitive detection of BCR-ABL1 transcripts, but mRNA levels are not directly related to the number of leukemic cells and cannot detect transcriptionally silent leukemic stem cells. Methods Here we will propose a new sensitive approach to directly detect the number of leukemic cells using a DNA-based biomarker specific for each patient. We applied targeted next-generation sequencing for the identification of genomic BCR-ABL1 fusion junctions, and we developed a sensitive new approach to detect the number of leukemic cells by a DNA Q-PCR assay based on the genomic break-point, with a formula to calculate the number of Ph+ cells. The percentage of the leukemic cells (LC) was calculated using the following formula: %LC= (2/(2Δct+1))*100, where ΔCt is the difference between the amplification cycles of the BCR-ABL1 and BCR reactions. The number of LC was calculated by multiplying the total number of cells analyzed in each sample by the percentage of LC calculated by the ΔCt formula. We then defined a limit of quantization and a limit of sensitivity in the evaluation of minimal residual disease (MRD), as described by guidelines for the detection of MRD by genomic Q-PCR in acute lymphoblastic leukemia (ALL). We defined a “quantitative range” of detection, the portion of the standard curve in which the MRD levels can be quantified reproducibly and accurately, and we defined the “limit of sensitivity”, the lowest MRD level that still can be detected, although not in all replicates. We thus calculated the exact number of leukemic cells only when the MRD fell within the range of quantization. The detection of MRD at the limit of sensitivity was indicated as positive but not quantified. Results We monitored eight CML patients treated with Imatinib for 8 years. We tested the same samples by patient specific Q-PCR, and in parallel by cytogenetic analysis and by standard qRT-PCR. In all samples positive for chimeric transcripts we measured corresponding chimeric genomic DNA (gDNA) by Q-PCR, confirming the sensitivity of the Q-PCR method. According to conventional criteria, undetectable levels of BCR-ABL1 mRNA assessed by qRT-PCR are indicative of complete molecular response (CMR), but in 33.3% (45/135) samples with undetectable levels of mRNA, we detected the persistence of transcriptionally-silent leukemic cells. However, we never found samples negative by gDNA Q-PCR and positive by RNA-based qRT-PCR (Figure 1). Thirty-six of 135 samples were also analyzed cytogenetically until the achievement of CCyR. As expected, Ph+cells were detected only in 25% (9/36) and 22,2% (8/36) of samples by CBA and I-FISH, respectively, whereas BCR-ABL1 mRNA was detected by qRT-PCR in 83.3% (30/36) of samples and Ph+ cells were detected by genomic Q-PCR in 91.7% (33/36) of samples (Figure 1). Finally, the separation of different cell populations from blood and bone marrow revealed the presence of a population of transcriptionally silent cancer stem cells. The gDNA based Q-PCR analysis performed on highly purified (immunomagnetically selected ) CD34+and CD3+ cells confirmed the presence of a population of transcriptionally silent cancer stem cells. Conclusions The demonstration of positive gDNA Q-PCR in 33.3% of samples negative for the RNA qRT-PCR could partially explain why some patients lose MMR and CMR and others do not, when IM is discontinued for brief periods. The gDNA based Q-PCR could be used to supplement conventional techniques, providing clinicians with additional information about disease status and response in determining whether to stop or alter therapy. Acknowledgments to AIRC and AIL. Disclosures: No relevant conflicts of interest to declare.

Description: 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.

Description: Abstract 2029 Poster Board II-6 In a prospective NILG (Northern Italy Leukemia Group) study, short IM pulses were added to chemotherapy in order to 1) reduce incidence of early failures, 2) obtain higher transfer rates to stem cell transplantation (SCT), and 3) improve survival in comparison with a prior patient cohort treated with the same chemotherapy program without IM. 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 the following consolidation courses (5x IDR/VCR/CY/DEXA; 2x HD-MTX/ARA-C). All pts. received CNS chemoradioprophylaxis 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. registered in NILG study 09/00 had Ph+ ALL (Ph chromosome and/or BCR-ABL rearrangement). M/F ratio was 1.17 and median age 46 years (range 19-66). 35 pts. constituted the control cohort (IM-) while, starting December '02, 59 pts. were included in the modified protocol (IM+), and 6 were excluded from analysis because treated on a continuous IM schedule. Of 59 IM+ pts., 53 received IM during induction/consolidation as planned and 6 during consolidation only (included in IM- group for remission induction analysis). Outcome to induction therapy of IM+ vs. IM- group was: CR 49/53 (92%) vs. 33/41 (80%), NR 2 (3.7%) vs. 5 (12%), ED 2 (3.7%) vs. 3 (7%) (P=NS). With a median observation interval from diagnosis of 5 years (range 0.6-9.2 years), 21 IM+ vs. 6 IM- pts. are alive in remission (CR1 pts.: 43% vs. 18%, P=0.02), and both OS (Figure) and DFS (0.39 vs. 0.21, P=0.044) rates at 5 years are significantly improved in IM+ group, especially when IM was administered from the induction cycle. The ability to perform a SCT increased from 53%(n=15: 11 allogeneic, 4 autologous) to 68%(n=37: 22 allogeneic, 5 autologous), partly owing to lower incidence of early relapse (26% vs. 56% at 1 year, P=0.005). SCT-related mortality was not different (P=0.58) and postgraft survival probability at 5 years was 0.45 overall, again with no difference related to SCT source or IM. Use of IM was not associated with greater reduction of BCR-ABL transcripts: by PCR analysis of BM samples taken at weeks 10, 16 and 22 in pretransplantation pts., a major response (absent/