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Background Frontline ASCT is the standard of care for patients with symptomatic NDMM less than 66 years of age. 3-drug combinations are the standard induction regimens prior to ASCT. Consolidation therapy after ASCT is aimed at improving disease control through deepening responses. Maintenance therapy is administered with the objective of prolonging response duration. The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone (IRd) was recently evaluated in NDMM, was generally well tolerated and appeared active (Kumar et al, Lancet Oncology 2014;13:1503-12). We analyzed the safety and efficacy of the triplet IRd combination prior to, and as consolidation after ASCT followed by ixazomib maintenance in the initial management of MM in patients younger than 66 years in a phase 2 study (NCT01936532). Methods Patients received 3 cycles of induction therapy with Ixazomib 4 mg on days 1, 8 and 15 plus Lenalidomide 25 mg on days 1 through 21 and dexamethasone 40 mg on days 1-8-15 and 22 of a 28-day cycle followed by Melphalan 200 mg/m2 and ASCT. Two months after ASCT, patients received an early consolidation with 2 cycles of IRd identical to induction therapy followed by a late consolidation phase with 6 additional cycles of IR without dexamethasone. One month after the last consolidation cycle, patients received maintenance therapy with Ixazomib single-agent 4 mg on days 1, 8 and 15 of a 28-day cycle, during 12 months. The primary end-point was the complete response (CR) rate after extended consolidation therapy. The secondary objectives were to evaluate the overall response rate (ORR) after induction, after ASCT, after consolidation and after maintenance, to evaluate the safety of induction therapy, the feasibility of extended consolidation, the feasibility of maintenance with Ixazomib, the duration of response, progression-free and overall survival. Responses (central lab, Dr Dejoie, Nantes) were assessed according to the IMWG criteria. Toxicity was evaluated according to NCI CTCAE, version 4.03. Results From 11/2014 to 04/2015, 42 patients (21 males, 21 females, median age 60 years (43-65)) with NDMM were enrolled in 10 centers from IFM. ISS was 1 in 12 cases (29%), 2 in 23 cases (54%) and 3 in 7 patients (17%), respectively. Adverse cytogenetics (17p deletion, and/or t(4;14); central lab, Dr Avet-Loiseau) was observed in 8 patients (19%). Induction with IRd was very well tolerated. Out of 120 cycles administered for 42 patients, only 13 cases of non-hematologic grade 3-4 toxicities were reported: infections (8 cases), abdominal pain (2), atrial fibrillation (1), thrombosis (1), and DRESS syndrome leading to study withdrawal (1). No renal or liver toxicity was reported. No cardiac failure and no ischemic heart disease was documented. No grade 3-4 peripheral neuropathy was described. Response rates increased at each step of the strategy. Following 3 induction cycles of IRd, the ORR was 81%, including 12% CR plus 24% very good partial response (VGPR), and 2 patients progressed (5%). Following ASCT, the VGPR rate or better was 78% including 38% CR. Following consolidation (early 2 cycles + extended 6 cycles), the VGPR rate or better was 80% including 44% CR. The feasibility of the consolidation phase with IRd (2 cycles) and IR (6 cycles) was excellent: 34 / 37 patients who started consolidation completed the 8 planned cycles (3 discontinuations: 2 patient decisions, 1 progression to plasma cell leukemia). 34/42 patients (81%) were able to receive maintenance therapy with Ixazomib following extended consolidation. Results of maintenance and of minimal residual disease evaluation will be presented during the meeting. At the cut-off date of June 30 2016, with a median follow-up of 16 months, 3 patients / 42 (7%) have progressed, 2 during induction and 1 during consolidation, and 2 (5%) died from progressive disease. Conclusions The all-oral triplet combination IRd administered as induction prior to, and as consolidation following ASCT is safe, convenient, and effective, leading to 80% VGPR and 44% CR before maintenance. Final results on response rates following maintenance and MRD data will be presented during the meeting. Updated results on PFS and OS will also be presented. Disclosures Moreau: takeda: Honoraria; celgene: Honoraria; janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Hulin:celgene: Honoraria; janssen: Honoraria; takeda: Honoraria. Facon:Millenium/Takeda: Consultancy; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Roussel:celgene: Honoraria; takeda: Honoraria; janssen: Honoraria. avet-Loiseau:takeda: Honoraria; janssen: Honoraria; celgene: Honoraria; amgen: Honoraria. Attal:sanofi: Consultancy; amgen: Consultancy, Research Funding; janssen: Consultancy, Research Funding; celgene: Consultancy, Research Funding.

Background. R-CHOP is the standard first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). However 30% of patients will relapse and 70% of relapsed patients will die within 2 years of diagnosis. The REMARC study (clinicalTrials.gov NCT01122472) is an international, multicenter, double-blind, randomized, placebo controlled, phase III trial that assessed the benefit of lenalidomide (LEN) maintenance after response to R-CHOP in patients aged 60 to 80 years with untreated DLBCL, FL3b or transformed lymphoma. Patients achieving CR or PR at the end of 6 or 8 cycles of R-CHOP21 or R-CHOP14 were stratified by CR/PR status and country and randomized 1:1 to receive 2 years of LEN maintenance (25 mg/day for 21 of every 28 days) or placebo (PBO). The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints were safety, PR to CR conversion rate, and overall survival (OS). Diagnosis was retrospectively centrally reviewed. In patients with adequate samples, GCB/nonGCB profile was assessed by the Hans algorithm and GCB/ABC/unclassified profile was assessed using NanoString gene expression profiling technology. Methods. From 05/2009 to 05/2014, 784 patients were enrolled either before R-CHOP (n= 437) or after completion of 6 or 8 cycles of R-CHOP (n= 347). At the end of R-CHOP therapy, 650 patients were randomized to maintenance, either in CR (n= 495) or in PR (n= 152). Central review found that 3 patients were randomized in SD or PD, all in LEN arm. At time of diagnosis, median age was 68 y (range 58-80), 43.5% were older than 70 y, and 56% were male. aaIPI was low in 38.5% and high in 57.5% of patients (missing data 4%). COO analyses are ongoing for both Hans algorithm and NanoString technology. Results. With a median follow-up of 40 months, median PFS (according to independent centralized radiology review) was not reached in the LEN group versus 68 months in the PBO group (hazard ratio favoring the LEN group, 0.708 (95% CI 0.537-0.932; p=0.0135))(See Figure). In the LEN group, 18 patients (21%) converted from PR to CR during maintenance compared to 13 patients (14%) in the PBO group. Immature overall survival data did not show any benefit for LEN arm, a lack of difference not attributable to an excess of lymphoma relapse, secondary cancer or safety problems in LEN arm. Deaths generally occurred off study drug (median time from last dose of study drug to death was 277 days (range 20, 1291) in LEN arm and 334 (41, 1594) in control arm. During maintenance, the most common observed grade 3 or 4 AEs were neutropenia (56% vs. 22%), rash (5% vs. 1%), infections (8% vs. 6%), and thrombocytopenia (2.5% vs. 0.6%) in LEN and PBO arms, respectively. Dose adjustments were necessary in 72% of the LEN patients and 42% of PBO patients. 59% of patients stopped LEN and 40% stopped PBO for toxicity (p Conclusion. This analysis of the REMARC study shows that 2 years of LEN maintenance in patients responding to R-CHOP significantly improved PFS (primary endpoint) without an early significant impact on OS. The COO analysis is currently ongoing. This is the first report finding that using an immunomodulatory agent as maintenance therapy prolongs PFS for patients with DLBCL after first line treatment with R-CHOP. Figure 1. Progression-free survival of elderly patients with diffuse large B-cell lymphoma in response to R-CHOP treated in maintenance with either lenalidomide or placebo Figure 1 Figure 1. Disclosures Thieblemont: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gomez da Silva:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; ROche: Consultancy, Membership on an entity's Board of Directors or advisory committees; takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Haioun:Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cabecadas:celgene: Consultancy, Honoraria. Salles:Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Coiffier:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background. The prevalence of diffuse large B-cell lymphoma (DLBCL) in patients aged over 80 years is reported to have tripled compared to patients in their sixties. Treating very elderly patients is particularly challenging given the likelihood of comorbidities and concerns over risks of toxicity. One of the most devastating and rapidly fatal complications in DLBCL is central nervous system (CNS) relapse. Most studies reporting incidence and risk factors of CNS relapse concern DLBCL patients under the age of 80 years, and little is known about CNS recurrence in the very elderly, aged over 80 years. CNS prophylaxis is rarely implemented in this population due to the burden of comorbidities, frequent antiplatelet or anticoagulant treatment along with renal failure and hypoalbuminemia, as well as potential prophylaxis toxicity of IV high dose methotrexate and/or the invasiveness of IT therapy. Aim. We retrospectively evaluated the incidence of CNS relapse, risk factors and specific survival in very elderly DLBCL patients aged 80 years Patients and Methods. Data were collected retrospectively from two multicentre, open-label, single arm phase II LYSA trials (LNH 03-7B (NCT01087424) between 2004 and 2007, LNH09-7B (NCT01195714) between 2009 and 2013) evaluating the addition of rituximab or ofatumumab to miniCHOP as front-line therapy. Results. A total of 270 elderly patients were included in the two trials, 150 treated with R-miniCHOP and 120 with O-miniCHOP. Median age was 83 years (range 79-95) and none received CNS prophylaxis. At inclusion, most patients (76%) presented with disseminated disease (Ann Arbor stage III or IV), and 37% had at least two extra-nodal sites. Overall 18% of patients had bone marrow involvement, while renal, adrenal, testis or cavum involvement was rare (4%, 2%, 3%, and 2%, respectively). After a median follow-up of 28.7 months (range 0.1-72.1), 8 (3%) cases of CNS relapse were reported. Median time between inclusion and CNS relapse was 19.2 months (range 3.2 - 32.6). Cumulative 1 and 2-year incidence of CNS relapse was 1.4% (95% CI 3.2-25.4) and 2.5% (95% CI 6.9-9.2), respectively. At inclusion, clinical characteristics of the CNS relapse patients were not significantly different from patients without relapse. At CNS relapse, all patients except one present a performance status ECOG > 2. neurological symptoms were either mild with loss of autonomy, asthenia, hearing impairment, urinary incontinence, or more prominent with delirium, aphasia, intracranial hypertension, or consciousness disorder. Treatment of CNS relapse was a supportive care based- treatment with corticosteroid only in 5 patients, radiation therapy in one patient, and chemotherapy for 2 patients including rituximab-temodal (5 cycles) in one patient and rituximab -aracytine-vepeside (2 cycles) for the other one. Patients survived for a median of 1.5 months after CNS relapse diagnosis (range, 0.4 to 4). The CNS international prognostic index (CNS-IPI) classified 33 (12%) patients in the low-risk group, 164 (62%) in the intermediate-risk group, and 71 (26%) in the high-risk group. The low-risk and intermediate-risk CNS-IPI groups showed 2-year rate of CNS disease of 3%, and the high-risk of 2.8% (p=0.9483). Conclusion. Incidence of CNS relapse in very elderly previously untreated patients is approximately 3% and is associated with a very poor survival. The absence of prophylaxis in this population did not appear to have a strong impact on CNS relapse incidence. Higher number of patients is warranted to identify risk factors for CNS relapse in this population Disclosures Coiffier: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salles:Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Thieblemont:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Waldenström's macroglobulinemia (WM) is a clonal B-cell lymphoproliferative disorder (LPD) of post-germinal center nature. Despite the fact that the precise molecular pathway(s) leading to WM remain(s) to be elucidated, a hallmark of the disease is the absence of the immunoglobulin heavy chain class switch recombination. Using two-dimensional gel electrophoresis, we compared proteomic profiles of WM cells with that of other LPDs. We were able to demonstrate that WM constitutes a unique proteomic entity as compared with chronic lymphocytic leukemia and marginal zone lymphoma. Statistical comparisons of protein expression levels revealed that a few proteins are distinctly expressed in WM in comparison with other LPDs. In particular we observed a major downregulation of the double strand repair protein Ku70 (XRCC6); confirmed at both the protein and RNA levels in an independent cohort of patients. Hence, we define a distinctive proteomic profile for WM where the downregulation of Ku70-a component of the non homologous end-joining pathway-might be relevant in disease pathophysiology. journal article 2012 Sep 07 2012 09 07 imported

Abstract 4075 Introduction. The association of Melphalan-Prednisone and Thalidomide (MPT) is approved as first-line treatment in elderly patients with Multiple Myeloma (MM). This treatment demonstrated significant benefit in terms of overall survival (OS) and Progression Free Survival (PFS) as opposed to MP alone. Lenalidomide (Len), used in combination with Dexamethasone (Len/Dex), is recommended to treat patients with relapsed MM who received a prior therapy. Len is an oral immunomodulator similar to Thalidomide (T). Both these drugs have identical activity but their safety profiles are different. So, in case of successive use of MPT and Len/Dex, it is legitimate to think that the efficacy of Len is affected by the previous use of T, probably because of the resistance to Len developed by relapsed or refractory patients. Therefore, we carried out a retrospective, multicentric study in order to assess the efficacy and safety of Len in patients with relapsed MM previously treated by MPT. Method. Our survey included 64 elderly patients with symptomatic MM from three French hematology centers. All the patients showed a relapsed MM treated with first-line treatment of MPT. Len was administered at first or second relapse. The main objective was to assess the efficacy of Len in terms of response rate, OS and PFS. Another objective was to evaluate the tolerance to Len and MPT treatments and to identify the predictive factors of efficacy of Len like the response rate, the duration of remission after MPT treatment and the line number of treatment before using Len. Results. The median age of patients at diagnosis was 73.5 years old and the sex ratio was 1. The M-protein was IgG for 64% of patients, IgA for 20%, light chains for 14% and IgD for 2%. Concerning the International Staging System, 35% of patients were stage I, 28% were stage II and 37% were stage III. MPT was administered with a 100mg/d thalidomide dose to 83% of patients. The median duration of T treatment was 13 months [range: 0.1 – 29.5]. The overall response rate (ORR) was 90% with 53% of partial response (PR), 27.5% of very good partial response (VGPR) and 9.5% of complete response (CR). Five patients stopped T because of progression on therapy, 36 because of toxicity out of which 26 because of peripheral neuropathy and 2 thromboembolic events. The median response duration after MPT was 25.5 months. Len was administered at first relapse to 47 patients (73.5%) and at second relapse for the others (n=17). The second-line treatment for these 17 patients was bortezomib-based regimen treatment. The daily dose of Len was 15 to 25 mg, always associated with low dose of Dex, for 83% of patients. Ten cycles of Len/Dex were administered on average. For 23/64 patients, the Len/Dex treatment is going on, 21/41 patients stopped because of progression and 17/41 because of toxicity (hematologic toxicity: 8/17, thromboembolic events: 2/17, general and gastrointestinal disorder: 7/17). The Len ORR was 78% (CR: 3.5%, VGPR: 27.5%, PR: 47%). The median SSP after initiation of Len is 12.8 months. The median OS after initiation of Len is 43 months and the OS rate is 58% at 3 years. Since the diagnosis, No predictive factor has a significant impact on the efficacy of Len. No second primary malignancies were reported. Conclusion. Our study shows that the efficacy and safety of Len is satisfactory, even after a Thalidomide treatment. The ORR and median PFS are similar to published data. There is no increase of toxicity for patients on Len, especially concerning thromboembolic events. With the development of new drugs like Carfilzomib, Pomalidomide and Eculizumab, the perspective of treatment increased as well as the number of lines. The choice of therapeutic sequences must be taken into account. In this study, we show that the MPT – Len/Dex sequence is effective and safe for elderly MM patients. Disclosures: Roussel: celgene: Honoraria; janssen: Honoraria. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Leleu:celgene: Honoraria; janssen: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Hulin:celgene: Honoraria; janssen: Honoraria.

Abstract 2964 Background. Lenalidomide is an oral IMiD®, immunomodulatory compound, approved for use in combination with dexamethasone (Len/Dex) in patients with RRMM who have received one prior therapy. Len/Dex is indicated until evidence of disease progression at the best-tolerated dose of both Len and Dex (Dimopoulos et al. Leukemia 2011). However, the tolerability profile of long term exposure to Len/Dex is not well described, and evidence that long term exposure to Len/Dex would improve on the response rate and survival has yet to be determined. We sought to determine the efficacy and safety profile of long term exposure to Len/Dex in RRMM pts in a multicentre study. Method. We retrospectively reviewed the medical records of 50 RRMM pts treated with Len/Dex and remaining on Len for ≥2 years with a special focus on pts receiving Len for ≥3 years. All pts included had complete follow up records. Results. The median (range min-max) age was 58 years (39–79) with 30% (n=15) > 65 years (elderly MM), the sex ratio M/F was 1.2, 49% (n=24) ISS 2 and 3, 12% (n=6) severe renal insufficiency (CrCl < 30mL/min), and 8% (n=4) adverse FISH [del17p and/or t(4;14)]. Overall, 25 pts (50%) had Len/Dex at first relapse, 19 pts (38%) at second relapse and 6 (9%) pts in subsequent relapses. Len/Dex was given at first relapse in 10 (66%) elderly patients. The median time from diagnosis to starting Len/Dex was 4.5 years (1–16) for overall cohort and 3 years (1–8) for elderly patients (p=0.05). 28 pts (56%) received Len/Dex for ≥3 years. The median duration on Len/Dex was 3 (2–7) years for the overall cohort, and was 4 (3;7) years for patients exposed to Len ≥3 years. Treatment duration was similar across age categories and across number of previous relapses. With a median follow up of 4 years, 19 patients had stopped Len/Dex. The response rate (ORR, ≥PR) was 96% (n=48), including 37 (74%) patients with ≥VGPR, similar across age categories. Interestingly, the ORR and ≥VGPR were similar irrespective of whether patients have stopped Len/Dex in our study. The ORR was also similar across number of previous relapses, but the ≥VGPR rate was lower in patients at third relapse and beyond, (50%; p=ns). The ORR and ≥VGPR rate was 93% and 77% in patients exposed to Len ≥3 years, similar to the whole cohort. The median time to first response and best response were 2 (1–5) months and 4.5 (2–9) months, respectively. Overall, 9 (18%) patients stopped treatment due to toxicity, 9 (18%) progression of MM, and 1 (0.5%) patient decision. With a median follow up of 4 years, the median (95%CI) TTP was not reached, the estimated 4-yr TTP was 51.5%. There was no imbalance in the incidence of toxicity based on age, number of previous relapses, and patients exposed to Len ≥3 years did not discontinue more often due to toxicity, 14% versus 19% for those receiving Len < 3 years. The hematological safety profile was similar across age categories, number of previous relapses, and patients exposed to Len ≥ 3 years; overall, 8 (16%) patients experienced grade 3–4 neutropenia, 6% thrombopenia, and 6% anemia. Ten (20%) patients experienced a thromboembolic event (VTE), all of them of venous type. Two patients had previous history of VTE, but none of them experienced VTE on Len/Dex, likely related to adequate VTE prophylaxis. The median time to first occurrence was 5 (1;28) months, although 4/10 occurred in patients with ≥3 years on Len. All VTE occurred while on VTE prophylaxis except for 1 patient, 5 on aspirin, 2 on prophylactic doses of LMWH, and 2 on VKA (target INR 2–3). The incidence rate of second primary malignancy (SPM) was 3 (6%) (larynx, lung, and MDS). The SPMs occurred at a median time of 4 years from start of Len, while Len was already stopped in 2/3 patients, the latter stopped len at time SPM was diagnosed. Interestingly, none of the patients with more than 3 years exposure on Len had SPM. Conclusions. The current study provides estimates of responses, TTP and safety in a series of MM pts with long-term exposure to Len-based regimen at relapse. 62% of patients remained on Len beyond 3 years reflecting the efficacy and good safety profile of Len in relapsed MM, irrespective of age and number of prior therapies. Furthermore, no excess of long term side effects, including SPM, was observed with a prolonged long follow-up in this study. Disclosures: Robinson: Celgene: Employment. Miljkovic:Celgene: Employment. Morel:Celgene: Employment. Boccacio:Celgene: Employment. Facon:millenium: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees. Hulin:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Leleu:Onyx: Honoraria, Speakers Bureau; Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau.

Abstract 2603 Purpose Although CBF-AML (i.e. with t(8;21) or inv(16)/t(16;16)) represents a favorable cytogenetic AML subgroup (Döhner, Blood 2010), 35–45% of these patients still relapse after standard intensive chemotherapy. The immunoconjugate gemtuzumab ozogamicin (GO) was shown to be effective in patients with relapsed AML in non randomized studies and has been recently demonstrated in a Phase 3 trial as associated with a significant benefit in younger adults with CBF-AML (Burnett, JCO 2011). In this study, we thus investigated the impact of GO-based salvage at first relapse in this specific subgroup of patients with CBF-AML. Patients and Methods We retrospectively analysed the medical records of 84 patients aged 60 years or less with CBF-AML in first relapse after intensive chemotherapy and treated in 18 French centers. None of these patients received allogeneic (alloSCT) or autologous (autoSCT) hematopoietic stem cell transplantation in first complete remission (CR). As salvage, 27 patients received GO, combined with high-dose cytarabine in most of them; 21 patients received high-dose cytarabine and anthracycline without GO; 36 patients received conventional chemotherapy based on standard-dose cytarabine and anthracycline. Post-remission therapy was alloSCT in 49 patients, autoSCT in 17 patients, and chemotherapy alone in 11 patients. Results Among 84 patients with a median age of 39 years [16–58], 36 patients had t(8;21) AML and 48 patients had inv(16)/t(16;16) AML. Median CR1 duration was 12.9 months [2.6–55.3]. Second complete remission (CR2) rate was 92% (77/84), and early death rate was 1% (1/84). The median follow up was 4.0 years. The 5-year overall survival (5y-OS) and relapse-free survival (5y-RFS) was 52% [39–64%] and 48% [36–60%] respectively. Patients receiving alloSCT in CR2 had a better outcome (5y-OS, 56% versus 43%; p=0.05). In patients not allografted in CR2, RFS was similar after autoSCT and chemotherapy alone (5y-RFS, 44% versus 47%, respectively). Patients treated with GO had similar CR rate but a lower risk of second relapse and a better survival than other patients (5y-RFS, 89% versus 55%; p=0.05 and 5y-OS, 90% versus 45%; p=0.03). In univariate analysis, other factors associated with a better OS were younger age, longer CR1 duration, but not CBF subtype (p=0.03, 0.01, and 0.20, respectively). In multivariate analysis adjusted on age, CR1 duration, and CBF subtype, GO salvage was still associated with a significant benefit in OS (HR=0.16 [0.04–0.69], p=0.01) and RFS (HR=0.19 [0.04–0.80], p=0.02). With a median post-relapse follow-up of 2.2 years, no relapse nor death were observed in the 19 patients who received GO salvage followed by alloSCT in CR2 (p=0.007 for RFS; p=0.008 for OS). Moreover, in patients who received alloSCT, previous GO therapy significantly improved post-transplantation outcome. Conclusion Younger patients with CBF-AML in first relapse had a high second complete remission rate regardless the intensive chemotherapy salvage. More interestingly, the outcome of these patients was significantly improved by the addition of GO-based salvage, especially when followed by alloSCT. Disclosures: Off Label Use: GO is available in Europe as a compassionate treatment for relapsed AML.

Abstract 1577 Poster Board I-603 INTRODUCTION The prognosis of acute myeloid leukemia (AML) in patients over 60 years of age remains very poor, especially in those with unfavorable cytogenetic abnormalities. Breems et al. recently identified in AML patients under 60 years old, a monosomal karyotype (MK), defined by the presence of at least two autosomal monosomies or one monosomy plus one structural abnormality. MK provides a significantly better prognostic prediction than the conventionally defined complex karyotype (CK) in such young patients [J Clin Oncol 2008;26:4791-7]. METHODS In order to investigate the prognostic relevance of MK in the elderly, a retrospective study of 186 previously untreated AML patients with classically defined unfavourable cytogenetic was performed. All were aged 60 years or more and were selected among patients enrolled in 3 prospective GOELAMS trials (SA4, SA2002 and R04) between 1996 and 2006. In the three consecutive trials, patients were treated with standard dose cytarabine + idarubicin, followed by monthly re-inductions and maintenance. Poor-risk cytogenetics' patients were well-balanced between the treatment's arms and no significant influence of the hypotheses tested in the trials could be demonstrated (beneficial effect of fludarabine, androgenotherapy or gemtuzumab-ozogamicin, respectively) [manuscripts submitted]. RESULTS The median age of the patients was 68 years (range: 60-79 y) and the M/F ratio 95/91. Thirteen percent of the patients had secondary AML. Leukocytosis >30 G/L was noted in 15% of the cases. Poor cytogenetic features included monosomy 5 or del 5q in 89 patients (48%) and monosomy 7 or del 7q in 86 (46%). Only 9 patients ( CONCLUSION These results, obtained within a cohort of elderly patients with cytogenetically unfavourable AML, show that MK, according to the criteria proposed by Breems et al., is also an independent factor of very poor prognosis in older age, further stratifying prognostic subgroups. Disclosures No relevant conflicts of interest to declare.

We report the case of a 59 year old man presenting a regenerative microcytic hypochromic anaemia. The investigations revealed the presence of haemoglobin H, suggesting abnormalities in the alpha-globin chains synthesis. Alpha-thalassemia was thus suspected. The patient had no personal or familial history. The association with aniso-poïkilocytosis and a marked iron overload (ferritinemia1,500 microg/L) suggested a myelodysplastic syndrome, which was confirmed with a bone marrow aspiration. The pattern was consistent with the Acquired alpha-Thalassemia-Myelodysplastic Syndrome (ATMDS). About a hundred cases are listed worldwidely and collected in an international registry. The causes of ATMDS are ignored, but recent reports indicate that the ATRX gene may be implicated in the pathogenesis. ATRX is a chromatin-associated protein, involved in the transcription of several genes. The alpha globin genes could be one of the targets of the ATRX protein.

Peripheral T-cell lymphoma (PTCL) is an aggressive disease with poor outcome. First line therapies are usually unsatisfactory with frequent need for second-line therapies. Median progression free survival (PFS) and overall survival (OS) for relapse PTCL patients are very short with few available therapeutic options. Bendamustine has been shown to be effective in this setting. In order to assess the efficacy of bendamustine outside clinical trials, we conducted a national retrospective study of patients with the diagnosis of PTCL and who were treated with bendamustine. Between 2011 and 2013, about 200 patients with the diagnosis of PTCL have been treated in 27 centers with bendamustine. We present the results of 142 patients with complete clinical and biological data. The population median age was 64y (range 28-89) with male/female sex ratio of 1,4 (83/59). Histologies were: angio-immunoblastic (AILT=63), PTCL-NOS (n=44), anaplasic-large (ALCL=13), NK/TCL (n=3), mycosis fungoides (MF=7), subcutaneous panniculitis-like-TCL (n=2), hepato-splenic-TCL (n=1) and others (n=9). The majority of patients (96%, n=130) had stage-disseminated disease and 72% (n=102) of them had extranodal localisations. The median number of chemotherapy lines prior to bendamustine was 2 (range 0-8). Seven patients (5%) had received allogeneic stem cells transplantation (SCT) and 16 autologous SCT (11%) prior to bendamustine. The median duration of response (DoR) after the last prior to bendamustine chemotherapy was 4.3 months (range 1-70) and 50% of patients had refractory disease at bendamustine treatment. Seventy-four patients (52%) received less than 3 cycles, mostly because of disease progression. Overall, they received a median of 2 cycles (range 1-8) with a median dose of 90mg/m2 (range 50-150). The best overall response rate (ORR) was 32% (45/141) with complete response of 24% (CR=34). The median DoR was 3.3 months (1-39). For AITL patients, ORR was 52% (33/63) with CR of 41%, whereas it was 18% (8/44) with 11% of CR, in patients with PTCL-nos, respectively (p=0.01). Nine patients (6%) received allogeneic SCT in CR. Median PFS was 3 months (range 0.2-46.3) and median OS was 4.4 months (range 0.2-55.4). On multivariate analysis, chemotherapy refractory (p=0.001) patients' and extranodal disease localization (p=0.028) before bendamustine influenced adversely the ORR. With a median follow up 4.4 months, 72% of patients (102/142) died. The most frequent cause of death were: disease progression (92%) or toxicities (6%). Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22%, 17% and 23% of cases, respectively. Bendamustine as single agent must be considered as a therapeutic option for relapsed or refractory PTCL, particularly in patients with AITL. The safety profile was good. Combination of bendamustine with other drugs should be evaluated prospectively. Disclosures Off Label Use: Bendamustine, single molecule, alkylant agent with antimetabolite properties. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Cartron:Sanofi: Honoraria; GSK: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Roche: Consultancy, Honoraria.

Introduction: CD38 is highly and uniformly expressed on myeloma cells (1). Daratumumab is a human anti-CD38 IgG1κ monoclonal antibody that has previously shown a favourable safety profile as a single agent in patients with relapsed and refractory (RR) multiple myeloma (MM) (2). This study further assesses the efficacy of Daratumumab in combination with Dexamethasone in heavily pre-treated myeloma patients that are refractory to Lenalidomide, Pomalidomide, and Bortezomib. Methods: This study is an ongoing, open-label phase II study of Daratumumab in combination with Dexamethasone (NCT02626481). Sixty-four, heavily pretreated Patients were recruited in thirty centres in France and Belgium from November 2015, to receive Daratumumab and Dexamethasone. Daratumumab 16 mg/kg was administered weekly during the first two 28-day cycles, every other week during Cycles three through six, and monthly in Cycle seven and beyond until disease progression or unacceptable toxicity. Patients were all refractory to Lenalidomide (Len), Pomalidomide (Pom) (defined by a progression within 60 days from last drug dosing) and Bortezomib (Bz) (defined by a progression within 6 months from last drug dosing). The primary objective was overall response rate as per the International Myeloma Working Group criteria. A planned safety and efficacy interim analysis was performed after the first 19 patients were enrolled. The last patient was enrolled on the 1stof August 2016. Results: Sixty-four patients were recruited onto the study. The median age (range) at screening was 61 (30-80). The median number (range) of prior lines of therapy was 6 (2-9). Sixty-seven percent of patient had previously received an autologous stem-cell transplant. At the time of screening, 20% of patients (n=13) had a t(4;14) and 12.5% (n=8) a del(17p). Planned interim analysis after the first 19 patients were enrolled did not find any unexpected toxicity. Safety and efficacy results (data cut May 15, 2016) of Daratumumab 16 mg/kg are presented here. No patient discontinued treatment due to Treatment Emergent Adverse Event such as infusion related reactions. Ten (15%) patients discontinued treatment due to disease progression after a median of one-cycle. The most common non-haematological TEAEs included infusion related (IRR, n=5, 8%), and fatigue (n=6, 9.3%). All patients with IRRs recovered and continued to receive treatment. Only six (9.5%) patients experienced hyperthermia. Thrombocytopenia and neutropenia were the most frequently reported grade 3 or 4 TEAE (11 and 5% respectively). Planned interim efficacy assessment showed a response rate (defined as a Partial Response (PR) or greater) in 3/19 patients at the end of the first cycle and 4/19 at the end of the second cycle, and a clinically relevant response (Stable Disease (SD) or greater) at the end of the second cycle for 11 of 19 patients, thus meeting the planed futility criteria and enabling the trial to go forward. As per the 15thof May, among the 40 evaluable patients (that had received at least 2 treatment cycles or progressed within the first) the overall response rate (3) was 25%, with eight (20%) partial responses (PR) and two (5%) very good partial responses (VGPRs) after a median of two cycles (range 1-5). An additional seven patients (17.5%) obtained a Minimal Response (MR) according to the EBMT criteria (4). This is consistent with prior results. Updated results will be presented at the time of ASH. Conclusions: Daratumumab in combination with Dexamethasone is a safe treatment option with a favourable benefit/risk profile for the treatment of triple relapsed or refractory (Len, Pom and Bz) myeloma patients. 1. Stevenson GT. CD38 as a Therapeutic Target. Mol Med. 2006;12(11-12):345-6. 2. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. 3. Kyle R, Rajkumar S. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leuk Off J Leuk Soc Am Leuk Res Fund UK. 2009 Jan;23(1):3-9. 4. Bladé J,et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. Br J Haematol. 1998 Sep;102(5):1115-23. Disclosures Boyle: Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Leleu:Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; TEVA: Membership on an entity's Board of Directors or advisory committees. Hulin:Amgen: Honoraria; Janssen: Honoraria; Bristol: Honoraria; celgene: Honoraria; takeda: Honoraria. Moreau:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Fohrer:amgen: Consultancy; celgne: Consultancy. Decaux:SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding; The Binding Site: Other: supply of free light chain assays , Research Funding. Avet-Loiseau:celgene: Consultancy; amgen: Consultancy; janssen: Consultancy; sanofi: Consultancy. Attal:celgene: Consultancy, Research Funding; amgen: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy. Facon:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and expense, Speakers Bureau.