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In MM, as well as in most hematological malignancies, deficiency in p53 pathway (mainly because of TP53 deletion and/or mutation) is associated with resistance to treatments (Tessoulin Blood Reviews 2017; 31:251). Recent clinical studies have shown that deletion or mutation of TP53 are the most adverse prognostic values for patients (Thakurta Blood 2019;133:1217). Although these patients are easily identified, there is no dedicated therapies for them. p53 pathway is central for homeostasis and cell adaptation/response to many stresses, including DNA repair orchestration and survival regulation. In p53 deficient cells, DNA damaging drugs don't induce massive apoptosis and cells escape to death. In normal cells, DNA damaging drugs induce cell cycle arrest and DNA repair, mainly orchestrated by p53 target genes. Cell cycle arrest in S phase, which is critical for allowing homologous DNA repair, is activated by cell cycle check-point inhibitor such as Chk1, an ATR target. In p53 deficient cells, inhibiting check point inhibitor using ATR inhibitor should allow DNA damaged cells to progress into cell cycle despite the lack of repair and in fine induce replicative/mitotic catastrophe. The aim of this study was to assess whether inhibiting ATR in p53 deficient myeloma cells could overcome chemotherapy resistance. ATR inhibitor, VE-821, was assessed in 13 human myeloma cell lines (HMCLs) alone and in combination with DNA damaging agents, CX5461, a G quadruplex inhibitor, or melphalan, the « myeloma » alkylating drug. The HMCL cohort included 8 HMCLs, 5 TP53Abn and 5 TP53wt. Cell viability was assessed using Cell Titer Glo assay or using flow cytometry (loss of AnnexinV or CD138 staining in HMCLs or primary myeloma cells, respectively). In our cohort of 13 HMCLs and by contrast to previous results, CX5461 was more efficient in TP53wt than in TP53abn HMCLs (mean of death at 0.5mM was 43% versus 24%, p=0.04). Melphalan was also more potent in TP53wt than in TP53abn HMCLs (LD50 values were 26 mM versus 10 mM, p=0.008). By contrast, ATR inhibitor VE-821 (2.5mM) was efficient in both types of HMCLs (mean of death in TP53wt was 45% and 28% in TP53abn HMCLs, p=0.6). Combination of CX5641 (0.5mM) with VE-821 (2.5mM) was more efficient than each drug alone and efficacy was not dependent on TP53 status (mean of death in TP53wt was 69% versus 56% in TP53abn HMCLs, p=0.6): interestingly, combo was efficient in all TP53abn HMCLs, being either additive (n=5) or even synergistic (n=3). By contrast, combo was not efficient in all TP53wt HMCLs (either additive or antagonist). Combination of melphalan (10 mM) with VE-821 (2.5mM) was also synergistic in TP53abn HMCLs (mean of cell death was 9% with melphalan and 73% for combo, p To decipher the molecular pathway involved in cell response, we monitored cell cycle using BrdU/IP assay, replicative stress response using Chk1 phosphorylation and DNA double strand breaks using Comets assays in 3 TP53abn HMCLs. At 24h, CX5641 induced an increase of cells in S (mean of increase 12%) and G2M phases (11%), while VE-821 didn't modify cell cycle. Combination of CX5641 with VE-821 induced a dramatic increase of cells in G2M (20%) (and in subG2 phase), and a decrease of cells in S phase (10%), indicating that cells blocked in S phase by CX5641 were released by VE-821.CX5641 induced Chk1 phosphorylation, which was inhibited by addition of VE-821, confirming the CX5641/ATR/Chk1 signaling. Finally, CX5641 and VE-821 induced comets, confirming irreversible DNA double strand breaks. All these results show that inhibition of ATR after inducing DNA damage in TP53abn myeloma cells efficiently induces cell death, while preserving normal cells. Disclosures Moreau: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Introduction The use of autologous haematopoietic cell transplantation (auto-HCT) in the treatment of myeloma (MM) has greatly increased over the last twenty-five years. There are, however, few large datasets detailing the overall trends in transplant use, patient selection, induction regimen, choice of mobilisation regimen, stem cell yield, response to transplant and survival. We performed a retrospective analysis of all patients who underwent first auto-HCT for MM in EBMT centres between 1993 and 2017 and analysed these trends over consecutive five-year cohorts: (1) 1993-1997, (2) 1998-2002, (3) 2003-2007, (4) 2008-2012 and (5) 2013-2017. Methods Data on patients with MM who underwent a first auto-HCT at EBMT centres between 1993 and 2017 were obtained from the EBMT registry. Med-A forms consist of registration and follow-up forms. More detailed information in captured in Med-B forms. Results A total of 103,032 patients in 568 centres in 54 countries were included in this analysis. The number of transplants increased seven-fold between the first and fifth cohorts: (1) 5,246, (2) 12,554, (3) 21,153, (4) 28,390 and (5) 35,689. The gender breakdown has been consistent over time: 58% Male, 42% Female. Over these years, the median patient age at transplant has increased significantly, as follows: (1) 54, (2) 57, (3) 58, (4) 59, and (5) 61 years. The percentage of patients >65 years at transplant has also increased: (1) 3%, (2) 9%, (3) 14%, (4) 14%, and (5) 22%. Between 1993 and 1997, IgG, IgA and Light Chain (LC) MM constituted 58%, 22% and 16%, respectively. The corresponding percentages between 2013 and 2017 were 52%, 18% and 27%, respectively. Data on the choice of first induction regimen was available in 19,882 (21%) cases (Med-B forms) though only cohorts 4 (2008-2012) and 5 (2013-2017) had specific data in more than 80% of cases. The trends in the percentage use of these regimens in the two cohorts since 2008 are as follows: VTD: 11% to 32%; VCD: 5% to 20%; CTD 15% to 10%; VD: 19% to 7%; PAD 5% to 4%; VRD 2% to 3%; VAD: 8% to 3%. The CR rates pre-ASCT have improved: (1) 16% (2) 14% (3) 13% (4) 20% and (5) 21%; >PR rates pre-ASCT also reveal deeper responses over time: (1) 65%, (2) 68%, (3) 70%, (4) 72%, and (5) 73%. Stem cell mobilisation regimen data was available in 19,882 (19%) cases. In these centres, the use of cyclophosphamide has steadily increased: (1) 31%, (2) 54%, (3) 63%, (4) 64%, and (5) 65%. Conversely, the use of single agent G-CSF has declined: (1) 69%, (2) 45%, (3) 36%, (4) 31%, and (5) 28%. G-CSF + Plerixafor was used in 3.5% of cases from 2008-2012 and 5% in 2013-2017. The median number of stem cells collected (CD34+cells x 10^6/kg) has gradually increased: (1) 5.1, (2) 5.2, (3) 6.3, (4) 6.6, and (5) 6.5, though the median cell dose infused has remained relatively constant: (1) 3.6, (2) 4.1, (3) 4.0, (4) 3.8, and (5) 3.8. Almost all (99%) patients received peripheral blood (PB) stem cells. The number of months from diagnosis to auto-HCT has been stable since 1998: (1) 8.9, (2) 7.7, (3) 7.4, (4) 7.4, and (5) 7.3. Finally, three-year overall survival (OS) post-transplant has risen from 65% to 81% and Progression-Free Survival (PFS) from 41% to 46% (Figure 1). Conclusions This very large dataset shows consistently increasing numbers of auto-HCT for MM in Europe over the last 25 years. Although it is still sometimes stated that 65 years is the upper age limit for auto-HCT in Europe, 22% of auto-HCT recipients in the most recent cohort were older. Analysis of MM subtypes shows an increasing rate of auto-HCT for patients with LC MM, possibly facilitated by the deeper responses which are now being achieved, overall CR rates having risen from 16% to 21% and >PR rates from 65% to 73%. Most patients (59%) in the most recent cohort (2013-2017) received bortezomib-based triplet induction regimens: VTD: 32%; VCD: 20%; PAD 4%; VRD 3%. Data from a subset of centres confirm the use of cyclophosphamide-based stem cell mobilisation in two-thirds; only 5% used G-CSF + Plerixafor. The median stem cell yield has increased by a quarter. As the median cell dose infused remains unchanged, this most likely reflects increasing rates of storage for subsequent transplants. Finally, serial cohort analysis reveals rising rates of OS and PFS over the 25 years, reflecting the deeper responses achieved pre-transplant and the increasing availability of novel agents, whether in the setting of consolidation or maintenance. Figure 1 Disclosures Hayden: Alnylam: Honoraria; Amgen: Honoraria. Goldschmidt:MSD: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Research Funding. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Benjamin:Gilead: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Eusapharm: Consultancy; Servier: Research Funding; Allogene: Research Funding; Pfizer: Research Funding. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Gribben:Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Beksac:Celgene: Consultancy; Amgen: Consultancy; Janssen&Janssen: Consultancy; Takeda: Consultancy. Schönland:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant.

Introduction: Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody approved as monotherapy in heavily pretreated relapsed/refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens for transplant-ineligible NDMM and RRMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently demonstrated a near doubling of complete response (CR) rates, tripling of minimal residual disease (MRD)-negativity rates, and reduction in the risk of disease progression or death by ≥44% in patients with transplant-ineligible NDMM or RRMM. In the primary analysis of the phase 3 MAIA study (median follow-up: 28.0 months), a significant progression-free survival (PFS) benefit (median not reached [NR] vs 31.9 months; hazard ratio [HR], 0.56; P3-fold increase in MRD-negativity rates (10-5 sensitivity threshold; 24.2% vs 7.3%; P Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA. Stratification factors included International Staging System stage (ISS [I vs II vs III]), region (North America vs other), and age ( Results: A total of 737 patients were randomized (D-Rd, N = 368; Rd, N = 369). Patient baseline characteristics were well balanced between the two treatment arms. Median (range) age was 73 (45-90) years, with 44% of patients ≥75 years of age. 27%, 43%, and 29% of all patients were ISS stage I, II, and III, respectively. Among 642 patients evaluable for FISH/karyotyping analysis, 86% had standard and 14% had high cytogenetic risk. After a median follow-up of 36.4 months, median PFS was NR with D-Rd vs 33.8 months with Rd (HR, 0.56; 95% confidence interval [CI], 0.44-0.71; P Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (51%/35%), lymphopenia (15%/11%), pneumonia (15%/9%), anemia (14%/21%), leukopenia (11%/6%), and hypokalemia (10%/10%); grade 3/4 infection rates were 36%/27%. The most common serious TEAE was pneumonia (14%/9%). 9% of patients in the D-Rd arm and 18% of patients in the Rd arm discontinued treatment due to TEAEs. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion: After longer follow up, the addition of DARA to Rd continues to demonstrate a significant PFS benefit and improved rates of deeper and more durable responses vs Rd alone in patients with transplant-ineligible NDMM. The longer follow-up also demonstrated a significant improvement in PFS2 favoring D-Rd, and no new safety concerns were observed. These results continue to support the use of D-Rd in the first line of treatment for transplant-ineligible patients with NDMM. Disclosures Bahlis: Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Plesner:Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genmab: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Quach:Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt:ArtTempi: Honoraria; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Molecular Partners: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding. O'Dwyer:GlycoMimetics Inc: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy. Venner:Janssen: Honoraria; J&J: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Weisel:GSK: Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Celgene Corporation: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Krevvata:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Wang:Janssen: Employment. Van Rampelbergh:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Uhlar:Janssen: Employment. Kobos:Janssen: Employment. Perrot: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; Takeda: Honoraria; Amgen: Honoraria; Sanofi: Honoraria.

Introduction: Recently, a significant impact of the kinetics of Fms-like tyrosine kinase 3 ligand concentration (FLc) during induction (day[D]1 to D22) has been reported on survivals in first-line acute myeloid leukemia (AML) patients (pts) (Peterlin et al, 2019). Three different FLc profiles were disclosed i) sustained increase of FLc (FLI group, good-risk), ii) increase from D1 to D15, then decrease at D22 (FLD group, intermediate-risk) and iii) stagnation of low levels ( Methods: Between 05/2016 and 01/2018, 62 AML pts at diagnosis (median age 59 yo [29-71], Results: FLI, FLD and FLL profiles were observed for 26, 22 and 14 pts respectively. A total of 372 samples were assayed for the 6 other cytokines. Median concentrations at D1, D8, D15, D22 for these 6 cytokines were as follows, considering the whole cohort (and healthy donors): TNFa: 0.53, 0, 0, 0 (0); SCF: 5.91, 0, 0, 0 (3); IL-1b : 0, 0, 0, 0 (0); IL-6: 4.85, 16.28, 10.11, 7.1 (0), IL-10: 0, 0, 0, 0 (0) and GM-CSF:1.63, 1.8, 0.67, 1.34 (9.98). Median IL-6 and GM-CSF levels, compared to healthy controls, were respectively higher and lower during induction. No significant difference was observed in terms of median cytokine concentrations at any time when comparing the three FL sub-groups or FLI vs FLD pts. With a median follow-up of 28 months (range: 17-37), FLI and FLD pts show now similar 2-y LFS (62.9% vs 59%, p=0.63) and OS (69.2% vs 63.6%, p=0.70). FLL pts have a significantly higher rate of relapse (85,7% vs FLI 19,2% vs FLD 32%, p=0,0001). Comparing FLL vs FLI+FLD pts disclosed significantly different LFS (7.1% vs 61.1%, p In univariate analysis, 2y LFS and OS were not affected by the concentration (< or > median) of the 7 cytokines studied except for LFS and GM-CSFc at D8 (p=0,04) and D15 (p=0,08), for LFS and FLc at D1 (p=0.06), D8 (p=0,03), D15 (p=0,04) and D22 (p=0,03) and for OS and GM-CSF at D15 (p=0.08). A significant association between LFS was observed with ELN 2017 risk stratification (2-y LFS: favorable: 68,1% vs intermediate: 48,1% vs unfavorable: 30,7%, p=0.03) but not OS (2 y: 77% vs 55,5% vs 46,1%, p=0.09). Multivariate analysis showed that no factor was independently associated with OS while LFS remained significantly associated with the FLc profile (FLL vs others, HR: 5.79. 95%CI: 2.48-13.53, p Cytokine levels were then assessed to try to better discriminate FLI and FLD pts. A significant higher IL-6 level at D22 was found in relapsed or deceased FLI/FLD pts (median:15,34 vs 5,42 pg/mL, p=0,04). FLI/FLD pts with low IL-6 at D22 (< median, 15.5 pg/mL, n=35 vs n=14 with high level) had significant better 2y LFS and OS (74,2% vs 38,4%, p=0,005 and 77,1% vs 38,4%, p=0,009, respectively). A new prognostic risk-stratification could thus be proposed, i.e. FLI/FLD with IL-6 15.5 pg/mL (intermediate) and FLL (unfavorable). This new classification was considered for a second multivariate analysis, showing that it is the strongest factor associated with OS (p=0.006, ELN p=0.03, FL profile p=0.04) and LFS (p Conclusion: This study confirms stagnation of low FLc during AML induction as a strong poor prognosis factor. Moreover, IL-6 levels at D22 further discriminate FLI/FLD pts. Thus, a new cytokine-based risk-stratification integrating FL kinetics and IL-6 levels during induction may help to better predict outcomes in first-line AML patients. These results need to be validated on a larger cohort of AML patients while anti-IL-6 therapy should be tested in combination with standard 3+7 chemotherapy. Figure 1 Disclosures Peterlin: AbbVie Inc: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy; Astellas: Consultancy. Moreau:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria.

Backgound: High-dose post-transplant cyclophosphamide (PTCY) is currently used for GVHD prophylaxis both in the matched and the haplo transplant settings. However, peripheral blood stem cells (PBSC) as source of graft are significantly associated with a higher incidence of GVHD after transplant with PTCY compared to the use of bone marrow, especially with haplodonors. New strategies are needed to decrease GVHD incidence in this setting. Methods: This retrospective study included 115 adults (males n=68, median age: 60 yo (range: 23-71) allotransplanted with PTCY or PTCY+ATG between March 2014 and March 2019 in a single institution. Three conditionings were used: the Baltimore regimen (n=40, period: 11/2013-05/2017) consisting of Fludarabine 30 mg/m²/day (d), d -6 to -2, cyclophosphamide 14.5 mg/kg day -6, low dose total body irradiation 2 Grays d-1; the Clo-Baltimore regimen (n=37, period: 03/2014-04/2017), consisting of Clofarabine 30 mg/m²/d, d -6 to -2, cyclophosphamide 14.5 mg/kg d -6, low dose total body irradiation 2 Grays d-1; and the CloB2A1 regimen (n=38, period: 05/2017-03/2019) consisting of Clofarabine 30 mg/m²/d, d -6 to -2, busulfan 3,4 mg/kg d -3 and d-2, ATG 2,5 mg/kg d-1. The three groups shared most characteristics (gender, disease risk index, type of donor [matched vs haplo], ABO compatibility, donor/recipient CMV status, previous allograft, median age of the donor, median CD34+ and CD45+ graft cells counts). Baltimore patients were younger (median 56 years vs Clo-Baltimore: 61 years and CloB2A1: 60 years, p=0.02) and mostly transplanted for lymphoid diseases (65% vs 8% vs 19%, p Results: The median follow-up was 42 (29-64), 33 (7-63) and 15 (3-25) months for the Baltimore, Clo-Baltimore and CloB2A1 groups, respectively. Primary graft failure was significantly higher in the CloB2A1 group (at day+60: 22% (6 haplo, 1 10/10 and 1 9/10) vs Baltimore 5.2% (1 haplo, 1 10/10) vs Clo-Baltimore 0% (p=0.003). Similar 18-month survivals were observed for the three groups (Baltimore/Clo-Baltimore/CloB2A1): OS: 65% (51-81) vs 67.1% (53-84) vs 51.2% (35-73), p=0.27; DFS: 60% (46-77) vs 56.7% (42-75) vs 37.8% (23-62) p=0.20); GRFS (50% (36-68) vs 37.8% (25-57) vs 36.7% (22-60), p=0.63). The incidences of relapse and death as well as the causes of deaths (no more death by infection in the CLOB2A1 sub-group) were also comparable. Conversely, considering engrafted patients, the incidence of grade 2-4 acute GVHD was significantly lower in the CloB2A1 sub-group (19% vs Baltimore: 50% vs Clo-Baltimore: 51.4%, p=0.009) and despite higher numbers of CD3+ T cells infused in this group. The incidence of grade 3-4 acute GVHD and chronic GVHD (considering engrafted patients alive at day+100) was lower also in the CloB2A1 sub-group (6.2% vs 16.6% vs 13.5%, p=0.32 and 16% vs 29.4% vs 31%, p=0.51). Considering only haplotransplants, 18-month OS (p=0.95), DFS (p=0.98) and GRFS (p=0.39) were similar between the three groups (Baltimore: 57.1%, 50% and 35.7%; Clo-Baltimore: 60%, 53.5%, 35.7%; CloB2A1: 57.9%, 48.3%, 46.6%). The incidence of grade 2-4 acute GVHD remained significantly lower in the CloB2A1 haplo sub-group (p=0.01). Considering only matched transplants, 18-month survivals were significantly lower for the CLoB2A1 sub-group (OS: 44.4% vs Baltimore 83.3% vs Clo-Baltimore: 88.8%, p=0.05; DFS: 33% vs 83.3% vs 66.6%, p=0.008; GRFS: 22.2% vs 75% vs 44.4%, p=0.008). Conclusion: The CloB2A1 + PTCY regimen does not appear to be a good platform, neither for haplotransplant nor for matched transplant since 1) the incidence of primary graft failure is relatively high for the former and 2) survivals are lower for the latter. However, this study shows that the addition of one day of ATG to PTCY decreases the incidence of GVHD after transplant without increasing the incidence of relapse or death by infection. The use of ATG +PTCY should be tested in patients receiving PBSC haplo-transplant but with other conditioning regimens allowing for a good engraftment, such as Baltimore-based regimens. These data have to be validated prospectively. Disclosures Chevallier: Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria. Peterlin:Daiichi-Sankyo: Consultancy; AbbVie Inc: Consultancy; Astellas: Consultancy; Jazz Pharma: Consultancy. Le Gouill:Janssen-cilag: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Roche Genentech: Consultancy, Honoraria; Gilead-Kite: Consultancy, Honoraria; Servier: Consultancy; Novartis: Consultancy; Takeda: Consultancy; loxo: Consultancy, Honoraria. Moreau:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

Background Venetoclax (Ven) is a selective, small molecule inhibitor of anti-apoptosis protein Bcl-2 that has antitumoral activity against multiple myeloma (MM), notably those with translocation t(11;14). Dexamethasone (d) has shown to enhance the expression of BCL-2 and pro-apoptotic protein Bim, shifting its binding towards Bcl-2 and sensitizing MM cells to Ven. This Phase 1/2 open-label trial is evaluating the safety and efficacy of the combination of Ven+d as a therapeutic approach to improve clinical outcomes in patients with t(11;14) Relapsed/Refractory (R/R) MM. Methods This ongoing study (NCT01794520) has 2 distinct phases. Phase 1 (P1) consisted of separate dose escalation, safety expansion, and Ven+d combination cohorts. The phase 2 (P2) portion is an expansion cohort of Ven+d to further evaluate its efficacy. The safety and efficacy of the Ven+d cohorts from P1 and P2 are reported here. Eligible patients (pts) were adults with t(11;14) R/R MM ≥18 years of age. Key eligibility criteria for the Ven+d cohort in P1 included prior treatment with a proteasome inhibitor (PI) and an immunomodulatory drug (IMID), and an ECOG score ≤1. In P2, eligibility included an ECOG score ≤2, disease progression on or within 60 days from the last dose on previous treatment and having received at least two lines of therapy with a PI, IMID, daratumumab, and glucocorticoids. Additional inclusion criteria for both phases included measurable disease and adequate bone marrow function in all pts, and the presence of t(11;14) determined by fluorescence in-situ hybridization. In both phases, pts received oral Ven 800 mg/day + oral d 40 mg (20 mg for pts ≥75 years of age) on days 1, 8, and 15 of each 21-day cycle. In P1, preliminary efficacy was assessed as the overall response rate (ORR), time to progression (TTP), progression free survival (PFS), and duration of response (DOR) of Ven+d based on the 2011 International Uniform Response Criteria for MM. Efficacy in P2 further evaluated ORR, very good partial response (VGPR) or better, PFS, DOR, TTP, and overall survival (OS) using 2016 IMWG response criteria. Results In P1, as of 15thApril, 2019, 20 pts were enrolled (17 [85%] male; median age, 63 years [range, 46-77]). The median number of prior therapies received was 2.5 (range: 1-7). Nineteen pts (95%) discontinued the study (18 due to progressive disease and 1 underwent transplant). The treatment-emergent adverse events (TEAEs) are summarized in the Table. Most frequent TEAEs were insomnia (45%), hypophosphatemia (40%), hyperglycemia (35%), diarrhea (35%), and thrombocytopenia (30%). Predominant Grade 3 or 4 TEAEs included neutropenia (21%), lymphopenia (29%), and hypophosphatemia (20%). The most common serious TEAE was tumor lysis syndrome (TLS) (10%). No deaths were reported in the treatment-emergent period. ORR was achieved by 13 (65%) and ≥VGPR was achieved by 6 (30%) pts respectively. Partial response (PR) was observed in 7 (35%) pts and stable disease (SD) in 4 (20%) pts. Median time to first response was 1.4 mos (95% CI: 0.7, 2.8). The DOR was 13.1 mos (95% CI: 10.9, 21.9). Median PFS and TTP were both 12.4 mos (95% CI 3.6, 20.9). In P2, as of March 18, 2019, 31 pts were enrolled (18 [58%] male; median age, 65 years [range, 48-80]). The median number of prior therapies received were 5 (range: 1-9). Eight (26%) pts discontinued the study (6 deaths, 1 withdrew consent, 1 due to physician's decision). The most frequent TEAEs reported were diarrhea (32%), nausea (26%) and lymphopenia (32%). The most frequent Grade 3 or 4 TEAEs were lymphopenia (32%), thrombocytopenia (11%), and hypertension (10%). Most common serious TEAE was sepsis (10%). Six (19%) deaths were reported (5 due to progressive disease and 1 due to adverse event). In the intention to treat population, the median TTR was 0.7 mos (range: 0.6-1.5). ORR was achieved by 14 (45%) and >VGPR was observed in 8 (26%) pts. PR was observed in 6 (13%) pts and SD in 8 (26%) pts. Median PFS, DOR, and OS were not reached at the time of data analysis. The 9-mo estimates for PFS, DOR, and OS were 57% (95% CI: 19% 82%), 66% (95% CI: 16%, 91%), and 71% (95% CI: 44%, 87%) respectively. Conclusion In both phases of this study, Ven+d was efficacious and demonstrated tolerable safety in pts with t(11;14) R/R MM. These results support further investigation of Ven combinations in this pt population. This combination is also being investigated in the ongoing Phase 3 trial M13-494 (CANOVA) in t(11;14) positive R/R MM. Disclosures Kaufman: Takeda: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; TG Therapeutics: Consultancy. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Schjesvold:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyliteDX: Honoraria. Moreau:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Boise:Genentech Inc.: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding. Alzate:AbbVie Inc: Employment, Other: Stock/stock options. Macartney:AbbVie Inc: Employment, Other: Stock/stock options. Pesko:AbbVie: Employment, Other: Stock/stock options. Salem:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Hong:Genentech Inc.: Employment, Equity Ownership; Roche: Equity Ownership. Maciag:AbbVie: Employment, Other: Stock/stock options. Pauff:AbbVie Inc: Employment, Other: may own stock or stock options. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in multiple myeloma, which is not an approved indication.

Introduction : Daratumumab (DARA) 16 mg/kg intravenous (IV) is approved as monotherapy for relapsed or refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma (NDMM). A subcutaneous (SC) co-formulation of DARA (DARA SC; 1,800 mg) with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) is under investigation in a number of ongoing studies. In the phase 3 COLUMBA study, DARA SC was shown to be noninferior to DARA IV, demonstrating similar efficacy and pharmacokinetics (PK), with a significantly decreased rate of infusion-related reactions (IRRs) and reduced administration time (median, 5 minutes; Mateos MV, et al. J Clin Oncol. 2019). This phase 2, open-label, multicenter study (PLEIADES) assessed the efficacy and safety of DARA SC combined with bortezomib, lenalidomide, and dexamethasone (D-VRd) and bortezomib, melphalan, and prednisone (D-VMP) in patients with NDMM, and combined with lenalidomide and dexamethasone (D-Rd) in patients with RRMM. The primary analysis of PLEIADES is to be presented at an upcoming meeting; here, we report updated results with longer follow-up. Methods: Transplant-ineligible NDMM patients received DARA SC (QW for Cycle 1 and Q3W for Cycles 2-9 in 42-day cycles, and Q4W for Cycles 10+ in 28-day cycles until disease progression) in combination with VMP for 9 cycles (V 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 for Cycle 1 and Days 1, 8, 22, and 29 for Cycles 2-9; M 9 mg/m2 orally [PO] Days 1-4 for Cycles 1-9; P 60 mg/m2 PO Days 2-4 for Cycles 1-9) and dexamethasone (20 mg PO QW for Cycle 1, Days 1 and 22 for Cycles 2-9, and Day 1 for Cycles 10+). RRMM patients with ≥1 prior line of therapy received DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, Q4W for Cycles 7+ until disease progression in 28-day cycles) in combination with Rd (R 25 mg PO Days 1-21 and d 40 mg IV or PO QW for each cycle until disease progression). Transplant-eligible NDMM patients received 4 cycles of DARA SC (QW for Cycles 1-3, Day 1 for Cycle 4 in 21-day cycles) in combination with VRd induction therapy for 4 cycles (V 1.3 mg/m2 SC Days 1, 4, 8, and 11 for each cycle; R 25 mg PO Days 1-14 for each cycle; d 20 mg IV or PO Days 1, 2, 8, 9, 15, and 16 for each cycle); subsequent therapy/autologous stem cell transplant were performed off study. Primary efficacy endpoints were overall response rate (ORR) for D-VMP and D-Rd and rate of very good partial response (VGPR) or better for D-VRd. Secondary endpoints included rate of VGPR or better for the D-VMP and D-Rd treatment cohorts and ORR for the D-VRd cohort. Secondary endpoints included rate of complete response or better, duration of response, minimal residual disease (MRD)-negativity rate, and DARA serum concentrations. Safety data included rates of treatment-emergent adverse events and IRRs. Results: 199 patients were enrolled (D-VMP, n = 67; D-Rd, n = 65; D-VRd, n = 67). At the clinical cutoff date (8 July 2019), median duration of follow up was 11.0 months for D-VMP, 11.2 months for D-Rd, and 7.1 months for D-VRd. ORR for D-VMP was 89.6% (90% confidence interval [CI], 81.3 - 95.0) and for D-Rd was 93.8% (90% CI, 86.5 - 97.9). Rate of VGPR or better for D-VRd was 70.1% (90% CI, 59.6 - 79.3). Response rates were comparable to published ORRs from the ALCYONE (Mateos MV, et al. N Engl J Med. 2018) and POLLUX (Dimopoulos MA, et al. N Engl J Med. 2016) studies of DARA IV plus VMP and Rd, respectively. The median duration of DARA SC administration was 5 minutes in all cohorts for the first, second, and all subsequent injections. The safety profiles in all cohorts were consistent with DARA IV in combination with various backbone standard-of-care regimens. Rates of IRRs and injection site reactions were consistent with those observed with DARA SC monotherapy in the COLUMBA study. The PK of DARA SC and each regimen was consistent with historical data and immunogenicity of DARA and rHuPH20 were comparable to previous reports. Updated efficacy data based on longer follow-up, including MRD-negativity rate, and updated safety data will be presented at the meeting. Conclusions: With longer follow-up, DARA SC in combination with standard-of-care regimens demonstrated comparable clinical activity and safety to corresponding DARA IV regimens, with considerably lower IRR rates and substantially shorter durations of administration. Disclosures Chari: Janssen, Celgene, Novartis Pharmaceuticals, Amgen, Bristol Myers Squibb, Pharmacyclics, Karyopharm, Sanofi, Seattle Genetics, OncoPeptides, Millenium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. McCarthy:Janssen: Honoraria, Other: Educational grant to attend meetings . Suzuki:Celgene: Honoraria; Janssen: Honoraria; Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria. Hungria:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sureda:Sanofi: Honoraria; BMS: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Amgen: Membership on an entity's Board of Directors or advisory committees. Perrot:jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees; takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Hulin:Janssen, AbbVie, Celgene, Amgen: Honoraria; celgene: Consultancy, Honoraria. Iida:Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Abbvie: Research Funding; MSD: Research Funding; Sanofi: Research Funding; Teijin Pharma: Research Funding; Astellas: Research Funding; Gilead: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Maisnar:Janssen, Amgen, Celgene, Takeda, BMS: Consultancy, Honoraria. Karlin:Takeda: 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, Other: Travel Support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Parasrampuria:Janssen: Employment, Equity Ownership. Masterson:Janssen: Employment, Equity Ownership. Kosh:Janssen: Employment, Equity Ownership. Yang:Janssen: Employment, Equity Ownership. Delioukina:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Carson:Janssen: Employment, Equity Ownership. OffLabel Disclosure: This abstract includes data from a phase 2 clinical trial of a subcutaneous formulation of daratumumab in combination with standard-or-care regimens. Subcutaneous daratumumab is currently under investigation in several clinical trials, but has not yet been approved. However, the intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of multiple myeloma.

Introduction: Prophylactic T cell depletion with antithymocyte globulin (ATG) remains a standard of care for GVHD prophylaxis during allotransplant (ASCT). Although the optimal ATG dosing strategy is still unknown, recent studies have reported that recipient absolute lymphocyte counts (ALC) at the time of ATG administration may predict survivals in ASCT with unrelated donors, suggesting that the dose (especially at the cut off of Materials & Methods: All adults transplanted in our department between 01/2009 and 03/2019 with a Purine analogue/Busulfan/ATG based conditioning regimen and PBSC as source of graft from a matched or 9/10 mismatched donor were eligible. Reduced-intensity conditioning (RIC) regimen consisted of fludarabine 30mg/m²/day (d) from d-6 to d-2, busulfan 3,4 mg/kg/d from d-4 to d-3 and ATG (Thymoglobuline, Sanofi, Lyon, France) 2,5 mg/Kg/d, d-2 and d-1 (FB2A2) or the same but with clofarabine 30mg/m²/d in replacement of fludarabine with 1 or 2 d of ATG (CloB2A2/CloB2A1). Reduced-toxicity myeloablative conditioning regimens (RT-MAC) consisted of the same as FB2A2 but with 3 or 4 d of busulfan instead of 2 (FB3A2/FB4A2). All grafts were administered freshly on the day of the collection while patients (pts) had already received ATG. GVHD prophylaxis was ciclosporine alone for pts with a sibling donor while pts grafted with a matched (MUD) or a 9/10 mismatch (mmUD) unrelated donor received ciclosporine+MMF. We exhaustively looked at pts for whom a blood differential was available at the time of ATG administration in order to study the impact on OS, DFS and GRFS (no grade 3-4 acute GVHD, no moderate/severe chronic GVHD and no relapse) of a profound lymphopenia vs not. Results: Of 395 eligible pts, 116 (median follow-up for alive pts: 49 months) were documented with a differential at time of ATG administration, confirming that this analysis is not a routine practice in our department and probably in many centers. RIC was administered in 80 (69%) of the pts including 39 FB2A2, 12 CLOB2A2 and 29 CLOB2A1. RT-MAC was administered in 36 (31%) pts, including 27 FB3A2 and 9 FB4A2. Seventy-six pts had a myeloid disease while 40 had a lymphoid disease. Donor types were siblings (n=33), MUD (n=70) or 9/10 mmUD (n=13). For the entire cohort, 4y OS, DFS and GRFS were 56.2% (47-66), 40.9% (32-51) and 34.5% (26-45), respectively. No difference in survivals was observed between lymphoid vs myeloid pts, pts transplanted with sibling vs other donors, pts receiving a RIC vs a MAC or a CloB2 vs a FB2 RIC regimen. Median ALC at time of start of conditioning was .915x109/L (range: .010-15.780). No difference in terms of survivals was observed when considering pts under this threshold vs others. ROC curve analysis failed to identify a cut-off allowing to predict better survivals according to ALC at the time of ATG administration (ALC/ATG). Median ALC/ATG was .070x109/L (range: 0-2.300). No difference in terms of survivals was observed when considering pts under this threshold vs others. The same was true when considering .100x109/L as ALC/ATG cut-off. Regarding MAC, the median ALC/ATG was .100x109/L with no difference in survivals between pts under or above this value. The same was true for RIC with ALC/ATG cut-offs < median (.055x109/L) or .100 x109/L as only 4 of them received 1d of ATG vs 23 2d. The dose of CD34+ and CD3+ T cells infused had no impact also on survivals. Conclusion: This study demonstrates that profound lymphopenia at the time of ATG administration as part of a RIC as well as a RT-MAC Purine analogue/Busulfan/ATG based conditioning regimen has no impact on outcomes. Moreover, a reduced dose of ATG in RIC pts with profound lymphopenia at the time of ATG administration did not translate into better survivals. Other unknown factors rather than recipient lymphopenia remain to be discovered to optimize individualized dosing of ATG. Disclosures Peterlin: AbbVie Inc: Consultancy; Astellas: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Chevallier:Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria.

Over the last decade, thalidomide, bortezomib, and lenalidomide have been introduced into the armamentarium of myeloma therapies. These novel agents have improved the rate of complete remission both before and after autologous stem cell transplantation (ASCT) without substantially increasing toxicity, which has important implications as the achievement of high-quality responses is a significant prognostic factor for outcome. This review will focus on the most recent results of novel agent-based induction therapies, as well as on interesting developments in the transplant phase that are aimed at improving the results of conditioning regimens.

The feasibility and efficacy of high-dose melphalan followed by autologous hematopoietic stem cell transplantation in newly diagnosed elderly patients with multiple myeloma was analyzed prospectively. Fifty-six multiple myeloma patients, aged 65 years or over, from 6 French centers were studied. The induction therapy was bortezomib-based in combination with dexamethasone and either thalidomide, cyclophosphamide or lenalidomide, for 4-6 cycles. Peripheral blood stem cells were collected after high-dose cyclophosphamide plus G-CSF or G-CSF alone, with plerixafor if needed. The conditioning regimen consisted of melphalan at 140 mg/m2 in 18 patients (36%) and 200 mg/m2 in 32 (64%). Three months post autologous hematopoietic stem cell transplantation, a 2-month consolidation phase with either lenalidomide plus dexamethasone or bortezomib-based combination therapy was allowed, but maintenance treatment was not given. All but 6 patients underwent autologous hematopoietic stem cell transplantation and 3 had tandem transplantations. The treatment-related mortality was 0% at 100 days post transplantation. Sixty-eight percent received consolidation therapy following transplantation. The best response achieved was 40% complete response, 36% very good partial response, and 18% partial response. After a median follow up of 21 months (range 6-31), the estimated progression-free and overall survival rates at two years were 76% [95%CI: (61.6-94.1)] and 88% [95%CI: (76.7-100)], respectively. The higher dose of melphalan (200 mg/m2) afforded superior progression-free and overall survival rates. This prospective study provides evidence for the safety and efficacy of autologous hematopoietic stem cell transplantation as a first-line treatment approach in elderly multiple myeloma patients. (clinicaltrials.gov identifier: 01671826).

International audience; BH3 profiling as a tool to identify acquired resistance to venetoclax in multiple myeloma Venetoclax/ABT-199 is the first in the class of BCL2-specific BH3 mimetics and the most promising targeted therapy in oncology (Souers et al, 2013). Venetoclax is currently under investigation in multiple myeloma (MM), which is heterogeneous and includes either patients with a translocation on chromosome 14 with different chromosomes (4, 6, 11 or 16) or a hyperdiploidy. We demonstrated that venetoclax induces cell death in a subgroup harbouring the t(11;14) transloca-tion, expressing a high BCL2/MCL1 gene expression ratio, and that intrinsic venetoclax resistance is mediated by high MCL1 expression in MM cells (Touzeau et al, 2014). Preliminary results from an ongoing phase I clinical trial testing venetoclax in relapsed/refractory MM patients indicate that BCL2 inhibition has a tolerable safety profile and single agent activity mostly in t(11;14) patients (Kumar et al, 2015). The anticipated use of venetoclax in the treatment of MM lead us to explore the mechanisms of acquired veneto-clax resistance. We generated two venetoclax-resistant mye-loma cell lines using in vitro selection and derived resistant sublines (named-199R) from KMS12-PE and XG5 t(11;14) myeloma venetoclax-sensitive cell lines (Figs 1A, 2A) (Data S1). Both resistant sublines showed a strong reduction in V

Mantle cell lymphoma (MCL) accumulates in lymphoid organs, but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support their proliferation. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (insulin-like growth factor-1, B-cell activating factor, interleukin-6, interleukin-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures (ie, proliferation, NF-κB, and survival signatures). We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression, leading to a consequent loss of mitochondrial priming. Of interest, this loss of priming was overcome by the type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-xL induction through NF-κB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche.

High-dose therapy with autologous stem cell transplantation (HDT–ASCT) has been considered to be the standard frontline treatment for younger, fit patients with multiple myeloma (MM) since the 1990s. Efforts continue to optimize the use of HDT–ASCT with the aim of improving outcomes. One strategy has been the incorporation of novel agents (thalidomide, lenalidomide and bortezomib) in the pre-transplantation setting as an induction therapy or in the post-transplantation setting as a consolidation or maintenance therapy. Given their high response rates, three-drug induction therapy regimens (for example, bortezomib–thalidomide–dexamethasone, lenalidomide–bortezomib–dexamethasone and cyclophosphamide–bortezomib–dexamethasone) are now the standard of care. Thalidomide and bortezomib are well suited for consolidation therapy, and regimens using these agents can improve the depth of response following HDT–ASCT. Lenalidomide is particularly well suited for long-term maintenance therapy following HDT–ASCT, and initial results are promising and have shown improvements in disease outcomes such as progression-free survival and overall survival in some cases, although a low incidence of second primary malignancies have been observed. Further studies are needed to determine the optimal regimen and duration of induction therapy, the impact of maintenance on overall survival and the safety of long-term treatment. Many of the studies currently underway in MM will help address these aspects.

BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics

Extramedullary myeloma (EMM) is defined by the presence of plasma cells (PCs) outside the bone marrow in a patient with multiple myeloma (MM). Using sensitive imaging techniques including magnetic resonance imaging and positron emission tomography/computed tomography, EMM may be found in up to 30% of MM patients across the overall disease course. The molecular mechanisms underlying the hematogenous spread of PCs outside the bone marrow are only partially known and involve hypoxia and an altered expression of adhesion molecules. Extramedullary disease is associated with adverse prognostic factors (ie, high lactate dehydrogenase level, 17p deletion, and high-risk gene expression profile). The prognosis of EMM is poor, and the median overall survival of patients who experience an extramedullary relapse is

Purpose: Mantle cell lymphoma (MCL) is considered to be incurable. ABT-737 is a BH3 mimetic that targets Bcl-2, which is overexpressed in MCL and implicated in drug resistance. The present work investigated the antitumor effect of ABT-737. Experimental Design: Six MCL cell lines and primary MCL cells (n = 13) were used. Sensitivity to ABT-737 was assessed, and expression levels of Bcl-2 and Mcl-1 were analyzed. Finally, ABT-737 was combined with other cytotoxic agents to promote tailored therapy. Results: MINO and GRANTA-519 cell lines were highly sensitive to ABT-737 [the median lethal dose (LD50) = 20 and 80 nmol/L, respectively], whereas other cell lines were resistant. In primary MCL cells, 46% of patients' samples were sensitive to ABT-737. The analysis of protein expression levels revealed that both sensitive cell lines and primary MCL cells could be characterized by a Bcl-2high/Mcl-1low profile, whereas resistant MCL cells contained high levels of Mcl-1. ABT-737 induced a rapid disruption of both Bcl-2/Bax and Bcl-2/Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT-737. Similarly, flavopiridol, which induces Mcl-1 downregulation, in combination with ABT-737 led to a synergistic anti-MCL effect in ABT-737–resistant cell lines. This synergy was also observed when ABT-737 was combined with either bortezomib or cytarabine. Conclusions: The present work shows that ABT-737 induces strong apoptosis in MCL cells expressing a Bcl-2high/Mcl-1low profile. In ABT-737–resistant MCL cells, downregulation of Mcl-1 overcomes Mcl-1–induced resistance and synergizes ABT-737 effects. Our results strongly support the use of ABT-737 according to the Bcl-2/Mcl-1 tumor cell profiles in the treatment of MCL. Clin Cancer Res; 17(18); 5973–81. ©2011 AACR.

Le lymphome a cellules du manteau (LCM) est une pathologie qui ne represente que 5 a 8 % des lymphomes malins non hodgkiniens. Le LCM se caracterise par la presence de la translocation reciproque entre les chromosomes 11 et 14 (11;14)(q13;q32). Celle-la induit une augmentation de l’expression de la cycline D1, aboutissant au dereglement du cycle cellulaire. A ce jour, le LCM est considere comme une pathologie incurable, mais l’esperance de vie des patients a presque double sur la derniere decennie, et se situe actuellement autour de 5 ans. Dans cette revue, nous presentons les caracteristiques cliniques et biologiques du LCM, puis nous abordons la prise en charge therapeutique en premiere ligne. Les nouvelles options therapeutiques sont aussi discutees. Les progres faits ces dernieres annees, tant sur le plan fondamental que therapeutique, ont modifie notre approche de la maladie, et d’autres avancees majeures sont a attendre dans les annees a venir.

The cytokine Fms-like tyrosine kinase 3 ligand (FL) is a key regulator of hematopoiesis. In a previous Phase 1 study testing a radioimmunotherapy regimen for relapsed/refractory acute lymphoblastic leukemia (ALL), responders showed increased soluble FL serum concentration (sFLc) after salvage regimen (Chevallier, Lancet Haematol., 2015). This prospective monocentric study (ClinicalTrials.gov NCT02693899) aimed to assess the impact of sFLc in ALL and acute myeloid leukemia (AML) patients treated according to standard-of-care intensive first-line chemotherapy regimens. Serum samples were collected on days 1, 8, 15, 22 of induction, at days 1, 8, 15 of each intensive consolidation or day 1 of each non intensive consolidation when appropriate, frozen-stored then tested by ELISA (DY308, R&D Systems, Minneapolis, MN). The following outcomes were considered to assess the impact of sFLc: refractory status after induction (≥5% bone marrow blasts or persistent aplasia >45 days), morphologic, immunophenotypic, cytogenetic or molecular relapses, event-free (EFS) and overall survival (OS). All patients provided informed consent. Between May 2016 and January 2018, 80 patients were included. Data were ultimately available for 16 ALL and 62 AML patients. A total of 579 samples were assayed. Analysis of the results disclosed 3 sFLc kinetic profiles during induction i) sustained increase from days 1 to 22 (FLI group), ii) increase from days 1 to 15, then decrease at day 22 (FLD group) and iii) stagnation of low levels all along ( The 16 evaluable ALL patients were classified as FLI (n=2), FLD (n=7) and FLL (n=7). All reached a cytologic complete remission after induction and only 2 relapses have been documented so far in this group. No impact of sFLc kinetic profile was seen in this context. Conversely, a significant impact of sFLc during induction (but not during consolidation) was observed in AML patients. The median age in this group was 59 years old (range: 29-71, When comparing the 3 sFLc groups, almost all refractory patients (n=6) were found in the FLL group (n=5, FLD n=1, FLI n=0, p=0.0007). Three cytologic relapses occurred in the FLI group, 7 in the FLD group (cytologic n=4, molecular n=2, immunophenotypic n=1) and 7 in the FLL group (cytologic n=4, molecular n=2, immunophenotypic n=1). There were more relapses in the FLL group (n=7/9 [78%] vs FLD n=7/21 [33%] vs FLI n=3/26 [11.5%], p=0.0009). In univariate analysis, 2-year EFS and OS were significantly better for the FLI group (79.1+-8 vs FLD 54.9%+-11 vs FLL 11.4%+-10,p In multivariate analysis considering age, ELNrs, sFLc at days 15 and 22 levels, and sFLc kinetic profile during induction, the latter remained the most powerful factor independently associated with EFS (HR: 3.62; 95%CI: 1,65-7,94, p=0,001; ELNrs: HR: 1.74; 95%CI: 0,98-3.10, p=0.05; sFLc at day+15 p=0,37; sFLc at day+22, p=0.24, age p=NS). sFLc kinetic profile was the sole factor that was also independently associated with OS (HR: 2.60; 95%CI: 1.12-6,07, p=0.02). In conclusion, sFLc kinetic profile during induction appears to be a new powerful early prognostic parameter in AML patients. These results need to be validated on a larger cohort of patients and the mechanism by which induction sFLc levels may impact AML outcome remains to be elucidated. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Abbvie: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Although associated with a higher incidence of acute GVHD, peripheral blood stem cells (PBSC) are increasingly used for haploidentical allogeneic transplantation with post-transplant cyclophosphamide (PTCY). Data reporting whether or not the composition of the PBSC graft impacts outcomes of patients receiving PTCY are still scarce. Materials and Methods This retrospective study included all adults allografted in our department who received a PBSC allotransplant after reduced-intensity conditioning (RIC) with PTCY. Grafts originated from a matched or haploidentical donor and recipients received a Baltimore-based or a Clo-Baltimore (where fludarabine is replaced by clofarabine)-based RIC regimen. All patients received cyclosporine + mycophenolate mofetyl and PTCY as GVHD prophylaxis. CD34+ and CD3+ graft cell contents were considered to study their potential impact on the following outcomes: OS, DFS, GRFS, acute grade 2-4 and 3-4 GHVD and chronic GVHD, early immune reconstitution (IR, lymphocytes and monocytes counts at days+30 and +100 post-transplant, CD4+, CD8+, NK and B cells at day+100 post-transplant). Results Between November 2013 and May 2017, 77 patients met the inclusion criteria. There were 48 males and 29 females with a median age of 58 years (range: 22-71) and a median follow-up for alive patients of 29.2 months (range: 8.4-53.2). Initial diagnoses were mainly acute myeloid (n=21) or lymphoid (n=6) leukemia, lymphoma (n=13), myelodysplastic syndrome (SMD, n=12), myelofibrosis (n=9). Thirty-eight patients were in complete remission at time of transplant (CR1 n=23; CR2 n=12, CR3 n=3) while 22 had active disease and 17 were in partial remission. Donors were sibling in 6 cases, matched unrelated (MUD) in 14, 9/10 mismatched unrelated in 1 and haploidentical in 56. Forty patients received a Baltimore RIC regimen and 37 a Clo-Baltimore RIC regimen. Analyses were performed in July 2018. Median infused CD34+ and CD3+ graft cell counts, based on recipients' weight, were 7.8 106/Kg (range: 1.45-14.24) and 22.23 107/kg (range: 1.95-66.75), respectively. All patients but three engrafted, the latter being 1 patient transplanted with a haplodonor, 1 with a MUD and 1 who died of infection during induction. Two-year OS, DFS and GRFS were 62.6% (52-74), 51.5% (40-63) and 36.6% (27-49), respectively. The incidences of grade 2-4 and 3-4 acute GVHD were 46.7% and 14.2%, respectively, while the incidence of moderate + severe chronic GVHD was 14%. Relapse occurred in 26 patients and non-relapse mortality (NRM) was 15.5%. Baltimore vs Clo-Baltimore patients shared similar median infused CD34+ and CD3+ graft cell counts and outcomes. The same was observed for patients allografted with a haplodonor or not, except for the incidence of grade 2-4 acute GVHD which was significantly higher for the haplo group at 57.1% vs 19% (p=0.006). This difference was first attributed to the higher CD3+ cell content infused in this group (median: 24.05 vs 18.85 107/kg, p=0.04). However, using the median of CD3+ cell graft content as threshold, the incidence of acute grade 2-4 GVHD was not different between low vs high groups when considering haplo patients. This suggests that it was rather the type of donor that did influence acute GVHD occurrence and that PTCY is of particular interest for GVHD prophylaxis when using matched donors. Partitioning the patients according to the median level of CD34+ cells, there was no difference in terms of 2-year OS (57.1% vs 60.7%, p=0.53), DFS (44.5% vs 55.6%, p=0.47) , GRFS (31.7% vs 44.3%, p=0.32), acute grade 2-4 (59% vs 39%, p=0.13) and 3-4 GVHD (17% vs 6.4%, p=0.29), and moderate + severe chronic GVHD (19.5% vs 20%, p=0.57). Similarly, partitioning patients according to median graft CD3+ cell content, outcomes were similar for 2-year OS (64.8% vs 55.8%,p=0.45), DFS (46.3% vs 55.8%, p=0.62), GRFS (36.3% vs 40.4%, p=0.63), acute grade 2-4 (44.7% vs 56.4%, p=0.42) and 3-4 GVHD (10.5% vs 15.3%, p=0.76), and moderate + severe chronic GVHD (14% vs 17.6%, p=0.91). Finally, early IR was not influenced by CD34+ and CD3+ graft cell contents. Conclusion: PBSC CD34+ and CD3+ graft cell contents have no impact on survivals, GVHD incidence nor early IR after a RIC allotransplant using PTCY as GVHD prophylaxis. As a consequence, there is no need to manipulate the graft nor cap the stem cells dose to be infused. These data have to be confirmed prospectively on a larger cohort of patients. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau: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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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.

The aggressive clinical behavior of mantle cell lymphoma (MCL) and its short-term response to treatments highlight a need for novel options. The microenvironment strongly controls MCL cell survival, proliferation and chemoresistance, nevertheless little is known regarding the interactions that occur in the tumor niches. Here, we studied the interplay between primary MCL cells (n=55) and macrophages and identified mechanism-based targeted strategies to disrupt this dialogue. Using ex vivo co-cultures of peripheral blood MCL cells and monocytes (healthy donors), we showed that monocytes greatly improved MCL cell survival, whereas MCL cells poorly survived when cultured alone (co-culture, 85.9%; alone, 6.5%; D7; n=17; p During co-culture, primary MCL cells polarized monocytes into MCL-associated-macrophages (MϕMCL). To define the nature of MϕMCL, we studied their phenotype and function with 12 markers differentially expressed in M1 and M2 macrophages (CD14, CD68, CD163, CD11b, CD86, HLA-DR, CD16, CD23, IL10, IL6, IGF1, BAFF). The analysis showed that even though MϕMCL distinctly clustered from both M1 and M2, they shared more similarities with M2 (CD163high, CD11blow, IL10+, IGF1+). To determine how MCL cells polarized monocytes into CD163high MϕMCL, we analyzed the expression of known M2-polarizing factors and observed that CSF1 and IL10 were overexpressed in MCL cells compared to normal B cells (GEP, p In vivo, we showed higher levels of CSF1 and IL-10 in the plasma of MCL patients (n=28) compared to match-aged HD (p In conclusion, through secretion of IL-10 and CSF1, MCL cells polarized monocytes into M2-like macrophages (MϕMCL), which in turn support tumor survival and proliferation. Ibrutinib counteracts the MCL/MϕMCL dialogue through inhibition of CSF1 production and, consequently, impairs the MϕMCL-dependent expansion of ibrutinib-sensitive MCL cells. Of note, our in vivo retrospective analysis highlights that CSF1, IL-10 and CD163 modulations might be early markers of ibrutinib response. A larger cohort of MCL patients treated with ibrutinib is now necessary to confirm the strength of this soluble and cellular signature. Lastly, targeting the CSF1R is an alternative to disrupt the MCL/MϕMCL pro-tumoral dialogue, especially for ibrutinib-refractory patients for which no therapeutic alternative is available. Disclosures Moreau: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Le Gouill:Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Background: Recently, we have reported the good results of a clofarabine-based reduced-intensity conditioning (RIC) regimen for peripheral blood stem cell (PBSC) allografts, using either matched (Le Bourgeois, ASH 2017) or haploidentical (haplo) donors (Chevallier, ASH 2017). However, the influence of donor type in this setting is unknown. Patients and Methods: We conducted a retrospective study including all adults (≥18 yo) allografted in our department with a clofarabine-based RIC regimen for a myeloid malignancy. All types of donors were accepted, and patients received allogeneic peripheral blood stem cells (PBSC) or cord blood (CB) transplants. The aim of this study was to assess whether or not the donor type (sibling, matched unrelated (MUD), haplo or CB) impacted outcomes. Results: Between October 2009 and February 2018, 122 patients met the inclusion criteria. Donors were sibling in 36 cases, "MUD" in 55 (including one 9/10 mismatched donor), haplo in 27 and CB in 4. The sibling+MUD patients received a CloB2A1/A2 RIC regimen consisting of clofarabine 30 mg/m²/day 4 to 5 days (Clo), busulfan 3.2 mg/kg/day 2 days (B2) and 2.5mg/kg/day of rabbit anti-thymocyte globulin 1 or 2 days (A1 or A2). Haplo and CB recipients were conditioned by a Baltimore-like RIC regimen and a Minneapolis-like regimen, respectively, where fludarabine were replaced by clofarabine. All patients received cyclosporine (CsA) + mycophenolate mofetyl as GVHD prophylaxis, except sibling recipients who were given CsA alone. Haplo recipients received also 2 days of post-transplant cyclophosphamide. All non-CB patients received PBSC as source of graft. The median age of the whole cohort was 61,5 years old (range: 18-73) and the median follow-up 31 months (range: 4,5-106). All patients engrafted except 1 CB patient and 1 haplo recipient who died of infection before engraftment. All CB cases died at 1, 8, 9 and 11,5 months post-transplant, respectively (infection n=1, relapse n=2, chronic GVHD n=1). As a consequence, we thereafter compared outcomes only between the three other donor groups. There were no significant differences between sibling, MUD or haplo recipient groups in terms of gender, median age, type of disease, ELN 2010 classification for AML, status at transplant (complete remission vs active), disease risk index, donor/recipient CMV status or median graft quantity of CD34+ stem cells. The only differences were the partition of ABO compatibility, less frequent in the MUD group (42% vs sibling 69% vs haplo 67%, p=0,02) and a history of previous allograft (haplo n=7, sibling n=0, MUD n=6, p=0,005). Neutrophils (>0,5 Giga/L) and platelets (50 Giga/L) recoveries were significantly delayed in the haplo-group (19 days, vs sibling 15 vs MUD 15, p=0.0003; and 31 days vs 11 vs 12, p Acute grade 2-4 or 3-4 graft versus host disease (GVHD) incidences were similar between the three groups at 50% and 22% for sibling, 34,5% and 14,5% for MUD and 48% and 11% for haplo (p=0,18 for grade 2-4 and p=0,45 for grade 3-4) as well as moderate+severe chronic GVHD incidences (sibling 14%, MUD 16%, haplo 15% p=0,94). Follow-ups were similar at 34.2 (6-74), 33.7 (4.5-106) and 21.4 (7-53) months respectively for sibling, MUD or haplo donors. This was associated with similar 2-year overall survivals (OS) at 64,7% (50-83), 73,9% (62-87) and 60,2% (43-83) respectively (p=0.4) and 2-year disease-free survivals (DFS) at 57,7% (43-76), 70,9% (59-84) and 53,6% (37-77) respectively (p=0.1). Two-year GVHD-relapse free survival (GRFS) was also similar at respectively 37,9% (24-57), 54,3% (41-70) and 38,9% (23-63) (p=0.2) as well as 2-year non-relapse mortality (NRM) at 14%, 11% and 18,5% (p=0,63). When considering only AML patients, again similar 2-year survivals were observed between the three groups. OS was 71.4% (54-93) for sibling (n=21), 75.1% (62-90) for MUD (n=40) and 66.6% (46-95) for haplo (n=15, p=0.65) and DFS respectively 66,6% (49-90), 70,8% (57-87) and 66,6% (46-95 p=0.47). The same was observed for GRFS at 38% (22-65), 56% (41-75) and 40% (21-74, p=0.14) and NRM at 14%, 7,5% and 7%, p=0.34). In multivariate analysis, donor type remained independent of outcomes in this series. Conclusion: These data confirm that since no difference was observed in terms of outcomes, haplodonors represent a valid alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack a matched sibling donor. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Abbvie: 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; Takeda: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

(18)F-fluorodeoxyglucose (FDG) PET is a non-invasive imaging technique recommended for the management of both diffuse large B-cell and Hodgkin's lymphomas. This retrospective study investigated the value of FDG PET for initial staging and its prognostic impact on patients with mantle cell lymphoma (MCL).A total of 44 untreated MCL patients assessed by both conventional evaluations (CE) and FDG PET for initial staging were included. The maximum standardized uptake value (SUV(max)) in the most intense pathological area was recorded for each patient. Disease status after chemotherapy completion was assessed according to the International Workshop Criteria (IWC) for non-Hodgkin's lymphoma (NHL) response and IWC+PET.FDG PET uptakes at diagnosis were abnormal in all cases. Compared to CT scan, nodal and extranodal sites were only detected by FDG PET. Due to insufficient sensibility for bone marrow (BM) and gastrointestinal (GI) involvement, FDG PET did not modify initial staging. Positive and negative predictive values of IWC+PET for relapse at 1 year were 62.5 and 100%. With a median follow-up of 21 months, only the International Prognostic Index (IPI) and IWC+PET modified both event-free survival (EFS) (p = .02 and .0001, respectively) and overall survival (p = .03 and .05, respectively) duration. When combining IPI and SUV(max) at diagnosis, we were able to identify patients with low (29%; no relapse/progression), intermediate (42%; median EFS: 37 months) and high risk (29%, median EFS: 22 months) (p = .004).In MCL, FDG PET at diagnosis is complementary to CE, but BM and GI biopsies remain mandatory. IWC+PET criteria are highly efficient to identify patients with high risk for early relapse. Combining IPI and SUV(max) may predict patient outcome and warrant further prospective investigations towards designing risk-adapted strategies.

Unrelated umbilical cord blood (UCB) is being increasingly used as an alternative stem cell source for allogeneic stem cell transplantation (allo-SCT). This retrospective study assessed infectious complications occurring in adult patients after UCB transplantation (UCBT). 31 patients received a single (n=4) or double UCBT (n=27) with a median dose of 4.7x10(7) nucleated cells/kg (range: 2.4-7.7). Patients received either a reduced-intensity conditioning (RIC; n=23) or a standard myeloablative (MA) regimen (n=8). The cumulative incidence of neutrophil recovery was 90%. Neutrophil recovery was achieved at a median time of 24 (range: 8-60) days after UCBT. The cumulative incidences of bacterial, fungal, and parasitic infections were, respectively, 16%, 10%, and 6%. Bloodstream infections were neither lethal nor required any intensive care therapy. Similarly, invasive fungal infections and parasitic infections did not cause any death in those patients with sustained engraftment. Although the cumulative incidence of cytomegalovirus (CMV) recurrence was 21%, no CMV disease was observed. With a median follow-up of 10 (range: 3-30) months, 10 patients have died (relapse, n=5; nonrelapse mortality, [NRM] n=5). Overall, the cumulative incidence of infectious-related mortality (IRM) was 8%. In conclusion, this data suggests that UCBT can be performed in adult patients with hematologic malignancies with an acceptable incidence of IRM provided a sufficient dose of nucleated cells is infused to the patient.

Background and Objectives Diffuse large B-cell lymphomas (DLBCL) are common lymphomas that have been classified into three subgroups on the basis of their patterns of gene expression. The aim of this study was to characterize the clinical, biological, immunophenotypic and cytogenetic features of DLBCL with concurrent t(14;18) and 8q24/c-MYC rearrangement.Design and Methods Sixteen cases of DLBCL with the dual translocation were identified between 1998 and January 2006. The clinical features of these cases were examined and morphological, immunohistochemical, flow cytometric and cytogenetic analyses were performed.Results All patients had aggressive features: B symptoms (81%), ECOG performance status >2 (81%), elevated lactate dehydrogenase (100%), stage IV disease (100%) with at least one extra-nodal localization (bone marrow, blood and central nervous system involvement in 93%, 50% and 50%, respectively) and age-adjusted IPI score of 3 in 81%. Despite intensive chemotherapy regimens (including allogeneic transplants), all patients died of disease progression. Progression-free and overall survival was 4 and 5 months, respectively. Immunophenotyping analysis (CD20, CD10, Bcl-6, Mum-1, Bcl-2 CD138, MIB1, CD19, CD5, CD38 and sIg) was performed and showed DLBCL with a germinal center (GC) profile. Ki-67 staining ranged from 70 to 90%. All cases assessed by cytogenetics analysis [conventional cytogenetic and/or fluorescence in situ hybridization (FISH)] had a complex karyotype. In one case, we identified a 8q24/c-MYC translocation variant never reported in DLBCL before: t(8;9)(q24;p13) and t(14;18)(q32;q21). The BCL-6 rearrangement was investigated by FISH and found to rearranged in four cases.Interpretation and Conclusions In conclusion, DLBCL with concurrent t(14;18) and 8q24/c-MYC rearrangement is a subgroup of GC-DLBCLwith poor outcome. It is worth searching for the coexistence of dual translocations in Bcl-2-positive DLBCL with unusual aggressive presentation.

// David Chiron 1 , Christelle Dousset 1, 2, 3, * , Carole Brosseau 1, * , Cyrille Touzeau 1, 2 , Sophie Maiga 1, 2 , Philippe Moreau 1, 2 , Catherine Pellat-Deceunynck 1, 2 , Steven Le Gouill 1, 2, 3 , Martine Amiot 1, 2 1 INSERM, UMR892 - CNRS, UMR 6299, Universite de Nantes, France 2 Service d’Hematologie Clinique, Unite d’Investigation Clinique, Centre Hospitalier Universitaire de Nantes, France 3 CIC, INSERM, Nantes, France * These authors have contributed equally to this work Correspondence to: Martine Amiot, e-mail: martine.amiot@inserm.fr Keywords: ABT-199, mantle cell lymphoma, apoptosis, Bcl-2 family members, ibrutinib Received: February 04, 2015 Accepted: February 08, 2015 Published: March 05, 2015 ABSTRACT The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested ( n = 8), only three were sensitive (LD 50 < 200 nM). In contrast, all primary MCL samples tested ( n = 11) were highly sensitive to ABT-199 (LD 50 < 10 nM). Mcl-1 and Bcl-x L both confer resistance to ABT-199-specific killing and BCL2/(BCLXL+MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x L up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors.

This phase 1/2 dose-escalation study investigated the combination of carfilzomib with melphalan and prednisone (CMP) in patients aged65 years with newly diagnosed multiple myeloma (MM). Melphalan and prednisone were administered orally on days 1 to 4; carfilzomib was IV administered on days 1, 2, 8, 9, 22, 23, 29, and 30 of a 42-day cycle. Patients received up to 9 cycles of CMP. In the phase 1 dose-escalation portion, the primary objectives were to determine the incidence of dose-limiting toxicities during the first cycle of CMP treatment to define the maximal tolerated dose (MTD) of carfilzomib. In the phase 2 portion, the primary objective was to evaluate the overall response rate (ORR) of CMP. In the phase 1 portion of the study, 24 patients received CMP at carfilzomib dosing levels of 20 mg/m(2), 27 mg/m(2), 36 mg/m(2), and 45 mg/m(2). The MTD was established as 36 mg/m(2). In the phase 2 portion of the study, 44 patients were enrolled at the MTD. Among 50 efficacy-evaluable patients treated at the MTD, the ORR was 90%. The projected 3-year overall survival rate was 80%. The combination of CMP was observed to be effective in elderly patients with newly diagnosed MM. This trial was registered at www.clinicaltrials.gov as #NCT01279694 (Eudract identifier 2010-019462-92).

Consolidation with VTd significantly improves the complete remission rate and time to progression following VTd induction and single autologous stem cell transplantation in multiple myeloma

Imaging myeloma is often performed when complications occur which may reveal the disease. Since the malignant plasma cell proliferation characteristic of this disease can affect the whole of the bony skeleton to various degrees, examination of the bones should be as complete as possible. The radiographic images must be studied for lytic lesions or signs of diffuse osteopenia, as well for fracture complications such as vertebral compression. Slice imaging has the advantage of being more sensitive and showing extra-osseous extension well. With a CT scan and MRI, spinal compression can be detected or a surgical procedure planned, while MRI or a PET scan can be used to assess extension of the disease and the response to treatment.

Few data are available on the efficacy of the combination of lenalidomide plus dexamethasone (Len/Dex) in very elderly patients above 75 years of age with relapsed multiple myeloma (MM). We report here a single-center series of 45 consecutive patients aged 75 years or older with relapsed MM treated with this combination. The overall response rate was 62% and the median progression-free survival was 14 months, which compares favorably to that described in the two pivotal prospective studies that formed the basis for the approval of Len/Dex in the relapse setting. Our study confirms that Len/Dex is an effective combination in very elderly patients with relapsed MM.

ABSTRACT: New agents are awaited for the treatment of multiple myeloma and research is ongoing for the development of monoclonal antibodies (MoAbs) targeting the tumor cells. One of the most promising MoAb is elotuzumab, the only humanized IgG1 MoAb specifically targeting CS1 (SLAMF7), a cell surface glycoprotein that is highly expressed in plasma cells. Preclinical and clinical data on elotuzumab will be presented in this article.

Autologous stem cell transplantation (ASCT) is considered as an attractive treatment option for young mantle cell lymphoma (MCL) patients. This retrospective SFGM-TC study analyzed the outcome of 500 MCL patients treated with ASCT and investigated parameters that may modify the outcome of patients who proceeded to ASCT upfront (n = 396). For all patients, median age at ASCT was 56 years (range, 26–71). Median follow-up was 34 months. Three-year progression free survival (PFS) and overall survival (OS) were 63.5 % [95 % CI, 58.7–68.6 %] and 79.5 % [95 % CI, 75.3–83.4 %], respectively. Median time from ASCT to relapse was 22 months (range, 0–136 m). For patients transplanted upfront and in multivariate analysis, age (HR = 2 [1.2–3.4], p = .01, and HR = 2.3 [1.2–4.5], p = .01), disease status at time of ASCT (HR = 1.7 [1.1–2.6], p = .01 and HR = 1.8 [1.1–3.1], p = .03), and use of rituximab (HR = 0.5 [0.3–0.8], p = .002 and HR = 0.5 [0.3–0.9], p = .01) were statistically predictive for both PFS and OS. Also, first line treatment including anthracycline and high-dose cytarabine followed by ASCT conditioned with TAM improved PFS. To conclude, this study suggests that ASCT in MCL can provide a high response rate but may not be sufficient to cure MCL even when ASCT is performed upfront, highlighting the need for innovative approaches before ASCT, aiming to increase complete response rate, and after ASCT, to maintain response.

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: BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecular inhibitor of BCL-2. When combined with bortezomib, which can inhibit MCL-1, VEN can enhance the activity of bortezomib in MM cell lines and xenograft models. Methods: In this Phase 1b, open label, dose escalation study, patients with relapsed/refractory (R/R) MM received daily VEN (50 - 1200 mg per designated dose cohort) with bortezomib and dexamethasone. The objectives of the study were to assess the safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose (R2PD), and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of combination therapy in this patient population. Results: As of 01July2016, 66 patients were enrolled, with 54 in the dose escalation cohort and 12 in the safety expansion at R2PD of 800 mg. The median age was 64 years and 39 (59%) were ISS stage II/III. The median number of prior therapies was 3 (range: 1 - 13), and 21 (32%) were refractory to prior bortezomib, 37 (56%) were refractory to prior lenalidomide, and 41 (62%) had prior stem cell transplant. Forty-three (65%) patients discontinued the study for the following primary reasons: 33 related to disease progression, 5 due to AEs (1 each: respiratory failure and cardiac failure, lung adenocarcinoma, sepsis, renal impairment, and Guillain-Barre syndrome; none were considered by the investigator as related to VEN), 2 withdrew consent, and 3 for other reasons not specified. Adverse events (AEs) were reported in 65 (99%) patients, with common AEs in ≥20% of patients being diarrhea (41%), thrombocytopenia (39%), constipation (38%), nausea (36%), insomnia (32%), peripheral neuropathy (30%), peripheral edema (29%), anemia (27%), peripheral sensory neuropathy (27%), dyspnea (24%), fatigue (24%), and asthenia (24%). Grade 3/4 AEs in ≥10% of patients included thrombocytopenia (29%), anemia (15%) and neutropenia (14%). Serious AEs in ≥2 patients were febrile neutropenia, thrombocytopenia, cardiac failure, pyrexia, influenza, lower respiratory tract infection, pneumonia, sepsis, acute kidney injury, respiratory failure, embolism, and hypotension. One dose-limiting toxicity of lower abdominal pain was reported for a patient who received 1200 mg VEN. Five deaths were reported during the study, 4 due to disease progression and 1 due to respiratory syncytial virus infection (not considered by the investigator as related to VEN). After co-administration with bortezomib and dexamethasone, dose-normalized VEN exposure at steady-state appeared to be within the exposure range observed with VEN monotherapy in patients with MM. The ORR for all evaluable patients was 68% (44/65) and 26 (40%) achieved very good partial response (VGPR) or better (3 stringent complete response [sCR], 8 CR, 15 VGPR) (Figure). For all patients, median DoR was 8.8 months (95% CI: 7.2, 15.8) and TTP was 8.6 months (95% CI: 5.7, 10.2), with a median follow up of 4.9 months (range: .03 - 26.7). High ORR of 89% was seen in patients who were non-refractory to prior bortezomib (39/45) or who had 1 - 3 prior therapies (31/35). In 31 patients who were non-refractory to bortezomib and had 1 - 3 prior therapies had ORR of 94% (29/31), 68% (21/31) with VGPR or better; median DoR was 10.6 months and TTP was 11.3 months for this subgroup. Moreover, patients who were bortezomib naïve and had 1 - 3 prior lines of therapy had ORR of 100% (12/12), and median DoR was 15.8 months and TTP was 17.1 months. In patients who were non-refractory to prior bortezomib but who were refractory to lenalidomide, the ORR was 86% (19/22) as compared with 91% (20/22) in those non-refractory to lenalidomide. Clinical responses were comparable in patients with t(11;14) MM (ORR, 78% [7/9]) and without t(11;14) MM (ORR, 66% [37/56]). In the t(11;14) group, 3 patients were bortezomib-refractory, and 2 of them achieved a PR as best response. Also, 4 patients had more than 3 prior lines, with 3 of them achieving PR. Conclusions: VEN in combination with bortezomib and dexamethasone has an acceptable safety profile in patients with R/R MM. Efficacy results, including 68% ORR in all patients and 94% ORR in patients not refractory to bortezomib and who received 1 - 3 prior lines of therapy, indicates promising efficacy of this novel combination and supports the ongoing Phase 3 trial with this regimen in patients with R/R MM. Figure. Figure. Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Roberts:Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding. Agarwal:AbbVie: Honoraria, Research Funding; Millennium: Consultancy; Amgen: Consultancy; Janssen: Speakers Bureau; Onyx: Speakers Bureau; Celgene: Speakers Bureau. Facon:Amgen: Consultancy, Speakers Bureau; Millenium/Takeda: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Kumar:Glycomimetics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; BMS: Consultancy; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Touzeau:AbbVie: Research Funding. Cordero:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment. Jia:AbbVie: Employment. Salem:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Harrison:Janssen Cilag: Research Funding, Speakers Bureau; AbbVie: Research Funding.

Background: Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those with t(11;14), which mostly have a favorable high BCL-2, low BCL-XL, and low MCL-1 profile. Methods: In this Phase 1, open-label study, patients (pts) with relapsed/refractory (R/R) MM received VEN monotherapy. Objectives of the study were to assess safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose, and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of VEN. After a 2-week lead in period with weekly dose escalation, VEN was given daily at final doses of 300, 600, 900, or 1200mg in dose escalation cohorts and 1200mg in the safety expansion. Pts who progressed during VEN monotherapy could receive VEN plus dexamethasone and continue in the study. Results: As of 01July2016, 66 pts were enrolled in the study (30 in dose escalation cohorts and 36 in safety expansion). Median age was 63 years and 39 (62%) pts were ISS stage II/III. The median number of prior therapies was 5 (range: 1-15), and 62 (94%) pts had received bortezomib (46 [70%] refractory), 62 (94%) received lenalidomide (51 [77%] refractory), and 50 (76%) had prior autologous stem cell transplant. Thirty (46%) pts had t(11;14) MM. Median time on VEN monotherapy for all pts was 2.5 months (.2-23); 17 (26%) elected to receive VEN and dexamethasone combination after disease progression for a median of 1.4 months (.1-11). Fifty-one (77%) pts discontinued the study for the following primary reasons: 39 related to disease progression, 5 due to AEs/toxicity, 2 withdrew consent, 1 was lost to follow up, and 4 for other reasons not specified. Common adverse events (AEs) in ≥20% of pts were nausea (48%), diarrhea (36%), neutropenia (32%), thrombocytopenia (32%), fatigue (27%), anemia (23%), back pain (21%), and vomiting (21%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (15%), anemia (14%), and decreased white blood cells (12%). Serious AEs in ≥2 pts were pneumonia (n=5), sepsis (3), pain, pyrexia, cough, and hypotension (2 each). Two pts experienced dose-limiting toxicities at 600mg of abdominal pain and nausea. Eight deaths were reported: 6 due to disease progression, 1 due to lung disorder, and 1 due to brain hemorrhage following injury; neither were considered by the investigator as related to VEN. Steady state VEN exposures were approximately dose proportional at all doses but 900mg. As of 20July2016, ORR for all pts on VEN monotherapy was 21% (14/66) and 10 (15%) achieved very good partial response (VGPR) or better (2 stringent complete response [sCR], 2 CR, 6 VGPR) (Figure); median DoR and TTP was 9.7 and 2.6 months, respectively. Most objective responses (12/14 [86%]) were reported in the subset of pts with t(11;14) MM. In this group, ORR was 40% (12/30) and 27% (8/30) achieved a response of ≥VGPR; median DoR for pts with t(11;14) was 9.7 months (95% CI: 6.3, -). Pts who achieved at least minimal response in the t(11;14) group (14/30) had a median of 4 prior therapies and were mostly refractory to bortezomib, lenalidomide, or double refractory (71% [10/14] each). For two pts with response in the non-t(11;14)/undetermined group, 1 had a translocation of chromosome 14 with an unidentified partner, and the other had no cytogenetics data available. DoR was 9.5 and 7.2 months in these pts and both are still ongoing. Median TTP for pts with or without/undetermined t(11;14) was 6.6 and 1.9 months, respectively. The median best percent change in primary M protein for pts with t(11;14) (n=23) was -53% vs +11% in the non-t(11;14)/undetermined group (n=23). Additional biomarker subgroup analyses (n=32) showed that efficacy was primarily observed in pts with myeloma cells expressing a favorable BCL-2 family expression profile (high BCL-2, low BCL-XL, low MCL-1) by immunohistochemistry, which was significantly enriched in the t(11;14) population. Indeed, although high BCL-2 expression was observed in a majority of bone marrow core biopsy samples (88%), the t(11;14) subgroup was enriched (81% vs 25%) for tumors expressing high BCL-2, low BCL-XL, and low MCL-1. Conclusions: VEN monotherapy has an acceptable safety profile and clear anti-myeloma activity in pts with R/R MM, primarily with t(11;14) having a high BCL-2, low BCL-XL and low MCL-1 expression levels. Figure Figure. Disclosures Kumar: Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy. Kaufman:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Facon:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol: Consultancy; Millenium/Takeda: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Benboubker:Takeda: 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; Amgen: 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. Moreau:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Alzate:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Xu:AbbVie: Employment. Agarwal:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Touzeau:AbbVie: Research Funding.

Mantle cell lymphoma (MCL) accumulates in lymphoid organs but disseminates early on in extranodal tissues. However, there is relatively little information regarding the nature of surrounding cells and soluble factors and the resulting molecular regulations induced in MCL. Further investigations that integrate the key role of the microenvironment are now needed to overcome tumor drug resistance in protective niches. The benefits of such an approach have been recently reinforced by studies reporting that selective inhibition of BTK or PI3Kδ, critical kinases of the BCR and CXCR4 pathways, prevents the homing of MCL, leading to peripheral lymphocytosis. However, the consequences of cell egress in the peripheral blood on proliferation and survival are still unclear and need further investigations. In spite of the significant level of the proliferation index Ki67 in secondary lymphoid organs and the elevated percentage of circulating malignant cells, we did not detect any proliferating peripheral blood MCL cells, which were arrested in the G1-phase of the cell cycle. The proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem. In situ, lymphoma B-cells are in close contact with cells of mesenchymal or immune origin. To determine whether stromal (hMSC) or lymphoid-like (CD40L) interactions could support survival and proliferation of MCL, primary circulating MCL cells from 21 patients were cocultured several weeks ex vivo. In all samples tested we showed that CD40L signal, but not hMSC, induced cell-cycle progression, which was amplified by a MCL-specific cytokine cocktail, defined by assessment of cytokine receptor expression in situ. Using this system, we were able to maintain proliferation of primary MCL cells for several weeks, and most MCL samples remained dependent on the extrinsic signal over time. Of major interest, using RNA-seq, we showed that 70% of genes induced ex vivo are expressed in lymph nodes, confirming the relevance of the coculture. We further observed that our model recapitulated in situ MCL molecular signatures such as proliferation, BCR/NFkB and survival signatures. Among the genes related to survival, coculture resulted in anti- and pro-apoptotic Bcl-2 family member modulation. We demonstrated that an anti-apoptotic Bcl-xL protein increase was associated with a striking downregulation of pro-apoptotic Bim, Bax and Bak. Of note, this unbalanced regulation seemed to be specific to MCL cells as it did not occur in naïve CD5+ B cells or memory B cells. We provided evidences that Bcl-xL upregulation was responsible for loss of mitochondrial priming and drug resistance. Using BH3-profiling, we showed a dynamic sequestration of the BH3-only activator Bim by Bcl-xL proteins at the mitochondrial level. In addition, we showed that the mitochondrial priming directly correlated with the sensitivity toward BH3-mimetics (venetoclax) and alkylating drugs (bendamustine). Our results thus highlight molecular basis for microenvironment-dependent modulation of the mitochondrial priming and consequent drug resistance in primary MCL cells. Thus, whereas venetoclax is highly efficient in inducing apoptosis in peripheral blood MCL cells, tumor cells protected into their niches could be resistant and in fine induce relapse. Using our ex vivo model, we further demonstrated that, in rational combinations, anti-CD20 antibody (obinutuzumab) can suppress survival and overcomes drug resistance to venetoclax exploiting NFkB/Bcl-xL-specific dependence of primary MCL cells. Moreover, ibrutinib, which mediates indirect Bcl-xL down-modulation upon BTK-dependent lymphocytosis, could also increase in vivo venetoclax efficacy. Our ongoing OAsIs Trial for MCL patients (obinutuzumab, ibrutinib and venetoclax, NTC#02558816) will rapidly determine in vivoefficacy. In summary, we reported here the development of a reproducible ex vivo coculture model for primary MCL cells. This model has provided new insights into microenvironment-dependent proliferation and Bcl-2 family regulation, which are central components of survival and drug resistance. Our increased understanding of intrinsic abnormalities, the development of highly selective inhibitors and integration of the microenvironment offer new opportunities to design mechanism-based strategies that should overcome drug resistance in MCL and potentially other B cell malignancies Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal [M] protein and skin changes) syndrome is a rare plasma cell disorder. The pathogenesis is mainly driven by pro-angiogenic (vascular ...

8032Background: The anti-apoptotic protein BCL-2 has been implicated in the survival of multiple myeloma (MM) cells. Venetoclax (VEN) is an oral, highly selective BCL-2 inhibitor, which induces cel...

International audience; The impact of HLA-DPB1 mismatches after unrelated hematopoietic stem cell transplantation (HSCT) remains controversial. We retrospectively analyzed the impact of permissive/non-permissive HLA-DPB1 mismatches on the outcome of 141 patients who underwent 10/10 HLA allelic-matched unrelated HSCT. Each pair was classified according to the 3 (TCE3) and 4-group (TCE4) algorithm based on DPB1 alleles immunogenicity. Outcome analysis revealed that TCE3 and TCE4 non-permissive HLA-DPB1 disparities were not associated with worsened overall survival, relapse risk neither risk of acute GvHD. Overall, this single center retrospective study does not confirm the adverse prognostic of non-permissive HLA-DPB1 mismatches.

Introduction: Allogeneic stem cell transplantations (allo-SCT) using alternative donors are increasingly used in patients lacking suitable matched sibling or unrelated donor. Recently, the use of post-transplant cyclophosphamide (CY) has allowed to re-consider first-generation relatives (brother, sister, father, mother, son or daughter) as haplo-identical donors for allo-SCT. Indeed, the incidence of severe acute GVHD is lowered by post-transplant administration of CY, due to the early destruction of putative alloreactive T cells. Still, some patients may not have a suitable relative donor for various reasons such as older age of the parents, no siblings nor children, no cord blood available, or because use of a graft from a first-generation haplo-identical relatives is contra-indicated. The probability of having a haplo-identical donor among siblings is 50% while it is almost 100% when considering both biological parents and offspring. When considering as a potential donor the child of a matched or haplo-identical sibling, the probabilities for the donor to be haplo-identical with the recipient remain 50% and 25%, respectively. Thus, second-generation relative donor (i.e. nephew or niece) may be finally considered as a source of stem cell graft. Methods: Here we report the case of a 61-year old man who received a T-replete haplo-identical allo-SCT with high-dose post-transplant CY from his second-generation relative nephew. In 2010, the patient was diagnosed with ALK- CD30+ anaplastic T-cell lymphoma and received 8 cycles of CHOD allowing to obtain morphologic and metabolic partial response. The patient received an allo-SCT from a sibling matched donor (brother) on November 2010 after an FB2A2 reduced-intensity conditioning regimen but secondary graft failure was rapidly documented in spite of donor lymphocyte infusions. Relapse occurred in September 2014 and brentuximab vedotin was administered each 21 days for seven cycles allowing to obtain a complete morphologic and metabolic response. It was decided to perform a second allograft using a different donor. The patient was childless and no unrelated donor or cord blood units were available. It was thus chosen to ask for donor the son of the matched brother, who was haplo-identical and had no antibodies directed against the patient's HLA specificities. This nephew had a O- blood group and negative CMV serology while the recipient was O+ and CMV+. Results: The second allograft was performed on April 2nd 2015 using the Baltimore (Luznik, BBMT 2008) conditioning regimen with 2 days of post-transplant CY. A megadose of peripheral blood stem cell was administered (14.16x106 CD34+ cells/Kg) at day 0. Neutrophils and platelets recovery (>50 Giga/L) were achieved as early as days +18 and +33, respectively, with full donor whole blood chimerism (99.8%) at day +30, persisting on day +60 and +100 (both whole blood 99.9%, CD3+ T cells: 99.9%).Grade 2 acute cutaneous GVHD occurred at day +21. The evolution was favorable after initiating corticosteroids at 2 mg/kg/day with tapering thereafter. Not surprisingly, CMV reactivation was documented at day+22, controlled by ganciclovir treatment. Immune reconstitution evaluated at days +30, +60 and +100 showed normal monocyte counts while B lymphocytes were undetectable. NK cells increased from 42/mm3 at day+30 to 453/mm3 at day +60 and 665/mm3 at day +100. Interestingly, after profound lymphopenia within the first 100 days post-transplant, CD8+ T large granular lymphocytes expansion was documented at day + 110. At four months post-transplant, the patient is alive in persistent metabolic remission with no active acute or chronic GVHD nor active infection. His outcomes will be updated for the meeting. Conclusion: T-replete haplo-identical allo-SCT with high-dose post-transplant CY using a second-generation relative donor was feasible allowing for full engraftment and moderate acute GVHD in our patient. This result expands the possibility to find a donor for a selected patient, meanwhile paving the way for using unrelated haplo-identical donor, which could be of interest when considering solid transplantation. Indeed, combining solid organ transplantation and allo-SCT from the same haplo-identical donor may open the door to withdraw immunosuppression in this particular setting, because stable tolerance may be induced, as it has been already reported for kidney transplant (Kawai, NEJM 2013). Disclosures Moreau: Celgene: Honoraria, Other: Adboard; Amgen: Other: Adboard; Takeda: Other: Adboard; Janssen: Other: Adboard; Novartis: Other: Adboard.

Introduction: Previous trials have shown that autologous stem cell transplantation (ASCT) is superior to conventional chemotherapy in terms of remission rate and PFS in younger MM patients. Concerns about toxicity and potential efficacy of ASCT in older MM patients lead most centers to limit ASCT indications to patients aged Patients and Methods: We prospectively analyzed the outcomes of 56 consecutive MM patients who had received ASCT between September 2012 and September 2014 in 6 institutions in France (protocol ClinicalTrials.gov Identifier: NCT01671826). Patients were newly diagnosed MM. For induction therapy, all patients received a bortezomib-based induction regimen (VD, VTD, VCD, or VRD, 4 to 6 cycles) according to center's local guidelines. Mobilization was performed with G-CSF or G-CSF+cyclophosphamide and plerixafor whenever needed. High-dose chemotherapy consisted of either 140 mg/m2 or 200 mg/m2 Melphalan. A short two months consolidation phase post ASCT was allowed (lenalidomide-dexamethasone, VD, VTD, VCD or VRD). No maintenance treatment was given. Response, disease progression and relapse were defined according to the IMWG uniform response criteria. All patients signed an informed consent form according to the EBMT guidelines. Results: At time of diagnosis, median age was 67 (range, 64-74) years with 23% of patients being >70 years. There were 30 males and 26 females. The immunoglobulin subtype was IgG (n=29), IgA (n=15), light chain (n=10), other (n=2). The Salmon and Durie stage was III in 89% of cases (n=47), and the ISS score was I (n=18; 35%), II (n=19; 37%), III (n=14; 27%). Patients had high risk cytogenetics features (t(4;14) and/or del17p) in 9 cases (16%). 10% of patients had a serum creatinine level >176 micromol/L. None of the patients underwent hemodialysis. The Sorror comorbidity score was 0 (34), 1 (6), 2 (2), 3 (6), 6 (1), unknown (7). The median age at time of ASCT was 68 years, and the median time from diagnosis to ASCT was 5 months. In an intention to treat analysis, out of 56 patients, 6 patients could not proceed to ASCT because of an early infectious death (n=1), serious comorbidity (n=2), disease refractoriness to induction (n=1), and failure to collect an adequate PBSC graft (n=2). A median of 5.31x106/Kg CD34+ cells could be collected. Disease status at time of ASCT was: CR (n=12; 24%), VGPR (n=19; 38%), PR (n=17; 34%), and SD/non-responding (n=2; 4%). The conditioning regimen consisted of 140mg/m² melphalan in 18 cases (36%) and 200mg/m2 in 32 patients (64%). Moreover, 4 patients (8%) received a tandem ASCT. The median time for neutrophils and platelets engraftment was 12 days. The day-100 post ASCT non-relapse mortality was 0% and the 2-year NRM was 4.2% (95% CI:[0.3-18.3]). The overall response rate at day 100 was 96% (CR: 34%, VGPR: 47%, PR: 15%, SD/non-responsive: 4%). At 3 months post ASCT, 82% patients were able to receive the planned post ASCT consolidation treatment. After a median follow-up of 12 months, the estimated progression-free (PFS) and overall survival (OS) rates at 2 years were 76% (95%CI: [61.6-94.1]) and 88% (95%CI: [76.7-100]), respectively. The incidences of infectious complications post ASCT, and response rates were comparable between the two melphalan dose levels (p=0.28). However, in the univariate analysis, the 200 mg/m2 melphalan conditioning group showed a better OS rate compared to the 140 mg/m2 group (1-year OS: 100% vs. 67%; p=0.012). Conclusion: These prospective multicenter results indicate that ASCT is a safe and effective treatment modality for elderly, but fit MM patients at the era of novel induction agents. Of note, patients above age 70 did not experience a worse prognosis. Thus, age per se should not be used as an exclusion criterion for ASCT. Longer follow-up data will be presented, but these results already set the frame for a randomized comparison to the non-transplant approaches in this patients' subgroup. Disclosures Garderet: Bristol-Myers Squibb: Consultancy. Touzeau:AbbVie: Research Funding. Stoppa:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Karlin:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

Introduction: Recently, theuse of high-dose post-transplant cyclophosphamide (PTCY) has contributed to reconsider T-replete haplo-identical allo-SCT because of the lower incidence of severe graft-versus-host disease (GVHD) observed in patients. However, the influence of PTCY on early outcomes has been poorly studied so far, especially in comparison to the standard use of anti-thymoglobulin (ATG) as GVHD prophylaxis. Patients and Methods: This retrospective study was conducted at the University Hospital of Nantes with the aim to compare the incidence of early outcomes (engraftment, neutrophils and platelets recovery, viral infections (HHV-6, CMV, EBV, BKv, ADV), acute GVHD, relapse or deaths and day+100 non-relapse mortality (NRM)) between patients receiving either PTCY (n=30) or ATG (n=46) as part of GVHD prophylaxis for a RIC allo-SCT. In the PTCY group, RIC was the Baltimore regimen (Luznic, BBMT 2008) in 17 patients while 9 patients received clofarabine instead of fludarabine because of a myeloid malignancy and 4 patients a sequential approach. In this group, 6 and 24 patients received 1 or 2 days of PTCY, respectively, while donors were matched (sibling n=2, unrelated n=5) in 7 cases and haplo-identical in 23, respectively. All patients received cyclosporine + MMF with PTCY as GVHD prophylaxis. In the ATG group (2 days of ATG for siblings and 10/10, 3 days for 9/10), 13, 11 and 22 patients received respectively a FB2, FB3 or CloB2 RIC regimen (Chevallier, Haematologica, 2014). Donors were siblings in 18, matched unrelated in 23 and mismatched unrelated (9/10) in 5. GVHD prophylaxis was cyclosporine alone in case of sibling donors and cyclosporine +MMF for all other cases. The characteristics of both groups (PTCY vs ATG) were similar in terms of gender (male: 63% vs 54%), type of disease (myeloid: 67% vs 63%) and disease status at transplant (complete remission: 43% vs 67%). PTCY patients were significantly younger (median age: 55.5 vs 63 years, p=0.01) and had been previously allografted in a significantly higher proportion (40% vs 4%, p=0.003). Patients were transplanted between March 2012 and April 2015 and were considered up to day+100 post-transplant. All patients received peripheral blood stem cells as stem cell source except one patient in the PTCY group who received bone marrow. Results: All patients engrafted except one in the ATG group. The median time of neutrophils recovery was similar between both groups (PTCY 18 days vs ATG 19 days, p=0.9). Conversely, median time of platelets recovery was significant higher for the PTCY group (27 vs 13 days, p Conclusion: When considering early outcomes, PTCY is associated with a longer time to platelets recovery and higher early median donor chimerism compared to the use of ATG for GVHD prophylaxis after allo-SCT. The dosage of PTCY and type of donor when using PTCY may also influence the occurrence of viral infections. Prospective larger studies are warranted to confirm these results in the future. Disclosures Moreau: Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

Background: Gemtuzumab Ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody linked to calicheamicin. It was developed to treat relapsed CD33+ AML patients, first at the dose of 9 mg/m² administered twice at day +1 and +14, than combined with chemotherapy but with reduced dose to lower toxicity. In 2008, we reported a 63% (50% of complete remission (CR) + 13% of CR with incomplete platelets recovery (CRp), platelets Materials and Method: This was a single center retrospective study including all CD33+ relapsed/refractory AML patients who received the MIDAM regimen, from 2008 to March 2015. Between 2008 and July 2012, all patients received GO as a single dose at 9 mg/m² day +4 (s-MIDAM group) and after until March 2015 it was decided to fractionate the GO dose according to Castaigne'schedule at 3 mg/m²/day day +1 +4 and +7 (fra-MIDAM group). All patients were treated as part of a compassionate use program as GO is not available in France for routine use. The main objective was to compare the incidence of SOS and related-deaths between both groups (s-MIDAM vs fra-MIDAM). Secondary objectives were to compare ORR (CR+CRp), median time of neutrophils and platelets (>20 Giga/L, >50 Giga/L, >100 Giga/L) recovery and overall survival (OS). Results: 33 patients were included in the study, 15 in the fra-MIDAM group and 18 in the s-MIDAM group. Characteristics of patients were similar between the former and the latter in terms of age (median: 55 vs 52 years, p=NS), gender (male: 60% vs 66%, p=NS), cytogenetics risk (favorable 33% vs 28%, intermediate 60% vs 39%, high: 7% vs 33%, p=NS) or median CD33+ expression (99% vs 99.5%, p=NS).There were more refractory patients in the s-MIDAM group (39% vs 7%, p=0.04) but more patients for whom adapted lower dose of Ara-C (4 g/m² instead of 10 g/m² total dose, for one patient) or mitoxantrone (3 patients did not received any, and 1 received 2 days instead of 3 days) were prescribed in the fra-MIDAM group (27% vs 0%, p=0.04). Also, 20% and 28% of patients received a reduced dose of GO (6 mg/m², administered in 2 fractionated dose (3 mg/m² twice) or a single dose) in the fra-MIDAM and the s-MIDAM groups, respectively (p=NS). ORR was similar between both groups (fra-MIDAM: 53% vs s-MIDAM: 61%, p=NS) as well as the CR rate (33% vs 39%, p=NS) or the CRp rate (20% vs 22%, p=NS). Median time to neutrophils and platelets (>20 Giga/L, >50 Giga/L and >100 Giga/L) recovery were also similar (fra-MIDAM: 29 days vs s-MIDAM: 26 days, p=0.25; 24 vs 26 days, p=NS; 27 vs 34 days, p=0.13 and 38 vs 36.5 days, p=NS). Among patients in response, 40% vs 67% were allotransplanted after the fra-MIDAM and the s-MIDAM regimens, respectively, (p=NS). With a median follow-up of 139 days and 782 days for the fra-MIDAM and the s-MIDAM groups, respectively, median OS was 7.2 months for the former and 10.2 months for the latter (p=NS). Sixty percent of patients died in the fra-MIDAM group vs 72% in the s-MIDAM group (p=NS), with no significant differences in terms of causes of death. Regarding our primary objective, 2 and 3 cases developed SOS after the fra-MIDAM and the s-MIDAM regimen, respectively, and these 5 patients died of SOS. Conclusion: Use of fractionated GO doses compared to single GO dose as part of the MIDAM salvage regimen for relapsed/refractory AML patients showed no advantages in terms of outcomes or lower toxicity, especially regarding incidence of SOS or death due to SOS. Both schedules are equivalent and can be used. Disclosures Mohty: Janssen: Honoraria; Celgene: Honoraria. Moreau:Novartis: 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; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of multiple myeloma (MM) cells. Venetoclax is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. Venetoclax induces cell death in MM cell lines in vitro and primary MM samples ex vivo. Certain genetic subtypes of MM cells are particularly sensitive to venetoclax, including t(11;14) cells, which express a high ratio of BCL2 to MCL1 (venetoclax resistance factor). The current Phase 1 study evaluates safety, efficacy, and pharmacokinetics (PK) in patients (pts) with relapsed/refractory MM. Methods: Primary objectives are to evaluate safety, PK, and recommended phase two dose; other objectives include assessing preliminary efficacy and the impact of chromosomal abnormalities. In dose-escalation (DE) cohorts, venetoclax was given orally daily at 300, 600, 900, or 1200 mg after a 2-week dose ramp-up (3+3 design). Patients in the safety expansion (SE) cohort received 1200 mg daily after ramp-up. All patients were monitored for tumor lysis syndrome (TLS). Results: As of June 17, 2015, 37 patients were enrolled in the study: 30 from DE cohorts and 7 from the SE. Median (range) age was 66 years; 19 (51%) were female. Fourteen were ISS stage I, 13 stage II, 8 stage III, 2 unknown. The median (range) number of prior lines of therapy was 6 (1-19). Thirty-two had prior bortezomib (20 refractory), 35 lenalidomide (18 refractory), and 26 had prior stem cell transplant. Fourteen patients had t(11;14), 4 had t(4;14), 5 had del 17p, and 17 had del 13q. Adverse events (AEs) in ≥20% of patients were nausea (49%), diarrhea (38%), vomiting (30%), anemia (27%), fatigue (24%). Grade 3/4 AEs (≥10%): thrombocytopenia (22%), anemia (19%), neutropenia (11 %). Serious AEs (≥2 patients): pyrexia (n=3), cough, malignant neoplasm progression, and sepsis (2 each); 2 (upper abdominal pain and anemia) were possibly related to venetoclax. Thirty (81%) patients have discontinued venetoclax: 24 due to PD, 3 for AEs (worsening shortness of breath, hypokalemia, and nausea), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). Four deaths occurred (2 due to PD, 1 due to brain hemorrhage, 1 due to pneumopathy). Two of the 6 patients in the 600 mg cohort experienced DLTs of upper abdominal pain and nausea with abdominal pain. No patients met the criteria for laboratory or clinical TLS. Based on preliminary PK (n=21), the mean Cmax and AUC24 were ~dose-proportional at all studied doses (300, 600, 1200 mg) except 900 mg, and dose-normalized venetoclax exposure in MM was similar to that in CLL and NHL pts. Thirty-two of the 37 patients were evaluable for preliminary efficacy (Table). Two patients, both t(11;14), achieved a complete response (1 at 600 mg and 1 at 900 mg). Responses were first achieved at 1.8 and 1.1 months and were maintained for 9.7 and 9.0 months, respectively (900 mg pt remains in CR). Among the 16 patients receiving 1200 mg in the DE or SE cohort, 6 of whom had t(11;14), 5 achieved SD, 6 experienced PD, and 5 are not yet evaluable. Conclusions: Venetoclax monotherapy had a tolerable safety profile in heavily-pretreated relapsed/refractory MM, and no new safety signals were observed compared to other venetoclax studies. The study continues to enroll in the SE cohort at 1200 mg. Responses (including CR) and longer time on venetoclax were observed in t(11;14) patients. These early results suggest that venetoclax has single agent activity, most prominently in t(11;14) patients. Figure 1. Figure 1. Disclosures Kumar: Celgene: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Kaufman:Janssen: Consultancy; Spectrum: Consultancy; Merck: Research Funding; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Novartis: Research Funding; Onyx: Research Funding. Mikhael:Sanofi: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Onyx: Research Funding. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Celgene: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard. Alzate:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Agarwal:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Touzeau:AbbVie: Research Funding.

Introduction: Allogenic stem cell transplantation (Allo-SCT) remains currently the only curative treatment for primary myelofibrosis (PMF) or myelofibrosis secondary (SMF) to essential thrombocythemia (ET)/polycythemia vera (PV). Indication of allo-SCT refers to high-risk patients defined by various scores such as Lille score, IPSS, DIPSS or more recently DIPSS+. However, JAK2, CALR, MPL or triple negative mutation profiles have recently been shown to impact on the outcome of PMF patients and thus may challenge the indication of allo-SCT in the future. CALRmut patients seem to have the best survival conversely to triple-negative patients, while JAK2mut and MPLmut status can be considered as an intermediate molecular signature (Tefferi, Leukemia 2014). The outcome of MF patients with a validated allo-SCT indication who do not proceed to transplant is generally unknown although relatively long survival can be documented, especially since the availability of JAK inhibitors such as ruxolitinib. Also, data regarding impact of mutational status on outcome after allo-SCT remain scarce. Patients and Methods: This single-center retrospective study considered MF patients with a validated indication of allo-SCT between 2000 and 2013. The main objective was to compare the overall survival (OS) between patients who ultimately received allo-SCT or not. Secondary objectives were to analyze the impact of mutational molecular status on OS and the use of ruxolitinib in patients not allografted. Results: An indication of allo-SCT was validated in 67 patients (males: 64%; PMF: 59%; SMF post-ET 25%, SMF post-PV 16%). At the time of indication of ASCT, the median age was 59 years (range: 41-69); DIPSS+ score was: int-2 in 40%, high risk in 60%. Mutational status, available for 86% of patients, was as follows: JAK2V617F (n=37), CALRmut (n=12); MPLmut (n=3), triple-negative (n=6). Thirty-three patients proceeded to allo-SCT (reduced intensity conditioning: 82%) while 34 did not for lack of donor (31%), comorbidity (28%), progressive disease (14%), stable disease on conventional therapy (18%), refusal (9%). The two groups (allo/non-allo SCT) were comparable for gender, year of indication of allo-SCT, type of MF, number of prior lines of treatment before allo-SCT, DIPSS+ categorization, mutational status and median follow-up. Patients who did not proceed to allo-SCT were significantly older (61 vs 57 years, p65%) (median OS: NR vs 18 months, HR: 0.18, 95%CI:0.03 -1.11, p=0.065). Interestingly, the survival of patients who did not proceed to allo-SCT was increased by the use of ruxolitinib (median OS: NR vs 20 months, HR: 2.3, 95%CI: 0.08-0.6, p=0.003). Conclusion: Allo-SCT remains a valid strategy for high-risk MF patients with unfavorable karyotype, high DIPSS+ score and secondary MF while impact of mutational status and JAK2V617F burden have to be confirmed in larger studies. MF patients who cannot proceed to transplant likely benefit from JAK2 inhibitor prescription. Disclosures Milpied: Celgene: Honoraria, Research Funding. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs Conclusion At this first prespecified IA, addition of ixazomib to Rd in pts with RRMM increased median PFS to 20.6 from 14.7 mos without a substantial increase in overall toxicity, including cardiac and PN toxicity. Benefit with IRd was also noted in pts with high-risk cytogenetics, including those with del(17), in whom median PFS was similar to all IRd-treated pts indicating that ixazomib may have a favorable impact on the adverse prognosis associated with genetic mutations. If approved, this all-oral combination of IRd may become a new standard of care in this setting. Table. Key efficacy data IRd Rd HR / OR Median PFS, mos 20.6 14.7 HR 0.742; 95% CI: 0.587-0.939; p=0.012 Confirmed ORR, % 78.3 71.5 OR 1.44; p=0.035 CR 11.7 6.6 OR 1.87; p=0.019 ≥VGPR 48.1 39.0 OR 1.45; p=0.014 Median time to first response (ITT analysis), mos 1.1 1.9 Median duration of response (≥PR), mos 20.5 15.0 Disclosures Moreau: Bristol-Myers Squibb: 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; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sandhu:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Ganly:Novartis: Honoraria; Roche: Honoraria; Medipics: Equity Ownership. Baker:Janssen-Cilag New Zealand: Membership on an entity's Board of Directors or advisory committees. Stoppa:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Simpson:Celgene: Honoraria; Janssen-Cilag: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Gimsing:Amgen: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Garderet:Bristol-Myers Squibb: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Kumar:AbbVie: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding. Touzeau:AbbVie: Research Funding. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Lin:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. DiBacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.