ALBERT

Description: Background :AZA improves overall survival (OS) in higher risk MDS, but only 50-60% of the patients respond, and median OS with AZA is only 20-24 months. As OS improvement is obtained at modest response rates, OS rather than response should probably remain the primary endpoint for all combinations with AZA, requiring large phase III trials with significant follow up. On the other hand, combinations that do not increase response will likely not improve OS. We therefore tested, based on a "pick the winner" approach, AZA combinations with the HDAC inhibitor VPA, LEN or IDA to identify, based on response, the most promising combination with AZA in higher risk MDS, that could be subsequently compared with AZA alone in a larger phase III study. Methods : AZA-PLUS (#NCT01342692)was an adaptive two-stage phase II trial based on Jung design (Stat Med.2008;27:568) that randomly assigned higher-risk MDS, low blast count AML (20-30%) and CMML to: AZA (75 mg/m2/d d1-7 of 28-day cycles); AZA plus LEN (10 mg/d on d1-14); AZA plus VPA( 50 mg/kg/d on d1-7; 35 mg/kg/d in patients〉 60y) or AZA plus IDA (10 mg/m2on d1 for the first 9 cycles). The primary end point was response rate (RR, including CR, PR, marrow CR, based on IWG 2006) of the combination arms vs AZA alone. Given a 30% RR with AZA alone, we considered that a ≥45% RR would make combination(s) promising. Controlling for type I and type II errors at 0.15 and 0.20, 40 patients per arm were to be enrolled at each stage. Any experimental arms with RR lower than those observed in the AZA arm at the first stage should be stopped. At the second stage, any arm with 〉 6 more responses than AZA alone should be selected for further testing. Secondary endpoint were ORR (RR+ stable disease with HI (HI) and OS. Results : After inclusion of 40 pts/arm (first stage) all experimental arms had at least the same number of responses as the control arm and were continued in second stage. Overall, 322 pts were enrolled from 06/2011 to 07/2017: 81, 80, 80, 81 in the AZA, AZA+VPA, AZA+LEN and AZA+IDA arms, respectively. Baseline characteristics were well-balanced across arms. Median age was 74.6 y, 213 pts were male, IPSS was INT-2 in 54% and High in 46%. IPSS Karyotype was fav, int and poor in 40%, 26% and 34%, respectively. Pts received a median of 7 cycles and median follow-up was 15.1 months. Prevalence of trial discontinuation due to adverse events was 32%, 29%, 28% and 31% in the AZA , AZA+VPA , AZA+LEN and AZA+IDA arms, respectively (p=0.95). Rates of hospitalization during the first 6 cycles were 38%, 44.7% , 55.1%, 59.7% in the AZA, AZA +VPA, AZA+LEN and AZA+IDA arms, respectively (p=0.028), suggesting increased myelosuppression in the experimental arms, especially in the LEN and IDA arm. In the control arm, 29 responses (CR+PR+mCR) after 6 cycles were observed, with 29, 25 and 29 responses observed in AZA+VPA , AZA+LEN and AZA+IDA arms, respectively. Thus, no combination demonstrated benefit over AZA. The RR was estimated at 34.8% (18.6% CR, 3.1% PR, and 13.0% mCR) and the ORR after 6 cycles was 40.4%. The RR after 6 cycles (35.8% for AZA, 36.2% for AZA+VPA, 31.2% for AZA+LEN, and 35.8% for AZA+IDA) and the ORR after 6 cycles (41.9% for AZA; 41.2% for AZA+VPA, 40.0% for AZA+LEN and 38.3% for AZA+IDA) were close across study arms. By multivariate analysis, factors associated with better ORR were higher Hb level (p=0.05), low fibrinogen (p=0.008) and low LDH (p=0.01). 17 (5%) pts were bridged to allogeneic SCT: 6 on AZA, 5 on AZA+VPA, none in the AZA+LEN arm and 6 on AZA+IDA arm (p=0.03). At the reference date of July 2018, median EFS was 16.6 months for in AZA, 14.5 months for in AZA+VPA, 15.1 months for in AZA+LEN and 13.2 months for in AZA+IDA (p=0.74) (Fig A). Multivariable Cox model selected Hb level (p=0.02), presence of circulating blasts (p

Description: Background: The treatment of Acute Myeloid Leukemia (AML) in elderly patients remains unsatisfactory, with an expected survival time of about 1 year post diagnosis. In an attempt to improve outcome for these patients, the prospective open-label phase 3 LAMSA-2007 trial (Clinicaltrial.gov ID, NCT00590837) repeated, at decreasing doses in consolidation and reinduction courses, a standard induction regimen with cytarabine and idarubicin (IC), with or without the randomized addition of lomustine (ICL). This alkylating agent with significant anti-leukemic activity is widely used in France for AML therapy. This study was performed as a confirmatory trial, following our previous report of the French experience in which this compound stood out as a favorable factor of improved outcome for patients with non-unfavorable cytogenetics (Pigneux, JCO 2010). Methods: Eligible patients were adults 60 years old or more, with previously untreated AML, fit to receive intensive chemotherapy (ECOG and SORROR

Description: BACKGROUND Few Tx options are available for pts with inadequately controlled PV. European LeukemiaNet defined resistance/intolerance was seen in ≈25% pts treated with HU (Alvarez-Larran et al, 2012). In the HU-resistant/intolerant PV pts evaluated in the pivotal RESPONSE study (week [wk] 208), RUX was well tolerated and superior to standard therapy in achieving durable hematocrit (HCT) control, hematologic response, and spleen size and symptom reductions. This Ph 3b ETP study was planned to provide RUX Tx to HU-resistant/intolerant PV pts, who have no alternative standard Tx, and are not eligible for any ongoing clinical studies. Results from wk 24 data cutoff of this study (Devos et al) were presented at ASH 2017. Here, we report consolidated findings from the ETP study at wk 96 data cutoff (Dec 29, 2017 [final database lock]) to further support the use of RUX in this pt population with an unmet medical need. METHODS RUX Tx was initiated at a starting dose of 10 mg bid (could be titrated to a maximum of 25 mg bid). Visits were scheduled every 4 wks until wk 24 and every 12 wks thereafter; final analysis was done when all pts had been followed for 30 days after discontinuation of Tx or completion of Tx per protocol (transitioned to commercial RUX or until Dec 31, 2017, whichever date occurred first). The primary endpoint was to assess the safety of RUX. Secondary endpoints included change in HCT level, change in spleen length, and pt-reported outcomes (change in MPN-SAF TSS score). HCT control at wk 24 was defined by absence of phlebotomy (PBT) eligibility starting at wk 8 and continuing through wk 24, with no more than 1 PBT eligibility occurring after first dose date and prior to wk 8. PBT eligibility was defined by confirmed HCT 〉45% (at least 3 percentage points higher than HCT at baseline [BL]), or confirmed HCT 〉48%. Blood count remission at wk 24 was defined by HCT control, and white blood cell count

Description: This prospective phase II trial (Nov 2011- Dec 2012), supported by the LYSA group, aimed to evaluate the impact on PFS of the RiBVD regimen in newly diagnosed, previously untreated, elderly MCL patients (〉65 years or not eligible for ASCT) (NCT01457144). Inclusion criteria were: WHO 2008 MCL not previously treated, CD20 positive, ECOG 0-2, AA stage II-IV, no CNS involvement or active HBV/HCV/HIV infection. Patients were scheduled to receive a total of 6 cycles of the RiBVD regimen, if they responded (IWG criteria) after 4 cycles. The regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1 and 2, Dexamethasone 40 mg/m² IV on D2 and bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with acyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Herein we present preliminary analysis of the trial after 4 RiBVD cycles. Results: A total of 76 patients were included, one was excluded because of HBV active disease and 5 had insufficient data reported in the database. To date we analyzed 70 patients. Patients characteristics: sex ratio M/F 49/21, median age 72 years (y) [64-83] (2 patients were 64 y old), AAstage II/III-IV 5/65, ECOG 0-1/2 59/11, MIPI score low/intermediate/high 3/19/48. Response: 61 responded (ORR=87%), with 19 in PR (26%) and 42 in CR/CRu (60%). Four patients died from pneumonia (n=1), cardiac arrest (n=2) and one following Progressive Multifocal Leukoencephalopathy. Three patients have progressed after 3 cycles. Sixty one patients were analysed by PETscan after 4 cycles, 39 (64%) reached a CR (30 were in CR/CRu and 9 in PR) and 22 remained PET positive (11 patients were in CR/CRu, 10 in PR and 1 stable). RiBVD cycles: 271 cycles were administered out of 280 planned (97%). Twenty four (9%) were delayed, 10 for toxicity. All but one planned Bendamustine doses (n=542) were administered with dosing modified 17 times (3%), mostly for hematological toxicity (n=14). Regarding Bortezomib, 79% (1028/1084) of planned doses were administered, it was prematurely stopped (56, 4%) for neurotoxicity (10 instances) or hematological side effects (46). Rituximab was not administered in 4 instances. Hematologic toxicities: Over the 271 cycles administered, neutropenia was reported in 104 cycles [56 grade 3/4 (g3/4) (21%)], 2.5% with fever; thrombopenia in 181 cycles [41 g3/4 (15%)]; anemia in 210 cycles, [6 g3/4 (2%)]. Non-hematologic toxicities:Reported in 〉10% of the cycles were : allergic reactions (10.3%, g3/4

Description: Background: Eight RCHOP/21 cycles followed by Rituximab maintenance is considered the standard of care for first line therapy in elderly MCL patients in Europe (1). However,complete clinical (CR) and molecular responses (MR) to therapy remain suboptimal(CR rate 30-35%, MR after 8 cycles 67 %). Regimen combining Rituximab and Bendamustine and more recently proteasome inhibitor Bortezomib (Velcade®) with CHOP regimen (VcR-CAP) demonstrated superior CR rates and PFS compared to R-CHOP. We have investigated the RiBVD regimen (Rituximab, Bendamustine,Velcade® and Dexamethasone) in a prospective phase II trial by the LYSA group. Aims of the study: The primary objective was to improve the median PFS by 6 months over the current 18 months PFS obtained with RCHOP when given without maintenance (ref Lenz, JCO 2005). The secondary objectives were to investigate the prognostic impact of molecular and FDG-PET responses on survival.. Methods and Material: All patients aged 65 or older with a diagnosis of MCL were treated by the RiBVD regimen if they fulfilled the following inclusion criteria: AAstage II-IV, PS 〈 3, no other neoplasm, no active HIV or HBV or HCV infections, no renal (creatinin clearance 〉 20ml/mn) or cardiac dysfunction, no diabetes. The RiBVD regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1, 2, Dexamethasone 40 mg IV on D2 and Bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with valacyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Patients were scheduled to receive a total of 6 cycles, if they achieved at least PR at 4 cycles. The IWG criteria, with and without FDG-PET, were used to define responses after 4 and 6 cycles. FDG-PET response was evaluated in each center with the five-point scale visual method of Deauville. Molecular responses (MR) were evaluated centrally by RQ-PCR using patient specific IGH VDJ targets as previously described (2). Results: Seventy six patients were recruited in one year (from November 2011 to December 2012), 74 were evaluable [2 patients were excluded because HBV positivity (n=1) or misdiagnosis (n=1)]. Fifty four samples were centrally reviewed for diagnosis, 45 were classic form of MCL, 9 pleomorphic variant and one patient had a DLBCL. Clinical characteristics of the 74 patients were: Median age 73 yo (64-83), sex ratio M/F = 2 (49/25), AAstage II/III-IV = 4/70, PS 0-1/2 = 63/11, MIPIscore low/intermediate/high= 3/19/50 (2 undetermined). The median follow-up is 21 months. Thirteen patients died because of lymphoma progression (n=7), cardiac arrest (n=2) or in one case each,pneumonia, Progressive Multifocal LeukoEncephalopathy, pancreatic carcinoma or of unknown causes. After 4 cycles the ORR was 86% (n=64) and CR/CRu 57% (n=42). After 6 cycles, the CR/CRu raised to 74% (n=55) the PR rate was 9% (n=7), 2 patients had a stable disease, 4 progressed and 5 had died during the treatment. The complete MR rate after 6 months on blood samples or bone marrow was respectively 83% (43/50) and 74 % (32/43). At 24 months, the PFS was 69% and the OS 80%. The MIPI score (high vs low/int) and the blood MR after 6 cycles were the only two statistically prognostic factors for PFS and OS. Toxicities were essentially hematologic with grade 3 or 4 neutropenia and thrombocytopenia in 51% and 36% of the cases, respectively. The main grade 3 or 4 extra-hematologic toxicities were fatigue (19%), neuropathy (14%), cardiac (7%) or febrile neutropenia (5%). Conclusion: The RiBVD regimen can be safely administered as first line therapy to elderly patients with MCL. Toxicities are mild and manageable. With 74% of CR/CRu, a 2 year PFS of 69% and 86% of patients achieving an MRD negative status in the blood after 6 cycles, without maintenance therapy, the RiBVD regimen is identified as a highly effective, well tolerated, first line treatment for elderly MCL patients. Reference : 1 - Kluin Nelemans HC et al, NEJM 2012, 2 - Gimenez E et al, BJH 2012 Disclosures Gressin: mundipharma: Consultancy. Off Label Use: Bendamustine and Bortezomib did not have authorization to their use in first line for MCL in France. Karlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Le Gouill:Mundipharma: Honoraria; Roche: Honoraria; Janssen: Consultancy.

Description: Background. Once complete remission (CR) is achieved in young (18–60) acute myeloid leukemia (AML) patients (pts), the main question is about the best post remission treatment. For pts not eligible for allogeneic bone marrow transplantation (AlloBMT) high-dose cytarabine-based chemotherapy (HiDAC) followed by autologous stem cell transplantation (ASCT) is an interesting option. However, the number of courses of cytarabine to apply before ASCT is not determined. The aim of this randomized study was to evaluate the impact of a second HiDAC before ASCT. Pts and methods. Pts received an induction by daunorubicine 60 mg/m2/d 3d + cytarabine 100 mg/m2/d (CI) 10 d. followed by a consolidation based on cytarabine 50 mg/m2/12h SC 7d + daunorubicine 60 mg/m2/d 2d. Pts 〈 45 with a sibling donor had an alloBMT (cyclophosphamide 60 mg/kg IV 2d + fractionated TBI 12 Gy). The others had a superconsolidation (cytarabine 3 g/m2/12h IV 4d + daunorubicine 45 mg/m2/d) followed by stem cell collection (either BM or PBSC). Then was the randomization between ASCT (busulfan 4 mg/kg/d po 4d + melphalan 140 mg/m2 on d5) immediately (SC1 group) or after 1 more course of HiDAC (cytarabine 3 g/m2/12h IV 4d) (SC2 group). Results. Between 05.1995 and 02.2001 a total of 437 pts entered the study. The median age of these pts (M/F = 238/199) was 47 years (18–60) with 203 of them under 45. Median WBC count was 12.5 (0.2–335) and WBC was 〉 30 109/L for 140 pts. The FAB distribution was: M1/M2 = 227; M4/M5 = 151; M0/M6/M7 = 59. The cytogenetics risk groups distribution was: low risk = 56 (13.8%); intermediate risk = 265 (65.4%); high risk = 84 (20.8%). CR was achieved in 2 courses for 46 pts (10.5 %). Out of the 437 initial pts, 351 achieved CR (80 %), 65 were eligible for alloBMT, 277 for randomization, and 128 were randomized (65 for SC1, 63 for SC2). The only difference between randomized and non-randomized pts was for number of course to achieve CR (7 % vs 16.8 % respectively, p = .01). This turn into a difference for cumulative incidence of non relapse deaths (CINRD) (8.7 % vs 20.6 % ; p = .01) but not for cumulative incidence of relapse (CIR). Overall survival (OS), leukemia free survival (LFS) and CIR and CINRD were 57.7, 50.9, 35.5, 19.9 for alloBMT. For SC1/SC2 results were : 41.3/53.7 for OS (p = .10), 39.2/49.6 for LFS (p = .11), 56.7/45.1 for CIR (p = .08), 8.5/8.4 for CINRD (p = .95). Multivariate analysis for LFS showed the independent impact of initial WBC count, cytogenetics and number of course to achieve CR. However, type of treatment (SC1 vs SC2) had no impact on LFS (p = .41). This lead us to conclude that one course of HiDAC was enough before ASCT despite the rather low proportion of randomized pts.

Description: Mantle cell lymphoma (MCL) accounts for approximately 6% of non-Hodgkin's Lymphoma (NHL) in adults. MCL commonly responds to initial therapy but inevitably patients relapse and response duration decreases from one salvage therapy to the next. Indeed, there is an urgent need to control and/or eradicate residual MCL cells that are responsible for early and late relapses. Maintenance with Rituximab (RM) after R-CHOP has been shown to prolong OS in elderly MCL patients treated with R-CHOP (Kluin-Nelemans et al. NEJM). Induction with high-dose cytarabine followed by autologous stem cell transplant (ASCT) consolidation is standard of care for young patients but RM after ASCT has never been investigated so far. The LyMa trial (ClinicalTrials.gov, NCT00921414) is a prospective international randomized phase III trial that investigated RM after ASCT in young previously untreated MCL patients. Patients were included at diagnosis (I, untreated, diagnosis of MCL according to WHO 2008 classification). Induction immuno-chemotherapy consisted of 4 courses of R-DHAP every 21 days (Rituximab, Dexamethasone, High-dose cytarabine, salt Platinum) followed by ASCT consolidation. Patients who were not in response (CR/CRu or PR) after R-DHAP received 4 additional courses of R-CHOP-14 before ASCT. The conditioning regimen for ASCT was R-BEAM. Patients in response after ASCT were randomized (1:1) between RM or no RM. RM consisted of one infusion of Rituximab (375mg/m2) every 2 months for 3 years. The primary endpoint was event-free survival (EFS) calculated from time of randomization; events were defined as disease progression, relapse, death, severe infection or allergy to Rituximab. Progression-free survival (PFS) and overall survival (OS) from time of diagnosis and time of randomization were secondary endpoints. The interim analysis showed a trend for a longer EFS and PFS in favor of RM arm. (Le Gouill et al, ASH 2014, abs 146). Herein, we present the results of the final analysis. RESULTS. Two hundred and ninety nine patients were enrolled from September 2008 to August 2012. Demographic and clinical characteristics of the patients were as followed: median age of 57y (27-65), 79% of male, MIPI-low in 53.2%, MIPI-I in 27.4% and MIPI-H in 19.4%. After inclusion, 277 patients completed the 4 courses of R-DHAP. The CR/CRu rate after R-DHAP was 77.3% and ORR was 89.3%. Twenty patients received R-CHOP. In all, 257 patients (including 12 patients who received R-DHAP/R-CHOP) underwent ASCT. After ASCT, 240 patients were randomized (RM, n=120; no RM, n=120). Median follow-up (mFU) from inclusion and from randomization were 54.4m (52.7-59.2) and 50.2m (46.5-54.2), respectively. The mPFS and mOS from inclusion in an intention to treat analysis were not reached; the 4y-PFS and OS were 67.8% (95%CI, 62.1 to 72.8) and 78% (95%CI; 72.8 to 82.3), respectively. According to EFS definition, 47 (39.2%) patients had an event in the no RM versus 25 (20.8%) in the RM arm. The mEFS from randomization was not reached in both arms. The 4y-EFS was 61.4% (95%CI; 51.3 to 69.9) in the no RM arm vs 78.9% (95%CI; 69.6 to 85.6) in the RM arm (p=0.0012). The EFS duration was significantly superior in the RM arm with a 54.3% reduction in the risk of event (Hazard ratio (HR)= 0.457; 95%CI, 0.28 to 0.74; p=0.0016). The median PFS and OS from randomization were not reached in both arms. The 4y-PFS and OS from randomization were superior in the RM arm: 82.2% (95%CI; 73.2 to 88.4) vs 64.6% (95%CI; 54.6 to 73) (p=0.0005) and 88.7% (95%CI; 80.7 to 93.5) vs 81.4% (95%CI; 72.3 to 87.7)(p=0.0413). Patients in the RM arm had a 60% reduction of risk of progression (HR=0.4; 95%CI, 0.23 to 0.68; p=0.0007) and a 50% reduction of risk of death (HR=0.5; 95%CI, 0.25 to 0.98; p=0.0454). The per protocol analysis yielded similar results. In conclusion, The LyMa trial demonstrates for the first time that RM after ASCT prolongs EFS, PFS and OS. Thus, 4 courses of R-DHAP plus ASCT (without TBI) followed by RM maintenance (one infusion every 2 month for 3 years) is a new standard of care for young MCL patients. Disclosures Thieblemont: Gilead: Consultancy; Roche: Consultancy; Janssen: Consultancy. Ribrag:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding. Haioun:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermine:Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Novartis: Research Funding; Alexion: Research Funding.

Description: Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous and accounts for approximately 10% of all lymphomas. Outcome of relapse/refractory (R/R) PTCL is poor with median progression-free survival (PFS) and overall survival (OS) of 3 and 6 months in the absence of stem-cell transplantation (SCT). [Mak, JCO, 2013]. Brentuximab vedotin (BV) monotherapy is approved for R/R systemic anaplastic large cell-lymphoma (ALCL) based on 86% overall response rate (ORR) and 57% complete remission (CR). [Pro, JCO, 2012]. In other CD30-positive (CD30+) R/R PTCL, the ORR of BV is 41%. Gemcitabine (G) used as monotherapy in control arm in the randomized phase 3 LUMIERE trial, provided ORR and CR rates of 35 and 22% respectively. [O'Connor, JCO, 2019]. Considering these results we designed a phase 2 study for R/R CD30+ PTCL combining G and BV with the primary end point to increase the ORR by 15%, compared to G monotherapy. Patients (pts) and Methods: Pts with histologically confirmed CD30+ (≥5%) PTCL who failed or were refractory to 1-3 prior lines of systemic therapy, with measurable disease and ECOG performance status 〈 3 were eligible. Pts received an induction of 4 cycles of G-BV (28-days cycles; G: 1000 mg/m² at D1 and D15 plus BV: 1.8 mg/kg at D8). Pts with CR or partial remission (PR) and non-eligible for SCT, received BV maintenance 1.8 mg/kg at D1 (21-days cycles) up to 12 cycles. The primary endpoint was the ORR (CR + PR) according to Lugano criteria based on CT-scan. Secondary objectives included tolerance and safety, DOR, PFS, OS and impact of BV maintenance. Eligible pts were censored at time of SCT. (NCT03496779). Results: From April 2018 to October 2019, 71 pts were included. Pathology central review according to WHO 2017 criteria, so far available for 50 patients, confirmed angioimmunoblastic T-cell lymphoma (AITL) (22 ; 31%); nodal PTCL-TFH (5 ; 7%); PTCL-NOS (5 ; 7%); ALK- ALCL (10 ; 14.1%) ; ALK+ ALCL (4 ; 5.6%), Enteropathy associated T-cell lymphoma (EATL) (2 ; 2.8%); unclassified PTCL (2 ; 2.8%). There were 47 male and 24 female with a median age of 66 years (20-79) and 17 pts were 〉 75 years. Median time from diagnosis to enrolment was 9.4 months (range, 6-21). Sixty-five pts (91.6%) presented with stage III-IV. The number of prior lines of therapy were 1 (57 pts), 2 (11 pts) or 3 (3 pts), all pts had received previous CHOP-like chemotherapy, 11 pts previous autologous SCT, 5 pts epigenetic modifiers and 39.4% were refractory to their last line of treatment prior to inclusion. The cut-off date of this analysis was 01/31/2020. The 4 cycles of G-BV induction were completed in 45 pts (63%). The reasons for early discontinuation were progression (21 pts), death (3 pts) or adverse event (2 pts). In intention-to-treat analysis, the ORR at the end of induction (EOI) was 47.9% including CR (14 pts; 19.7%), PR (20 pts; 28.2%). PET performed in all patients reaching EOI showed overall and complete metabolic responses in 45.1 and 23.9%, respectively. During G-BV induction 58 pts (81.7%) had at least one G 〉 3 adverse event (AE) including neutropenia (67.2%), thrombopenia (17.2%), infections (15.5%), peripheral neuropathy (PN) (5.2%) and cardiac event (5.2%). Overall PN of any grade was recorded in 8/71 patients (11%) during G-BV induction and caused BV withdrawal in one case. Among the 34 responding pts after EOI, 27 pts began BV maintenance and 7 pts remain on maintenance at cut-off date. Eight pts were removed from the study due to SCT eligibility, either after the 4 GBV induction (4 pts) or after 1 or 2 maintenance BV cycles (4 pts). With a median follow-up (FU) of 9.5 (0.5-19.4) months, median PFS is 4.5 months (95%CI [3.5 - 10]) and median OS is 12 months (95%CI [8.6 - NR]). Among the 34 patients in PR/CR after induction, the duration of response (DOR) is 12.8 months (95%CI [10.3 - NR]). At last FU were recorded 32 deaths. Disease status at time of death was PD (25 pts), CR (1 pt) NE or missing (6 pts). Conclusion: The addition of BV to G increases the overall response rate by 15% in the treatment of R/R CD30+ PTCL. OS data are encouraging for this overall R/R patient population but PFS is overall short and a longer FU is mandatory. Especially the DOR of pts achieving CR or PR after 4 cycles of G-BV exceeds 1 year on BV maintenance. This combination is generally well tolerated and this study suggests that G-BV combination could be an interesting alternative for R/R CD30+ PTCL. Disclosures Tournilhac: Janssen: Consultancy, Honoraria, Other: Travel grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; ABBVIE: Consultancy, Honoraria, Other: Travle grant; Takeda: Consultancy, Honoraria, Other: Travel grant. Laribi:novartis: Honoraria, Research Funding; amgen: Research Funding; abbvie: Honoraria, Research Funding; takeda: Research Funding. Ysebaert:AbbVie: Consultancy; Roche: Consultancy; Janssen: Consultancy. Guidez:BMS: Honoraria; TAKEDA: Honoraria; Service Hématologie et Thérapie cellulaire CHU POITIERS: Current Employment; AMGEN: Honoraria; CELGENE: Honoraria; JANSEN: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. André:Celgene: Other, Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy; Seattle Genetics: Consultancy. Dupuis:Henri Mondor University Hospital Creteil France: Current Employment. Thieblemont:Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding; Cellectis: Speakers Bureau. Bachy:Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria. Morschhauser:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Servier: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feugier:janssen: Consultancy, Honoraria, Research Funding; gilead: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding; astrazeneca: Consultancy, Honoraria, Research Funding; abbvie: Consultancy, Honoraria, Research Funding. Cartron:F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Gilead: Honoraria. Camus:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); JANSSEN: Honoraria; AMGEN: Honoraria; PFIZER: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sibon:takeda france: Consultancy. Snauwaert:roche: Other: travel; janssen: Other: travel; abbvie: Other. Delarue:BMS: Other: stock options ; Celgene/BMS: Current Employment. De Leval:Abbvie: Honoraria; Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Roche Diagnostics: Honoraria; Lunaphore Technologies SA: Consultancy, Honoraria. Gaulard:CHU Henri Mondor, Assistance Publique-Hôpitaux de Paris: Current Employment; TAKEDA: Consultancy, Honoraria, Research Funding; INNATE PHARMA: Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

Description: Background Ixazomib (IXA) is an orally-administered proteasome inhibitor approved in Europe in November 2016 for relapsed and/or refractory multiple myeloma (RRMM). It became available in France in May 2017 via a compassionate use program (CUP) and from October 2018 via the classical market access (non-CUP). In addition to pivotal clinical trials, real-world evidence (RWE) is required to evaluate effectiveness and safety in clinical routine practices. A non-interventional study, has been conducting in France to evaluate IXA use in combination with lenalidomide and dexamethasone (IRD) in real life. Methods REMIX is a non-interventional, multicentric study to assess IRD effectiveness and safety, conducted in 59 sites (public and private) in patients with RRMM. IRD was initiated in second line or more during the CUP and afterwards. After inclusion, patients were assessed every 3 months (mo) during 24 mo then every 6 mo as per standard practice. This interim analysis assessed IRD effectiveness (median Progression Free Survival (mPFS), 12 and 24-mo overall survival (OS) rates and tolerance in the CUP patients initiating IXA concomitantly to RD (patients who started lenalidomide more than 6 weeks before IXA were excluded). The analysis was conducted globally and per subgroups (age, number of lines of treatment, frailty as defined by Facon T & al.in Leukemia 2020). The CUP-patient median study follow-up was 17.4 mo for this interim analysis. Results The 198 eligible CUP patients were 47% of males, with a median age of 69 years (26% ≥75y). Out of them, 45% were frail and 7% had renal failure (CrCl ≤30 ml/min). Comorbidities were reported in 64% of patients including diabetes (9%), renal disease (10%), solid tumor (9%). At diagnosis, the cytogenetic risk was standard, high or unknown in respectively 46%, 13% and 41% of patients; 11% presented a plasmacytoma. 41% had multiple or severe bone lesions and 25% peripheral neuropathy. MM was diagnosed at a median of 4 years before IRD initiation. IXA was initiated after one (L2) / two (L3) / three or more lines of treatment (L4+) in respectively 58%, 18% and 24% of patients. Of them, 38% had received lenalidomide during prior line(s), mainly in patients with L3 and L4+ (78%, 65/84) vs L2 (8%, 9/114). The median washout period between lenalidomide discontinuation and IRD start was 18 mo 95%CI [17.6 - 29.6]. The mPFS was 19.2 mo 95%CI [13.3; 21.9] for the CUP cohort. mPFS was 21.5 mo 95%CI [13.3; 21.9] for L2 (104 patients), 17,8 mo 95%CI [12.2; 26.7] for L3 (29 patients) and 5.6 mo 95%CI [4.1; 8.8] for L4+ (38 patients) (c.f. Figure1). mPFS was similar in

Description: Background: Rituximab/chemotherapy is still one of the cornerstones of treatment for patients with Waldenström's macroglobulinemia (WM) despite the emergence of BTK inhibitors. Beside Rituximab-Bendamustine the combination Dexamethasone, Rituximab and Cyclophospamide (DRC) is the most widely recommended immunochemotherapy in national and international guidelines based on its low myelotoxicity and anti-lymphoma activity in WM. In addition, the proteasome inhibitor Bortezomib (B) has shown significant activity in WM as single agent or combined with Rituximab and/or Dexamethasone. This study aimed at evaluating the efficacy and toxicity of Bortezomib-DRC (B-DRC) as first line treatment in WM. Methods: In this prospective randomized multicenter European phase II study, patients with the diagnosis of WM confirmed by reference pathology and in need of treatment were randomized 1:1 to DRC (Dexamethasone 20 mg orally d1, Rituximab 375 mg/m2 IV d1 cycle 1 and 1400 mg SC d1 cycle 2-6, Cyclophosphamide 100 mg/m2 x 2 orally d1-5) or to B-DRC (DRC plus Bortezomib SC 1,6mg/m2 day 1, 8, 15) for 6 cycles (28d interval). Primary endpoint was progression free survival (PFS). Secondary endpoints included response rates, overall survival (OS), and toxicity. Results: Of 204 registered patients, 2 patients were excluded due to incorrect randomization. Median follow-up was 27.5 months at the time of the data cut. Median age was 68 years (range 34-89) in both arms. According to the ISSWM prognostic score 14 % of patients were at low, 73 % at intermediate and 13 % at high risk in both treatment arms. Median baseline hemoglobin for B-DRC and DRC was 10.0 and 9.8 g/dl and median baseline IgM 31.7 and 31.9 g/dl, respectively. Mutational status was available for 72 patients: in the B-DCR vs DRC treatment arm 26 and 16 patients were MYD88 mutated (MYD88MT) and CXCR4 wildtype (CXCR4WT), 8 and 12 patients were MYD88MT/CXCR4MT and 5 and 5 patients MYD88WT/CXCR4WT, respectively. Median PFS has not been reached in the B-DRC arm (95% CI: 33.5; --) compared to 50.1 months in the DRC arm (95% CI: 31.1; --) with an estimated PFS at 24 months of 80.6 % (95% CI: 69.5; 88.0) and 72.8 % (95% CI: 61.3; 81.3), respectively (p=0.32). Median OS has not been reached in either treatment arm with 5 deaths and 6 deaths in the B-DRC and DRC arm, respectively. At the end of treatment B-DRC induced major responses (at least PR) in 79.1 % of patients (vs 68.9% for DRC) and a CR/VGPR in 18.7 % of patients (vs 11.1 % for DRC) with an overall response of 91.2 compared to 86.7 % for DRC. Compared to baseline IgM decreased by 79 % and 73 % and Hb increased by 28 % and 32 % in the B-DRC and DRC arm, respectively. Responses and PFS were independent of the mutational status in both treatment arms. B-DRC and DRC were well tolerated: grade ≥3 AEs occurred in 48% of all patients (B-DRC 48%, DRC 47%). Most common grade ≥3 AEs included neutropenia (25%), anemia (6%), and thrombocytopenia (5%). Overall, 16 pts (8%) developed infections (1% grade ≥3). Serious AEs occurred in 40 pts (20%) (DRC: 26 (26%), B-DRC: 14 (14%)). Peripheral sensory neuropathy occurred in 18 patients treated with B-DRC (2 patients with grade 3, 16 patients grade 1-2) and in 3 patients treated with DRC (all grade 1 and 2). Conclusions: This is the first and largest prospective randomized trial to evaluate bortezomib in combination with standard immunochemotherapy, demonstrating that B-DRC is a well-tolerated regimen which induces a high rate of major responses including deep remissions after 6 months of treatment with a 2-year PFS of 81%, independently of the mutational status of MYD88 and CXCR4. At this time point of analysis, adding Bortezomib to DRC did not induce significant differences in PFS compared to DRC alone. Future trials will have to compare chemotherapy-free approaches such as continuous treatment with BTK inhibitors with fixed duration treatments exemplified by B-DRC to understand which of the two treatment approaches offers the highest long - term sustained clinical benefit to WM patients. Disclosures Buske: Roche, Janssen, Bayer, MSD: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau. Dimopoulos:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau. Kastritis:Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Tomowiak:Roche: Research Funding; Gilead: Research Funding; Janssen: Honoraria; AbbVie: Honoraria; Beigene: Honoraria; Takeda: Honoraria. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Viardot:Roche: Honoraria, Other: advisory board; Kite/Gilead: Honoraria, Other: advisory board; Novartis: Honoraria, Other: advisory board; Amgen: Honoraria, Other: advisory board. Aurran:Janssen: Honoraria. Lepretre:Gilead: Honoraria; Astra Zeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Leblond:AbbVie: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Janssen: Honoraria; Roche: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Beigene: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees. de Guibert:Gilead Sciences: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding. Gomes da Silva:roche: Consultancy; abbvie: Consultancy; BMS: Consultancy; MSD: Consultancy; Janssen: Consultancy; Gilead: Consultancy. Morel:Janssen: Honoraria. OffLabel Disclosure: Bortezomib in combination with DRC in Waldenström's Macroglobulinemia