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The BCL2 inhibitor venetoclax is transforming the management of patients with chronic lymphocytic leukemia (CLL), given its high efficacy in relapsed/refractory CLL as observed in both early-phase and randomized clinical trials. The present study aimed to determine whether venetoclax is effective and well tolerated in patients with CLL or Richter's syndrome (RS) in a real-world setting and to highlight factors impacting survival. Data from a venetoclax French compassionate use program were collected for 67 patients (60 with CLL and 7 with RS). Most patients presented adverse genetic features, such as TP53 disruption (74%) or complex karyotype (58%). Tumor lysis syndrome was observed in 14 (22%) patients, and 16 (24%) patients were hospitalized for grade III/IV infection. In the CLL cohort, ORR was 75 %, 1-year PFS was 61% (95% CI = 47-72%) and 1-year OS 70% (95% CI = 56-80%). No impact of TP53 disruption was noted while complex karyotype was identified as a predictor of both inferior PFS (HR = 3.46; 95% CI = 1-12; log-rank p = 0.03) and OS (HR = 3.2; 95% CI = 0.9-11.4, log-rank p = 0.047). Among the seven patients with RS, two achieved an objective response to venetoclax; however, the median OS was only 1.1 month. The well-balanced safety/efficacy profile of venetoclax is confirmed in this real-world setting. Complex karyotype should be evaluated as a predictive factor of survival for patients treated by venetoclax.

Background: High dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in multiple myeloma (MM) patients as upfront and salvage therapy. However, the safety and efficacy of ASCT in patients with renal insufficiency (RI) is controversial, which have led to an inconsistent arbitrary cut-off for creatinine clearance (CrCl) for performing ASCT. Here we analyzed prospectively the outcomes of MM patients with severe RI who underwent ASCT. Methods: We enrolled prospectively 50 newly diagnosed MM patients who had a serum CrCl of Results: The patients characteristics at enrollment are given in Table 1. We focused on 44 patients who were beyond 3 months post-ASCT. Light chain MM was frequent (12%), 10% had high risk cytogenetics, 36% increased serum LDH and 10% extramedullary disease. Induction chemotherapies included bortezomib plus IMiDs in 25/44 patients with ≥2 lines of chemotherapy in 12/44. The pre-transplant disease status was sCR in =5%, CR in =15%, VGPR in =39%, and PR in =41% of patients. The number of days of cytapheresis was 2 or less in 95% of cases and the median number of CD34+ cells collected was 3.3 x 106 (1.3-9.5). The median time from diagnosis to ASCT was 175 days (103-307). HDM was 140 mg/m2 in 42/44 patients and 200 mg/m2 in 2/44. All, except two, received consolidation post ASCT (34% missing) and 52% had maintenance therapy (all lenalidomide except two receiving bortezomib) and 7% had no maintenance (41% pending). Toxicity: We observed one death during the first 100 days post-ASCT, secondary to a septic shock on day 42. The median time to neutrophil engraftment was 12 days (9-68) and to platelet engraftment 13 days (10-70). Among patients receiving RBC transfusions (75%) and platelet transfusions (84%), the median number of RBC transfusions was 3 (1-6) and that of platelet transfusions was 3 (1-10). Response: Nine patients (70%) achieved dialysis independence from the time of diagnosis: 13 patients were on dialysis at diagnosis, 5 at the time of ASCT and 4 three months post-ASCT. Renal function improved post-ASCT in 34% of patients, 14% moving from a CrCl of Conclusions: In this preliminary analysis, HDM with ASCT proved to be safe and effective in MM patients with RI at transplant. We observed one death among 44 patients within the first 3 months post-ASCT. A more detailed report of the toxicity will be presented during the meeting along with the survival. Disclosures Vincent: takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; janssen: Membership on an entity's Board of Directors or advisory committees, Other: Congress support. Mohty:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Karlin:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees; Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Morel:Janssen: Honoraria. Rubio:Medac: Consultancy; Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding.

Introduction.The BCL-2 inhibitor venetoclax has demonstrated high efficiency in relapsed/refractory (R/R) CLL patients with an overall response rate (ORR) of 79%, regardless of the TP53gene status. Venetoclax has then been EMEA-approved for CLL patients with TP53disruption who are unsuitable for or have failed a BCR inhibitor (BCRi) and those without TP53 inactivation who have failed both immunochemotherapy and a BCRi. Whether this agent provides a well-balanced safety/efficacy profile and a prolonged survival in real-world practice remains to be investigated. Methods. An early access program (ATU) of venetoclax was available in France between July 22thand December 4th, 2016 for R/R CLL patients as per EMEA label. We retrospectively analyzed the outcome of patients included in this program who had received at least one day of venetoclax. Data quality was ensured using on-site data verification and computerized discrepancy errors. Results. Data concerning both clinical features andoutcome were available for 72 of the 93 patients for whom venetoclax was requested in this program. Among them, only 63 patients received at least one day of venetoclax for progressive CLL or Richter syndrome (RS) and were included in the present analysis. Median age was 69 years (range, 25-89) and sex ratioM/F was 47/16. A total of 56 patients received venetoclax for CLL and 7 for RS. Patients had previously received a median of 4 prior therapeutic lines (range, 0-7) including FCR in 43 (68%) of them, BTK inhibitor (BTKi) in 46 (73%) and PI3Kδ inhibitor (PI3Kδi) in 21 (33%); 5 had prior autologous stem cell transplantation (SCT) and 4 allogeneic SCT. At time of treatment with venetoclax, 32 (76%) patients carried TP53disruption (data available for 42 patients) and 19 (61%) had complex karyotype (CK) defined as ≥ 3 abnormalities (data available for 31 patients). IGHV mutational status was available for 26 patients. Treatment was administered as per label recommandations with a 5-week ramp up phase until the target dosage of 400 mg per day. Median follow-up was 17 months. Median time on therapy was 11.9 months (range, 0.1-24.6). Among adverse events of interest, tumor lysis syndrome (TLS) was observed in 19% of case, most of them being biological TLS and 3% were clinical TLS, and 15 (24%) patients developed infections requiring hospitalization. Autoimmune cytopenia was seen in 9.5% of patients. Four (7%) patients developed RS while on venetoclax for progressive CLL. To date, a total of 30% of patients remains on therapy. Three patients proceeded to allo-SCT after venetoclax therapy. Among the 7 patients who received venetoclax for RS, 2 had an objective response that lasted 7 and 14 months. However, median overall survival (OS) was only 1.1 months (95% CI, 0.7-1.5). Regarding the CLL cohort, ORR was 73%. It did not significantly differ according to the TP53status (90% with TP53disruption vs 69%, P= 0.189). Conversely, CK was associated with a lower ORR (92% vs 56%, P= 0.024). No impact of the type of prior BCRi (BTKi vs PI3Kδ inhibitor) was noted. 2-year progression-free survival (PFS) was 62% without significant impact of the TP53status (59% in case of TP53disruption vs 68% if wt-TP53,P= 0.587). Patients with CK had 2-year PFS of 44% compared to 78% for those without CK (P= 0.182). 2-year overall survival (OS) was 65% for the whole cohort and significantly better for responding patients than for non responders (76% vs 31%, P< 0.001). TP53disruption was associated with 2-year OS of 65% vs 90% (P= 0.176). Patients with CK had 53% of 2-year OS vs 62% for the remaining cohort (P= 0.236). There was no difference for the type of prior therapies (BTKi, PI3Kδ inhibitor or prior SCT) or IGHV mutational status. Patients who stopped venetoclax therapy had a very poor outcome with a median OS of 5 months. Conclusions.Our real-life study shows response rates and survival data that are in line with those observed in pioneer venetoclax clinical trials. CK should be evaluated as a predictive factor for response to venetoclax. Disclosures Herbaux: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead Sciences, Inc.: Consultancy, Honoraria. Laribi:Roche: Other: Grant; Teva: Other: Grant; Hospira: Other: Grant; Sandoz: Other: Grant; Gilead: Other: Personal fees; Novartis: Other: Grant and personal fees; Takeda: Other: Grant and personal fees; Amgen: Other: Personal fees. Feugier:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guieze:abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria.