The SCHOLAR-1 international retrospective study highlighted poor clinical outcomes and survival among patients with refractory large B-cell lymphoma (LBCL) treated with conventional chemotherapy. Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, demonstrated durable responses in patients with refractory LBCL in the pivotal phase 1/2 ZUMA-1 study (NCT02348216). Here, we compared SCHOLAR-1 with the 2 year outcomes of ZUMA-1. Prior to comparison of clinical outcomes, propensity scoring (based on a broad set of prognostic covariates) was used to create balance between ZUMA-1 and SCHOLAR-1 patients. In the pivotal phase 2 portion of ZUMA-1, 101 patients received axi-cel and were evaluable for response and survival. In SCHOLAR-1, 434 and 424 patients were evaluable for response and survival, respectively. ZUMA-1 patients were more heavily pretreated than SCHOLAR-1 patients. The median follow-up was 27.1 months in ZUMA-1. The objective response rate and complete response rate were 83% and 54% in ZUMA 1 vs 34% and 12% in SCHOLAR-1, respectively. The 2-year survival rate was 54% in ZUMA-1 and 20% in SCHOLAR-1, and a 73% reduction in the risk of death was observed in ZUMA-1 vs SCHOLAR-1. These results were consistent with those of an additional standardization analysis in which strata were limited to 2 prognostic factors (refractory categorization and presence/absence of stem cell transplant after refractoriness to chemotherapy) to conserve sample size. Despite the limitations of a nonrandomized analysis, these results indicate that axi-cel produces durable responses and a substantial survival benefit versus non-CAR T-cell salvage regimens for patients with refractory LBCL.

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 (<66y; stage >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.

No abstract

Obinutuzumab and lenalidomide (GALEN) is an active immunomodulatory combination with a manageable safety profile in multiple types of lymphoma. We report efficacy and safety results for the phase 2 GALEN study in previously-untreated patients with advanced follicular lymphoma (FL). Eligible patients aged ≥ 18 years had ECOG PS ≤ 2, high-tumor burden, grade 1-3a FL. Induction treatment was obinutuzumab (1000 mg IV, days 8/15/22, cycle 1; day 1, cycles 2-6) plus lenalidomide (20 mg/day, days 1-21, cycle 1; days 2-22, cycles 2-6) for 6 cycles. Maintenance included obinutuzumab (1000 mg every 2 cycles) plus lenalidomide (10 mg, days 2-22) for ≤ 12 cycles (year 1) followed by obinutuzumab (1000 mg every 56 days) for 6 cycles (year 2). The primary endpoint was complete response rate (CRR) after induction per IWG 1999 criteria. From October 2015 to February 2017, 100 patients were enrolled. CRR after induction was 47% and overall response rate (ORR) 92%. Post-hoc analyses per 2014 Lugano classification including patients with missing bone marrow assessments identified an additional 13 patients fulfilling CRR criteria, resulting in a complete metabolic response of 80% and ORR of 94%. At a median follow-up of 3.7 years, 3-year progression-free and overall survival were 82% and 94%, respectively. The most common adverse event was neutropenia (48% any-grade; 47% grade ≥ 3) but only 2% of patients presented febrile neutropenia; others were mainly grade ≤ 2. No other specific grade ≥3 toxicity occurred at a frequency higher than 3%. Overall, these results demonstrated promising clinical efficacy for the chemo-free backbone obinutuzumab and lenalidomide in previously untreated, high tumor burden FL patients. Except for neutropenia, the safety profile of the combination is remarkable. The study was registered with ClinicalTrials.gov, number NCT01582776

Introduction Atrial fibrillation (AF) occurs in 5-9% of patients treated with ibrutinib for CLL. We previously reported on the clinical characteristics and management outcomes of 56 patients with ibrutinib-associated AF (n=52) or atrial flutter (n=4) retrospectively identified from centers of the FILO group (French Innovative Leukemia Organization, France/Belgium, n=29), MD Anderson Cancer Center (USA, n=21), and Peter MacCallum Cancer Centre (Australia, n=6) (Thompson et al BJH 2016). We found that (1) the median time from the initiation of ibrutinib to AF was 3.8 months (range: 6 - 1410 days); (2) AF recurred or became persistent in 63% despite medical management; (3) AF and its management was associated with serious sequelae including severe cardiac failure (n=3, 1 fatal), ischemic stroke (n=3) and severe bleeding events (n=8); (4) immediate cessation of ibrutinib therapy was required in 22/56 (39%). Given the reported poor outcomes for patients who discontinue ibrutinib for toxicity, we update the results of this cohort with respect to CLL outcomes and survival. Aim To describe long term overall and disease-specific outcomes in patients who develop ibrutinib-associated AF. Methods This is an update of an international, retrospective cohort of patients who developed ibrutinib-associated AF. Patients are managed according to local best standard practice. The median follow-up from onset of AF is 21 months. Results The median overall survival after development of AF is 43 months. Twenty-two (39%) patients stopped ibrutinib at the time of AF. Among these patients, 7 (32%) eventually died from CLL progression (n=3), infection (1), cardiac failure (1), pulmonary hemorrhage (1) and colon cancer (1). Of the 34 patients who initially continued ibrutinib, 5 (15%) died; causes of death were: Richter transformation (RT) (n=2), septic shock (1), CLL progression (1), and stroke in the context of AF (1). In order to gain insight into disease control in relationship to AF and its management, we examined PFS from the time of AF onset. The following features had no impact on PFS: single AF episode vs paroxysmal/permanent AF or time from ibrutinib initiation to onset of AF. However, patients who had ibrutinib interrupted at the time of AF onset (n=22) had a significantly inferior PFS (median 19 months) compared with those who had dose reduction without interruption (n=13) or those who continued full dose ibrutinib (n=21, median 27 months, p=0.023, Figure 1). There was a trend toward inferior overall survival in those who interrupted ibrutinib (62% at 3 years) compared with those who continued without interruption (74% at 3 years, p=0.10), but this did not reach statistical significance at the time of analysis. Only 3 of 22 (14%) patients who had initial interruption of ibrutinib successfully restarted ibrutinib following control of AF; all 3 remain in continuous partial remission. Four other patients restarted ibrutinib, but subsequently discontinued due to pulmonary hemorrhage (n=1), stroke (1), CLL progression (1) and RT (1). Among patients who discontinued Ibrutinib permanently, only 9 did so solely because of uncomplicated AF. The others discontinued because of: (a) complications of AF or its management such as cardiac failure (n=1), recurrent AF (n=5) and bleeding events (n=4; one each of hemopericardium, pulmonary hemorrhage, subdural hematoma and gastrointestinal hemorrhage); (b) complications related to CLL such as CLL progression (n=1) and RT (n=2); or (c) other causes such as lung cancer (n=1) or unknown reasons (n=2). Altogether, 21 patients were still on Ibrutinib among 44 patients alive at last follow-up. Conclusion Occurrence of AF at any time during ibrutinib treatment was associated with an initial discontinuation rate of 39%, and only 37.5% of patients remain alive and on drug after a median of 21 months follow-up. Patients who interrupted ibrutinib at the time of AF onset have an inferior PFS compared to those who continued ibrutinib or were managed with dose reductions. This inferior outcome in CLL control is likely related to the low rate of patients (14%) who subsequently successfully restarted ibrutinib. Development of AF was associated with serious complications, including hemorrhage, ischemic stroke and cardiac failure. Management of ibrutinib-associated AF is complex and requires international consensus guidelines and a multidisciplinary approach. Figure 1 Figure 1. Disclosures Thompson: Pharmacyclics: Consultancy, Honoraria. Levy:Abbive: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Tam:janssen: Honoraria, Research Funding; AbbVie: 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. Quinquenel:janssen: Honoraria, Research Funding. Dupuis:ABBVIE: Membership on an entity's Board of Directors or advisory committees; janssen: Honoraria. Cymbalista:Roche: Honoraria; Abbvie: Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Research Funding.