Fakhri, Bita

7501 Background: In patients (pts) with R/R CLL/SLL that progressed on BTKi and failed venetoclax (ven)-based regimens, achieving CR with current treatment is uncommon. New therapies that achieve deep and durable responses are needed. We report the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study evaluating liso-cel in pts with R/R CLL/SLL. Methods: Pts must have received at least 2 prior lines of therapy, including a BTKi. Eligible pts received liso-cel at a target dose of either 50 (DL1) or 100 (DL2) × 106 CAR+ T cells. The primary endpoint was rate of CR and CR with incomplete marrow recovery (CRi) by IRC per 2018 iwCLL criteria in the prespecified subset of efficacy-evaluable pts with disease progression on BTKi and ven failure (primary efficacy analysis set [PEAS]) at DL2 (null hypothesis [H0]: ≤ 5%). Key secondary endpoints were ORR (H0: ≤ 40%) and rate of undetectable minimal residual disease (uMRD; 10−4) in blood (H0: ≤ 5%). Results: Of 137 leukapheresed pts, 117 received liso-cel (safety set), 96 (DL1 = 9; DL2 = 87) were efficacy evaluable, and 53 (DL1 = 4; DL2 = 49) were in the PEAS. In the safety set, median (range) age was 65 y (49–82), 83% had high-risk features, median (range) lines of prior therapy was 5 (2–12), and all pts had prior BTKi. Median (range) on-study follow-up was 21.1 mo (0.4–55.6) for the safety set. In the PEAS at DL2, the primary endpoint of CR/CRi rate was met at 18.4% (95% CI, 8.8–32.0; 1-sided P = 0.0006; Table). ORR was 42.9% and was not statistically significant (95% CI, 28.8–57.8; 1-sided P = 0.3931). The uMRD rate was 63.3% in blood and 59.2% in marrow. Median (95% CI) DOR was 35.3 mo (11.01–not reached [NR]) with a median follow-up of 19.7 mo. Median duration of CR/CRi was NR. In the safety set, rate of any-grade CRS was 84.6% (gr 3, 8.5%; no gr 4/5) and neurological events (NE) was 45.3% (gr 3, 17.9%; gr 4, 0.9%; no gr 5); 69.2% received tocilizumab and/or corticosteroids for CRS/NEs. Rate of gr ≥ 3 infections, hypogammaglobulinemia, and prolonged cytopenia was 17.1%, 15.4%, and 53.8%, respectively. One death related to liso-cel was due to hemophagocytic lymphohistiocytosis. Liso-cel exhibited rapid in vivo expansion and was detected by qPCR in blood up to 36 mo after infusion. Conclusions: Liso-cel demonstrated durable CR/CRi, high uMRD rates, and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL and high unmet need. Clinical trial information: NCT03331198 . [Table: see text]

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Abstract Background: Bendamustine and rituximab (BR) is a commonly chosen frontline treatment for grade 1-2 (G 1-2) follicular lymphoma (FL). This regimen resulted in significantly longer progression-free survival (PFS) and less toxicity compared to R-CHOP in the STiL trial [Rummel et al., 2013] and similar results were observed when comparing BR vs. R-CHOP/R-CVP in the confirmatory BRIGHT trial [Flinn et al., 2014, updated ASCO 2017]. Importantly, patients (pts) with grade 3A (G 3A) FL were excluded from these studies, yet the conclusions are often extrapolated to the treatment of G 3A pts. Notably, G 3A pts were included in the GALLIUM trial which used both bendamustine as well as CHOP backbones. Several retrospective studies of FL pts treated with frontline R-CHOP have demonstrated equivalent or improved overall survival (OS) for G 3A relative to G 1-2 FL (Koch et al., 2016, Mustafa et al., 2017, Yuan et al., 2017, Maeshima et al., 2013). Early disease progression after diagnosis and treatment with frontline R-CHOP has been identified as a strong predictor of poor OS in FL pts [Casulo et al. 2015], but has not been assessed in pts treated with frontline BR. We retrospectively evaluated outcomes of a large cohort of FL pts treated with frontline BR and stratified the results based on histologic grade and early vs. late progression. Methods: We reviewed medical records of adult (age >18) pts with FL treated with frontline BR at 18 US cancer centers. There was no central pathology review; each academic institution confirmed the diagnosis and grade of FL. Pts with unknown grade, grade 3B, or cutaneous FL were excluded. Baseline characteristics between grades were evaluated with the Chi-Square test for categorical variables and the Mann-Whitney U for continuous variables. Outcomes were calculated from time of initiation of BR. Patients were grouped according to whether or not they had progression of disease within 24 months of BR initiation (POD24). OS and PFS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: 687 pts were included (616 G 1-2, 71 G 3A). Median age at diagnosis was 60 years (range 21-94) with 53% men. The median time from diagnosis to treatment with BR was 1 month (range 0-139). The median duration of follow up for the entire cohort was 39 months. Characteristics including age, gender, ethnicity, ECOG, stage, LDH, and FLIPI are shown in the Table, and did not significantly differ between G 1-2 and G 3A pts. Rates of complete response (CR) and partial response (PR) to BR were similar between G 1-2 and G 3A (72%/22% vs. 66%/21%, respectively, p=0.114) but progressive disease (PD) was higher in G 3A pts (11.9%) relative to G 1-2 (4.8%, p=0.025). As shown in the Figure (A and B), 3-year PFS and OS was significantly longer for G 1-2 vs. G 3A pts (75% vs. 65%, log rank p= 0.035 and 90% vs. 86%, log rank p=0.007, respectively). Seventy-six (12.3%) of the 616 G 1-2 pts and 13 (18.3%) of the 71 G 3A pts experienced POD24 (p=0.19). For pts with both G 1-2 and G 3A FL, POD24 was associated with inferior OS (3-year OS 95% vs. 57% for G 1-2 pts, log rank p<0.0001 and 3-year OS 93% vs. 37% for G 3A pts, log rank p<0.0001) compared to patients without POD24. Conclusions: G 3A FL pts have an inferior OS and are significantly more likely to have PD to frontline BR compared to G 1-2, which differs from the published experience with R-CHOP. Similar to outcomes after frontline treatment with R-CHOP, POD24 after frontline BR for FL is associated with very poor OS. Future studies are needed to address optimal frontline management of pts with G3A as well as for pts with any grade FL with POD24 after frontline BR. Disclosures Nastoupil: Novartis: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Merck: Honoraria, Research Funding; Spectrum: Honoraria; Janssen: Research Funding; Juno: Honoraria. Cerhan:Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding; Nanostring: Research Funding. Maurer:Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Smith:Genentech: Research Funding; Incyte Corporation: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Seattle Genetics: Research Funding. Lossos:Affimed: Research Funding. Portell:TG therapeutics: Research Funding; Amgen: Consultancy; Kite: Research Funding; AbbVie: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Research Funding; Infinity: Research Funding. Calzada:Seattle Genetics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy. Ghosh:Spectrum: Consultancy; SGN: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; Celgene: Consultancy; Juno: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Genentech: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Forty seven Inc: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Caimi:Kite Pharma: Other: Advisory Board Participation; Genentech: Other: Advisory Board PArticipation, Research Funding; Celgene: Speakers Bureau; Kite Pharma: Other: Advisory Board Participation. Danilov:Gilead Sciences: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Astra Zeneca: Consultancy; Genentech: Consultancy, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding. Martin:AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Kite: Consultancy; Gilead: Consultancy; Bayer: Consultancy. Kamdar:Seattle Genetics: Speakers Bureau; Genentech: Consultancy. Kahl:AstraZeneca: Consultancy; Acerta: Consultancy; Juno: Consultancy; CTI: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Pharmacyclics: 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

SummaryBendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R‐CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile.