No abstract

Prophylaxis is commonly used to prevent central nervous system (CNS) relapse in diffuse large B cell lymphoma, with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013-2019. Prophylaxis was administered intrathecally (IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7 %) had CNS relapse, after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4 vs 6.8%, p=0.4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected versus observed CNS relapse rates were nearly identical (5.8 vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.

Background: Brexucabtagene autoleucel (brexu-cel) is the first CD19 chimeric antigen receptor T-cell (CAR T) therapy approved for use in patients (pts) with relapsed mantle cell lymphoma (MCL). The ZUMA-2 trial demonstrated that brexu-cel induces durable remissions in these pts with an ORR of 85% (59% CR), estimated 12-month PFS rate of 61%, and similar toxicity profile to other CAR T therapies (Wang et al, NEJM 2020). We conducted a multicenter, retrospective study of pts treated with commercial brexu-cel to evaluate its safety and efficacy in the non-trial setting. Methods: We reviewed records of pts with relapsed MCL across 12 US academic medical centers. Pts who underwent leukapheresis between July 2020 and June 2021 with the intent to proceed to commercial brexu-cel were included. Baseline demographic and clinical characteristics were summarized using descriptive statistics. Survival curves were generated using the Kaplan-Meier method, and univariate models were fit to identify predictors of post-CAR T outcomes. Results: Fifty-five pts underwent leukapheresis. There were 3 manufacturing failures. Baseline characteristics of the 52 pts who received brexu-cel are summarized in Table 1. Median age was 66 yrs (range: 47-79 yrs) and 82% were male. Twenty of 29 (69%) pts with known baseline MIPI were intermediate or high risk. Seven pts had a history of CNS involvement. The median number of prior therapies was 3 (range: 2-8), including prior autologous stem cell transplant (ASCT) in 21 (40%) and prior allogeneic transplant in 2 pts (1 with prior ASCT and 1 without). Fifty percent had relapsed within 24 months of their initial therapy. All pts had previously received a Bruton's tyrosine kinase inhibitor (BTKi), including 29 (56%) with disease progression on a BTKi. Forty (77%) pts received bridging therapy (17 BTKi, 10 BTKi + venetoclax, 6 chemo, 3 venetoclax, 2 XRT only, 1 steroids only, 1 lenalidomide + rituximab). The ORR was 88% (CR 69%) among patients who received brexu-cel. Two pts had PD on initial restaging and 3 died prior to first response assessment (without evidence of relapse). Seven pts have not completed restaging due to limited follow-up (< 3 months) and were not included in the response assessment. Five pts have progressed, including 2 with CR and 1 with PR on initial restaging. With a median follow-up of 4.2 months, the estimated 6-month PFS and OS rates were 82.7% and 89.0%, respectively. All 7 pts with prior CNS involvement were alive without relapse at last follow-up. The incidence of cytokine release syndrome (CRS) was 84% (10% grade ≥ 3) with a median time to max grade of 5 days (range: 0-10 days). There were no cases of grade 5 CRS. The incidence of neurotoxicity (NT) was 57% (31% grade ≥ 3) with a median time to onset of 7 days (range: 4-15 days). NT occurred in 4/7 pts with prior CNS involvement (3 grade 3, 1 grade 4). Grade 5 NT occurred in 1 pt who developed cerebral edema and died 8 days after infusion. Thirty-five pts received tocilizumab, 33 received steroids, 7 received anakinra, and 1 received siltuximab for management of CRS and/or NT. Post-CAR T infections occurred in 8 pts, including two grade 5 infectious AEs (covid19 on day +80 and septic shock on day +40 after infusion). Rates of grade ≥ 3 neutropenia and thrombocytopenia were 38% and 37%, respectively. Among pts with at least 100 days of follow-up and lab data available, 5/34 (15%) had persistent grade ≥ 3 neutropenia and 4/34 (12%) had persistent grade ≥ 3 thrombocytopenia at day +100. Five pts have died, with causes of death being disease progression (2), septic shock (1), NT (1), and covid19 (1). Univariate analysis did not reveal any significant associations between survival and baseline/pre-CAR T MIPI, tumor pathologic or cytogenetic features, prior therapies, receipt of steroids/tocilizumab, or pre-CAR T tumor bulk. Conclusions: This analysis of relapsed MCL pts treated with commercial brexu-cel reveals nearly identical response and toxicity rates compared to those reported on ZUMA-2. Longer follow-up is required to confirm durability of response, but these results corroborate the efficacy of brexu-cel in a population of older adults with high-risk disease features. While all 7 pts with prior CNS involvement are alive and in remission, strategies to mitigate the risk of NT in this setting need to be evaluated. Further studies to define the optimal timing of CAR T, bridging strategies, and salvage therapies for post-CAR T relapse in MCL are warranted. Figure 1 Figure 1. Disclosures Gerson: TG Therapeutics: Consultancy; Kite: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Sawalha: TG Therapeutics: Consultancy, Research Funding; Celgene/BMS: Research Funding; BeiGene: Research Funding; Epizyme: Consultancy. Bond: Kite/Gilead: Honoraria. Karmali: Janssen/Pharmacyclics: Consultancy; BeiGene: Consultancy, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Takeda: Research Funding; Genentech: Consultancy; AstraZeneca: Speakers Bureau; Roche: Consultancy; Karyopharm: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; EUSA: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding; AstraZeneca: Research Funding. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Ghosh: Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Moyo: Seattle Genetics: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy; Seattle Genetics: Speakers Bureau; Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; MorphoSys: Consultancy; Kite (Gilead): Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Grover: Genentech: Research Funding; Novartis: Consultancy; ADC: Other: Advisory Board; Kite: Other: Advisory Board; Tessa: Consultancy. Maddocks: Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months; BMS: Divested equity in a private or publicly-traded company in the past 24 months; Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months; Novatis: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Divested equity in a private or publicly-traded company in the past 24 months; Morphosys: Divested equity in a private or publicly-traded company in the past 24 months; ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months; Beigene: Divested equity in a private or publicly-traded company in the past 24 months; Merck: Divested equity in a private or publicly-traded company in the past 24 months; KITE: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Lonza: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy; Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.

Most patients receiving CAR T-cell therapy (CAR-T) for aggressive B-cell lymphoma (B-NHL) will not experience a durable remission. There are several novel agents approved for the treatment relapsed, refractory aggressive B-NHL; however, it remains unclear how to sequence these therapies pre- and post-CAR-T (peri-CAR-T). We conducted a multicenter retrospective analysis for the purpose of describing peri-CAR-T practice patterns and survival predictors for patients receiving CD19-directed CAR-T. Patients (n=514) from thirteen centers treated with CAR-T for aggressive B-NHL between 2015-2021 were included. Clinical characteristics, CAR-T outcomes and treatment regimens administered pre- and post-CAR-T were collected. Survival curves were constructed using Kaplan Meier method. Multivariate Cox regression was used to determine the impact of variables on survival outcomes. For all patients receiving CAR-T, a greater number lines of therapy prior to CAR-T apheresis and receipt of bridging therapy were predictive of inferior progression-free survival (PFS) and overall survival (OS). From time of CAR-T infusion, median PFS and OS were 7.6 and 25.6 months (n=514). From time of progression post-CAR-T (n=254), median OS was 5.5 months. The median PFS of treatments given in the first-line post-CAR-T failure (n=167) was just 2.8 months. Patients with refractory disease at day 30 had inferior OS and were less likely to receive subsequent treatment(s) compared to other patients with CAR-T failure. AlloHCT for select patients at any time following CAR-T failure (n=16) led to durable responses in over half at one-year. These data provide a benchmark for future clinical trials in patients with progression post-CAR-T, an unmet clinical need.