Shadman, Mazyar

We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351 ) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD] neg ) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel–treated patients achieving MRD neg . Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRD neg . ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRD neg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.

Abstract Although follicular lymphoma (FL) typically follows an indolent course, patients with FL who experience early events, such as transformation or progression, have increased risk of death related to lymphoma. The FL24Cx is an algorithm based on a 45-target gene expression profiling (GEP) assay, which was developed and trained using 265 formalin-fixed, paraffin-embedded tissue samples on a reliable platform to predict, at the time of diagnosis, whether a patient will experience an event within 24 months. The modeling also confirmed and relied upon previously reported synergy between immune response (IR) gene expression signatures IR1 and IR2. Once locked, the 5-factor logistic regression FL24Cx model was independently validated in a retrospectively assessed cohort of 232 patients from 2 immunochemotherapy-treated arms of SWOG Cancer Research Network S0016 phase 3 clinical trial, in which it assigned 169 patients to the low-risk group with 29 events before 24 months (17.2%) and 63 patients to the high-risk group with 24 events before 24 months (38.1%). The relative risk of an event within 24 months after registration among patients who were classified into the high-risk group relative to patients who were classified into the low-risk group was 2.2 (95% confidence interval, 1.41 to 3.51). An up-front GEP biomarker, such as the FL24Cx, rigorously validated in a clinical laboratory and with a clinically relevant turnaround time, could identify and steer enrollment of patients at high risk for early events in clinical trials, thus enabling timely interpretation of such trials and increasing the pace of innovation.

ABSTRACT Transformed follicular lymphoma (tFL) is typically associated with chemotherapy resistance and a poor prognosis. There are limited data regarding outcomes after CD19‐directed chimeric antigen receptor T‐cell (CAR T) therapy in relapsed/refractory (R/R) tFL. A total of 923 adult patients with R/R tFL who received commercial CD19 CAR T therapy between 2017 and 2023 were identified in the Center for International Blood and Marrow Transplant Research registry. Median age was 64 years (range: 30–86) and median prior lines of therapy was 4 (range: 1–18). Most patients (78%) received axicabtagene ciloleucel, with 67% of patients having resistant disease at the time of CAR T infusion. At a median follow‐up of 25 months (range: 1–72) from CAR T infusion, the 2‐year overall survival (OS) was 57% (95% CI: 53–60) and progression‐free survival (PFS) was 43% (95% CI: 40–47). The 2‐year cumulative incidences of relapse or progression (rel/prog) and non‐relapse mortality (NRM) were 47% (95% CI: 44–51) and 9% (95% CI: 7–11), respectively. The overall response rate to CAR T was 76%, with a complete response rate of 63%. Grade ≥ 3 cytokine release syndrome (CRS) was observed in 7.1% and grade ≥ 3 immune effector cell–associated neurologic syndrome (ICANS) in 21.6% of patients. Multivariable analysis suggested that resistant disease status at the time of CAR T, use of bridging therapy, and high comorbidity index ≥ 3 were associated with inferior PFS and OS. Older age ≥ 60 significantly increased the risk of NRM. Our study suggests that CD19 CAR T is effective and safe for tFL.

Abstract Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T-cell therapy approved for relapsed/refractory mantle cell lymphoma (R/R MCL). Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with R/R MCL, including subgroups based on prior treatment with Bruton's tyrosine kinase inhibitor, bendamustine, or autologous hematopoietic cell transplant (auto-HCT) and number of prior therapy lines, using Center for International Blood and Marrow Transplant Research registry data. A total of 476 patients with R/R MCL who received brexu-cel between July 2020 and December 2022 were included in the analysis. With a median follow-up of 13.5 months, the overall response rate was 91% and complete response rate was 82%. One-year overall survival and progression-free survival rates were 76% and 63%, respectively. One-year cumulative incidence of nonrelapse mortality was 8%. Prior auto-HCT was associated with better duration of response within 6 months after infusion (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.28-0.85) but greater risk of immune effector cell–associated neurotoxicity syndrome (odds ratio [OR], 1.66; 95% CI, 1.06-2.60). Prior bendamustine was associated with increased risk of prolonged thrombocytopenia (OR, 1.90; 95% CI, 1.13-3.21). In patients with 1 to 2 prior therapy lines, relapse or progression was less frequent compared with those with ≥3 prior lines (HR, 0.64; 95% CI, 0.42-1.00). Collectively, our results suggest that real-world outcomes with brexu-cel were consistent with those of the ZUMA-2 trial, regardless of prior therapy type or number of prior therapy lines.

Abstract Checkpoint inhibitors (CPIs) have shown remarkable efficacy in Hodgkin lymphoma (HL), and are now used routinely. While allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for HL, there are concerns prior CPIs may exacerbate post–allo-HCT complications, particularly graft-versus-host disease (GVHD), and lead to worse outcomes. Given the relative paucity of data, we performed a Center for International Blood and Marrow Transplant Research/European Society for Blood and Marrow Transplantation study to examine the impact of prior CPIs in allo-HCT. We included 2186 adult patients aged >18 years who received a first allo-HCT using a matched related, unrelated, or haploidentical donor from 2008 to 2023. Twenty-seven percent of patients received prior CPIs. GVHD prophylaxis was posttransplant cyclophosphamide (PTCy) in 55.8% of patients in the CPI cohort, and 35% in the non-CPI cohort. Median follow-up among survivors was longer for the non-CPI (39 months) than CPI cohort (16.5 months). In multivariate analysis, prior CPI exposure did not affect overall survival (OS) or nonrelapse mortality, but resulted in improved progression-free survival (non-CPI vs CPI hazard ratio [HR], 0.81; 0.67-0.98; P = .03) and lower relapse incidence (HR, 0.58; 0.45-0.76; P < 001). While grade 2 to 4 (HR, 1.26; 1.04-1.53; P = .02) and 3 to 4 (HR, 1.41; 1.04-1.92; P = .03) acute GVHD (aGVHD) were increased, differences in chronic GVHD (cGVHD) were not significant. PTCy–based GVHD prophylaxis resulted in improved OS, lower grade 2 to 4 aGVHD, and cGVHD in patients with prior CPI exposure. In summary, allo-HCT should still be considered a curative option for patients with HL in the era of CPIs.

ABSTRACTAlthough recent studies have demonstrated the efficacy of chimeric antigen receptor T‐cell (CAR‐T) therapy in relapsed large B‐cell lymphoma (LBCL) with MYC rearrangement (R‐MYC), the data comparing CAR‐T to autologous hematopoietic cell transplant (auto‐HCT) in such patients who achieve a complete or partial response (CR/PR) after salvage therapies are limited. We compared the clinical outcomes of patients with R‐MYC LBCL (including double and triple hit lymphomas) who underwent CAR‐T or auto‐HCT after achieving a CR/PR with salvage therapies using the Center for International Blood & Marrow Transplant Research registry. Among the 252 patients (auto‐HCT = 98, CAR‐T = 154), relative to auto‐HCT, CAR‐T was associated with significantly lower overall survival (OS) (Hazard Ratio [HR] 2.09, 95% CI 1.38–3.15, p < 0.001) on multivariate analysis. There were no differences in progression‐free survival (PFS) (HR 1.21, 95% CI 0.81–1.8 p = 0.36), risk of relapse (HR 1.1, 95% CI 0.71–1.69 p = 0.68), nonrelapse mortality (NRM) (HR 1.74, 95% CI 0.64–4.7 p = 0.28) while the post‐relapse survival was longer in auto‐HCT relative to CAR‐T (HR 1.93, 95% CI 1.21–3.06 p = 0.01). On propensity score matched analysis accounting for differences in characteristics across the two cohorts, we detected no significant differences in OS (HR 1.72, 95% CI 0.92–3.21 p = 0.09), PFS (HR 1.04, 95% CI 0.64–1.68 p = 0.88), NRM (HR 1.22, 95% CI 0.35–4.2 p = 0.76), relapse (HR = 0.93, 95% CI 0.54–1.6 p = 0.8) and post‐relapse survival (HR 2.25, 95% CI 0.98–5.17, p = 0.06). These data, although retrospective, support consideration for auto‐HCT in patients with R‐MYC LBCL who achieve a CR/PR after salvage therapies, particularly in regions with no or limited access to CAR‐T.

Abstract T-cell/histiocyte–rich large B-cell lymphoma (THRLBCL) is a rare histologic variant of LBCL. Limited data regarding CD19–directed chimeric antigen receptor T-cell (CART) therapy in relapsed/refractory (R/R) THRLBCL suggest poor efficacy. We investigated CART outcomes for R/R THRLBCL through the Center for International Blood and Marrow Transplant Research registry. A total of 58 adult patients with R/R THRLBCL who received commercial CD19-CART therapy between 2018 and 2022 were identified. Most patients (67%) had early relapse of disease (45% primary refractory) with a median of 3 (range, 1-7) prior therapies and were treated with axicabtagene ciloleucel (69%). At median follow-up of 23 months after CART therapy, 2-year overall and progression-free survival were 42% (95% confidence interval [CI], 27-57) and 29% (95% CI, 17-43), respectively. In univariable analysis, poor performance status before CART therapy was associated with higher mortality (hazard ratio, 2.35; 95%CI, 1.02-5.5). The 2-year cumulative incidences of relapse/progression and nonrelapse mortality were 69% and 2%, respectively. Grade ≥3 cytokine release syndrome and immune effector cell–associated neurologic syndrome occurred in 7% and 15% of patients, respectively. In this largest analysis of CD19-CART therapy for R/R THRLBCL, ∼30% of patients were alive and progression free 2 years after CART therapy. Despite a high incidence of progression (69% at 2 years), these results suggest a subset of patients with R/R THRLBCL may have durable responses with CARTs.