Search

Chaitra Ujjani, 1 Anthony Mato, 2 Brian T Hill, 3 John N Allan, 4 Erick Lansigan, 5 Ryan Jacobs, 6 Hande Tuncer, 7 John Pagel, 8 Danielle Brander, 9 Bruce Cheson, 10 Paul Barr, 11 Lindsey E Roeker, 2 Jeffrey Pu, 12 Nirav N Shah, 13 Andre Goy, 14 Stephen J Schuster, 15 Nicole Lamanna, 16 Alison Sehgal, 17 Constantine S Tam, 18 Mazyar Shadman 1 1Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2Division of Hematological Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA; 4Division of Hematology and Medical Oncology, New York Presbyterian & Weill Cornell, New York, NY, USA; 5Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 6Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Charlotte, NC, USA; 7Lowell General Hospital, Tufts Medical Center, Boston, MA, USA; 8Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA, USA; 9Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC, USA; 10Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA; 11Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; 12Division of Hematology/Oncology, SUNY Upstate Medical University, Syracuse, NY, USA; 13Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 14John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 15Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 16Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; 17University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 18Peter McCallum Cancer Centre, University of Melbourne, East Melbourne, VI, AustraliaCorrespondence: Chaitra UjjaniSeattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, 825 Eastlake Ave E, Mail Stop CE3-300, Seattle, WA, USATel +1 206-606-1955Fax +1 206-606-1130Email ujjani@uw.eduIntroduction: Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.Methods: Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices.Results: Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients > 65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3).Conclusion: These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.Keywords: CLL, ibrutinib, elderly

Mosunetuzumab and other CD20/CD3 bispecific antibodies (BsAbs) have efficacy in B-cell lymphomas relapsing after or refractory to CD19-directed chimeric antigen receptor-modified T cells (CAR-T). The optimal timing of BsAbs and biomarkers of BsAb response after CAR-T are unknown. We addressed these questions using clinical data and blood samples from patients previously treated with CAR-T treated on a phase I/II study of mosunetuzumab (clinicaltrials.gov; NCT02500407). Thirty patients had paired samples at baseline and after 1 cycle of mosunetuzumab. Median time from CAR-T to mosunetuzumab was significantly longer for responding than for nonresponding patients (p=0.006, unadjusted for multiple comparisons). Most patients (20/30) did not receive intervening therapy between CAR-T administration and mosunetuzumab. The remainder of patients received one intervening therapy after a protocol-mandated drug washout. After mosunetuzumab, responding patients had higher lymphocytes (995 vs 400 cells/µL, p = 0.02) and greater increases in CD4 and CD8 cells (median change, 73 vs -90 cells/µL, p=0.005; 243 vs -103 cells/µL, p=0.004, respectively). Additionally, responding patients had an increase in activated CD8 cells (median 1.7-fold-change, p=0.02). Non-responders had a relative decrease in CAR transgene levels (N=16; p=0.04). This is the first study to assess changes in lymphocytes, T cells, and CAR transgene levels in patients treated with BsAb after CAR-T. These findings suggest an interaction between prior CAR-T and BsAb outcomes, and have implications for optimal timing of BsAb after CAR-T., (Copyright © 2024 American Society of Hematology.)

Significance: Genomic features of LBCL that can be detected by clinical laboratory assays may predict for resistance to first-line immunochemotherapy, as well as support the exploration of genomic features as biomarkers of response to therapies which could be offered to patients who experience disease progression., (©2024 The Authors; Published by the American Association for Cancer Research.)

Mosunetuzumab, a CD20xCD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate (ORR) were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7-not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of complete response was not reached (NR) (95% CI, 33.0-NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE-NE). Median progression-free survival was 24.0 months (95% CI, 12.0-NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) following 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or Grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe and effective treatment for patients with R/R FL, including those with high-risk disease. Trial registration: www.clinicaltrials.gov (NCT02500407)., (Copyright © 2024 American Society of Hematology.)

Abstract: CD19-directed chimeric antigen receptor T-cell (CAR T) therapies, including axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), have transformed the treatment landscape for B-cell non-Hodgkin lymphoma, showcasing significant efficacy but also highlighting toxicity risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The US Food and Drug Administration has mandated patients remain close to the treatment center for 4 weeks as part of a Risk Evaluation and Mitigation Strategy to monitor and manage these toxicities, which, although cautious, may add to cost of care, be burdensome for patients and their families, and present challenges related to patient access and socioeconomic disparities. This retrospective study across 9 centers involving 475 patients infused with axi-cel, tisa-cel, and liso-cel from 2018 to 2023 aimed to assess CRS and ICANS onset and duration, as well as causes of nonrelapse mortality (NRM) in real-world CAR T recipients. Although differences were noted in the incidence and duration of CRS and ICANS between CAR T products, new-onset CRS and ICANS are exceedingly rare after 2 weeks after infusion (0% and 0.7% of patients, respectively). No new cases of CRS occurred after 2 weeks and a single case of new-onset ICANS occurred in the third week after infusion. NRM is driven by ICANS in the early follow-up period (1.1% until day 28) and then by infection through 3 months after infusion (1.2%). This study provides valuable insights into optimizing CAR T therapy monitoring, and our findings may provide a framework to reduce physical and financial constraints for patients., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: T-cell lymphomas (TCLs) are a group of heterogenous cancers with poor rates and duration of response. There remains a great challenge in risk stratification of these cancers. Cluster of differentiation (CD) 5 has shown prognostic implication in many subtypes of B-cell lymphoma; however, its role in TCLs is not known. Methods: We performed a single-institution retrospective analysis of newly diagnosed patients with TCL. CD5 positivity was determined based on positive results via immunohistochemistry and/or flow cytometry. We used univariate and multivariable analysis of biological factors to assess their association with survival outcomes. Results: A total of 194 patients with TCL spanning 14 subtypes were identified. CD5 positivity was noted in 63% of patients, with the highest proportion of CD5 expression in TFH TCL (93.9%), PTCL-NOS (82.9%), and ATLL (77.8%) ( p = 0.00004). Older age at diagnosis ( p = 0.001), stage III or IV disease ( p = 0.05), and bone marrow involvement ( p = 0.003) were also associated with CD5 expression. Complete response rates were numerically lower in patients with CD5+ TCL across all subtypes. OS/PFS was not statistically associated with CD5 status in the overall cohort; however there was significantly decreased OS in CD5+ TFH TCL ( p = 0.04) and CD5+ ATLL ( p = 0.04) patients. Conclusions: This study represents the first to examine CD5 expression as a prognostic biomarker for outcomes in TCL. The frequent expression of CD5 in the most common nodal TCL in the Western world underpins its potential as an attractive target for cellular therapies. Confirmation of these findings in a larger cohort and investigation of potential pathophysiological mechanisms explaining our observations are planned.

Background: Large B cell lymphoma (LBCL) is the most common form of lymphoma. Polatuzumab vedotin (polatuzumab) is an effective therapy for patients diagnosed with LBCL; however, only limited information regarding pathologic features detected by clinical laboratory assays is available to determine which patients are most likely to benefit from polatuzumab based therapies., Patients and Methods: We collected data from real world patients with relapsed or refractory LBCL whose tumors underwent next generation sequencing and were treated with polatuzumab based therapy at a single large academic cancer center. Tumor and patient characteristics were analyzed to look for factors that predict response to polatuzumab based therapies., Results: We identified high grade B cell lymphoma (HGBL) -NOS or MYC/BCL2 histology and presence of MYC rearrangement as factors that predict inferior response to polatuzumab based therapy. Patients with germinal center B cell of origin (GCB COO) LBCL without these factors had a high response rate (73%) to polatuzumab based therapy., Conclusion: In a single center real world retrospective analysis of R/R LBCL patients with available genomic data, polatuzumab based therapy may be less effective in patients with HGBL-NOS or MYC/BCL2 histology and MYC rearrangements, but not in patients with GCB COO LBCL without these features. Routine performance of more comprehensive pathologic analysis of tumors may inform the use of polatuzumab based therapy in patients with LBCL., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19-positive B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR-T cells manufacturing. To investigate the impact of 1-2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy. We found that low dose fractionated RT had a positive effect on generating abscopal systemic antitumor responses beyond the irradiated site. The combination of RT with CART-19 therapy resulted in additive effects on tumor growth in irradiated masses. Notably, a significant additional increase in antitumor effect was observed in non-irradiated tumors. Mechanistically, our results validate activation of the cGAS/STING pathway, tumor-associated antigen (TAA) cross-priming, and elicitation of epitope spreading. Collectively, our findings suggest that RT may serve as an optimal priming and bridging modality for CAR-T cell therapy overcoming treatment resistance and improving clinical outcomes in patients with CD19-positive hematologic malignancies., (Copyright © 2024 American Society of Hematology.)

Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. Severe acute respiratory syndrome coronavirus 2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic messenger RNA vaccine response in retrospective and prospective cohorts with lymphoma and chronic lymphocytic leukemia, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active treatment, but nonresponse was also common within observation and posttreatment groups. Total immunoglobulin A and immunoglobulin M correlated with successful vaccine response. In individuals treated with anti-CD19-directed chimeric antigen receptor-modified T cells, nonresponse was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to individualize vaccine timing., Competing Interests: Potential conflicts of interest. E. A. C. receives research support from Genentech/Roche and AbbVie and has served as a consultant for Beigene, AstraZeneca, and TG Therapeutics. J. S. has served as a consultant for ATARA, AstraZeneca, Celgene Corporation, Adaptive, and Genmab, and receives research support from AstraZeneca, Merck, Incyte, Bristol-Myers Squibb, Pharmacyclics, TG Therapeutics, Seattle Genetics, and Adaptive. S. K. B. received honoraria from Acrotech, Seagen, Kyowa Kirin, and Daiichi Sankyo. S. D. N. receives research support from Roche, Rafael, ATARA, Pharmacyclics, and Takeda/Millennium; is a data monitoring committee member for Merck; and has served as a consultant for Epizyme and Morphosys. D. J. L. received research funding from Curis and Triphase; is a data and safety monitoring board member for Karyopharm; and has served as a consultant for Morphosys/Incyte, Epizyme, and ADC Therapeutics. J. N. G. received research funding from Loxo and has served as a consultant for Genentech, AbbVie, and Kite. E. L. P. received funding from Roche Diagnostics Corporation for the evaluation of serologic tests for SARS-CoV-2. E. J. W. is consulting or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine, and Surface Oncology; is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences; and is an inventor on a patent (US patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. S. J. S. reports research funding from Acerta, Celgene, Genentech/Roche, Merck, Novartis, Pharmacyclics, and TG Therapeutics; received honoraria/consulting fees from Acerta, AstraZeneca, Celgene, Incyte, Janssen, Loxo Oncology, Morphosys, and Nordic Nanovector; is a steering committee member for Celgene, Nordic Nanovector, and Novartis; and has a patent for combination therapies of CAR T cells and PD-1 inhibitors. M. R. holds patents related to CAR T cells; has served as a consultant for nanoString, BMS, GSK, Bayer, Sana Therapeutics, and AbClon; receives research funding from AbClon, nanoString, viTToria biotherapeutics, Oxford Nanoimaging, and Beckman Coulter; and is the scientific founder of viTToria Biotherapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.

Abstract: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody administered as an off-the-shelf, fixed-duration treatment in an outpatient setting. We report an updated analysis of the durability of response, by investigator assessment, after an overall median follow-up of 3.5 years in patients with relapsed/refractory indolent or aggressive B-cell non-Hodgkin lymphoma (iNHL/aNHL) from the dose-escalation stage of a phase I/II study of mosunetuzumab (ClinicalTrials.gov identifier: NCT02500407). Across dose levels, 65.7% of patients with iNHL and 36.4% with aNHL achieved a complete or partial response to mosunetuzumab. Median duration of response (DoR) in patients with iNHL for all responders was 23.2 months (95% CI, 13.8 to not estimable [NE]), but was not reached in complete responders (95% CI, 21.0 to NE). After a median time on study of 38.9 months, no relapses were observed beyond 26 months in complete responders. In patients with aNHL, median DoR for all responders was 7.8 months (95% CI, 4.6 to 22.8). Among 12 complete responders who progressed postmosunetuzumab treatment and were retreated with mosunetuzumab, 83.3% had an objective response and 58.3% achieved a second complete response. Our study reports the longest follow-up using bispecific antibodies in patients with B-cell non-Hodgkin lymphoma and demonstrates that mosunetuzumab can mediate durable remissions with time-limited treatment.

Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory mantle cell lymphoma (MCL). During a fludarabine shortage, we used bendamustine as an alternative to standard cyclophosphamide/fludarabine (cy/flu) lymphodepletion (LD) prior to brexu-cel. We assessed MCL patient outcomes as well as CAR T-cell expansion and persistence after brexu-cel following bendamustine or cy/flu LD at our center. This was a retrospective single institution study that utilized prospectively banked blood and tissue samples. Clinical efficacy was assessed by 2014 Lugano guidelines. CAR T-cell expansion and persistence in peripheral blood were assessed on day 7 and at ≥month 6 for patients with available samples. Seventeen patients received bendamustine and 5 received cy/flu. For the bendamustine cohort, 14 (82%) received bridging therapy and 4 (24%) had CNS involvement. Fifteen patients (88%) developed CRS with 4 (24%) ≥grade 3 events. Six (35%) patients developed ICANS with 4 (24%) events ≥grade 3. No patient had ≥grade 3 cytopenias at day 90. Best objective (BOR) and complete response (CRR) rates were 82% and 65%, respectively. At 24.5 months median follow-up, 12-month progression-free survival (PFS) was 45%, 24-month PFS was 25%, and median duration of response was 19 months. Median OS was not reached. BOR was 25% (1/4) for patients with CNS involvement. CAR transgene expansion after bendamustine LD was observed on day 7 in all (4/4) patients tested and persisted at ≥6 months (2/2), regardless of response. Bendamustine LD before brexu-cel for MCL is feasible and safe with a lower frequency and shorter duration of cytopenias than reported for cy/flu. Both CAR T-cell expansion and persistence were observed after bendamustine LD. Outcomes appear comparable to the real world outcomes reported with cy/flu LD., (Copyright © 2024. Published by Elsevier Inc.)

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abstract: Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Administration of anti-CD19 chimeric antigen receptor T-cell (CART19) immunotherapy for large B-cell lymphomas (LBCLs), a subset of non-Hodgkin lymphoma (NHL), involves high costs and access to specialized tertiary care centers. We investigated whether minority health populations (MHPs) have equal access to CART19 and whether their outcomes are similar to those of non-MHPs., Methods: We analyzed the prevalence and clinical outcomes of patients treated with commercial CART19 at two geographically and socioeconomically different institutions: the Abramson Cancer Center (ACC, Philadelphia, Pennsylvania) and the Knight Cancer Institute (KCI, Portland, Oregon)., Results: In the ACC catchment area, 8956 patients were diagnosed with NHL between 2015 and 2019 (latest available data from the state registry), including 17.9% MHPs. In the ACC, between 2018 and 2022 (CART became available in 2018), 1492 patients with LBCL were treated, and 194 received CART19. The proportion of MHPs was 15.7% for the entire LBCL cohort but only 6.7% for the CART19 cohort. During the same time, in the KCI catchment area, 4568 patients were diagnosed with NHL, including 4.2% MHPs. In the KCI, 396 patients with LBCL were treated, and 47 received CART19. The proportion of MHPs was 6.6% for the entire LBCL cohort and 4.2% for the CART19 cohort. The 3-month response, survival, and toxicities after CART19 infusion showed similar results, although the number of patients who were treated was limited., Conclusions: This study shows that the access of MHPs to tertiary centers for LBCL care was preserved but appeared reduced for commercial CART19 immunotherapy. Although clinical outcomes of MHPs seemed similar to those of non-MHPs, the small sample size precludes drawing firm conclusions. Further studies are needed. (Funded by the Laffey McHugh Foundation and others.).

We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8 + cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In 2003, the Eastern Cooperative Oncology Group initiated a randomized phase III clinical trial (E4402) comparing two different rituximab dosing strategies for patients with previously untreated low-tumor burden follicular lymphoma. Rituximab-responsive patients (n = 299) were randomly assigned to either a retreatment rituximab (RR) strategy or a maintenance rituximab (MR) strategy. Each dosing strategy was continued until treatment failure. The primary end point of the study was time to treatment failure (TTF). In the original report, there was no difference in TTF between the two dosing strategies. Here, we report on the long-term outcomes for secondary end points of time to first cytotoxic therapy, duration of response, and overall survival (OS). At 7 years, 83% of MR patients had not required first chemotherapy compared with 63% of RR patients (hazard ratio, 2.37 [95% CI, 1.5 to 3.76]). At 7 years, 71% of MR remained in their first remission compared with 37% of RR patients. Despite the improved first remission length with MR, there was no difference in OS at 10 years (83% v 84%). With mature long-term data, we confirm that prolonged maintenance rituximab does not confer an OS advantage in low-tumor burden follicular lymphoma.

Regulatory approvals of tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) have established the feasibility of chimeric antigen receptor T-cell therapies for the treatment of adults with relapsed or refractory follicular lymphoma (r/r FL). This study used individual patient data from ELARA (tisa-cel) and aggregate published patient data from ZUMA-5 (axi-cel) to compare efficacy and safety outcomes in r/r FL using matching-adjusted indirect comparison methods. After adjustment for baseline differences in the trial populations, the results suggested that tisa-cel ( n  = 52), compared with axi-cel ( n  = 86), had similar effects on overall response rate (91.2% vs. 94.2%; p  = .58), complete response rate (74.0% vs. 79.1%; p  = .60), progression-free survival (HR [95% CI]: 0.8 [0.4, 1.9]; p  = .67), and overall survival (HR [95% CI]: 0.5 [0.2, 1.5]; p  = .21). Tisa-cel ( n  = 53) was associated with better safety outcomes than axi-cel ( n  = 124), reflected by lower rates of any grade and grade ≥3 cytokine release syndrome and neurological events.