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Chimeric antigen receptor T-cell therapy (CAR-T) has been successful in treating relapsed/refractory B-cell lymphomas. However, its role in the treatment of diseases involving the central nervous system (CNS) is not well studied. We performed a multicenter retrospective cohort study to evaluate the outcomes of patients with secondary CNS lymphoma (SCNSL) who received CAR-T. Eligibility required active CNSL at the time of apheresis. The objectives included evaluation of overall survival (OS), progression-free survival (PFS), identification of predictors of complete response (CR) post-CAR-T, and assessment of risk factors for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Sixty-one patients were included in the analysis. The overall response rate was 68% with a CR rate of 57%. In the multivariable analysis, patients who experienced any grade CRS had higher odds of achieving CR (OR = 3.9, 95% CI = 1.01–15.39, p  = 0.047). The median PFS was 3.3 months (95% CI = 2.6–6.0 months) with 6- and 12-month PFS rates of 35% and 16%, respectively. The median OS was 7.6 months (95% CI = 5.0–13.5 months) with 6- and 12-month OS rates of 59% and 41%, respectively. Any grade CRS and ICANS were 70% (n = 43) and 57% (n = 34), respectively with grade ≥ 3 CRS and ICANS rates of 16% and 44%. Factors associated with increased risk of CRS and ICANS included receiving axi-cel or having leptomeningeal ± parenchymal + CNS involvement, respectively. Despite achieving high response rates, most patients experience early relapse or death following CAR-T in SCNSL. The current study provides a benchmark for future trials exploring novel therapeutic options in SCNSL.

T-cell-engaging bispecific antibodies (BsAbs) are monoclonal antibodies that redirect the cytotoxic activity of T-cells to target malignant neoplasms. B-cell non-Hodgkin lymphoma (B-NHL) is a heterogenous group of aggressive and indolent malignancies with significant therapeutic challenges due to high relapse rates and limited options for relapsed/refractory disease. BsAbs function by simultaneously binding to CD3 on endogenous T-cells and a tumor-associated antigen, creating an immunologic synapse which results in the death of the target cell. The widespread T-cell activation that occurs with BsAb administration can result in cytokine release syndrome and neurological adverse events. Mosunetuzumab, epcoritamab, and glofitamab are CD20-targeting BsAbs that have demonstrated promising single-agent activity in both indolent and aggressive B-NHL. BsAbs are now being evaluated in combination with other anti-lymphoma agents and in earlier lines of treatment, and the results of ongoing clinical trials involving these agents have the potential to reshape the treatment landscape for B-NHL. In this review, we describe the structural features, clinical data, and toxicity profile associated with the BsAbs currently used to treat B-NHL and then discuss ongoing studies and future directions for this exciting new class of therapeutic agents.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma that is largely a disease of older adults with a median age at diagnosis of 67 years. MCL is considered incurable with current therapies and has historically been associated with a poor prognosis. A subset of patients will present with features of more indolent disease and can be safely observed for a period of time after diagnosis, but the majority will require treatment at some point in the disease course. Younger patients who are eligible to undergo intensive induction chemotherapy followed by consolidation with an autologous stem cell transplant can experience prolonged survival times with a median overall survival of 13 years; however, there are limited data to support this treatment approach in older adults and these patients often have medical comorbidities that preclude such intensive therapy. Fortunately, an increased understanding of the disease biology has led to the development of novel therapies in recent years that are well-tolerated and have led to improved outcomes in this patient population. In this article, we will review the current treatment landscape for older adults with MCL, with a focus on the safety and efficacy of chemotherapy regimens and novel agents such as lenalidomide, bortezomib, and the Bruton’s tyrosine kinase inhibitors that have been formally studied in this population.

Autoimmune diseases (AIDs) are associated with the development of B-cell non-Hodgkin lymphomas (B-NHLs). Autologous chimeric antigen receptor T-cell therapy (CART) is an effective therapy approved for the treatment of lymphoma; however, patients with AIDs were excluded from trials that led to CART approval. The goal of this retrospective study was to compare clinical outcomes for patients treated with CART for aggressive B-NHL with and without underlying AIDs. We found that the safety profile and efficacy of CART were comparable between these two cohorts. We also provide data on the impact of CART on AID control. This provides real-world information on the utility of CART as treatment for lymphoma in patients with AIDs, as well as insight into its possible use in the treatment of AIDs alone.

Double-hit (DHL) and double expressor (DEL) DLBCL have poor prognosis with standard therapy but CART may overcome this poor prognostic impact. In this multicenter retrospective study, we sought to confirm this observation by evaluating survival outcomes among patients with relapsed/refractory DHL and DEL treated with CART and evaluate outcomes of relapse post-CART. A total of 408 adult patients with relapsed/refractory DLBCL from 13 academic centers were included based on the availability of DHL and DEL. All 408 patients were included in the DHL ( n  = 80) vs non-DHL ( n  = 328) analysis, while 333 patients were included in the analysis of DHL ( n  = 80) vs DEL ( n  = 74) vs non ( n  = 179). On MVA, there were no differences for PFS for DHL vs non-DHL (HR 0.8, 95%CI 0.5–1.3, p  = 0.35) or DHL vs DEL vs other (three-way p value, p  = 0.5). Response rates and toxicities were similar among groups. Patients with DEL had the highest relapse rates post-CART, while DHL had the worst overall survival after CART relapse. In sum, our data support the notion that CART cell therapy can overcome the poor prognostic impact of DHL and DEL DLBCL in the relapsed/refractory setting. Additionally, patients with DHL that relapse after CART have a very poor prognosis.

Follicular lymphoma (FL) 3B is considered an aggressive lymphoma, however recent studies have challenged this paradigm. Additional controversy involves the clinical implication of pure FL3B (FL3Bp) vs FL3B with concurrent diffuse large B cell lymphoma (DLBCL) (FL3Bc). To address these questions, we performed a pooled study of the MER and LEO cohorts comparing 464 newly diagnosed, R-CHOP-treated patients with FL1-2 ( n  = 216), FL3A ( n  = 170), FL3B ( n  = 78) and 739 DLBCL. Among FL3B patients, 19 (24%) had FL3Bc and 59 (76%) FL3Bp. Baseline characteristics and outcomes were similar between the two FL3B subtypes. Compared to FL1-3A, FL3B showed similar clinical features, except for a lower tumor burden. After R-CHOP, FL1-2 patients had an inferior event-free survival (EFS) than those with FL3B, whereas there was no difference with FL3A. Survival was similar across the FL grades. Although FL1-2 patients failed to achieve EFS24 more frequently than FL3B and FL3A, FL3B patients who failed EFS24 had three-fold higher risk of subsequent mortality than other FLs. At 5-year follow-up FL3B patients had twice the risk of relapse with an aggressive subtype than those with FL1-2 and FL3A. Compared to DLBCL, FL3B patients had more favorable clinical features, but similar outcomes to GCB subtype. Our data suggest that most FL3B have a good outcome, while a subset has an aggressive behavior.

Kaplan–Meier methods were used to estimate survival, with log-rank tests and Cox regression models for comparisons with 95% confidence intervals calculated using Greenwood's method to estimate variance. CAR T-exposed patients were compared with a matched sub-cohort of CAR T-naive patients using propensity score matching (1:1, nearest neighbor, no replacement), accounting for age, Eastern Cooperative Oncology Group (ECOG) performance status, lactate dehydrogenase (LDH), and disease refractoriness—factors previously independently linked to PFS on multivariate analysis.8 Refractoriness was defined as less than complete response (CR) or progression within 6 months of last treatment. Total No prior CAR T Prior CAR T P-value n = 174 (%) n = 124 (71) n = 50 (29) Gender Female 85 (49) 58 (47) 27 (54) 0.41a Male 89 (51) 66 (53) 23 (46) Age at tafa initiation (years) Median (range) 74 (26−93) 77 (26−93) 66 (37−78) <0.001b <70 56 (32) 24 (19) 32 (64) <0.001a ≥70 118 (68) 100 (81) 18 (36) Histology (DLBCL, NOS; transformed LBCL; HGBCL; other) DLBCL, NOS 94 (54) 68 (55) 26 (52) 0.25a tLBCL 59 (34) 44 (35) 15 (30) HGBCL 16 (9) 8 (6) 8 (16) Otherc 5 (3) 4 (3) 1 (2) Cell of origin Non GCB 61 (35) 46 (37) 15 (30) 0.65a GCB 98 (56) 67 (54) 31 (62) Unknown 15 (9) 11 (9) 4 (8) ECOG PS 0–1 103 (59) 70 (56) 33 (66) 0.18d 2 40 (23) 30 (24) 10 (20) 3+ 21 (12) 17 (14) 4 (8) Missing 10 (6) 7 (6) 3 (6) Elevated LDH No 52 (30) 41 (33) 11 (22) 0.19a Yes 113 (65) 77 (62) 36 (72) Missing 9 (5) 6 (5) 3 (6) IPI at tafa initiation Median (range) 3 (0−5) 3 (1−5) 3 (0−5) 0.30a Missing 21 (12) 14 (11) 7 (14) 0–2 43 (25) 34 (27) 9 (18) 0.41d 3 45 (26) 30 (24) 15 (30) 4–5 65 (37) 46 (37) 19 (38) Missing 21 (12) 14 (11) 7 (14) Prior lines of therapy overall Median (range) 2 (1−15) 2 (1−9) 5 (2−15) <0.001b Missing 1 (1) 1 (1) - 1 41 (24) 41 (33) - <0.001d 2 46 (26) 45 (36) 1 (2) 3+ 86 (49) 37 (30) 49 (98) Missing 1 (1) 1 (1) - Prior lines of therapy for DLBCL Median (range)e 2 (0−11) 2 (0−7) 4 (0−11) <0.001a Missing 1 (1) 1 (1) - 0–1 60 (34) 56 (45) 4 (8) <0.001d 2 48 (28) 44 (35) 4 (8) 3+ 65 (37) 23 (19) 42 (84) Missing 1 (1) 1 (1) - Primary refractory disease No 88 (51) 64 (52) 24 (48) 0.74a Yes 85 (49) 59 (48) 26 (52) Missing 1 (1) 1 (1) - Disease status after last treatment Relapse 58 (33) 44 (35) 14 (28) 0.38a Refractory 115 (66) 79 (64) 36 (72) Missing 1 (1) 1 (1) - Prior autotransplant No 147 (84) 112 (90) 35 (70) 0.0012a Yes 21 (12) 8 (6) 13 (26) Missing 6 (3) 4 (3) 2 (4) In the overall cohorts, the complete response rate (CRR) was 19% (95% CI 9%–34%) in CAR T-exposed versus 20% (95% CI 13–28) in CAR T-naïve patients (P > 0.99). The overall response rate (ORR) in CAR T-exposed patients was 19% (95% CI 9%–34%) versus 36% (95% CI 27%–46%, P = 0.052) in CAR T-naïve patients.