Nelarabine, an antimetabolite prodrug, is approved as monotherapy for children and adults with relapsed and refractory T-cell acute lymphoblastic leukemia and lymphoma (R/R T-ALL/LBL), although it is often used in combination regimens. We sought to understand differences in efficacy and toxicity when nelarabine is administered alone or in combination. We retrospectively analyzed 44 consecutive patients with R/R T-ALL/LBL; 29 of whom were treated with combination therapy, most with cyclophosphamide and etoposide (23, 79%) and 15 with monotherapy. The median age was 19 years (range, 2-69), including 18 children (<18 years). After a median of 1 (range, 1-3) cycle of treatment, 24 patients (55%) achieved complete remission, 62% (18/29) with combination therapy and 40% (6/15) with monotherapy (P = .21). Most responders (21, 88%) pursued allogeneic stem cell transplant (alloSCT). Overall survival (OS) was 12.8 months (95% confidence interval, 6.93-not reached) in the entire cohort and was higher in the combination therapy than in the monotherapy group (24-month OS, 53% vs 8%; P = .003). The rate of neurotoxicity was similar between groups (27% vs 17%; P = .46) and grade 3/4 anemia and thrombocytopenia were more frequent in the combination group (76% vs 20%; P < .001% and 66% vs 27%; P = .014, respectively). In a multivariate analysis, nelarabine combination therapy and alloSCT post nelarabine were associated with improved OS (hazard ratio, 0.41; P = .04 and hazard ratio, 0.25; P = .008, respectively). In conclusion, compared with monotherapy, nelarabine combination therapy was well tolerated and associated with improved survival in pediatric and adult patients with R/R T-ALL/LBL.

PURPOSE: On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS: We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS: At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION: Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

Immune effector cell-associated hematotoxicity (ICAHT) was recently introduced as a distinct toxicity category of CAR-T therapy. While a grading system based solely on neutrophil counts was proposed (hereafter termed N-ICAHT), the prevalence and prognostic impact of thrombocytopenia remains poorly defined. In this multicenter observational study, we systematically examined patterns of thrombocytopenia in 744 patients treated with commercial CD19 CAR-T for B-cell Non-Hodgkin Lymphoma (B-NHL). We developed a grading system termed T-ICAHT with thresholds that closely aligned with N-ICAHT - based on depth, duration and timing of thrombocytopenia. In the core NHL dataset, 43% of patients developed any-grade early T-ICAHT (day 0-30), with 23% developing severe (G3+) manifestations. Late T-ICAHT (day 31-100) was observed in 42% (G3+: 13%). While T-ICAHT and N-ICAHT gradings showed some correlation, considerable discordance was noted. On multivariate analysis, bridging therapy, poor performance status, and high Hematotox scores were associated with increased risk of severe early T-ICAHT. Patients with higher T-ICAHT grades showed increased platelet and red blood cell transfusion burden (p<0.001) and more bleeding events (p=0.01). T-ICAHT grades were inversely associated with overall survival (OS), with landmarked 2-year estimates ranging from 67% (G0), to 48% (G1-2) and 35% (G3+). In multivariable Cox regression analysis, the independent prognostic capacity of T-ICAHT for OS was confirmed. Finally, we validated T-ICAHT's clinical and prognostic utility in 3 external cohorts spanning an additional 599 pediatric and adult patients (NHL, MM, B-ALL), confirming its broad applicability. These findings support integrating T-ICAHT into the ICAHT framework to standardize thrombocytopenia grading in CAR-T recipients.

Immune effector cell–associated hematotoxicity (ICAHT) is a major B-cell targeted chimeric antigen receptor (CAR) T-cell related toxicity. Although ICAHT incidence and severity is documented in large B-cell lymphoma (LBCL), mantle cell lymphoma (MCL), and multiple myeloma (MM), ICAHT has not been described in B-cell acute lymphoblastic leukemia (B-ALL). Similarly, the CAR-HEMATOTOX (CAR-HT) model, designed to predict severe prolonged neutropenia (≥14 days of absolute neutrophil count [ANC] <500/μL), has been validated in LBCL, MCL, and MM, but not in B-ALL. As B-ALL bone marrow (BM) infiltration can impact cytopenias, we sought to describe ICAHT and assess CAR-HT for predicting hematotoxicity in B-ALL. In a cohort of 156 children and young adults with relapsed/refractory B-ALL, the median duration of severe neutropenia (ANC <500/μL) was 13 days (95% confidence interval, 10-16 days), with 83 (53%) experiencing grade ≥3 ICAHT. Applying CAR-HT, nearly 90% were classified as high risk, demonstrating limited discriminative power and prompting further development. Using the association identified between BM disease burden and postinfusion neutropenia (r = 0.64, P < .0001), we developed the ALL-Hematotox (ALL-HT) score, which substitutes BM disease burden for ferritin in CAR-HT. The ALL-HT score associated with severe prolonged neutropenia (area under the curve = 0.84, P < .0001), and appropriately discriminated high-risk patients (47%) who had more cumulative days of neutropenia (26 vs 4 days; P < .0001), fewer rates of complete response (88% vs 98%; P = .03), and shorter median overall survival (9.8 vs 24 months; log-rank P = .0002). ALL-HT was also validated in 2 independent cohorts. The ALL-HT score refines a widely accepted predictive model of postinfusion hematotoxicity, which is applicable in B-ALL.

PURPOSE: We designed a CD19-targeted chimeric antigen receptor (CAR) comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3ζ and 4-1BB/CD3ζ CARs. Preclinical data demonstrated that 1XX CARs generated potent effector function without undermining T-cell persistence. We hypothesized that 1XX CAR T cells may be effective at low doses and elicit minimal toxicities. METHODS: In this first-in-human, phase I, dose escalation and expansion clinical trial, patients with relapsed or refractory large B-cell lymphoma received 19(T2)28z-1XX CAR T cells at four dose levels (DLs), ranging from 25 to 200 × 10 ⁶ . RESULTS: Twenty-eight patients underwent apheresis and received CAR T cells. Sixteen and 12 patients were treated in the dose escalation and expansion cohorts, respectively. The overall response rate (ORR) was 82% and complete response (CR) rate was 71% in the entire cohort. The lowest dose of 25 × 10 ⁶ was selected for dose expansion. In 16 patients treated at this DL, 88% achieved ORR and 75% CR. With the median follow‐up of 24 months, the 1-year event-free survival was 61% (95% CI, 45 to 82) and 14 patients remain in continuous CR beyond 12 months. In all cohorts, grade ≥3 cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome rates were low at 4% and 7%, respectively. 1XX CAR T-cell products contain a higher proportion of CD8 T cells with memory features, and CAR T-cell persistence has been detected beyond 1-2 years in patients with ongoing remission. CONCLUSION: The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses with favorable toxicity profiles and may benefit the treatment of other hematologic malignancies, solid tumors, and autoimmunity.