Nicholson, Emma

Background: In 2015 the first B-cell acute lymphoblastic leukemia (B-ALL) patient receiving CAR T-cell therapy in Europe was reported to the EBMT registry. Today, the EBMT registry counts with more than 9000 patients treated with CAR T-cell therapies across all indications. Here, on behalf of the GoCART coalition, we present the outcomes of the largest European cohort of B-ALL patients treated with autologous, second generation, CD19-targeted CAR T-cells to date. Methods: Adult and paediatric patients with B-ALL received treatment with CAR T-cell therapy using either academic or commercially available products in 40 centres across 17 different countries. Safety was retrospectively assessed as per ASCTC 2019 consensus grading and CTCAE, and efficacy as per NCCN guidelines. Relapse incidence was defined as haematological relapse or progression after CART with non-relapse mortality as competing event. Leukemia free survival (LFS) was defined as being alive without occurrence of relapse. Follow-up includes patients treated from 2016 to Dec 2023 until data cutoff in June 2024. Results: A total of 345 patients (173 adults and 172 pediatrics) received therapy from 2016 to 2023 with tisagenlecleucel (65.2%), varnimcabtagene autoleucel (25.8%), brexucabtagene autoleucel (5.5%), and others (3.5%). Median age at infusion was 18 yrs. (range, 1.1-78.2) and 41.7% were females. High-risk features were identified including cytogenetic/genomic high-risk as per ELN guidelines (33.8%), relapse after allo-HCT (57.7%), early relapse (<1 year) after prior allo-HCT (30.4%), ≥3 prior treatment lines (55.5%) including prior exposure (and refractoriness) to blinatumomab and inotuzumab in 27.3% (34%) and 28.8% (32.3%), respectively. Median time from diagnosis to CART infusion was 2.8 years (0.1-17.9). Median time from last relapse prior CART to infusion was 2 months (range, 0.9-38.4). Bridging therapy was administered in 86.4% (298) of patients based on high or low intensity chemotherapy (32.1% or 26.5%, respectively), inotuzumab-ozogamicin (13.4%), TKI (8.2%), involved-site therapy (intrathecal chemotherapy, radiotherapy, orchiectomy) (3.5%), and blinatumomab (2.6%), alone or in combination. Prior to infusion, 34.7% had more than 5% BM blast count, 16.3% had circulating blasts in PB, and 20.6% had extramedullary disease. Lymphodepletion was performed in all but one patient, based on fludarabine and cyclophosphamide regimens. The reverse Kaplan-Meier median follow-up was of 2.2 years. The incidence of any grade (and severe) CRS was 71.6% (14.5%), and for ICANS was 15.7% (7.6%). The cumulative incidence of MRD-negative CR at month +3 was 76.9% (71.9-81.1), followed by a 2-year overall survival of 64.6% (58.7-69.8), leukemia-free survival of 48% (42.1-53.7), and relapse incidence of 45.5% (39.6-51.2). Non-relapse mortality at 2 years was 6.5% (4-9.6), 2-year cumulative incidence of subsequent HSCT of 33.3% (28-38.7) and second CAR-T infusions of 12.4% (8.8-16.6). Allogeneic HSCT after CAR-T was performed in 113 cases including 67 (59.3%) HSCT-naïve patients, due to molecular or overt disease relapse (60.9%), and other non-relapse reasons including suboptimal CAR-T persistence/B-cell aplasia (19.1%), pre-CAR-T high-risk features (13.6%), second malignancies (1.8%), and others. Second CAR-T infusions were performed in 39 cases due to molecular or overt disease relapse (79.5%) or suboptimal CAR-T persistence/B-cell aplasia in the absence of relapse (20.5%). Conclusions: The results from this European study demonstrate that CD19-targeted CAR T-cell therapy is an effective treatment for patients with high-risk B-cell ALL, providing substantial leukemia-free survival and overall survival rates despite the high-risk nature of the patient population. The necessity for bridging therapies and subsequent consolidative approaches, such as HSCT and second CAR T infusions, underscores the complexity and tailored nature of managing R/R B-ALL. These findings support the continued use and further investigation of CAR T-cell therapy in diverse clinical settings, emphasizing the importance of post-infusion strategies to sustain long-term remission. This will provide deeper insights into the factors influencing outcomes and help refine treatment protocols to improve patient care.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.