Michel, Eva

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.

Background: The prognosis of patients (pts) with relapsed or refractory B ALL (r/r B-ALL) treated with CAR T-cells and receive a 2nd CART infusion is unknown. Few reports with limited numbers of patients suggest that 2nd CART infusion is feasible with questionable efficacy. This GoCART coalition registry study aimed at compiling data to investigate the indications, efficacy, and toxicity of CART2 infusion in pts with r/r B-ALL. Methods: This is a multicenter, retrospective registry study that included pediatric and adult patients with r/r B-ALL who received autologous CD19-targeted CAR T-cell therapy (CART1) and subsequently were treated with a second administration of CD19 and/or CD22-targeted CAR-T cell therapy (CART2) from 2017 to 2023. Baseline features, prior stem cell transplant (SCT), indications for CART2 and outcomes were collected. Relapse incidence (RI) was defined as overt recurrence, non-relapse mortality (NRM) as death without relapse occurrence, leukemia free survival (LFS) as being alive without occurrence of relapse and overall survival (OS) as being alive. RI and NRM were estimated using cumulative incidence function and OS and LFS Kaplan-Meier estimation. Results: Out of 345 pts who received CART1, 39 (2y cumulative incidence of second CART: 12.4% (95%CI: 8.8-16.6)) received CART2. Reasons for CART2 were overt relapse (n= 26; 66.7%), molecular relapse by measurable residual disease (MRD+) (n=5; 12.8%), and B-cell recovery (BCR) in the absence of relapse (n=8; 20.5%). Seventeen pts (43.6%) were female and median age at CART2 infusion was 19 yrs (range: 6.9-67.1), including 19 children and 20 adults. 74.4% of the pts had received a prior SCT, 25 pts (64%) before CART1, 2 (5.1%) only between CART1 and CART2, and 2 (5.1%) before CART1 and between CART1 and CART2. Among the 31 pts who received CART2 for relapse, this was CD19+ in 24 (92.3%), CD19- in 2 (7.7%), and unknown in 5. CART1 products were varnimcabtagene autoleucel (ARI-0001) (23), tisagenlecleucel (13), brexucabtagene autoleucel (1), and other experimental (2). All CART2 products targeted CD19 except 2 (1 CD22 and 1 dual CD19-CD22). Median time between CART1 and CART2 was 11.0 months. For patients who received CART2 for BCR, median time between CART1 and CART2 was shorter than for those who received it for relapse: 2.4 (IQR: 2.3-3.3) months vs. 12.4 (IQR:6.4-19.3) months. Regarding leukemic burden at the time of CART2 infusion, 19 pts (48.8%) were in overt relapse (14/19 with extramedullary disease, including 7 in CNS), 12 (30.1%) were in complete remission (CR) MRD+ and 8 (20.5%) CR MRD-. With a median follow-up time of 2.3 yrs [95% CI: 1.2-3.4], the 2-yr OS and LFS after CART2 were 47.1% [95% CI: 27.8-64.3] and 39.9% [95% CI: 24-55.3], respectively. 2-yr RI was 54.5% (95% CI: 36.5-69.4) and NRM was 5.6% (95% CI 1-16.8). 2-yr OS, LFS and RI for pts in CR at CART2 infusion irrespective to MRD were 76.1%, 63.3% and 25.6% while for those not in CR these outcomes were 17.7%, 15% and 85%, respectively (p= 0.007, 0.006 and 0.002). 2-yr LFS (71.4% [95% CI 25.8-92]) and RI (0%) was significantly better for pts receiving CART2 for BCR than in those who received it for relapse (31.6% [15.6-48.9] and 68.4% [46.7-82.8]; p= 0.036, p=0.002). Conclusion: This is a large registry study describing indications and outcome of CART2 in patients with r/r B-ALL. At 2-yrs after CART2, the LFS was of 39.9% and for patients receiving CART2 due to B-cell recovery was of 71.4%. These results show that CART2 is associated with low NRM and might be a bridge to SCT or other additional therapies. Updated results with data about subsequent therapies after CART2 will be presented at ASH meeting.

Introduction: Despite the success of anti-CD19 Chimeric Antigen Receptor T cells (CART19) in patients with B-cell acute lymphoblastic leukemia (B-ALL), an allogeneic haematopoietic stem cell transplantation (HSCT) might rescue patients with disease recurrence. However, in patients at high risk of relapse, indication and timing of HSCT are challenging. Whether waiting for detectable disease or proceeding to consolidative HSCT in remission, is still controversial. This GoCART Coalition registry study aimed at investigating the outcome of patients who received HSCT after CART19. Methods: We retrieved data from the EBMT registry on adults and children with B-ALL who received autologous CART19 from 2016 and 2023. Baseline, previous treatment, bridging therapy, CART19 therapy, B cell aplasia duration, outcome, disease status at follow-up were collected. Kaplan Meier estimates were used for overall survival (OS), leukemia-free survival (LFS) and non-relapse mortality (NRM) from date of HSCT, whereas cumulative incidence was used for relapse after HSCT. The relapse was defined as molecular or hematologic recurrence of the disease. Relapse and NRM were mutually competing events. Results: Of 345 patients (173 adults and 172 children) infused with CART19 (Tisagenlecleucel in 65.2%, Varnimcabtagene autoleucel 25.8%, brexucabtagene autoleucel 5.5%, and others 3.5%), 113 subsequently received an HSCT (37 adults and 76 children; median age 13.5 years, IQR 8.2-22.2) at a median of 6.2 months (3.7-11.8) after CART19 infusion. Median follow-up was 1.6 years (95%CI 1.1-1.9). Overall, 67/113 (59.3%) patients were transplant-naive (17 adults; 50 children). 78.2% received a myeloablative conditioning, 36.8% were grafted from a mismatched related donor. Most of the patients (64.2%) were transplanted in CR3 or more. Disease status at HSCT was relapsed disease for 9% of the patients, whereas among patients in CR with reported MRD 26/95 (27%) received HSCT with MRD positivity (MRD+). Among the patients with disease recurrence after CART19, 19/60 (32%) detected a CD19-negative clone. Indication for the subsequent HSCT was reported for 110 patients, as follow: (I) Rescue HSCT in 68 (62%) patients with molecular/morphological disease after CAR-T (including one patient with MDS post CAR-T); (II) Pre-emptive HSCT in 22 (20%) patients with B-cell aplasia loss with no signs of disease recurrence; (III) ConsolidativeHSCT in the 20 patients (18%) who were transplanted for the high risk of relapse, despite ongoing B cell aplasia and no disease recurrence. Median time elapsed between CART19 and HSCT was 9.5, 4.4 and 3.4 months in the three groups, respectively. The 2-yr OS was 71.1% (95%CI 59.8-79.7) and 2-yr LFS was 53.5% (41.9- 63.8), relapse incidence was 32.7% (22.4-43.5), while NRM was 11.6% (6.1-19.1). The 2-years LFS was 59.6% (45.2-71.4) vs 42% (19.2-63.4), for patients transplanted with negative or positive MRD, respectively. 5/11 patients transplanted with overt disease (including one with MDS) relapsed or died, the 6 survivors free of disease had follow-up inferior to 2 years. Children compared with adults showed better OS (76.8%, 62.1-86.4; 59.9%; 40.8-74.6; p=0.02), and better LFS (64.3%, vs. 36.4%; p= 0.02). Patients receiving a rescue HSCT for MRD+ or overt relapse had a significant lower LFS (43.6% and 33.2%), as compared to pre-emptive (77.3%) and consolidative HSCT (83.6%, p= 0.001). In univariate analysis, no significant differences in OS (74.5% vs 65.6%, p=0.32), LFS (54.3% vs 52.4%, p=0.75) and NRM (10.7% vs 12.9%, p=0.68) were reported for those patients having a previous HSCT before CART19. Conclusion: To the best of our knowledge this is the largest cohort of transplanted patients after CART19. In this “real-world” registry-based study we found that patients transplanted without disease recurrence had a better LFS, also accounting for MRD. For those who experienced molecular or overt relapse, achieving MRD negativity appeared to be relevant for a better outcome. The low NRM, with no differences between pre-transplanted and transplant naive patients, suggest that HSCT after CART19 is well tolerated, and represent a valid strategy to reduce the risk of relapse. As it remains unclear for which patients autologous CART19 cells remains a stand-alone treatment, future studies should focus on strategies for early identification of patients at higher risk of treatment failure.