Risk Factors Associated with Sub-Optimal Outcomes Following Obecabtagene autoleucel (obe-cel) for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-ALL): What We Have Learned from the FELIX Trial

Background: Obe-cel, an anti-CD19 autologous CAR T with a fast off-rate CD19 binding domain to improve persistence/reduce toxicity, is being investigated for the treatment of adult R/R B-ALL. Immune effector cell-associated hematotoxicity is the most common side effect of CAR T therapy but the pathophysiology of prolonged hematotoxicity is poorly understood and the lack of consensus for its treatment presents challenges. The CAR-HEMATOTOX (HT) model was developed in large B-cell lymphoma for risk-stratifying patients (pts) prior to CAR T therapy for hematotoxicity and outcomes. Here, we report an analysis exploring outcomes for pts with R/R B-ALL, risk-stratified using the HT model.

Methods: FELIX (NCT04404660) is a Phase Ib/II study evaluating the efficacy and safety of obe-cel in adult pts (≥18 yrs) with R/R B-ALL. Pts received bridging therapy as appropriate and underwent lymphodepletion (LD; fludarabine, 4x30mg/m²; cyclophosphamide, 2x500mg/m²), followed by tumor burden-guided infusions on Days 1 and 10 to a target dose of 410x10⁶ CAR T-cells. HT scores were calculated using the HT model (Rejeski K, et al. Blood 2023;142[10]:865-77); parameters comprise pre-LD platelet count, absolute neutrophil count, hemoglobin, and inflammatory parameters (C-reactive protein [CRP] and ferritin). The score discriminates between low-risk (0-1) and high-risk (≥2) of hematotoxicity. Associations between hematotoxicity risk, immunotoxicity risk, and outcomes were assessed (data cut-off: 7 February 2024).

Results: In FELIX, most pts infused with obe-cel were high-risk (102/127 [80%]), while 25/127 (20%) pts were low-risk or unknown. Baseline characteristics were generally similar across the two groups but a higher proportion of pts were male in the low-risk group vs the high-risk group (72% vs 47%), with increased rates of pre-treatment in low-risk pts vs high-risk pts: ≥3 prior therapies (48% vs 32%); previous allo-stem cell transplant (allo-SCT; 56% vs 41%), and previous inotuzumab ozogamicin or blinatumomab (80% vs 51%). Median bone marrow blasts at LD were increased in high-risk pts (45.5%, range: 5.0-90.0) vs low-risk pts (7.0%, range: 2.0-38.0), representing greater disease burden. Overall remission rate was numerically lower for high-risk pts (73.5%, 95% confidence interval [CI]: 63.9, 81.8) vs low-risk pts (96.0%, 95% CI: 79.6, 99.9). High-risk pts experienced worse survival outcomes, with median event-free survival (EFS; 95% CI) 9.0 months (5.8, 15.1) vs not estimable (NE) and median overall survival (OS; 95% CI) 14.1 months (10.7, 17.1) vs NE for high- and low-risk pts, respectively. Additionally, 12-month EFS (95% CI) and OS (95% CI) rates were 45.4% (34.6, 55.6) vs 65.5% (40.2, 82.1) and 57.6% (47.4, 66.5) vs 75.0% (52.6, 88.0) for high- and low-risk pts, respectively. Median duration of remission (95% CI) was 14.2 months (8.2, NE) vs NE for high- and low-risk pts, respectively. While in remission, 17% of high-risk pts and 21% of low-risk pts proceeded to allo-SCT. Rates of any-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were increased in high-risk pts vs low-risk pts (72% vs 56% and 25% vs 12%); however, rates of Grade ≥3 CRS and ICANS were comparable (3% vs 0% and 7% vs 8%). High-risk pts experienced slightly prolonged CRS vs low-risk pts (median [range]: 6.0 days [1.0-21.0] vs 4.0 days [1.0-6.0]), while duration of ICANS was comparable (median [range]: 8.5 days [1.0-53.0] vs 8.0 days [5.0-8.0]). Among responders, rates of Grade ≥3 infections within 3 months post-infusion were higher in high- vs low-risk pts (27% vs 13%), reflecting their underlying baseline and disease characteristics. Time to recovery of neutrophil (1x10⁹) and platelet (100x10⁹) counts was longer in high- vs low-risk pts (median [95% CI]: 1.9 months [1.5, 2.0] vs 0.8 months [0.7, 1.9] and 2.1 months [1.9, 2.3] vs 0.6 months [0.0, 1.9], respectively).

Conclusions: The HT score was found to be correlated with disease burden. Risk-stratification for hematotoxicity, using pre-LD clinical parameters together with disease burden, has the potential to be a useful tool for identifying pts more likely to benefit from obe-cel treatment and experience reduced toxicity. Pts with high-risk HT scores had consistently worse outcomes than pts with low-risk HT scores. Further studies are warranted.