Obe-Cel Is Effective in R/R B-ALL Patients with Low CAR-HT Risk
Obe-cel shows efficacy in R/R B-ALL, especially in those with a favorable CAR-HT risk profile, according to data from the phase 1/2 FELIX study.
Obe-cel shows efficacy in R/R B-ALL, especially in those with a favorable CAR-HT risk profile, according to data from the phase 1/2 FELIX study.
Patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) who have low-risk CAR-HEMATOTOX (CAR-HT) scores experienced improved outcomes with obecabtagene autoleucel (obe-cel; Aucatzyl) compared with those who had high-risk scores, according to an analysis of the phase 1/2 FELIX trial (NCT04404660) presented at the 2025 Tandem Meeting.1
Patients treated with obe-cel during the study (n = 127) were divided into subgroups based on low-risk or unknown (n = 25) or high-risk (n = 102) CAR-HT scores. At a median follow-up of 21.5 months (range, 8.6-41.4), patients in the low-risk group experienced an overall response rate (ORR) of 96.0% (95% CI, 79.6%-99.9%) compared with 73.5% (95% CI, 63.9%-81.8%) for those in the high-risk group. Additionally, 20.8% of patients in the low-risk group proceeded to allogeneic stem cell transplant (allo-SCT) vs 17.3% of patients in the high-risk group.
In the low-risk group, the median duration of remission (DOR), event-free survival (EFS), and overall survival (OS) were all not evaluable (NE). In the high-risk group, patients experienced a median DOR of 14.2 months (95% CI, 8.2-NE), a median EFS of 9.0 months (95% CI, 5.8-15.1), and a median OS of 14.1 months (95% CI, 10.7-17.1).
“The CAR-HT risk score correlated with disease burden in this patient population,” lead study author Karamjeet Sandhu, MD, said in a presentation of the data. “Risk stratification for hematotoxicity could provide an early indicator for [the] likelihood of treatment benefit and guiding treatment decisions for some of these subgroups.”
In November 2024, the FDA approved obe-cel for the treatment of adult patients with relapsed or refractory B-cell precursor ALL, based on previously reported data from FELIX.2
Digging into the CAR-HT Analysis Methodology
The CAR-HT model was created to stratify patients with large B-cell lymphoma into groups based on the risk of hematotoxicity prior to the receipt of CAR T-cell therapy.1 FELIX study investigators adapted this model for relapsed/refractory B-ALL with the goal of evaluating its potential role as an early indicator of treatment benefit with obe-cel.
The model accounts for baseline characteristics such as platelet count, absolute neutrophil count, hemoglobin level, c-reactive protein level, and ferritin level; between 0 and 1 points are assigned for each parameter, except for platelet count and ferritin level, where 0 to 2 points could be assigned. Patients with less than 2 total points are considered low-risk; those with 2 or more points are deemed high risk.
FELIX enrolled patients at least 18 years of age with relapsed/refractory B-ALL. The trial included 3 cohorts: cohort A enrolled patients with a bone marrow blast level of at least 5% at screening; cohort B included patients with minimal residual disease (MRD)–positive disease at screening; and cohort C enrolled patients with isolated extramedullary disease at screening.
After leukapheresis, patients were allowed to undergo bridging therapy prior to receiving lymphodepleting chemotherapy with 30 mg/m2 of fludarabine per day for 4 days and 500 mg/m2 of cyclophosphamide per day for 2 days. Obe-cel was administered as a split-dose infusion. Patients with a bone marrow blast level of no more than 20% received the agent at 100 x 106 CAR T cells on day 1, then 310 x 106 CAR T cells on day 10. Those with a bone marrow blast level above 20% received obe-cel at 10 x 106 CAR T cells on day 1 and 400 x 106 CAR T cells on day 10. Irrespective of the split-dosing regimen, the final target dose was 410 x 106 CAR T cells.
The trial’s key end points included complete response (CR)/CR with incomplete hematologic recovery rate; DOR; EFS; OS; MRD-negativity rate; safety; CAR T-cell expansion and persistence; and manufacture feasibility.
The median age was 54.0 years (range, 26-81) in the low-risk group vs 46.5 years (range, 20-77) in the high-risk group. Seventy-two percent of patients in the low-risk group were male compared with 47.1% of patients in the high-risk group. Twenty-eight percent and 30.4% of patients were Hispanic/Latino, respectively.
Patients in the low-risk group received a median of 2 prior lines of therapy (range, 1-5) vs 2 prior lines (range, 1-6) in the high-risk group. Forty-eight percent and 32.4% received at least 3 prior lines of therapy, respectively. Eighty percent of patients in the low-risk group received prior treatment with blinatumomab (Blincyto) or inotuxumab ozogamicin (Besponsa) vs 51.0% of patients in the high-risk group. Twenty-four percent and 14.7% of patients, respectively, received both agents. Prior allo-SCT was received by 56.0% of patients in the low-risk group vs 41.2% of patients in the high-risk group.
Sixteen percent and 5.9% of patients in the low- and high-risk groups, respectively, had Philadelphia chromosome (Ph)–like disease; the respective rates of Ph-positive disease were 36.0% and 26.5%. Twenty percent and 21.6% of patients, respectively, had extramedullary disease at lymphodepletion. The median bone marrow blast level at lymphodepletion was 7.0% (range, 0%-90%) in the low-risk group vs 45.5% (range, 0%-100%).
Eighty-four percent of patients in the low-risk group underwent bridging therapy during the study compared with 95.1% of patients in the high-risk group. Bridging therapy for low-risk patients included chemotherapy alone (48.0%), chemotherapy plus a TKI (8.0%), chemotherapy plus inotuxumab ozogamicin (8.0%), inotuxumab ozogamicin alone (4.0%), and a TKI alone (16.0%). In high-risk patients, bridging therapies comprised chemotherapy alone (66.7%), chemotherapy plus a TKI (7.8%), chemotherapy plus inotuxumab ozogamicin (6.9%), inotuxumab ozogamicin alone (7.8%), a TKI alone (2.9%), steroids (2.0%), and other (1.0%).
CAR-HT scores were correlated with disease burden at lymphodepletion. In the low-risk group, 60.0% of patients had a bone marrow blast level of no more than 20% compared with 36.3% of patients in the high-risk group. A bone marrow blast level of more than 75% was observed in 8.0% of patients in the low-risk group vs 37.3% of patients in the high-risk group.
Safety by CAR-HT Risk Group
The rates of any-grade cytokine release syndrome (CRS) were 56.0% in the low-risk group vs 71.6% in the high-risk group. The respective rates of grade 3 or higher CRS were 0% and 2.9%. The median time to onset of CRS was 10.0 days (range, 2.0-14.0) and 8.0 days (range, 1.0-23.0), respectively, and the respective durations of CRS were 4.0 days (range, 1.0-6.0) and 6.0 days (range, 1.0-21.0).
Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 12.0% of patients in the low-risk group vs 25.5% of patients in the high-risk group. The rates of grade 3 or higher ICANS were 8.0% and 6.9%, respectively. The respective times to onset of ICANS were 11.0 days (range, 3.0-15.0) and 12.5 days (range, 1.0-31.0). The duration of ICANS was 8.0 days (range, 5.0-8.0) in the low-risk group vs 8.5 days (range, 1.0-53.0) in the high-risk group.
Any-grade infections were reported in 50.0% of patients in the low-risk group vs 57.3% of patients in the high-risk group. The rates of grade 3 or higher infections were 12.5% and 26.7%, respectively.
Deaths at any time following obe-cel infusion occurred in 24.0% of patients in the low-risk group vs 56.9% of patients in the high-risk group.
The median time to neutrophil count recovery was 0.8 months (95% CI, 0.7-1.9) in the low-risk group vs 1.9 months (95% CI, 1.5-2.0) in the high-risk group. The respective times to platelet count recovery were 0.6 months (95% CI, 0.0-1.9) and 2.1 months (95% CI, 1.9-2.3).
A Look at the ALL-Hematotox Model
Since the majority of patients enrolled in FELIX were classified as high risk using the CAR-HEMATOTOX model, investigators also explored the ALL-Hematotox (ALL-HT) model released by the National Cancer Institute in 2024. The 2 models use similar parameters, except ALL-HT replaces ferritin levels with bone marrow blast percentage. Additionally, 3 total points or fewer is considered low risk in this model.
When reclassifying patients based on the ALL-HT model, 43.3% of patients (n = 55) fell into the low-risk/unknown group, and 56.7% (n = 72) were considered high risk.
Using the ALL-HT model, the median DOR and EFS were both NE for the low-risk group. For the high-risk group, the median DOR was 11.0 months (95% CI, 5.2-21.2), and the median EFS was 5.7 months (95% CI, 2.8-9.0).
“A preliminary analysis using the ALL-HT model identified a greater proportion of patients [as] low risk [compared with] the CAR-HT model. We look forward to presenting a full analysis [using the ALL-HT model] at a future congress,” Sandhu concluded.
Disclosures: Dr Sandhu reported serving as a consultant for Autolus Therapeutics.
References
- Sandhu KS, Park JH, Shaughnessy P, et al. Risk factors associated with sub-optimal outcomes and hematotoxicity following obecabtagene autoleucel (obe-cel) for relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Presented at: 2025 Transplant and Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Abstract 10.
- FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed February 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute
