Background Adult patients with B-cell acute lymphoblastic leukemia (B-ALL) harboring high-risk molecular alterations face an unfavorable prognosis. Traditional treatment modalities, including chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), are associated with a high recurrence risk in this population. Inaticabtagene Autoleucel (Inati-cel) injection, the only CD19-targeted chimeric antigen receptor T-cell (CAR-T) product approved by China's National Medical Products Administration (NMPA) for adult relapsed/refractory (R/R) B-ALL, has shown potential efficacy in real-world settings for subgroups with high-risk molecular alterations. However, its clinical effectiveness in this specific patient population requires further elucidation.

Methods This multicenter, non-interventional real-world study( ClinicalTrials.gov identifier: NCT06450067) enrolled 41 adult B-ALL patients with high-risk molecular alterations who received Inati-cel treatment between December 2023 and June 2025. The cohort included 12 males and 29 females with a median age of 42 years (range: 30-58 years) and a median follow-up duration of 166 days (95% confidence interval [CI]: 103-202 days).The timing of Inati-cel administration was determined based on physician's clinical judgment and patient preference. Following CAR-T cell infusion, patients were either administered combination therapy or underwent observational follow-up. The primary endpoint was defined as recurrence-free survival (RFS).

Results In the overall cohort, the median RFS and overall survival (OS) were both not reached. Among the 41 patients, the distribution of high-risk molecular alterations was as follows: 9 cases with MLL rearrangements, 19 cases with IKZF1 alterations (including 7 mutations and 12 deletions), 4 cases with TP53 mutations, and 9 cases with ≥2 high-risk factors. Statistical analysis revealed that the median RFS in the ≥2 high-risk factors group was 101 days (95% CI: 0-345 days). This values were significantly shorter than those in the MLL rearrangements/IKZF1 alterations groups (median RFS not reached, P=0.00064).Regarding treatment timing, 13 patients received Inati-cel during first complete remission with minimal residual disease negativity (CR1-MRD⁻), 3 patients in CR1 with minimal residual disease positivity (CR1-MRD⁺), and 25 patients in refractory or relapsed (R/R) status. The CR1-MRD⁻ group exhibited a trend toward superior median RFS compared to the combined CR1-MRD⁺ and R/R group (not reached vs. 404 days [95% CI: 30-777 days], P=0.073).In terms of post-CAR-T management, 20 patients received combination therapy (including three patients received tyrosine kinase inhibitors, one patients received zanubrutinib, two patients received pomalidomide, three patients received venetoclax, one patients received blinatumomab, one patients received inotuzumab ozogamicin, and four patients received allo-HSCT), while 21 patients underwent observation only. No significant difference in median RFS was observed between the two groups (404 days [95% CI: 104-703 days] vs. not reached, P=0.49).The incidence rates of CRS and ICANS were 68.3% and 7.3%, respectively, while grade ≥ 3 CRS and ICANS occurred in 2.4% and 4.9%, respectively. All patients recovered without sequelae.

Conclusion In adult B-ALL patients with high-risk molecular alterations, Inati-cel demonstrates favorable efficacy, partially mitigating the adverse prognosis associated with isolated MLL rearrangements or IKZF1 alterations. However, patients with ≥2 high-risk aberrations exhibit significantly shortened RFS. Front-line consolidation with CAR-T during CR1-MRD⁻ in patients with high-risk molecular alterations may yield better RFS outcomes compared to treatment administered in R/R or MRD⁺ settings. No RFS benefit from post-CAR-T combination therapy was observed in this cohort, highlighting the need for validation with longer follow-up durations and larger patient cohorts.

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2025
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