Adult B-cell acute lymphoblastic leukemia (B-ALL) with high-risk genetic abnormalities is associated with poor prognosis and a high risk of relapse despite advances in chemotherapy and transplantation strategies. Identifying effective therapeutic approaches for this challenging patient population remains a critical unmet need. Yorwida, a CD19-targeted CAR-T cell therapy, has shown promising activity in real-world settings, prompting further evaluation of its role in genetically high-risk adult B-ALL.
In this real-world study led by Professor Yuhua Li at Zhujiang Hospital of Southern Medical University, Yorwida demonstrated favorable clinical efficacy in adult B-ALL patients with high-risk genetic features, partially offsetting the adverse prognosis associated with isolated MLL rearrangements or IKZF1 alterations. However, patients harboring multiple high-risk genetic abnormalities experienced significantly shorter relapse-free survival. The findings also suggest that early use of CAR-T therapy as first-line consolidation in CR1-MRD-negative patients may provide improved outcomes compared with later-line or MRD-positive settings, while no clear RFS benefit was observed from post-CAR-T combination therapies, highlighting the need for longer follow-up and larger patient cohorts.
Background
Adult B-cell acute lymphoblastic leukemia (B-ALL) patients with high-risk genetic alterations have poor outcomes. Conventional treatments, including chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), are associated with high relapse rates in this population. Nakiolunxai Injection is currently the only CD19-targeted CAR-T cell therapy approved by China’s National Medical Products Administration (NMPA) for adult relapsed/refractory (R/R) B-ALL. Real-world studies suggest potential benefits in patients with high-risk genetic features; however, its clinical efficacy in this specific subgroup requires further clarification.
Results
Across the entire cohort, median RFS and overall survival (OS) were not reached. Among 41 patients, high-risk genetic abnormalities were distributed as follows: MLL rearrangement (n=9); IKZF1 alterations (n=19; 7 mutations, 12 deletions); TP53 mutations (n=4); and ≥2 high-risk genetic factors (n=9). Statistical analysis showed that patients with ≥2 high-risk factors had a median RFS of 101 days (95% CI: 0–345), significantly shorter than those with MLL rearrangement or IKZF1 alteration (median RFS not reached; P=0.00064).
Regarding treatment timing, 13 patients received Nakiolunxai in first complete remission with MRD negativity (CR1-MRD-negative); 3 patients in CR1-MRD-positive status; and 25 patients in the R/R setting. The CR1-MRD-negative group showed a trend toward improved RFS compared with CR1-MRD-positive and R/R groups (not reached vs. 404 days [95% CI: 30–777]; P=0.073).
Post-CAR-T management included combination therapy in 20 patients (TKIs n=3; zanubrutinib n=1; pomalidomide n=2; venetoclax n=3; blinatumomab n=1; inotuzumab ozogamicin n=1; allo-HSCT n=4), while 21 patients were observed without additional treatment. No significant difference in median RFS was observed between the two groups (404 days [95% CI: 104–703] vs. not reached; P=0.49).
The incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) was 68.3% and 7.3%, respectively. Grade ≥3 CRS and ICANS occurred in 2.4% and 4.9% of patients. All patients recovered without long-term sequelae.
