Abstract
Abstract： Background: Frontline treatments combining immunotherapy, particularly blinatumab, with tyrosine kinase inhibitors (TKIs) have shown strong efficacy in treating Philadelphia chromosome-positive B-acute lymphoblastic leukemia (Ph+B-ALL), providing a solid foundation for effective intervention. Recent studies suggest that CAR-T therapy not only achieves deep molecular remission but also effectively targets extramedullary disease. However, the potential of a single infusion of CD19 CAR-T as front-line consolidation, combined with TKI therapy, to further eliminate residual leukemia cells and reduce the risk of relapse in newly diagnosed adult Ph+B-ALL patients remains largely unexplored.
Methods: Building on these findings, we conducted a single-arm, Phase 2 clinical trial to assess this issue. This prospective study enrolled treatment-naïve adults (≥18 years) with Ph+B-ALL. Patients received the TKI combine with low-dose chemotherapy (overembatinib, vincristine, prednisone and venetoclax) as induction therapy, followed by 1-2 cycles of TKI combine with oral regimens (olverembatinib, venetoclax, and prednisone) as outpatient consolidation treatment. Then, a single infusion of murine-derived second-generation CD19-directed CAR T-cells (with a 4-1BB co-stimulatory domain) during first remission. Maintenance therapy included alternating administrations of vincristine, methotrexate, mercaptopurine, prednisone, venetoclax, and oral TKI. Intrathecal methotrexate (MTX), cytarabine, and dexamethasone were administered for central nervous system (CNS) prophylaxis. (ClinicalTrials.gov: NCT06481228).
Results: As of the cutoff date in February 2025, a total of 35 patients with newly diagnosed Ph-negative B-ALL received frontline CD19 CAR-T consolidation therapy and were included in the efficacy and safety analyses. The cohort had a median age of 39 years (range: 20–60), with 51.4% (18/35) being male, all patients were Asian. Transcript subtype analysis showed that 88.6% (n=31/35) expressed the p190 transcript, 8.6% (3/35) expressed p210, and 2.9% (1/35) had the e13a3/e14a3 BCR-ABL fusion. All patients achieved complete remission (CR) prior to CAR-T infusion. Baseline MRD assessment revealed that 5.7% (2/35) had flow cytometry evidence of disease (above the lower limit of detection), 22.9% (8/35) tested positive for BCR-ABL1 by RQ-PCR, and 14.8% (4/27) had detectable IgH clones by NGS before infusion (>10-6). Following CAR-T therapy, All (100%, 35/35) patients achieved MRD negativity by flow cytometry, 11.4% (4/35) remained BCR-ABL1 positive, including those with the e13a3/e14a3 subtype. Notably, NGS with a sensitivity of 10-6confirmed that leukemia clones were undetectable in all patients with in three months, indicating deep molecular remission despite the persistence of residual transcript expression.
After a median follow-up of 10.9 months, the 1-year overall survival (OS) rate was 100%, and the 1-year leukemia-free survival (LFS) rate was also 100%. No patients experienced bone marrow or extramedullary relapse, and 3 patients underwent hematopoietic stem cell transplantation (HSCT) during CR1 based on patient preference, with all remaining in sustained remission.
Regarding toxicity, a total of 26 patients (74.3%) experienced cytokine release syndrome (CRS), all of whom had grade 1 severity, with no occurrences of immune effector cell-associated neurotoxicity syndrome (ICANS).
Conclusion: Front-line CAR-T therapy as consolidation in newly diagnosed Ph⁺B-ALL patients is a safe and effective regimen, resulting in deep remission without the need for intensive chemotherapy, and offering hope for sustained remission.
Key words：Acute lymphoblastic leukemia, Front-line CAR-T, Consolidation therapy
