CD19 CAR-T Therapy for Patients with Relapsed or Refractory Philadelphia Chromosome-Positive B-Cell Acute Lymphoblastic Leukemia: A Multicenter Study

Background: Despite the increased remission rates achieved with chemotherapy-free regimens and other novel therapies for newly diagnosed Ph+ acute lymphoblastic leukemia (ALL), outcomes for patients with relapsed or refractory (R/R) Ph+ ALL remain unfavorable, highlighting the requirement for more potent treatments. In this study, we investigated the efficacy and safety of CD19 CAR-T therapy in these patients. Methods: From August 2015 to May 2024, a total of 80 patients with R/R Ph+ B-ALL were consecutively recruited from six centers for this study. All participants met the diagnostic criteria for Ph+ ALL as outlined by WHO classification, and their R/R status was defined according to the NCCN Guidelines, version 2.2021. Data on baseline characteristics, treatment details, CAR-T therapy toxicities, and clinical outcomes were systematically collected. Results: 80 patients with R/R Ph+ ALL were enrolled to assess the efficacy and safety of CD19 CAR-T therapy. The median age at infusion was 41 years (range 6-76), with 8 (10.0%) patients being ≥60 years. 18 (22.5%) had ECOG performance status of ≥3. The BCR::ABL1 p190 isoform was identified in 53 (66.3%) patients, while 25 (31.2%) had the p210 isoform, and 2 (2.5%) had both p190 and p210 isoforms. ABL1 kinase mutations were present in 51 (63.8%) patients, with 37 (46.3%) having the T315I mutation; 16 patients (20.0%) had a complex karyotype (≥3 abnormalities). Bone marrow blasts of ≥5% were found in 61 (76.2%) patients, and 40 (50.0%) had extramedullary disease. The median number of prior treatment lines was 6 (range 2-20), with 35 (43.8%) patients having been exposed to ≥2 TKIs, 5 (6.2%) having received prior blinatumomab, and 17 (21.3%) having undergone prior allo-HSCT. CRS was observed in 63 (78.8%) patients, with 13 (16.3%) patients experiencing grade ≥3 CRS, and one patient succumbing to grade 4 CRS. ICANS occurred in 8 (10.0%) patients, with two cases being grade ≥3. Treatment response was evaluated in 80 patients on day 30. The overall response rate (ORR; CR/CRi) for bone marrow (BM) disease was 87.5% (95% confidence interval [CI], 78.2-93.8). The MRD-negative rate was 86.3% (95% CI, 76.7-92.9), and the overall molecular remission rate (CMR/MMR) was 82.5% (95% CI, 72.4-90.1). Among CR patients, 18 (25.7%) bridged to allo-HSCT as consolidation therapy. At a median follow-up of 24.6 months (range 1.0-60.6), the median leukemia-free survival (LFS) was 8.5 months (95% CI, 5.9-11.1), with 6- and 12-month LFS rates of 65.6% and 41.9%, respectively. The median overall survival (OS) was 25.5 months (95% CI, 0-63.7), with 6- and 12-month OS rates of 91.5% and 70.1%, respectively. Multivariate analysis revealed that bridging allo-HSCT following CD19 CAR-T therapy was associated with superior LFS (p=0.024, HR=0.363, 95%CI 0.151- 0.875). The 6- and 12-month OS rates for the allo-HSCT group were 94.2% and 75.7%, respectively, compared to 90.4% and 68.1% for the non-allo-HSCT group. The 6- and 12-month LFS rates in the allo-HSCT group were 87.2% and 54.9%, respectively, compared to 57.6% and 36.9% in the non-allo-HSCT group. No statistically significant differences in LFS and OS were observed based on the presence or absence of prior allo-SCT, ABL1 kinase mutation, complex karyotype, high disease burden and the type of BCR::ABL1 isoform. Conclusions: These results indicate that CD19 CAR-T therapy can achieve a high response rate and potentially offer long-term clinical benefits to patients with R/R Ph+ ALL, with a manageable safety profile. In addition, CAR-T treatment bridging transplantation as consolidation therapy may suggest improved long-term survival. This analysis underscores the promise of CAR-T therapy as a viable treatment option for R/R Ph+ ALL.