Introduction Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a common hematological malignancy in adults, classified as a subtype of acute lymphoblastic leukemia (ALL). It accounts for approximately 20% to 30% of adult ALL patients, and reaches 50% among patients over 60 years old. Over the past two decades, the development of tyrosine kinase inhibitors (TKIs), particularly third-generation TKIs, along with advancements in novel therapies, has led to significant improvements in patient outcomes. The crucial role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a necessary treatment option is facing challenges.

Methods We conducted a single-center observational study on 740 Ph+ ALL patients diagnosed from January 2009 to September 2024 for a total of 15 years, to summarize the clinical, cytogenetic, and molecular genetic characteristics; to analyze the data of patients undergoing allo-HSCT or chimeric antigen receptor T-cell (CAR-T) therapy; to analyze the impact of clinical laboratory characteristics, types of frontline TKIs, and treatment regimens on the survival of Ph+ ALL patients.

Results Baseline characteristics of 740 patients with Ph+ ALL were analyzed, with a median age of 39 years and 51.0% male. The P190 type of BCR-ABL1 fusion gene transcripts was the most common (65.6%), and 11 rare BCR-ABL1 transcripts were detected. Treatment characterization revealed that 95.1% of patients received frontline TKIs and 91.8% achieved complete remission (CR) after induction therapy. 22.9% of patients achieved a complete molecular response (CMR), and 14.1% achieved a major molecular response (MMR). Among the frontline TKIs, the first-generation TKI imatinib has the highest usage rate (45.3%), followed by the second-generation TKIs dasatinib (32.3%) and flumatinib (8.7%). 4.8% of patients received frontline olverembatinib treatment. A total of 71.1% of patients received allo-HSCT or CAR-T, or CAR-T bridging allo-HSCT. Overall, patients had a 2-year overall survival (OS) rate of 73.8% and a 2-year relapse-free survival (RFS) rate of 59.1%. Patients undergoing allo-HSCT had superior survival, with the most common being haploidentical transplantation (50.9%), followed by matched sibling (26.1%) and matched unrelated (15.8%) transplantation, with no significant difference in OS and RFS among the three types. The optimal prognosis of transplant patients was achieved with transplantation in first complete remission and the attainment of CMR status. The molecular genetic alterations in Ph+ ALL were most frequent with RUNX1 mutations (11.4%), followed by SETD2 mutations (11.0%). The most common additional chromosomal abnormalities (ACAs) were complex karyotype (43.3%), +Ph (34.9%), -7/7q- (28.8%), and monosomal karyotype (27.0%). +Ph karyotype coexisted significantly with complex karyotype (p<0.001). Patients with ACAs had the worst prognosis compared to those with normal karyotype and Ph alone karyotype, but the prognostic difference was not significant among those undergoing allo-HSCT. Univariate analysis revealed that the diagnosis year between 2018 and 2024, frontline second-generation or third-generation TKIs, molecular response after induction, and CAR-T bridging allo-HSCT for consolidation were favorable factors for OS and RFS. Multivariate analysis showed that old age, high white blood cell count, and complex karyotype were independent unfavorable factors for OS and RFS.

Conclusions In the era of TKIs, novel therapies provide deeper responses and improved survival when incorporated in frontline treatment. Transplant patients should achieve a deep molecular response before transplantation. +Ph karyotype coexisted significantly with complex karyotype. The most common genetic alterations in Ph+ ALL patients are RUNX1 and SETD2 mutations. Patients with ACAs have the worst prognosis compared to those with normal karyotype and Ph alone karyotype, and the impact is less significant under the allogeneic transplantation model. A complex karyotype is an independent unfavorable factor that significantly impacts the prognosis.

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2025
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