Impact of P190 and P210 BCR-ABL1 Chimeric Protein on Outcomes of Acute Lymphoblastic Leukemia in the Current Era

Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) represents a biologically distinct subtype of ALL with improved outcomes following the introduction of tyrosine kinase inhibitors (TKIs). However, differences between the P190 and P210 BCR-ABL isoforms remain poorly characterized. Methods: We retrospectively analyzed 156 adult ALL patients treated at the Cleveland Clinic between January 2017 and August 2023, including 47 Ph+ and 109 Ph− cases. Baseline characteristics, mutational profiles, treatment responses, and survival outcomes were compared across Ph−, P190+, and P210+ ALL subgroups. Minimal residual disease (MRD) was assessed by flow cytometry. Results: Ph+ ALL patients were older, predominantly of B-cell lineage, and had fewer TP53 or NOTCH1 mutations than Ph− ALL ( P < 0.05). Among Ph+ ALL with available isoform ( n = 140), 19 (13.6%) were P190+ and 12 (8.6%) were P210+. Mutations in IKZF1 were restricted to P190+ ALL. No overall survival (OS) or event-free survival differences were observed between Ph+ and Ph− ALL. However, when stratified by isoform, P210+ ALL had significantly higher odds of achieving MRD-negative response (odds ratio = 6.98, 95% confidence interval 1.14–135) and superior 12-month OS (100%) compared with P190+ ALL (74%). P190+ ALL showed lower MRD negativity (18%) and a smaller decline in BCR-ABL1 transcript levels. TKI type (imatinib vs. second-generation) was not associated with survival differences. Conclusions: Ph+ ALL comprises biologically and prognostically distinct subgroups defined by BCR-ABL isoform. P210+ ALL exhibits deeper molecular responses and improved early outcomes compared with P190+ ALL. Larger multi-institutional studies are warranted to validate these findings and optimize isoform-specific therapeutic strategies.