PHILADELPHIA ACUTE LYMPHOBLASTIC LEUKEMIA (PH+ ALL) OR BLASTIC CRISIS OF CHRONIC MYELOID LEUKEMIA (CML-BC)?

Abstract

Introduction: The presence of BCR::ABL1 gene rearrangements (Philadelphia Chromosome) in acute lymphoblastic leukemia (Ph+ ALL) at diagnosis is critical for prognostic stratification and treatment decisions. Distinguishing between Ph+ ALL and lymphoid blast crisis of chronic myeloid leukemia (CML-BC) is challenging. While most Ph+ ALL cases present with a p190 (e1a2) fusion, a subset displays p210 (e13a2 or e14a2) or p230 fusions. It remains unclear whether these cases are true de novo Ph+ ALL or undiagnosed chronic phase CML progressing to blastic crisis. Methods: Retrospective analysis of patients diagnosed with ALL (characterized by > 20% lymphoblasts) referred for hematopoietic cell transplantation (HCT) between 2019 and 2024, who exhibited t(9;22)(q34;q11) or BCR::ABL1 rearrangements identified through cytogenetic analysis or RT-PCR. The relationship between transcript subtypes identified through molecular biology and clinical, morphological, and phenotypic characteristics, and minimal residual disease (MRD) via RQ-PCR (molMRD) and flow cytometry (flowMRD) were analysed in relation to survival outcomes. Results: 30 ALL patients assessed between 2016 and 2024 had Ph+ (24% of 125 ALL), 18M/12F, 22 adults median age 36.6 years (range 19-75.6) and 8 children (4.77 y, range 3.8-14). Twenty patients with p190 (e1a2) transcript were classified as Ph+ ALL (17 B-cell Ph+ ALL and 3 early T-cell Ph+ ALL) and 10 patients with p210 transcript were classified as having CML blastic crisis. In the CML group, transcript subtypes included e13a2 (b2a2) in 2 patients, e14a2 (b3a2) in 1, and multiple associated transcripts (b2a2 and/or b3a2 with e1a2) in 7 patients. Of these 10 patients, only 2 had a prior CML history with previous ITK use; 4 presented with extramedullary disease (2 CNS, 1 breast, 1 liver), and 4 had leukocytosis with neutrophilia in the initial CBC, suggesting myeloid involvement. The Ph+ ALL group had a lower median age at diagnosis (23.9 vs. 41.8 years) compared to the CML-BC group, lower median leukocyte (5,565 vs. 57,850/uL) and platelet counts (32,000 vs. 134,000/uL) at diagnosis. There were no differences in precursor left shift or blast predominance between groups. All patients received polychemotherapy including tyrosine kinase inhibitors (TKIs). Early death due to refractory disease occurred in five older adult patients (16.6%). Three children and two AYA patients maintained a complete response to TKI therapy. Twenty patients (7 BC-CML and 12 Ph+ ALL) underwent HCT; five of these relapsed, with three undergoing a second HCT and two dying due to relapsed disease. No differences was found in overall survival (63.6% vs. 50.0%, p = 0.25), median survival time (14.5 years vs. 2.5 years), or relapse rates between groups. MRD was evaluated using RQ-PCR and MFC at 1-, 2-, and 3 months post-transplantation. MRD analysis showed a strong correlation between MFC and RQ-PCR results (r = 0.643, 95% CI 0.50-0.74, p 0.01% MRD by PCR, the proportion of those containing ALL cells according to MFC remained high (28 of 30, 93.3%). Conclusion: In conclusion, this retrospective study underscores the complexity in distinguishing Ph+ ALL from CML-BC and highlight the importance of comprehensive molecular and phenotypic analyses in guiding treatment strategies and prognostication. Future research should focus on refining methodologies for MRD assessment of Ph+ ALL patients and exploring their synergistic potential to better distinguish between Ph+ ALL and CML-BC.