Sequential Philadelphia-Positive Pre-B Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia With Distinct BCR::ABL1 Fusion Transcripts.
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BACKGROUND: The sequential emergence of chronic myeloid leukemia (CML) following Philadelphia-positive acute lymphoblastic leukemia (ALL) is exceedingly rare, and its biological basis remains uncertain. CASE: We report a 15-year-old boy initially diagnosed at age 4 with Philadelphia-positive pre-B ALL expressing p190 BCR::ABL1. He achieved deep molecular remission following chemotherapy per the COG AALL0232-based high-risk B-ALL protocol plus imatinib. Approximately 5 years after his last documented follow-up, he re-presented with splenomegaly, leukocytosis, anemia, and thrombocytosis. Bone marrow findings supported chronic-phase CML, confirmed by detection of BCR::ABL1 p210 (b2a2 and b3a2) with no detectable p190. Responses to imatinib and dasatinib were suboptimal, and kinase-domain analysis identified a rare ABL1 c.1159T>A (p.Leu387Met) variant. He subsequently underwent matched-related allogeneic hematopoietic stem cell transplantation and remains BCR::ABL1-negative on nilotinib. CONCLUSION: This case expands the spectrum of sequential Philadelphia-positive leukemias by documenting p190-positive pre-B ALL followed by p210-positive chronic-phase CML, accompanied by detection of the rare L387M variant and suboptimal responses to imatinib and dasatinib. The biological relationship between the two Philadelphia-positive malignancies remains uncertain, with possible explanations including evolution from a shared Philadelphia-positive precursor, therapy-related leukemogenesis, or an independent second malignancy. This case provides unique insight into the biological complexity of sequential Philadelphia-positive leukemias and adds to the evolving literature regarding the clinical significance of the L387M variant in TKI response. The unsupervised TKI interruption underscores that any consideration of treatment discontinuation should occur only under specialist supervision with close molecular monitoring, while the discordance between the observed response and reported L387M sensitivity patterns warrants further investigation.