Asciminib is a novel inhibitor of ABL1 and ABL2 gene fusions in ALL but requires the ABL SH3 domain for efficacy.

High-risk Ph-like ALL includes genomic rearrangement of the ABL1 and ABL2 genes (collectively ABL-rearranged, ABLr), and novel treatments are required. For the first time, we demonstrate asciminib efficacy in ABLr ALL, but only when the ABL SH3 domain is present.

Case report: Rare case of donor cell-derived T-cell acute lymphoblastic leukaemia in a female patient after receiving an allo-transplant from her male sibling.

Donor-derived haematological neoplasms, in which recipients present with haematological malignancies that have evolved from transplant donor stem cells, have previously been described for myelodysplastic syndrome, myeloproliferative neoplasms, acute myeloid leukaemia and less often, leukaemias of lymphoid origin. Here we describe a rare and complex case of donor-derived T-cell acute lymphoblastic leukaemia with a relatively short disease latency of less than 4 years. Through genomic and in vitro analyses, we identified novel mutations in NOTCH1 as well as a novel activating mutation in STAT5B; the latter targetable with the clinically available drugs, venetoclax and ruxolitinib.

In-vitro modeling of TKI resistance in the high-risk B-cell acute lymphoblastic leukemia fusion gene RANBP2-ABL1 - implications for targeted therapy.

Acute lymphoblastic leukemia remains a leading cause of cancer-related death in children. Furthermore, subtypes such as Ph-like ALL remain at high-risk of relapse, and treatment resistance remains a significant clinical issue. The patient-derived Ph-like ALL RANBP2-ABL1 fusion gene was transduced into Ba/F3 cells and allowed to become resistant to the tyrosine kinase inhibitors (TKIs) imatinib or dasatinib, followed by secondary resistance to ponatinib. RANBP2-ABL1 Ba/F3 cells developed the clinically relevant ABL1 p.T315I mutation and upon secondary resistance to ponatinib, developed compound mutations, including a novel ABL1 p.L302H mutation. Significantly, compound mutations were targetable with a combination of asciminib and ponatinib. In-vitro modeling of Ph-like ALL RANBP2-ABL1 has identified kinase domain mutations in response to TKI treatment, that may have important clinical ramifications. Early detection of mutations is paramount to guide treatment strategies and improve survival in this high-risk group of patients.