New Genetic Alterations Identified in Philadelphia chromosome-ALL

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(ChemotherapyAdvisor) – Newly-identified genetic aberrations in high-risk childhood Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-ALL) might allow new targeted-inhibition therapies using existing anti-leukemia agents, reports a team of US and Canadian researchers in the journal Cancer Cell.

The new study reports a comprehensive genome-wide analysis of genetic alterations seen in Ph-ALL cells, including a number of alterations affecting kinase and cytokine receptors.

“Although a range of aberrations were identified in Ph-like ALL, the activation of ABL1 and/or JAK/STAT signaling pathways was the most common mechanism for transformation,” noted Christin J. Harrison, MD, Professor of Childhood Cancer Cytogenetics at the Northern Institute for Cancer Research, New Castle University, UK, in an accompanying essay.

“Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the outcome of these patients may be improved with targeted therapy,” lead study author Kathryn Roberts, MD, and colleagues report.

Ph-ALL is a subgroup of high-risk, poor-prognosis disease that represents 10% childhood B-cell leukemias and 15% of high-risk/poor-prognosis childhood B-cell ALL. The genetic translocation t(9;22)(q34;q11.2) causes the BCR-ABL1 fusion seen in Ph-positive ALL, leaving Ph-ALL patients more prone to relapse.

“The dramatic improvement in outcome observed in Ph+ B-ALL patients treated with chemotherapy and imatinib and our demonstration that Ph-like leukemic cells are sensitive to currently available TKIs provide a strong rationale to test chemotherapy plus TKI treatment in Ph-like ALL patients,” Dr. Roberts and her colleagues wrote.

Patients identified in initial screening as having Ph-ALL should undergo additional genetic testing to identify candidates for treatment combining chemotherapy with ABL1, PDGFRB or JAK inhibitors, they wrote.

“It is important to note that rare non-Ph-like patients that harbor kinase alterations (e.g., NUP214-ABL1) may also benefit from the addition of TKI therapy,” the authors reported.


Companion essay

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