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Strategy for Overcoming BCR-ABL1T315I–Positive Clones in Resistant CML

By: Sarah Campen, PharmD
Posted: Monday, January 13, 2020

Development of tyrosine kinase inhibitor resistance in BCR-ABL1T315I–mutated subclones carries a poor prognosis for patients with chronic myeloid leukemia (CML). A study reported in EBioMedicine (published by The Lancet) revealed that targeting CDK4/CDK6 may be an effective approach to overcome treatment resistance in CML exhibiting the BCR-ABL1T315I mutation. Karoline V. Gleixner, MD, of the Ludwig Boltzmann Institute for Hematology & Oncology in Vienna, Austria, and colleagues found that hydroxyurea and the CDK4/CDK6 inhibitor palbociclib each inhibit the growth of BCR-ABL1T315I–mutated cells.

“Our data suggest that the application of novel drug combinations, such as asciminib plus hydroxyurea or ponatinib plus palbociclib in multiresistant CML expressing BCR-ABL1T315I or T315I-including compound mutations, may represent effective new therapies,” stated the authors.

Dr. Gleixner and colleagues investigated the effects of hydroxyurea and palbociclib on treatment-resistant CML cells, observing that hydroxyurea decreased the expression of CDK4 and CDK6. Hydroxyurea induced growth inhibition in CML cells exhibiting BCR-ABL1T315I, both in vivo in heavily pretreated patients and those with highly resistant disease, as well as in vitro in various cell-line models. However, this effect was not nearly as pronounced in CML cells displaying native BCR-ABL1. Hydroxyurea also synergized with ponatinib and asciminib to inhibit the growth of tyrosine kinase inhibitor–resistant and –sensitive CML cells in vitro. Palbociclib suppressed the proliferation in primary CML cells and synergized with ponatinib to inhibit growth in BCR-ABL1T315I–positive cells as well, suggesting that “suppression of CDK4/CDK6 may be a promising concept to overcome BCR-ABL1T315I–associated [tyrosine kinase inhibitor] resistance.”

Disclosure: For full disclosures of the study authors, visit thelancet.com.



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