Synergistic effect of asciminib with reduced doses of ponatinib in human Ph + myeloid leukemia with the T315M mutation.

Abstract

In Philadelphia chromosome-positive (Ph +) leukemia, substitution of threonine at the 315 position of BCR::ABL1 with isoleucine (T315I) induces severe resistance to tyrosine kinase inhibitors (TKIs). Of clinical importance, the substitution of the baseline T315I mutation by methionine (I315M) was reported in a Ph + leukemia patient treated with ponatinib. The resultant T315M mutation induces severe TKI-resistance in a murine Ba/F3 model. Asciminib, an allosteric inhibitor of BCR::ABL1, is reportedly active in ponatinib-resistant patients with the T315I mutation. Although asciminib alone is not active in a murine Ba/F3 model with the T315M mutation, asciminib and ponatinib show synergistic activities. In the present study, we introduced the T315M mutation into the intrinsic BCR::ABL1 gene of two Ph + myeloid and one Ph + lymphoid leukemia cell lines using the CRISPR/Cas9 system to directly verify the utility of the combined asciminib and ponatinib in human models. All three T315M-acquired sublines were more resistant to TKIs including ponatinib than T315I-acquired sublines. Notably, asciminib exhibited a stronger synergistic effect with reduced doses of ponatinib in the T315M-acquired sublines of two myeloid cell lines, but not in the lymphoid cell line. This indicates that the combination of ponatinib and asciminib may have a clinical utility in human Ph + myeloid leukemia.