Ponatinib and palbociclib combination in TKI-resistant CML-A case report

Background Chronic myeloid leukemia (CML) is a hematological malignancy characterized by BCR-ABL1-derived permanent proliferation of myeloid progenitor cells. BCR-ABL1 tyrosine kinase inhibitors (TKI) are effective first-line therapeutic options to suppress tumor proliferation. However, TKI therapy is not always curative and drug-related side effects as well as drug resistance may evolve over time, necessitating salvage therapies. Methods In this case report we present a 68-year-old woman who developed second- and third-generation TKI therapy resistance with BCR-ABL1(T315I) and BCR-ABL1(E255V) mutation. Considering contraindication for hematopoietic stem cell transplantation, we treated the patient in an individual treatment attempt with a third-generation TKI ponatinib in combination with palbociclib, a CDK4/CDK6 inhibitor, which has been shown to effectively inhibit proliferation of BCR-ABL1(T315I)-mutated cells in vitro. Results Our case study shows strong antineoplastic effects using this combination in an advanced CML patient resistant to ponatinib monotherapy as a fourth-line treatment. Combined administration of ponatinib/palbociclib at full dose showed almost a tenfold decrease (42.6 to 4.4 (IS)%) of BCR-ABL1-positive cells but with simultaneous hematopoietic toxicity, necessitating dose reduction. Conclusion This combination treatment showed high clinical activity. However, biological activity needs to be further characterized in prospective clinical trials.

Automated summary

This case study presents a 68-year-old woman with resistance to second- and third-generation TKI therapy due to BCR-ABL1(T315I) and BCR-ABL1(E255V) mutations. An individualized treatment approach using the third-generation TKI ponatinib in combination with palbociclib showed strong antineoplastic effects in this patient resistant to ponatinib monotherapy. Further characterization of the biological activity of this combination treatment is needed in prospective clinical trials.