TKI rotation-induced persistent deep molecular response in multi-resistant blast crisis of Ph+ CML
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Peter Valent1,2, Susanne Herndlhofer1,2, Mathias Schneeweiß1, Bernd Boidol3, Anna Ringler3, Stefan Kubicek3, Karoline V. Gleixner1, Gregor Hoermann5, Emir Hadzijusufovic1,2, Leonhard Müllauer4, Wolfgang R. Sperr1,2, Giulio Superti-Furga3,6, Christine Mannhalter5
1Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
2Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria
3CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
4Department of Pathology, Medical University of Vienna, Austria
5Department of Laboratory Medicine, Medical University of Vienna, Austria
6Center for Physiology and Pharmacology, Medical University of Vienna, Austria
Peter Valent, email: [email protected]
Keywords: CML, ponatinib, nilotinib, BCR-ABL1 mutations, drug resistance
Received: December 14, 2016 Accepted: February 07, 2017 Published: February 18, 2017
In chronic myeloid leukemia (CML) resistance against one or more BCR-ABL1 tyrosine kinase inhibitors (TKI) remains a clinical challenge. Preclinical data suggest that TKI combinations may overcome resistance. We report on a heavily pre-treated 78 year-old female patient with CML who developed multi-resistant blast crisis with bone marrow fibrosis and a Ph- clone. Treatment with ponatinib resulted in blast cell clearance, decrease in fibrosis, and disappearance of BCR-ABL1, but also in severe thrombocytopenia with bleedings requiring platelet transfusions. We therefore switched from ponatinib to bosutinib. During bosutinib, platelet counts recovered. However, after 6 months, BCR-ABL1 mRNA levels increased to > 1%. Therefore, we ´switched back´ to ponatinib, and this was again followed by disappearance of BCR-ABL1 and a decrease in platelets. During the next 2 years, we applied ponatinib and bosutinib in continuous rotation-cycles and added hydroxyurea in order to suppress all sub-clones and to balance between efficacy and potential side effects following the principle of personalized medicine. With this approach the patient remained in complete molecular response and reached normal blood counts and a normal quality of life without vascular or other side effects. In conclusion, TKI rotation is a novel potent approach to suppress multiple resistant sub-clones and to balance between clinical efficacy and side effects in patients with advanced CML. Clinical trials are now warranted to show that TKI-rotation is in general safe and effective in these patients.
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