Ponatinib and Bosutinib Discontinuation in Chronic Myeloid Leukemia (CML): Single Center Experience
Authors: Alfayez Mansour , Kantarjian Hagop M. , Kadia Tapan M. , Garcia-Manero Guillermo , Ravandi Farhad , Borthakur Gautam , DiNardo Courtney D. , Rios Mary B. , Jabbour Elias J. , Cortes Jorge E. 
Published: October 2019

Abstract
Background: Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) approved for front-line and subsequent lines of therapy in CP-CML, and ponatinib is a potent TKI of unmutated and mutated BCR-ABL including (T315I). Both medication are commonly used in CML treatment. Multiple trials have demonstrate treatment-free remission in first and second generation TKIs, however discontinuation data on ponatinib and bosutinib are very limited. We herein report our experience on ponatinib and bosutinib discontinuation.
Methods: A retrospective review of CML patients receiving ponatinib and bosutinib at our institution was conducted. Patients who discontinued their treatment were included. Patient were assessed for status at time of TKIs discontinuation, outcome after discontinuation and subsequent therapies.
Results: Fifteen patient were included in our analysis (8 bosutinib, 7 ponatinib). Median age was 66 years (range, 38 - 86) and 40% were males. The median number of prior TKIs was 1 (range, 1-3). All patients were in chronic phase at the time of start of therapy except one patient in accelerated phase (ponatinib). The major reason of discontinuation was adverse events (87%), most commonly vascular events [Table. 1]. ABL kinase mutations had been detected in 40% before the start of therapy with bosutinib or ponatinib, including 3 patients with T315I mutation (all treated with ponatinib). With median follow up of 14.6 months, 4 of 12 (33.3%) patients with undetectable transcripts prior to discontinuation had detectable transcripts after discontinuation, however only 2 patients (17%) lost MMR. In the total cohort, 4 (27%) patients lost MMR (ponatinib n=2, bosutinib n=2). The median time to loss of MMR was 5.8 months (range, 5.1 to 6.7). Only 1 of 3 pts with T315I prior to therapy has lost MMR. None of the patients with undetectable transcripts for more than 15 months has had re-emergence of detectable transcripts. Failing to achieve MR4.5 prior to discontinuation was a strong predictor of relapse with hazard ratio 40.23 (95% CI 1.872 to 864.4) (p=0.0474) [figure. 1]. One patient died with undetectable transcripts >3 years after bosutinib discontinuation. Two of the 4 pts who lost MMR have resumed therapy (same drug as they were taking prior to stopping) and both re-gained MR4/4.5 by the time of this report. The other 2 had a recent relapse and had not resumed therapy.
Conclusion: With the constraints of the small numbers, treatment discontinuation ponatinib and bosutinib seems to be similarly safe as discontinuation of other TKI. Patients who lost MMR were able to regain response after resuming therapy. Achieving CMR was the strongest predictor of success in our date with no relapses seen in patients who achieved CMR for more than 15 months. Our sample size is small and our follow up was short, further confirmatory studies are needed.

Disclosures
Kadia: Takeda: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; BMS: Research Funding; Celgene: Research Funding. Ravandi:Amgen: Honoraria, Research Funding, Speakers Bureau; Xencor: Research Funding; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria. DiNardo:Agios: Consultancy; Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Karyopharm: Honoraria. Jabbour:Abbvie: Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding.