Efficacy of Ponatinib after Multiple Lines of Therapy for Chronic Myeloid Leukemia
Authors: Swaminathan Mahesh , Kantarjian Hagop M. , Sasaki Koji , Ravandi Farhad , Borthakur Gautam , Kadia Tapan M. , Garcia-Manero Guillermo , DiNardo Courtney D. , Konopleva Marina Y. , Estrov Zeev E. , Pemmaraju Naveen , Daver Naval G. , Wierda William G. , Ferrajoli Alessandra , Pierce Sherry A. , Dellasala MD Emogene , Jabbour Elias J. , Cortes Jorge E. 
Published: October 2019

Abstract
Background: Ponatinib, a third-generation pan-tyrosine kinase inhibitor (TKI), was found to be effective in heavily pretreated patients (pts) with chronic myeloid leukemia (CML). With the availability of multiple TKI, these agents are used in different sequences, and there is limited information on the value of various TKI in different lines of therapy. Since ponatinib has been effective in 3rd and subsequent lines of therapy, we performed an analysis of a cohort of pts with CML who received ponatinib as a different line of treatment.
Method: A total of 80 pts with chronic phase of CML and received ponatinib from 2009 to 2018 were analyzed. Only pts who received ponatinib as a second or subsequent line of therapy of CML were included. Major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), molecular response (MR) 4, and MR 4.5 were assessed. Event-free (EFS), transformation-free (TFS), failure-free (FFS) and overall survival (OS) were also analyzed.
Results: Nine pts (11%) received ponatinib as a 2nd line therapy (prior TKI imatinib in 6, dasatinib in 1, and nilotinib in 2 pts); 21 (26%) as a 3rd line, 26 (33%) as a 4th line, and 24 (30%) as a 5th and above line. The median age was over 50 years (Y) in all the groups except for pts who received ponatinib as a 3rd line [38 Y (23-76)]. Among pts who received ponatinib as 2nd line, 9 (100%) achieved CCyR and MR 4.5; the median time to achieve CCyR and MR 4.5 was 3 and 6.8 months (mo), respectively (Table 1). In pts treated in 3rd line CCyR and MR 4.5 were 67% and 57%, respectively and the median time to response was 4.8 and 19.3 mo, respectively. Of the 26 pts treated in 4th line, 13 (50%) achieved CCyR (median time to CCyR 3 mo) and 7 (27%) achieved MR 4.5 (median time 11.6 mo). In 5th line and above 14 (58%) achieved CCyR (median time 6.4 mo) and 8 (33%) achieved MR 4.5 (median time 12.3 mo) (Figure 1). After a median follow-up of 59.8 months (range, 4.7 to 114.3) for all pts, the median OS was not reached in pts treated in 2nd to 4th line and 81.4 mo in ≥5th line. The median FFS was not reached in 2nd line, and was 45.6, 20.2, and 17.8 mo in 3rd, 4th, and ≥5th line, respectively. The median EFS and TFS was not reached in any line of treatment. The TFS was significantly better in pts who received ponatinib as a 2nd-4th line therapy as compared to ≥5th [p=0.0026, HR-55.97 (4.076-768.7)] (Figure 2).
Conclusion: Our results suggest that CCyR and MR 4.5 were higher when ponatinib was used in up to 4th line of therapy for resistant CML, and it was particularly effective in 2nd or 3rd line where high rates of MR4.5 can be achieved. These results underscore the efficacy of ponatinib in these settings.

Disclosures
Sasaki: Otsuka Pharmaceutical: Honoraria. Ravandi:Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau. Kadia:Takeda: Consultancy; Jazz: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; BMS: Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. DiNardo:Agios: Consultancy; Bayer: Honoraria; Medimmune: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Konopleva:Stemline Therapeutics: Research Funding; abbvie: Research Funding; cellectis: Research Funding; Immunogen: Research Funding. Pemmaraju:stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; samus: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; celgene: Consultancy, Honoraria; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; abbvie: Research Funding. Daver:ARIAD: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Consultancy; Incyte: Research Funding; Karyopharm: Research Funding; Kiromic: Research Funding; Pfizer: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding; Alexion: Consultancy; ImmunoGen: Consultancy; Karyopharm: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding.