Outcomes of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) Surviving More Than 5 Years (yrs) after Initial Therapy with TKIs
Authors: Tallis Eran , Kantarjian Hagop M. , Major Catherine Kendall , Vazquez Maria , Borthakur Gautam , Bose Prithviraj , Ravandi Farhad , Garcia-Manero Guillermo , Kadia Tapan M. , Wierda William G. , Ferrajoli Alessandra , Pemmaraju Naveen , Daver Naval G. , DiNardo Courtney D. , Konopleva Marina Y. , Kornblau Steven M. , Champlin Richard E , Jabbour Elias J. , Pierce Sherry A. , Cortes Jorge E. 
Published: October 2019

Abstract
Background: The introduction of tyrosine kinase inhibitors (TKIs) as the first line of treatment for CP-CML changed the natural history of the disease. The life expectancy of CML pts is now approaching that of the general population, with more pts having the option to discontinue treatments after achieving deep molecular response (DMR). In this study we sought to explore long-term outcomes of CML survivors including late relapses, durability of response, comorbidities, and feasibility of treatment discontinuation.
Methods: We performed a chart review of pts with CP CML treated at our institution with frontline TKIs who have survived at least 5 yrs from initiation of their treatment.
Results: We analyzed 388 pts treated with frontline TKIs between the years 2000-2011: 57% started treatment with imatinib, 22% with nilotinib and 21% with dasatinib. We grouped pts into two cohorts: those who received only one TKI throughout the entire follow up period (n= 299; 77%) and those who changed TKIs due to relapse or toxicity (n=89; 23%). The median follow up duration was 12 yrs [5-19] for both groups. Median overall Survival (OS) for pts surviving at least 5 yrs was not reached for those remaining on one TKI whereas OS for those who changed TKIs was 151 mo (p=0.27). For those who changed therapy, there was an equal distribution of initial TKI (p=0.67). Seventy patients (18%) required a change in TKI more than 5 years after starting treatment. After 5 years of treatment best response was MR4.5 in 66%, major molecular response (MMR) in 20%, complete cytogenetic response (CCyR) in 8%, partial cytogenetic response (PCyR) in 1%, and complete hematologic response (CHR) in 3%. Nine patients had lost CHR (2%) and 4 had progressed to blast phase before the 5 yr mark. At last follow up, 77% of patients had achieved MR4.5, 12% MMR, 3% CCyR, 1% PCyR, and 4% CHR. Eleven patients lost CHR (3%) with 6 patients progressing into blastic phase. Ninety two percent of patients with MR4.5 at 5 years of treatment maintained their response, and 8% lost MR4.5: 6% to MMR, 1% to CCyR, and 1% to CHR. Sixty six percent of patients with MMR at 5 years of treatment improved their response to MR4.5, 21% maintained MMR and 13% lost response - 5% to CCyR, 5% to CHR, and 3% lost CHR. Fifty five percent of patients in CCyR at 5 years improved their response to MMR (35%) or MR4.5 (19%) while 26% of patients lost cytogenetic response. Out of the patients who improved their response, 29% did so after starting a new TKI. More patients who never changed TKI achieved MR4.5 compared to those who who changed TKIs at some point (70%) (p=0.0021). Treatment discontinuation was considered for pts who sustained MR4.5. Forty nine pts (13%) discontinued TKIs after a median time of 9 yrs [5-17]. Withdrawal symptoms were observed in 24% of pts and primarily included joint or muscle pain. After a median follow up of 2 yrs [0-7] after discontinuation, 90% of pts remained in MR4.5. Five pts (10%) lost MR4.5 after discontinuation: 4 (8%) remained in MMR and 1 (2%) lost MMR to CHR. All these patients resumed therapy except for one who has sustained MMR still with no treatment. Patient's comorbidities were evaluated at initiation of treatment, at 5 yrs of follow up and at last follow up. An increase in patients' comorbidities was more pronounced for HTN and cardiovascular disease reaching up to 47% and 37% of patients at last follow up vs 26% and 13% at baseline respectively. Depression and/or anxiety were seen in 7% of patients at baseline and increased to 20% of patients at last F/U. Secondary malignancies developed in 48 pts (12%), mainly prostate cancer in 11 pts, non-melanoma skin cancer in 10 pts and melanoma in 5 pts. GU and colon cancers were seen in 1% of pts.
Conclusion: Survivors of CML have a generally favorable outcome. However late relapses may occur (14% in our series) often requiring a change in treatment. This underscores the need to continued monitoring beyond 5 years. Co-morbidities and second malignancies may also occur in many patients, underscoring the need for a holistic follow-up of these patients.

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