Patients with Chronic Myelogenous Leukemia May Not Want to Discontinue Tyrosine Kinase Inhibitor Therapy
Authors: Goldberg Stuart , Hamarman Stephanie 
Published: October 2019

Abstract

Introduction: The oral tyrosine kinase inhibitors (TKIs) have revolutionized the medical management of chronic myelogenous leukemia (CML). More than 70% of patients (pts) can expect to achieve complete cytogenetic remission (CCyR) and 20-40% will suppress bcr-abl transcript levels to major molecular response (MMR) by the end of the first year of treatment. With TKI therapy pts enrolled on clinical trials have achieved 5-year survival rates exceeding 90%. However TKI therapy requires daily oral administration for prolonged, if not indefinite, timeframes. Recently several large studies (including STIM, A-STIM, TWISTER, and EURO-SKI) have suggested that approximately 40% of pts in prolonged deep molecular remission can be safely discontinued from TKI therapy without clinical relapse. These pts avoid the chronic low grade toxicities, administration inconveniences and financial costs of TKI treatment, but are at theoretical risk of disease recurrence. It is currently unknown whether pts with CML who are responding to therapy are willing to accept these risks for the chance to become medication free.
Methods: 210 pts with chronic phase CML with at least 1 visit to the John Theurer Cancer Center at Hackensack University Medical Center between January 2010 and July 2015 (identified via the COTA platform) were mailed a 27 item anonymous survey to determine their opinions regarding TKI discontinuation.
Results: 84 (40%) pts returned the survey; median age 62 (range 25-90), gender 43:41 M:F; with CML duration less than 1 year 4%, 1-5 years 34% and more than 5 years 62%. Current TKI treatment consisted of 1st line imatinib 35%, dasatinib 14%, and nilotinib 5%. Salvage treatment strategies (>1st line) included imatinib 3%, dasatinib 20%, nilotinib 11%, bosutinib 2%, ponatinib 5%, ABL001 1%, and BMT 3%, with 18% currently off TKI medications. Among pts who switched therapies 62% changed for lack of efficacy and 38% changed for toxicities. Among pts currently on TKI 48% reported no side-effect, 44% minimal side-effects, and 8% moderate/severe side-effects. By pt report, 75% were in MMR, 9% were in CCyR, 12% thought the TKI was working, and 4% were unsure of response or not yet in remission. Self-reported adherence was 74% fully, 23% missing 1-3 days per month, and 3% missing >3 days per month. 15% were currently off TKI therapy as part of planned discontinuation, 12% had attempted monitored discontinuation unsuccessfully, 40% had discussed discontinuation but have not attempted, and 33% had not discussed this option. If offered TKI discontinuation 42% would want to try, 34% would wish to continue TKI therapy, and 25% were unsure. The main reasons given to discontinue TKI were a reduction in side-effects 40%, reduction in costs 30%, and reduction in inconvenience 26%. The main reasons given not to attempt discontinuation were worries about disease recurrence 58% and lack of current toxicities 17% (with 1 person noting increased inconvenience of monitoring visits). When presented with a series of scenarios defining various risks and benefits of discontinuation 60% would be willing to discontinue if the success rate of stopping was 40% and 60% had salvageable relapses, 58% if success was 50% and salvageable relapse was 50%, and 67% if success was 60% and salvageable relapse was 40%. Faced with a 2% relapse mortality risk with discontinuation, 36%, 36%, and 41% would attempt discontinuation if the success rates were 40%, 50%, and 60%. Faced with a 5% relapse mortality risk, 26%, 26% and 31% felt discontinuation attempts would be taken for 40%, 50%, and 60% success rates.
Conclusions: Although a subset of CML deep molecular responding pts may be successfully discontinued from TKI therapy, in this pt survey only 42% of CML pts were willing to stop their TKI treatment. Acceptance of TKI discontinuation by pts varied between 26% and 60% depending on the perceived success rate and risks of recurrence and mortality. Any projections regarding the value of aggressive TKI induction regimens or economic benefits of TKI discontinuation programs must be tempered by CML pt preferences.

Disclosures
Goldberg: COTA: Employment, Equity Ownership; Ariad: Research Funding; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.