Tyrosine Kinase Inhibitor Therapy Discontinuation in Clinical Practice in Chronic Myeloid Leukemia - a US Physician Survey Conducted after Guideline Updates
Authors: Atallah Ehab L. , Sadek Islam , Cao Xiting , Latremouille-Viau Dominick , Pivneva Irina , Rossi Carmine , Guerin Annie , Kota Vamsi 
Published: November 2019

Background: This study assessed the clinical practice of US physicians managing patients with chronic myeloid leukemia (CML) with a focus on tyrosine-kinase inhibitor (TKI) therapy discontinuation following the publication of the first NCCN practice guidelines to include recommendations on TKI therapy discontinuation in Nov. 2016, with the latest update released in March 2019. Following this initial update, other clinical practice guidelines, such as ESMO, have also been updated to include specific considerations for TKI therapy discontinuation.
Methods: From July 3 to 31, 2019, US oncologists/hematologists completed a survey on their clinical practice with regards to the management of patients with CML in chronic phase (CML-CP) receiving TKI therapy. To be eligible to participate, oncologists/hematologists had to have completed their medical subspecialty training and be responsible for treatment decisions and follow-up for ≥1 adult with CML-CP who received TKI therapy outside of a clinical trial setting since January 2017. The survey collected information on physician practice setting and experience with CML management with a focus on molecular monitoring and TKI therapy discontinuation. A similar study was conducted prior to the availability of the first CML NCCN practice guidelines with recommendations on TKI therapy discontinuation (Ritchie et al. Leuk Lymphoma. 2019); this study is outlining a few changes to the previously reported TKI therapy discontinuation practice for CML in the US.
Results: A total of 111 physicians from all US census regions (18.9% Northeast; 19.8% Midwest, 39.6% South, and 21.6% West) participated in the study. These were from community- (56.8%) and academic-based practice (43.2%). Most (54.1%) were from large practices (10 physicians or more), with the remainder mostly being in small/intermediate practices of 2-9 physicians (42.3%) with a few in individual practice (3.6%). The practice setting environment was mainly urban (49.5%), followed by suburban (42.3%) and rural (8.1%). The majority of physicians had more than 10 years of practice since completing medical subspecialty training (55.9%), 32.4% had 5-10 years, and 11.7% had less than 5 years of practice. All physicians reported testing patients for molecular response and having access to molecular results reported on the international scale (IS). The most precise level of detection for molecular response monitoring varied: MR3.0 (BCR-ABL1 ≤0.1% IS) for 19.8% of the physicians, MR4.0 (BCR-ABL1 ≤0.01% IS) for 30.6%, and MR4.5 or better (BCR-ABL1 ≤0.0032% IS) for 49.5% of the physicians.
Of the 111 physicians, 86.5% reported having attempted TKI discontinuation after achieving an adequate response for ≥1 patient with CML-CP and 64.0% (N=71) did so outside of a clinical trial. Among these 71 physicians, the majority would consider TKI therapy discontinuation for medical reasons (62.0% adverse events, 60.6% pregnancy planning), with fewer for economic reasons (31.0% high deductible, 14.1% change in health plan coverage); 35.2% reported they would consider it for all of their patients who achieved an adequate response; reasons for TKI therapy discontinuation after achieving an adequate response were not mutually exclusive. Among these 71 physicians who have attempted TKI discontinuation outside of clinical trial, only 43 (60.6%) were aware of the updated clinical practice guidelines for TKI therapy discontinuation.
Conclusions: Although TKI therapy discontinuation after achieving an adequate response in patients with CML-CP outside of clinical trials is becoming more common both in community- and academic-based practices in the US (vs. Ritchie et al. Leuk Lymphoma. 2019), it appears to be attempted without the use of accurate and sensitive tools to assess the adequate response when determining patient eligibility for TKI therapy discontinuation. Half of the physicians surveyed did not have access to a reliable qPCR test with a sensitivity to detect at least MR4.5 (BCR-ABL1 ≤0.0032% IS). This finding highlights a need for an infrastructure to support a safe and adequate TKI therapy discontinuation practice to be nationally implemented so that all criteria can be met for US physicians to consider TKI therapy discontinuation per CML practice guidelines. As TKI discontinuation practice is likely to be increasingly adopted, these practice guidelines also need to be broadly communicated to physicians.

Disclosures
Atallah: Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy. Sadek:Novartis: Employment. Cao:Novartis: Employment, Equity Ownership. Latremouille-Viau:Novartis: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Novartis for the conduct of this study. Pivneva:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Rossi:Novartis: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Novartis for the conduct of this study. Guerin:Novartis: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Novartis for the conduct of this study. Kota:Amgen: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Xcenda: Honoraria.