Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Following the Discontinuation of Tyrosine Kinase Inhibitors
Authors: Haddad Fadi , Kantarjian Hagop , Jabbour Elias J. , Issa Ghayas C. , Garcia-Manero Guillermo , Ravandi Farhad , Konopleva Marina , Ferrajoli Alessandra , Kadia Tapan M. , Pemmaraju Naveen , Takahashi Koichi , Alvarado Yesid , Yilmaz Musa , Borthakur Gautam , DiNardo Courtney D. , Jain Nitin , Daver Naval , Short Nicholas J. , Pierce Sherry A. , Cortes Jorge E. , Sasaki Koji 
Published: November 2021

Abstract
Background:
Tyrosine kinase inhibitors (TKIs) discontinuation in patients with chronic myeloid leukemia (CML) is becoming an increasingly attempted practice. Evidence is not uniform regarding the optimal milestones to be reached before seeking treatment cessation. The objective of this analysis is to evaluate the outcomes of CML patients who stopped TKIs, and to determine the best targets that need to be achieved to allow for the longest treatment-free remission (TFR).
Methods:
We reviewed the medical records of all CML patients treated with TKIs at our institution between October 1999 and February 2017 and who subsequently discontinued therapy. We evaluated their time to response, the duration of TKI treatment, and the duration in best response before stopping therapy. Major molecular response (MMR) was defined as ≤0.1% BCR-ABL/ABL ratio in the international scale (IS) as determined by quantitative real-time polymerase chain reaction (qPCR), MR4 as a ratio of ≤0.01% IS, and MR4.5 as a ratio of ≤0.0032% IS. We performed a classification and regression tree (CART) analysis to determine the functional form of the durations of MR4.5 and TKI therapy. Cutoffs were then used to evaluate the association between these variables and the success of maintaining TFR after stopping treatment. Univariate and multivariate analyses were conducted to identify factors associated with loss of response following dug discontinuation.
Results:
We identified 297 patients with CML who attempted TKI discontinuation, with a median age at discontinuation of 63 years (range, 25-93). The characteristics of patients are summarized in Table 1. After a median follow-up of 38 months (95% confidence interval [CI], 33-44) after discontinuation, 28%, 26%, and 18% lost MR4.5, MR4, and MMR, respectively. The median time to MMR loss was 6 months (range, 1-75), with 26% of patients losing MMR 12 months or more after TKI discontinuation. The median TFR duration was not reached, with a 3-year TFR rate of 69% (Figure 1). The 3-year TFR rates were 91%, 76%, and 70% in patients with a sustained duration of MR4.5 of more than 72 months, 60-72 months, and less than 60 months, respectively (P &lt;0.0001). Two hundred one of 297 patients (68%) remained on their frontline TKI at the time of discontinuation. No significant difference was found in the rates of 3-year TFR failure between patients who received frontline imatinib, dasatinib, or nilotinib (22%, 44%, 22%, respectively; P =0.066).
The median overall duration of TKI treatment was 118 months (range, 16-242), while the median duration on treatment with the last TKI used before discontinuation was 96 months (range, 1-242). In univariate analysis, a consistent duration of 6 years or more in MR4.5 was associated with the lowest risk of loss of MMR following TKI discontinuation, with 3-year MMR loss rates of 9% versus 29% (P &lt;0.0001). A duration of 6 years or more in MR4.5 was also associated with the lowest risk of loss of MR4.5 following TKI discontinuation, with 3-year MR4.5 loss rates of 15% versus 39% (P &lt;0.0001). By multivariate analysis, a sustained MR4.5 duration of 6 years or more was the only significant predictor for maintained response (P&lt;0.0001). Patients who relapsed were restarted on TKI after a median of 14 days (range, 0-930), and among 73 evaluable patients, the majority achieved deep molecular responses: MR4.5 in 92% of cases, MR4 in 3%, and MMR in 5%.
Conclusion:
Treatment-free remission can be successful in patients with a sustained MR4.5 duration of 6 years or more. Overall, around one third of patients attempting TKI discontinuation will relapse, with the vast majority achieving deep molecular responses after resuming TKIs.
Figure 1 Figure 1.

Disclosures
Kantarjian: AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Konopleva: Calithera: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Cellectis: Other: grant support; Ablynx: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding. Ferrajoli: AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board . Kadia: Cure: Speakers Bureau; BMS: Other: Grant/research support; AbbVie: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; Pulmotech: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Ascentage: Other; Astellas: Other; AstraZeneca: Other; Pfizer: Consultancy, Other; Dalichi Sankyo: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Genentech: Consultancy, Other: Grant/research support; Jazz: Consultancy; Aglos: Consultancy; Genfleet: Other. Pemmaraju: Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; ImmunoGen, Inc: Consultancy; Clearview Healthcare Partners: Consultancy; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Pacylex Pharmaceuticals: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Blueprint Medicines: Consultancy; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Springer Science + Business Media: Other; Aptitude Health: Consultancy; CareDx, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Plexxicon: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other. Takahashi: GSK: Consultancy; Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Alvarado: Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; FibroGen: Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Borthakur: Astex: Research Funding; Protagonist: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Takeda: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; GSK: Consultancy. DiNardo: Takeda: Honoraria; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Novartis: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Jain: Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Incyte: Research Funding; Precision Biosciences: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Janssen: Honoraria; Beigene: Honoraria; TG Therapeutics: Honoraria. Daver: Novimmune: Research Funding; Astellas: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Glycomimetics: Research Funding; FATE Therapeutics: Research Funding; ImmunoGen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Hanmi: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Short: Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy; NGMBio: Consultancy; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy. Cortes: Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding.