Outcomes of Chronic Myeloid Leukemia with No Major Molecular Response within 2 Years of Tyrosine Kinase Inhibitor Therapy

Introduction: Achieving a major molecular response (MMR) defined as BCR::ABL1 ≤ 0.1% IS, is an important milestone for optimal response in patients with chronic myeloid leukemia (CML), and decreased risk of transformation to advanced CML. However, the long-term clinical impact of not achieving this milestone is unknown, especially whether it affects chances of survival in older patients. Therefore, we sought to examine responses and outcomes associated with BCR::ABL1 > 0.1% IS after 2 years of treatment with tyrosine kinase inhibitors (TKI).

Methods: In a retrospective analysis, we screened our databases for CML patients treated at our institution between 2001 and 2020 and identified those who never achieved MMR within 2 years of TKI therapy. Overall survival (OS) was measured from treatment start date to death from any cause or censored at last follow-up, whereas CML-specific OS assessed only death due to CML complications as events. Progression-free survival (PFS) was measured from TKI start date to progression to either accelerated or blast phase or death. The role of various prognostic factors on survival was evaluated in a multivariate analysis

Results: We identified 131 patients who never achieved MMR within 2 years (Table 1). Among them, 79 (60%) eventually achieved MMR at a median of 49.4 months from time of TKI start (range 27-187 months). 24 (30%) of these patients achieved MMR by continuing the same TKI, 48 (61%) by switching to a different therapy and 9 (11%) by undergoing stem cell transplant (Table 1). The remaining 52 patients had different levels of cytogenetic response as highlighted in (Table 1). The 10-year CML-specific OS of this cohort was 89%, with a 10-year OS of 76% and 10-year PFS of 74%. Patients who achieved only minor or no cytogenetic response (BCR::ABL1 > 10%) within the first two years had worse 10-year OS (64%) compared to those who achieved major cytogenetic response (BCR::ABL1 ≤ 10% - MCyR) (88%, P=0.01) or complete cytogenetic response (BCR::ABL1 ≤ 1% - CCyR) (85%, P=0.05) within the same period. These trends were similar when evaluating CML-specific OS (Figure 1). In patients aged ≥ 60 years at CML diagnosis, the 10-year OS was 55%; however, none of these deaths were attributed to CML complications (10-year CML-specific OS of 100%) and only 1 (4%) patient progressed to blast phase. In a multivariate analysis of patients included in this cohort, MCyR within 2 years was identified as the only independent prognostic factor associated with improved CML-specific OS with a hazard ratio of 0.19 (95% CI 0.04 - 0.89; P=0.04).

Conclusion: CML related mortality remains low among patients who do not achieve MMR within the first 2 years of TKI therapy. Favorable outcomes were seen even among patients with BCR:ABL1 levels between 1% to 10% IS. This is particularly evident for those above the age of 60, where mortality is mainly due to CML-unrelated comorbidities. These findings may help the new considerations in European LeukemiaNet (ELN) recommendations and National Comprehensive Cancer Network (NCCN) guidelines.

Kantarjian:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; ImmunoGen: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; Daiichi-Sankyo: Consultancy, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Issa:Novartis, Kura Oncology, Nuprobe: Consultancy; Celgene, Kura Oncology, Syndax, Merck, Cullinan and Novartis: Research Funding. Ravandi:AstraZeneca: Consultancy; Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Syos: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Novartis: Consultancy; Biomea Fusion, Inc.: Research Funding. Garcia-Manero:Genentech: Honoraria, Research Funding; Gilead Sciences: Research Funding; Astex: Consultancy, Honoraria, Research Funding; Curis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharma: Consultancy; BMS: Consultancy, Honoraria, Research Funding; Aprea: Honoraria. Borthakur:Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees. Kadia:Pfizer: Research Funding; Amgen: Research Funding; Delta-Fly: Research Funding; cellenkos: Research Funding; Novartis: Consultancy; cyclacel: Research Funding; BMS: Consultancy, Research Funding; PinotBio: Consultancy; Ascentage: Research Funding; Servier: Consultancy; Regeneron: Research Funding; JAZZ: Consultancy, Research Funding; Astex: Honoraria; Iterion: Research Funding; Genfleet: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Research Funding; AstraZeneca: Research Funding; Agios: Consultancy; Glycomimetics: Research Funding; Abbvie: Consultancy, Research Funding. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Jain:Pfizer: Research Funding; Cellectis: Honoraria, Research Funding; Medisix: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; Aprea Therapeutics: Research Funding; MEI Pharma: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; Servier Pharmaceuticals LLC: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Loxo Oncology: Research Funding; Takeda: Research Funding; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Newave: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Fate Therapeutics: Research Funding; Incyte Corporation: Research Funding; Novalgen: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Mingsight: Research Funding; TransThera Sciences: Research Funding; Dialectic Therapeutics: Research Funding; TG Therapeutics: Honoraria; Ipsen: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; CareDx: Honoraria. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. DiNardo:Foghorn: Honoraria, Research Funding; Gilead: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Astex: Research Funding; Jazz: Honoraria; Astellas: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Honoraria; Cleave: Research Funding; AbbVie: Consultancy, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; LOXO: Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Forma: Research Funding; ImmuneOnc: Honoraria, Research Funding. Jabbour:Takeda: Other: Advisory Role, Research Funding; Spectrum: Research Funding; AbbVie: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding. Sasaki:Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceuticals: Honoraria.