Low-Dose Dasatinib 50 Mg/Day Versus Standard-Dose Dasatinib 100 Mg/Day As Frontline Therapy in Chronic Myeloid Leukemia in Chronic Phase: A Propensity Score Analysis
Authors: Sasaki Koji , Jabbour Elias J. , Issa Ghayas C. , Naqvi Kiran , Skinner Jeffrey , Anderson Kristin , Dellasala Sara E , Yilmaz Musa , Ferrajoli Alessandra , Bose Prithviraj , Thompson Philip A. , Alvarado Yesid , Jain Nitin , Garcia-Manero Guillermo , Takahashi Koichi , Burger Jan A. , Borthakur Gautam , Pemmaraju Naveen , Haddad Fadi , Khouri Maria R , Paul Shilpa , Pierce Sherry A. , Cortes Jorge E. , Kantarjian Hagop 
Published: November 2021

Abstract
Background: Low-dose dasatinib was shown to be safe and effective in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). There is no randomized clinical trials to compare the outcome with the standard-dose dasatinib. The aim of this study is to compare responses and outcome of patients with newly diagnosed CML-CP treated with frontline dasatinib 50 mg/day with those who received standard-dose dasatinib 100 mg/day.
Method: We analyzed 233 patients with newly diagnosed CML-CP who were treated with low-dose dasatinib 50 mg/day (N=83) or standard-dose dasatinib 100 mg/day (N=150). Responses criteria were previously defined. Failure-free survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blast phases during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. Patients on low-dose dasatinib who had suboptimal response by European LeukemiaNet criteria had an option to increase the dose to 100 mg/day. Propensity score analysis with 1:1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.2. Multiple imputation was performed to minimize the bias. Propensity scores were calculated with logistic regression from baseline covariates including age, spleen size by examination, white blood cell count, hemoglobin, platelet count, percentage of basophils, percentage of blasts in peripheral blood and bone marrow, the presence of clonal evolution, and Sokal risk classification to minimize difference.
Results: Propensity score matching identified 77 patients in each cohort without significant baseline difference (Table 1). The overall median follow-up was 60 months: 48 months and 131 months for low-dose and standard-dose, respectively. The 12-month major molecular response (MMR) rates were 82% and 75% for low-dose and standard-dose groups, respectively (P=0.229). The cumulative incidence of molecular response (MR)4, MR4.5, and complete molecular response (CMR) rates within 1 year were higher in the low-dose dasatinib group compared with the standard-dose group (63% and 43%, 53% and 36%, and 46% and 33% for each)(P=0.009; P=0.031; P=0.060). The incidence of pleural effusion was 6% and 21% in the low-dose and standard-dose, respectively (P=0.016). The 4-year FFS rates were 89% and 77% in the low-dose dasatinib and standard-dose dasatinib, respectively (P=0.041) (Figure 1). The 4-year TFS rates were 100% and 100%, respectively (P=1.000); the 4-year EFS rates were 95% and 92%, respectively (P=0.556); the 4-year OS rates were 97% and 96%, respectively (P=0.781).
Conclusions: The low-dose dasatinib is as effective as standard-dose dasatinib with less intolerance, resulting in favorable outcome.
Figure 1 Figure 1.

Disclosures
Sasaki: Novartis: Consultancy, Research Funding; 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. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Bose: Incyte Corporation: Honoraria, Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; NS Pharma: Research Funding; BMS: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior: Research Funding. Thompson: Janssen: Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Alvarado: Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Beigene: Honoraria; Precision Biosciences: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Incyte: Research Funding; TG Therapeutics: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Takahashi: GSK: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy. Borthakur: GSK: Consultancy; Astex: Research Funding; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pemmaraju: HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; CareDx, Inc.: Consultancy; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Aptitude Health: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Sager Strong Foundation: Other; Celgene Corporation: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Cortes: Sun Pharma: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kantarjian: Precision Biosciences: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Taiho Pharmaceutical Canada: Honoraria; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Daiichi-Sankyo: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria.