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Response and Outcomes of Third-Line Tyrosine Kinase Inhibitor Therapy on Patients with Chronic Phase Chronic Myeloid Leukemia

Maliha Khan, Hagop M. Kantarjian, Jing Ning, Mary Akosile, Wen Li, Gautam Borthakur, Nitin Jain, Courtney D. DiNardo, William G Wierda, Farhad Ravandi, Guillermo Garcia-Manero, Marina Konopleva, Tapan Kadia, Naveen Pemmaraju, Philip A Thompson, Naval Daver, Elias J. Jabbour and Jorge E. Cortes

Abstract

Introduction: Patients with chronic phase chronic myeloid leukemia (CML) who fail to respond to first- and second-line tyrosine kinase inhibitor (TKI) therapy may be treated with third-line TKIs or undergo allogeneic hematopoietic stem cell transplant (alloHSCT). However, data demonstrating the efficacy of third-line TKI therapy is limited other than those coming from industry-sponsored studies for individual drugs.

Objective: evaluate the efficacy of various third-line TKIs and identify factors predicting outcomes and response in patients with chronic phase CML

Methods: A retrospective study was conducted on 185 patients with chronic phase CML with failure to first- or second-line TKIs. Demographic factors and clinical parameters were noted along with TKI therapies. Treatment response and outcomes, including cytogenetic response, molecular response, overall survival (OS), event-free survival (EFS) and transformation-free survival (TFS) were measured. Events were defined by death on third-line TKI therapy, loss of MCyR, loss of CHR, increased WBC, or progression to AP/BC; whichever occurred first.

Results: The median age of patients was 55.0 years (range: 19-92 years), and the majority were female (n=97; 52%). Patients received the following TKIs: bosutinib (n=13, 7%); dasatinib (n=64, 35%); imatinib (n=19, 10%); nilotinib (n=67, 36%); and ponatinib (n=22, 12%). Patients received third-line TKI for a median of 18.07 months (5.40 - 93.60), and 78 (42.16%) remain on their third-line TKI. The 25% percentile of OS for all treatments combined was 3.2 years (95% CI, 2.1-6.3) At the final data cut-off, 75% of patients on third-line TKIs were alive (47 deaths). At 5 years, median EFS was 55.1 months, median TFS was not reached.

Third-generation ponatinib was associated with significantly better OS compared with imatinib (HR, 0.248; 95% CI, 0.067-0.917; p=0.037). Compared with imatinib, patients treated with bosutinib also had better survival, and this association approached significance (HR, 0.147; 95% CI, 0.017-1.240; p=0.078). There was no difference by TKI in either TFS (p=0.134), or OS (p=0.315).

At baseline, 39 patients (32.77%) had CCyR and 76 (63.86%) did not, while at best response 71 patients (59.66%) had CCyR, 48 (40.33%) did not have CCyR, and the rest were excluded due to missing data. 8% also achieved major molecular response (MMR, based on international scale) as best response.

On univariate Cox regression analysis, the following factors were significantly associated with improved OS: age, best cytogenetics (CCyR vs not CCyR), best molecular response (MMR vs. not MMR), reason for TKI switch (resistance vs. intolerance to 2nd line TKI), baseline cytogenetics, baseline molecular response status, and stem cell transplantation. Baseline mutation status was not associated with OS (HR, 1.137; 95% CI, 0.438-2.948; p=0.792). Multivariate analysis identified the following as significant predictors of improved OS: age, gender, best molecular response, reason for TKI switch, stem cell transplant, and third-line treatment with ponatinib or bosutinib versus imatinib (Table 1).

Conclusion: In the largest cohort of chronic phase CML patients on third-line TKI therapy to date, we identified predictors of clinical outcomes in the context of this setting. In addition to confirming previous findings that third-line TKI therapy may prolong OS and EFS, we found that ponatinib is associated with significantly better OS than any other TKI used as third-line therapy.

Disclosures Kantarjian: Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding. Jain: Celgene: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; BMS: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo: Celgene: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Wierda: Juno: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Kite: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Merck: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding. Pemmaraju: Cellectis: Research Funding; Stemline: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria. Thompson: Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Daver: Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Jazz: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Immunogen: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Honoraria, Research Funding; Kiromic: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding. Jabbour: Bristol-Myers Squibb: Consultancy. Cortes: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

  • * Asterisk with author names denotes non-ASH members.