Outcomes of Second-Line Tyrosine Kinase Inhibitors after First-Line Imatinib in Chronic Myelogenous Leukemia: A Retrospective Cohort Study
Authors: Alsabbagh Alchirazi Muaz , Zureigat Hadil , Mohamed Ahmed N , Dhakal Aastha , Mushtaq Ali , Rehman Naveen , Berube Bryan , Govande Sneha , Zabor Emily C. , Jain Akriti G. , Molina John C. , Balderman Sophia , Singh Abhay , Gerds Aaron T. , Advani Anjali S. , Carraway Hetty E. , Kalaycio Matt , Mukherjee Sudipto , Mustafa Ali Moaath K. 
Published: December 2024

Background: Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm that results from the BCR-ABL1 fusion gene. The advent of imatinib, the first tyrosine kinase inhibitor (TKI) used in CML, since the early 2000s has significantly improved CML management and patient prognosis. However, resistance or intolerance to imatinib remains a clinical challenge, necessitating the use of second-line TKIs. This study evaluates the efficacy and outcomes of second-line TKI therapy in patients who received first-line imatinib.

Methods: We conducted a single-center retrospective cohort study to evaluate the efficacy of second-line TKIs in CML patients who exhibited failure or intolerance to first-line imatinib therapy. The study period ranged from January 2007 to December 2022. Patients were included if they showed documented failure or intolerance to imatinib. Collected data included age, gender, ethnicity, comorbidities, disease stage, cytogenetics, the reason for first-line discontinuation, and treatment outcomes. High-risk cytogenetics were: + 8, i(17q), second Ph, +19, and complex karyotype. Responses to the second-line TKI were determined using overall survival (OS), calculated from the initiation of second-line therapy to the time of death and response at the 12-month mark. Because response criteria to TKI varied throughout the years, we used the following criteria for 12-month response: 1. Latest years (≥2010): rate of achieving major molecular response three or more, 2. Middle years (~2008-2010): rate of achieving a total of 3 log reductions or more in BCR:-ABL1 PCR transcript or 3, Earliest years (~2007): rate of achieving a complete cytogenetic response on bone marrow exam. The 12-month response rate was the intention to treat, and no patients were excluded if the drug was discontinued for any reason (i.e., death less than 12 months or intolerance...etc.). Survival probabilities were estimated using the Kaplan-Meier method, with differences assessed by the log-rank test. Multivariable regression was utilized to adjust for confounders, including comorbidities.

Results: During the study period, 361 patients were diagnosed with CML, and 92 patients were treated with first-line imatinib followed by another TKI. The second-line treatments administered included dasatinib in 58% of cases (n=53), nilotinib in 36% (n=33), and bosutinib in 6.5% (n=6). The median ages at diagnosis were 54 years (IQR: 43-68) for dasatinib, 47 years (IQR: 38-58) for nilotinib, and 60 years (IQR: 52-72) for bosutinib. High-risk cytogenetics at diagnosis were seen in 0 (0%), 1 (3%) and 0 (0%) in the dasatinib, nilotinib, and bosutinib groups, respectively. Chronic phase CML was the diagnosis stage in 94%, 100%, and 100% of dasatinib, nilotinib and bosutinib groups, respectively.Clinically, 55% of these patients discontinued imatinib due to treatment failure and 45% due to intolerance. Notably, disease progression from the chronic to the blast phase occurred in only two patients after second-line TKI, both of whom were on dasatinib. Throughout a median follow-up of 79.8 months (range 4.9-183.7) the two-year OS probabilities were 92% (95%CI: 85-100) for dasatinib, 97% (95%CI: 91-100) for nilotinib, and 100% (95%CI: 100-100) for bosutinib (log-rank P&gt;0.9). On multivariable Cox proportional hazards analysis, there were no significant differences in OS across the TKI treatments [(mortality hazard ratio (HR) for nilotinib 1.66, 95%CI: 0.58-4.8), (HR for bosutinib 0.57, 95%: 0.06-5), reference: dasatinib]. However, age at diagnosis was significantly associated with survival outcomes in all groups (HR = 1.09, 95% CI: 1.05, 1.14, p &lt; 0.001). The response rates to treatment varied and were not significantly different from each other (P=0.2), with a 12-month response rate for dasatinib of 21%, nilotinib at 16%, and bosutinib at 0%.

Conclusion: In this single-center study, with a long follow-up period, there was no major difference in OS regardless the choice of second-line TKIs: dasatinib, nilotinib, or bosutinib after first-line imatinib in CML. Long-term survival was not compromised after switching from imatinib due to failure or intolerance to a second-line TKI. Given the side effects profile and financial toxicity of second/ third generation TKIs, the strategy of using imatinib as the first line followed by other TKIs in case of failure or intolerance should be explored further using prospective designs.