Comparison of Long-Term Outcomes Among Patients with Chronic Myeloid Leukemia Who Undergo Initial Tyrosine Kinase Inhibitor Dose Reduction Versus Tyrosine Kinase Inhibitor Switch

Background

BCR-ABL1 tyrosine kinase inhibitors (TKIs) improve life expectancy to that of the general population for the majority of patients with chronic myeloid leukemia (CML). Although 2nd- and 3rd-generation TKIs improved 3-month rates of major molecular remission (MMR), adverse events (AEs) are common. In patients who experience intolerable TKI related AEs, a switch in TKI has been traditionally recommended. However, TKI dose reduction is becoming a more common practice. A comprehensive review of treatment outcomes is needed to determine whether this approach compromises the ability to achieve an MMR long-term.

Methods

We conducted a retrospective chart review of 115 patients with CML seen at the James Comprehensive Cancer Center from 2012-2022. All data had been previously collected during standard clinical care. Patients who were intolerant to initial TKI and proceeded with dose reduction or TKI switch were included. We hypothesized that the percentage of patients achieving an MMR at the end of follow-up would be similar among these groups. We compared time to and number of subsequent TKI switches. Differences in the distribution of demographic, clinical and treatment response were analyzed for significance using Mann-Whitney or Fisher's exact test. Time to subsequent TKI switch was calculated from the date of first TKI switch/dose reduction to the start of the subsequent TKI switch treating those died without a TKI switch as a competing event and censoring alive patients without TKI switch at date of last follow up. Competing risk regression was used to evaluate the association with the time to subsequent TKI switch between TKI reduction and TKI switch groups.

Results

Fifteen patients underwent dose reduction and 100 patients underwent TKI switch. The median age for patients at diagnosis was 50. Fifty-four percent of patients were female and 83.5% of patients were White. The majority of patients were initially started on imatinib (60.9%), followed by dasatinib (27.8%). Compared to the dose reduction group, the TKI switch group had 64% vs 40% of patients initially started on imatinib. while 46.7% vs. 25% initially started on dasatinib. There were no significant differences in age, gender, race, WBC or PLT count at diagnosis.

At the end of follow up (median 6.5 years), there was no statistically significant difference between the proportion of patients achieving an MMR when comparing the TKI switch and dose reduction cohorts (68.2% vs. 71.4%, p=0.99). There was also no difference in the proportion of patients achieving a deep molecular remission (DMR) (45.9% vs. 57.1%, p=0.57). Fifty-eight patients required a subsequent switch in TKI, with 3 patients requiring 2 subsequent switches. There was no difference in the number of subsequent TKI switches between the dose reduction and TKI switch groups (p=0.23). Time to subsequent TKI switch (after initial TKI switch/dose reduction) was not different between the two groups (p=0.34).

Discussion

MMR is an important therapy goal in CML. Furthermore, achieving a DMR correlates with better long term outcomes. In this 115-patient cohort, there was no statistically significant difference between the proportion of patients achieving an MMR or DMR, or time to subsequent TKI switch when comparing those who initially underwent dose reduction to those who underwent TKI switch. This data adds to the currently available literature that suggests dose reduction is a reasonable approach to TKI intolerance and does not put patients at risk of developing resistance that would impede the ability to achieve optimal CML treatment goals. Further research including prospective randomized clinical trials should be done to evaluate TKI dose reduction as a potential treatment strategy.

Waller:Jazz Pharmaceuticals: Consultancy. Mims:Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Saynko: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Treadwell Therapeutics: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society Beat AML Study: Other: Senior Medical Director. Vaughn:novartis: Consultancy; Incyte: Consultancy.