Outcomes and responsiveness of standard tyrosine kinase inhibitor dose versus dose de-escalation in chronic myeloid leukemia: A single-center retrospective study.

Abstract

6598 Background: Treatment with tyrosine kinase inhibitors (TKIs) enables patients with chronic myeloid leukemia (CML) to achieve durable remission and a normal life expectancy. Despite this success, chronic TKI therapy is associated with cumulative toxicities. Although TKI dose de-escalation can be implemented to mitigate adverse events, its impact on the attainment and durability of response milestones is not completely defined. This study explored the impact of dose de-escalation of TKIs on clinical response milestones and treatment-free remission (TFR) outcomes. Methods: We retrospectively analyzed 407 adult CML patients treated with TKIs at Oregon Health & Science University. Outcomes of interest were TFR and achievement of undetectable BCR::ABL1 transcripts. Odds ratios (OR) or Cox proportional hazards regression hazard ratios (HR) were used to analyze covariates and predictors. Results: Overall, the median age at diagnosis was 48 years (range: 18-91) and 1 st -line therapies included: imatinib (n=252; 62%), dasatinib (n=95; 23%), nilotinib (n=42; 10%), and bosutinib (n=10; 2%); the remaining 2% of patients were treated with 3 rd generation or later TKIs. Median follow-up since diagnosis was 11.3 years (0.2-35.8); 189 patients (46%) remained on their initial TKI, while 218 patients (54%) received ≥2 TKIs. Only 13 patients (3.2%) received a bone marrow transplant. With respect to the primary outcome of TFR, 133 patients attempted TFR and were further analyzed with respect to de-escalation of dose. Fifty-two patients (39%) remained on standard dose while 81 patients (61%) underwent dose de-escalation prior to the 1 st TFR attempt. TFR rates were not significantly different between patients receiving standard dose vs de-escalated dose TKI (HR: 1.07 (95% CI: 0.59-1.96); p=0.818) at either 1 year (77% vs 74%) or 2 years (69% vs 69%). At the last follow-up, 89 patients remained in TFR, 62% of which had undergone dose de-escalation. Among the remaining 274 patients who have yet to attempt TFR, 162 (59%) continued treatment with their initial TKI: 98 (60%) on imatinib, 39 (24%) on dasatinib, 17 (10%) on nilotinib, 5 (3%) on bosutinib, 2 (1%) on ponatinib, 1 (1%) on asciminib. Among these patients, 56 (34%) had dose reduction, 9 (16%) of whom achieved undetectable disease. For the 106 patients on standard doses, only 5 (5%) had undetectable disease (OR: 3.83 (95% CI: 1.08-15.40); p= 0.020).More importantly, dose de-escalation led to significant reduction of adverse events. Conclusions: Our results show that patients who underwent dose de-escalation did not have significant differences in TFR duration and rate and are more likely to achieve undetectable diseases when compared with patients on standard doses. These findings support rational dose de-escalation as a strategy that preserves achievement of clinical outcomes while reducing adverse events.