Systematic Approach to Treatment De-Escalation While Maintaining Remission in CML, a Risk Mitigation and Cost Reduction Study

Background: Modern therapeutic agents, including tyrosine kinase inhibitors (TKIs) and Asciminib, have significantly improved outcomes for patients with chronic myeloid leukemia (CML). Despite their efficacy, prolonged use of tyrosine kinase inhibitors and Asciminib can lead to adverse effects and high medication costs. Only a small proportion of patients with CML successfully achieve treatment-free remission (TFR), while the majority require long-term therapy. Achievement of major molecular response (MMR) is predictive of excellent overall and progression-free survival. In contrast, deeper responses are not associated with superior clinical outcomes outside treatment discontinuation candidacy. This study explores dose reduction of active CML therapy to maintain therapeutic effectiveness, minimize side effects, mitigate long-term risks of therapy, and reduce cost.

Methods: This retrospective, single-center study included 36 patients with chronic phase CML who failed TFR or were not TFR-eligible and who have achieved at least MMR while on any of the FDA-approved therapies for CML. These patients had a reduction in the dose of active CML therapeutic agents to the lowest dose that maintains MMR. Re-escalation was implemented for loss of MMR. BCR-ABL1 levels were monitored at baseline and quarterly thereafter. The primary goal of this study is to examine the feasibility of this approach. Secondary objectives include cost reduction and changes in side effect severity.

Results: The study screened a total of 74 participants for eligibility. Thirty three patients were included in the final analysis. There were seventeen patients on dasatinib, seven patients on imatinib, seven patients on bosutinib, one patient on asciminib, and one patient on nilotinib. 68% of patients maintained their major molecular response on a reduced TKI dose, while 32% experienced intervention failure, necessitating a return to the initial dose and achieving MMR. None of the patients included in the study had loss of disease control or progression. The average cumulative reduction in TKI dose was 43.91% (±17.60%), ranging from 20% to 72.50%, with quartiles of 25% (Q1), 38.33% (Median), and 50.11% (Q3). Cumulative cost reduction averaged 41.95% (±17.44%), ranging from 0% to 65.62%, with quartiles of 23.80% (Q1), 44.52% (Median), and 50% (Q3). Quarterly reductions for dose and cost were 39.01% (±17.07%) and 37.82% (±17.27%), respectively. Additional follow up will be provided at time of presentation.

Conclusion: Reduction of TKI and Asciminib dose in patients with CML who have a stable response and are not candidates for TFR could preserve therapeutic efficacy while decreasing adverse effects and medication costs. Adverse events and long-term risks of the approved CML therapeutics are dose-dependent, and maintaining MMR with a lower dose of active agents is of substantial medical advantage. As this approach has been described in select agents prospectively, this work demonstrates the generalizability of this concept across all CML-approved agents. In addition, this work seeks to generate evidence to support a patient centered, cost conscious approach to treatment, potentially enhancing patient quality of life and adherence to treatment while maintaining adequate CML control.

Yacoub:AbbVie: Consultancy; Karyopharm Therapeutics INC: Consultancy; GSK: Consultancy; Pharmaessentia: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Servier: Consultancy; Blueprint Medicine: Consultancy; Apellis: Consultancy; Gilead: Consultancy; Notable Labs: Consultancy; Protagonist: Consultancy; CTI Pharma (SOBI), Stemline Therapuitics: Research Funding; Incyte, CTI Pharma (SOBI), Pharmaessentia, Pfizer (Feb 22), Novartis, Servier, ABBVIE, Karyopharm Therapeutics INC , GSK, Blueprint Medicine, Apellis, Gilead, Notable Labs, Protagonist: Consultancy; CTI Pharma: Consultancy.