Treatment Patterns, Tolerance, and Clinical Response of Chronic Phase Chronic Myeloid Leukemia (CML-CP) Patients (Including Those Harboring the T315I Mutation) Experiencing Multiple Tyrosine Kinase Inhibitor Failure: A Multi-Center Retrospective Chart Review Analysis

Background Despite the remarkable efficacy of adenosine triphosphate-competitive tyrosine kinase inhibitors (TKIs) for chronic phase chronic myeloid leukemia (CML-CP) treatment, about one-third of newly TKI-treated CML patients switch to an alternative TKI over time due to TKI-intolerance or -resistance. These patients currently represent a major clinical burden among patients previously exposed to TKIs. In addition, the presence of the BCR::ABL1 T315I mutation further complicates the clinical management of patients with CML-CP as the mutation is associated with worse prognosis. Objective The aim of this study is to describe "real-world” treatment patterns, clinical outcomes, and adverse events (AEs) in CML-CP patients receiving 3 or more lines of therapy (3L+) and those with the ABL1 T315I mutation. Methods A retrospective chart review study was conducted at 3 large clinical institutions for CML in France. De-identified demographic and clinical data for adult patients diagnosed with CML-CP and treated in 3L+ or harboring the T315I mutation between 2006 and 2021 were abstracted from medical charts using electronic case report form. Descriptive statistics were used to summarize patient characteristics, clinical outcomes during 3L treatment, and AEs. The Kaplan-Meier method was used to determine the cumulative incidence of patients with a major molecular response (MMR) or deep molecular response (DMR: MR4.0 or MR4.5). Results This study included 157 adult patients with CML-CP in 3L+ and 17 adult patients with the T315I mutation. In the 3L+ cohort (median age [interquartile range] at diagnosis, 56 [43-65] years; 44% female; Sokal scores: 22% low, 34% intermediate, 29% high, 15% unknown), 16% of patients had 5L+. In 1L (median duration: 23 [9-66] months), 80% of patients received imatinib. In 2L (median duration: 21 [6-41] months), almost 90% patients received either nilotinib or dasatinib. In 3L (median duration: 17 [5-47] months), TKIs received were dasatinib (32%), nilotinib (19%), imatinib (18%), ponatinib (17%), and bosutinib (14%). Treatment-free remission (TFR) was observed in 16 (10%) patients in 3L (median duration: 45 [22-64] months); the last reported treatments were dasatinib (n=10) and nilotinib (n=6) for these patients. Among the 16 patients in TFR, 5 (31%) were intolerant to 3L TKI. In 145 patients with documented responses in 3L, the rate of achieving MMR, MR4.0, and MR4.5 at 12 months was 42%, 27%, and 14%, respectively. AEs were documented in 139/157 patients (89%) in 3L. The median overall survival since 3L treatment initiation was 12 (8-16) years. The median number of AEs per patient was 2 in 3L; infections (18%) and asthenia (13%) were the most common AEs. Among patients harboring the ABL1 T315I mutation (median age at diagnosis, 52 [39-59] years; 24% female; Sokal scores: 6% low, 12% intermediate, 65% high, 18% unknown), 41% had 5L+. The T315I mutation was identified in 2L (N=6, 35%), 3L (N=5, 29%), 4L (N=4, 24%), and 5L (N=2, 12%). Median duration of the index line of treatment was 11 months. Ponatinib was the most common TKI used in these T315I+ patients (N=10, 59%) following the identification of the mutation. Other therapies included dasatinib (N=3, 18%), allogeneic stem cell transplant (N=2, 12%), and asciminib through compassionate use or clinical trial (N=2, 12%). Thrombocytopenia (18%) was the most common AE in patients with T315I mutation. The median OS since T315I identification was 5 (3-10) years. Conclusion In this analysis, CML-CP patients with at least 3 lines of treatment and patients harboring the T315I mutation switched up to 7 lines of therapy. In both 3L+ and T315I cohorts, patients switched between first-, second-, and third-generation TKIs (Figure 1). The most common reasons for treatment discontinuation in 1L, 2L, and 3L, including patients with T315I mutation were intolerance and resistance. Earlier lines of treatment lasted less than 2 years in CML-CP patients in 3L and less than 1 year in CML patients harboring the T315I mutation, indicating that there is a substantial unmet need for novel therapeutics with improved safety and efficacy profiles early in the treatment course. Figure 1. a. Sankey diagram for patients with chronic myeloid leukemia with at least three lines of treatment. b. Sankey diagram for patients with chronic myeloid leukemia with T315I mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal