Outcomes of Chronic Myeloid Leukemia with No Major Molecular Response within 2 Years of Tyrosine Kinase Inhibitor Therapy

Abstract

Introduction: Achieving a major molecular response (MMR) defined as BCR::ABL1 ≤ 0.1% IS, is an important milestone for optimal response in patients with chronic myeloid leukemia (CML), and decreased risk of transformation to advanced CML. However, the long-term clinical impact of not achieving this milestone is unknown, especially whether it affects chances of survival in older patients. Therefore, we sought to examine responses and outcomes associated with BCR::ABL1 > 0.1% IS after 2 years of treatment with tyrosine kinase inhibitors (TKI). Methods: In a retrospective analysis, we screened our databases for CML patients treated at our institution between 2001 and 2020 and identified those who never achieved MMR within 2 years of TKI therapy. Overall survival (OS) was measured from treatment start date to death from any cause or censored at last follow-up, whereas CML-specific OS assessed only death due to CML complications as events. Progression-free survival (PFS) was measured from TKI start date to progression to either accelerated or blast phase or death. The role of various prognostic factors on survival was evaluated in a multivariate analysis Results: We identified 131 patients who never achieved MMR within 2 years (Table 1). Among them, 79 (60%) eventually achieved MMR at a median of 49.4 months from time of TKI start (range 27-187 months). 24 (30%) of these patients achieved MMR by continuing the same TKI, 48 (61%) by switching to a different therapy and 9 (11%) by undergoing stem cell transplant (Table 1). The remaining 52 patients had different levels of cytogenetic response as highlighted in (Table 1). The 10-year CML-specific OS of this cohort was 89%, with a 10-year OS of 76% and 10-year PFS of 74%. Patients who achieved only minor or no cytogenetic response (BCR::ABL1 > 10%) within the first two years had worse 10-year OS (64%) compared to those who achieved major cytogenetic response (BCR::ABL1 ≤ 10% - MCyR) (88%, P=0.01) or complete cytogenetic response (BCR::ABL1 ≤ 1% - CCyR) (85%, P=0.05) within the same period. These trends were similar when evaluating CML-specific OS (Figure 1). In patients aged ≥ 60 years at CML diagnosis, the 10-year OS was 55%; however, none of these deaths were attributed to CML complications (10-year CML-specific OS of 100%) and only 1 (4%) patient progressed to blast phase. In a multivariate analysis of patients included in this cohort, MCyR within 2 years was identified as the only independent prognostic factor associated with improved CML-specific OS with a hazard ratio of 0.19 (95% CI 0.04 - 0.89; P=0.04). Conclusion: CML related mortality remains low among patients who do not achieve MMR within the first 2 years of TKI therapy. Favorable outcomes were seen even among patients with BCR:ABL1 levels between 1% to 10% IS. This is particularly evident for those above the age of 60, where mortality is mainly due to CML-unrelated comorbidities. These findings may help the new considerations in European LeukemiaNet (ELN) recommendations and National Comprehensive Cancer Network (NCCN) guidelines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal