Efficacy Predictors of the Third-Line Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase of Chronic Myeloid Leukemia: Results of a Multi-Center Study

Abstract

Background. The introduction of tyrosine kinase inhibitors (TKIs) into real-world clinical practice considerably improved the prognosis for patients with chronic myeloid leukemia (CML). However, during long-term follow-up, almost 1/2 and 2/3 of patients in the chronic phase (CP) discontinue TKI therapy of the first or second line, respectively. According to the Russian and International clinical guidelines, the third-line therapy should include allogeneic hematopoietic stem cell transplantation (allo-HSCT). And yet, some patients on the third-line therapy achieve and sustain optimal response on long-term TKI administration. Up to now, no clear-cut prognostic factors of TKI efficacy in the third-line therapy have been identified. This creates a challenge for treatment decision making after the failures of two lines of TKI therapy. Aim. To assess the efficacy of the third-line TKI therapy in real-world clinical practice and to identify the factors affecting the long-term therapy outcomes in CML-CP. Materials & Methods. The retrospective study enrolled 73 CML-CP patients aged > 18 years, treated with TKIs in the third-line at 5 specialized institutions in Saint Petersburg and Leningrad Region. Among the patients there were 26 men (35 %). The median age of the patients was 51 years (range 25-88 years). Results. With the median (range) third-line TKI therapy duration of 14 (1-120) months, the rate of complete cytogenetic response (CCR) was 30 % (п = 22) in the total cohort. The median time before achieving CCR was 9 (4-25) months. With the median follow-up time from the beginning of third-line TKI therapy till the last visit of 25 (3-136) months, progression to accelerated phase or blast crisis was observed only in 13 (17 %) out of 73 patients. Death was reported in 26 % (n = 19) of cases, among them 5 patients whose death was not CML-associated. At the last visit, 13/73 (18 %) patients were still on third-line TKI therapy. Direct and longterm therapy outcomes, including achievement of CCR and assessment of overall and progression-free survivals, were significantly better in patients with any cytogenetic response (CR) than in those without it or without complete hematologic response. Conclusion. The implementation of TKIs in the third-line CML-CP therapy seems to be suitable for patients with at least some CR, especially if an optimal donor of hematopoietic stem cells is unavailable or if the risk of severe allo-HSCT complications is too high.