Efficacy of tyrosine kinase inhibitors (TKIs) as third-line therapy in patients with chronic myeloid leukemia in chronic phase who have failed 2 prior lines of TKI therapy

Abstract

We analyzed a cohort of 26 patients with chronic myeloid leukemia who had failed imatinib and a second tyrosine kinase inhibitor but were still in first chronic phase and identified prognostic factors for response and outcomes. The achievement of a prior cytogenetic response on imatinib or on second-line therapy were the only independent predictors for the achievement of complete cytogenetic responses on third-line therapy. Younger age and the achievement of a cytogenetic response on second line were the only independent predictors for overall survival (OS). At 3 months, the 9 patients who had achieved a cytogenetic response had better 30-month probabilities of complete cytogenetic responses and OS than the patients who had failed to do so. Factors measurable before starting treatment with third line therapy and cytogenetic responses at 3 months can accurately predict subsequent outcome and thus guide clinical decisions.

Figure 1

Outcome of patients treated with third-line TKI according to the cytogenetic response obtained with the prior TKI therapy and to the cyto-genetic response obtained after 3 months on third-line therapy. The 14 patients who achieved at least MiCyR on imatinib or on second-line therapy (solid line) had a significantly better probability of achieving CCyR (A) and a better OS (B) on third-line nilotinib or dasatinib than the 12 patients who had primary cytogenetic resistance to the prior 2 lines of TKI therapy (broken line). The 30-month cumulative incidence of CCyR for the 2 groups was of 71.4% vs 0% (P = .0005), and the 30-month OS was 72.7% vs 20.4% (P = .03). When we excluded the only patient who died of nonleukemia-related reasons and in CCyR the OS were 90.1% vs 20.4% (P = .01). The 14 patients who achieved at least MiCyR on one of the prior TKI therapies also had a better EFS that the 14 patients with primary cytogenetic resistance, specifically 70.5% vs 16.2% (P = .02). (C-D) Results of the landmark analyses for the achievement of CCyR and OS (excluding the nonleukemia-related death) according to the cytogenetic response at 3 months on nilotinib or dasatinib as third-line therapy. At 3 months, 9 patients had achieved at least MiCyR (solid line). These patients had higher probabilities of achieving CCyR (C) and OS (D) than the 17 patients who had failed to do so (broken line), specifically 88.9% vs 13.3% (P < .0001), and 100% vs 35.0% (P = .04; see text).