Predictive Factors for Response and Outcome in Patients (pts) Treated with Second Generation Tyrosine Kinase Inhibitors (2-TKI) for Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Post Imatinib Failure.

The availability of 2-TKIs has provided new therapeutic options for pts with CML post imatinib failure. We assessed the predictive factors of outcome of pts in CML-CP treated with 2-TKI. A total of 128 pts with CML-CP after imatinib failure treated with dasatinib (n=76) or nilotinib (n=52) were analyzed. Median age was 56 years (range, 21-83). The median duration of CP (CML diagnosis to start of 2-TKI) was 66 months (range, 2-241). Their best response to imatinib was complete hematologic response only in 33%, and cytogenetic response in 55% (23% complete, 16% partial, 15% minor). 4 pts were refractory to imatinib, 3 had unknown response, and 8 were intolerant. At the start of 2-TKI, 94 (73%) pts had active disease. 23% had clonal evolution (CE), and 73% had more than 90% Philadelphia positivity. The median follow-up time was 39 months (range, 15-61) from the start of the 2-TKI. At the time of last follow-up, 108 of the 128 pts (85%) were alive, 86 (67%) in CP on 2-TKI therapy; 17 pts had died. Responses to 2-TKI are shown in Table 1. In the univariate analysis (UA) for event-free survival (EFS), factors associated with poor EFS were splenomegaly, anemia (hemoglobin ≤12g/dL), lack of any cytogenetic response to previous imatinib therapy, ≥ 90% Philadelphia-positive (Ph+) metaphases at the start of 2-TKI therapy, nilotinib therapy, and high sokal risk score disease. In the subsequent multivariate analysis (MVA), splenomegaly, anemia (hemoglobin ≤12g/dL), lack of any cytogenetic response to previous imatinib therapy, and ≥ 90% Ph+ metaphases were selected as independent factors associated with poor EFS. Factors associated with poor overall survival (OS) in the UA were CE, performance status (PS) ≥1, and high sokal risk score at the start of 2-TKI therapy. In the MVA, only CE and a PS ≥1 were selected as independent poor prognostic factors for OS. High hemoglobin level (≥12g/dL), 0% bone marrow blasts, previous cytogenetic response to imatinib therapy, ≤90% Ph+ metaphases, and low sokal risk score were associated with the achievement of a major cytogenetic response (MCyR) by 12 months of therapy with 2-TKI in the UA. In the subsequent MVA for response, the lack of any cytogenetic response to imatinib therapy, anemia (hemoglobin ≤12g/dL) and ≥90% Ph+ metaphases at the start of 2-TKI therapy were selected as poor predictive factors for 12-month MCyR. Pts with 0, 1, 2, or 3 adverse factors had a 12-month probability of achieving a MCyR with 2-TKI therapy of 85%, 79%, 35%, and 14%, respectively. Based on these findings, we developed a score model that included the factors identified as independent predictive for a MCyR by 12 months of therapy with 2-TKI. Three prognostic risk groups are proposed for the new score model: 1) low score (no adverse factors; 16% of pts), in which pts have a 12-month probability of achieving a MCyR of 85%, after therapy with 2-TKI; 2) intermediate score (1-2 adverse factors; 67% of pts), in which pts have a 12-month probability of achieving a MCyR of 56%; and 3) high score (3 adverse factors; 17% of pts), in which pts have a 12-month probability of achieving a MCyR of 14% (Table 2). This score model predicts significantly for EFS (p=0.003) with a trend for OS (p=0.18). In conclusion, the outcome of pts post imatinib failure treated with 2-TKIs is dependent on previous cytogenetic response to imatinib, absence of anemia, and disease burden at the start of therapy. Pts with no previous cytogenetic response to imatinib therapy with anemia and high disease burden have a low likelihood of responding to 2-TKI with poor EFS, and therefore should be offered alternative treatment options.

Jabbour:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Kantarjian:Novartis: Research Funding; Bristol Myers Squibb : Research Funding; Wyeth: Research Funding. Wierda:Bayer: Research Funding; Sanofi Aventis: Research Funding; Abbott: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Trubion: Consultancy; Ligand: Consultancy; Genetech: Consultancy, Honoraria; Medimmune: Consultancy; Celegene: Speakers Bureau. Borthakur:Novartis: Speakers Bureau; Bristol Myers Squibb : Speakers Bureau. Rios:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb : Consultancy, Honoraria, Speakers Bureau. Cortes:Bristol Myers Squibb: Research Funding; Novartis: Research Funding.