Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia

Abstract

Background: Second-generation tyrosine kinase inhibitors induce cytogenetic responses in approximately 50% of patients with chronic myeloid leukemia in chronic phase in whom imatinib treatment has failed. However, it has not yet been established which of the patients in whom imatinib treatment fails are likely to benefit from therapy with second-generation tyrosine kinase inhibitors.

Design and methods: We analyzed a cohort of 80 patients with chronic myeloid leukemia who were resistant to imatinib and who were treated with dasatinib or nilotinib while still in first chronic phase. We devised a scoring system to predict the probability of these patients achieving complete cytogenetic response when treated with second-generation tyrosine kinase inhibitors.

Results: The system was based on three factors: cytogenetic response to imatinib, Sokal score and recurrent neutropenia during imatinib treatment. We validated the score in an independent group of 28 Scottish patients. We also studied the relationship between cytogenetic responses at 3, 6 and 12 months and subsequent outcome. We classified the 80 patients into three categories, those with good risk (n=24), intermediate risk (n=27) and poor risk (n=29) with 2.5-year cumulative incidences of complete cytogenetic response of 100%, 52.2% and 13.8%, respectively (P<0.0001). Moreover, patients who had less than 95% Philadelphia chromosome-positive metaphases at 3 months, those with 35% or less Philadelphia chromosome-positive metaphases at 6 months and patients in complete cytogenetic response at 12 months all had significantly better outcomes than patients with lesser degrees of cytogenetic response.

Conclusions: Factors measurable before starting treatment can accurately predict response to second-generation tyrosine kinase inhibitors. Cytogenetic responses at 3, 6 and 12 months may influence the decision to continue treatment with second-generation tyrosine kinase inhibitors.

Figure 1.

Event-free, progression-free and overall survival and cumulative incidences of major and complete cytogenetic responses and major molecular response in the Hammersmith population of patients (see text). For outcome (upper three lines): the top line indicates overall survival, the middle line indicates progression-free survival, the bottom line indicates event-free survival. For clinical response (lower three lines): the top line indicates cumulative incidence of major cytogenetic response, the middle line indicates cumulative incidence of complete cytogenetic response and the bottom line indicates cumulative incidence of major molecular response. Vertical lines indicate censored patients.

Figure 2.

Hammersmith 3-criteria score for predicting cytogenetic responses to 2G-TKI therapy. The score can be calculated by allocating points to each of the three variables, as described in the text. Patients with a total score of <1.5 constitute the good risk group, those with a total score between 1.5 and 2.5 form the intermediate risk group, and those with a total score > 2.5 constitute the poor risk group. The 2.5-year cumulative incidences of complete cytogenetic response were 100%, 52.2% and 13.8%, respectively (P<0.0001). The score was validated with an independent sample of patients (see text). Vertical lines indicate censored patients.

Figure 3.

Cumulative incidence of complete cytogenetic response (CCyR) according to cytogenetic response at (A) 3 months, and (B) 6 months (see text). Panel A shows the cumulative incidence of CCyR according to the cytogenetic response at 3 months for the 58 patients who were not in CCyR at 3 months. Patients who were at least in minor cytogenetic response (MiCyR) at 3 months had a significantly higher probability of achieving CCyR than patients who had no cytogenetic response (79.3% vs. 0% P<0.0001). We found no difference in the probability of achieving CCyR between patients who were in partial cytogenetic response (PCyR) and those in MiCyR at 3 months (75% vs. 80.4%, P=0.7). Panel B shows the cumulative incidence of CCyR according to the cytogenetic response at 6 months for the 46 patients who were not already in CCyR at 6 months. The probabilities of achieving CCyR during the follow-up according to their cytogenetic response at 6 months were 85.7%, 50% and 0% (P<0.0001) for the patients who had achieved PCyR, MiCyR or no response respectively. The P values for the differences between partial and MiCyR and between MiCyR and no response were P=0.02 and P<0.0001 respectively. Vertical lines indicate censored patients.

Figure 4.

Patients’ overall survival according to the Hammersmith score (see text). The top line indicates good risk patients, the middle line intermediate risk patients, and the bottom line poor risk patients

Figure 5.

Landmark analyses for overall and event-free survival according to cytogenetic responses at 3 and 6 months. (A) and (B) At 3 months the 48 patients still in chronic phase who had achieved at least a minor cytogenetic response (upper lines) had better overall and event-free survivals (also progression-free survival, see text) than the 31 patients (lower lines) who had failed to achieve a minor cytogenetic response, namely 100% versus 76.8% (P=0.0005) and 89.5% versus 63.6 (P=0.002) respectively. (C) and (D) At 6 months 78 patients remained in chronic phase (76 with no “events”). The 40 patients who had achieved a major cytogenetic response (upper lines) had better event-free survival and overall survival (also progression-free survival, see text) than the 38 patients who were not in major cytogenetic response (lower lines), namely 100% versus 84.2% (P=0.01) and 90.3% versus 75.0% (P=0.03) respectively. Vertical lines indicate censored patients.