Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities

Abstract

Early responses to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML)-chronic phase (CP) are associated with improved outcome. We analyzed the impact of such a response on outcomes among patients treated with 4 TKI modalities as frontline therapy in CML-CP. A total of 483 patients who received 400 or 800 mg imatinib, nilotinib, or dasatinib were analyzed. The median follow-up was 72 mo. Landmark analysis at 3 mo by molecular response showed that the cumulative proportions of 3-y event-free survival (EFS) for 3-mo BCR-ABL levels was 95% for those with ≤1%, 98% for >1% to 10%, and 61% for those with >10% (P = .001). The corresponding values by cytogenetic responses were 97% if Ph+ = 0%, 89% if Ph+ = 1% to 35%, and 81% if Ph+ >35% (P = .001). Cytogenetic response at 3 mo significantly discriminated for 3-y overall survival (OS): 98%, 96%, and 92%, respectively (P = .01). In multivariate analysis, young patients, high Sokal index, and treatment with imatinib 400 significantly predicted for poor (>35%) cytogenetic response at 3 mo. Early responses are predictive for EFS and failure-free survival and to a lesser extent OS, regardless of the treatment modality, although therapies other than standard-dose imatinib result in higher rates of deep early responses.

Trial registration: ClinicalTrials.gov NCT00038649 NCT00048672 NCT00050531 NCT00129740 NCT00254423 NCT00333840.

Figure 1

Evaluable cytogenetic and molecular responses to different TKI modalities at 3- and 6-mo follow-up (imatinib 400, imatinib 800, nilotinib, and dasatinib). (A) Cytogenetic responses at 3 mo. (B) Molecular responses at 3 mo. * indicates that the majority of patients in the imatinib 400 group did not have molecular response values, as these patients were enrolled in the year 2000-2001, when PCR was not routinely done. (C) Cytogenetic responses at 6 mo. (D) Molecular responses at 6 mo.

Figure 2

EFS according to cytogenetic and molecular response at 3 and 6 mo. (A) EFS by cytogenetic response at 3 mo. (B) EFS by molecular response at 3 mo. (C) EFS by cytogenetic response at 6 mo. (D) EFS by molecular response at 6 mo. Molecular response analysis excludes patients treated with imatinib 400.

Figure 3

FFS according to cytogenetic and molecular response at 3 and 6 mo. (A) FFS by cytogenetic response at 3 mo. (B) FFS by molecular response at 3 mo. (C) FFS by cytogenetic response at 6 mo. (D) FFS by molecular response at 6 mo. Molecular response analysis excludes patients treated with imatinib 400.

Figure 4

TFS according to cytogenetic and molecular response at 3 and 6 mo. (A) TFS by cytogenetic response at 3 mo. (B) TFS by molecular response at 3 mo. (C) TFS by cytogenetic response at 6 mo. (D) TFS by molecular response at 6 mo. Molecular response analysis excludes patients treated with imatinib 400.

Figure 5

OS according to cytogenetic response at 3 and 6 mo. (A) OS by cytogenetic response at 3 mo. (B) OS by cytogenetic response at 6 mo.