Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study

Abstract

We present long-term follow-up of a dasatinib phase 3 study of patients with imatinib-resistant/-intolerant chronic myeloid leukemia (CML). In the CA180-034 study, 670 patients with imatinib-resistant/-intolerant CML in chronic phase (CML-CP) received dasatinib 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. At 6 years, 188 (28%) of 670 patients remained on study treatment. Estimated 6-year protocol-defined progression-free survival (PFS) rates were 49%, 51%, 40%, and 47%, respectively, and estimated 6-year overall survival (OS) rates were 71%, 74%, 77%, and 70%, respectively (intent-to-treat population, including protocol-defined progression or death after discontinuation). Estimated 6-year rates of survival without transformation on study treatment were 76%, 80%, 83%, and 74%, respectively. Major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of PFS and OS. Notably, estimated 6-year PFS rates based on ≤1%, >1% to 10%, and >10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively. Most adverse events occurred by 2 years. Imatinib-resistant/-intolerant patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 months. This study was registered at ClinicalTrials.gov: NCT00123474.

Figure 1

CONSORT diagram for the CA180-034 study. One of the 167 patients treated with dasatinib 50 mg twice daily had been randomly assigned to receive 100 mg once daily. Adapted from Shah et al and reproduced with permission from the American Society of Clinical Oncology. (*) Reasons for discontinuation are presented in Table 1.

Figure 2

Kaplan-Meier analyses (all patients). (A) PFS. (B) OS. bid, twice daily; qd, once daily.

Figure 3

Kaplan-Meier landmark analyses (landmark populations). (A) PFS according to molecular response at 3 months. For BCR-ABL ≤1% vs >1% to 10%, P = .003; for >1% to 10% vs >10%, P < .0001. Of note, 212 (90%) of the 235 patients with BCR-ABL >10% at 3 months in this analysis had CHR. (B) OS according to molecular response at 3 months. For BCR-ABL ≤1% vs >1% to 10%, P = .285; for >1% to 10% vs >10%, P < .0001. (C) PFS according to molecular response at 6 months. For BCR-ABL ≤1% vs >1% to 10%, P = .001; for >1% to 10% vs >10%, P = .017. (D) OS according to molecular response at 6 months. For BCR-ABL ≤1% vs >1% to 10%, P = .554; for >1% to 10% vs >10%, P = .001. Patients without a molecular assessment at 3 or 6 months were not included in the corresponding analyses. In addition, patients who progressed (for PFS) or died (for OS) before the landmark time point were excluded from those analyses.

Figure 4

PFS and OS by CHR and molecular response at 3 months (all treatment arms combined). Analysis excludes patients with CHR or BCR-ABL ≤10% at baseline; only those patients who had not progressed (n = 258) or had not died (n = 262) by 3 months were included in (A) and (B), respectively. Four patients who had progressed but had not died by 3 months were included in (B). P < .0001 (log-rank) for CHR plus ≤10% vs CHR plus >10% at 3 months for PFS and OS. For CHR plus >10% vs no CHR at 3 months, P < .0001 (log-rank) for PFS and P = .0001 (log-rank) for OS.