Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib

Abstract

We explored the impact of early molecular response (EMR; BCR-ABL ≤10% on the international scale [BCR-ABL(IS)] at 3 or 6 months) on outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with nilotinib or imatinib based on 4 years of follow up in Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients. Patients (n = 846) received nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily. At 3 months, more patients had EMR failure (ie, BCR-ABL(IS) >10%) on imatinib (33%) than on nilotinib (9%-11%); similarly at 6 months, 16% of patients in the imatinib arm vs 3% and 7% in the nilotinib arms had EMR failure. In all arms, EMR failure was associated with lower rates of molecular response, an increased risk of progression, and lower overall survival compared with EMR achievement. We also analyzed patient and treatment characteristics associated with EMR and found distinct patterns in the nilotinib arms vs the imatinib arm. High Sokal risk score was associated with a high rate of EMR failure on imatinib, but not on nilotinib. In contrast, reduced dose intensity and dose interruptions were strongly associated with EMR failure in nilotinib-treated, but not imatinib-treated, patients. This study is registered at www.clinicaltrials.gov as #NCT00471497.

Figure 1

BCR-ABL levels at 3 months from start of treatment in evaluable patients. Panels show BCR-ABL levels at 3 months from start of treatment overall (A) and by Sokal risk score at baseline (B) in patients treated with nilotinib 300 mg twice daily (n = 258), nilotinib 400 mg twice daily (n = 260), or imatinib 400 mg once daily (n = 264). Patients with unevaluable BCR-ABL transcript levels (n = 24 in the nilotinib 300 mg twice-daily arm, 21 in the nilotinib 400 mg twice-daily arm, and 19 in the imatinib arm) were excluded from the landmark analyses for the following reasons: atypical transcripts at baseline: nilotinib 300 mg twice daily (n = 5), nilotinib 400 mg twice daily (n = 1), and imatinib (n = 2); missing samples at 3 months: nilotinib 300 mg twice daily (n = 4), nilotinib 400 mg twice daily (n = 3), and imatinib (n = 5); or discontinued treatment by 3 months (3-month PCR analysis not performed): nilotinib 300 mg twice daily (n = 15, including 1 progression event), nilotinib 400 mg twice daily (n = 17), and imatinib (n = 12, including 1 progression event). INT, intermediate.

Figure 2

Cumulative incidence of MMR by BCR-ABL levels at 3 months in evaluable patients. Panels show MMR achieved in the nilotinib 300 mg twice-daily (A), nilotinib 400 mg twice-daily (B), and imatinib 400 mg once-daily (C) arms. Patients with atypical transcripts at baseline or unevaluable or missing PCR assessments at 3 months, or who achieved MMR by 3 months, were excluded.

Figure 3

Cumulative incidence of MR^4.5 by BCR-ABL levels at 3 months in evaluable patients. Panels show MR^4.5 achieved in the nilotinib 300 mg twice-daily (A), nilotinib 400 mg twice-daily (B), and imatinib once-daily (C) arms. Patients with atypical transcripts at baseline or unevaluable or missing PCR assessments at 3 months, or who achieved MR^4.5 by 3 months, were excluded.