Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia

Abstract

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP-CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3-log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2·9-fold lower than in the IM400 arm (P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3-4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression-free (P = 0·048) and relapse-free (P = 0·031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity.

Keywords: BCR-ABL1; chronic myeloid leukaemia; imatinib.

Figure 1

Molecular responses of CML-CP patients, by treatment arm and approximate time on study, during the first 12 months on treatment. Changes of Bcr-Abl mRNA level, relative to Group-specific median baseline values, are shown on a common log (log₁₀) scale for patients randomized to IM800 (solid line) or IM400 (dashed line) therapy. Boxplots showing the 25^th and 75^th percentiles are connected at the median values. Horizontal dashed lines indicate no change, 3-log (MMR) and 4-log (MR^4.0) reduction from baseline. Month 3: days 43–126; month 6: days 127–210; month 9: 211–294; month 12: days 295–420 (if a patient’s molecular response was tested more than once within a month’s range of days, only the result obtained closest to day 90, 180, 270 or 365, respectively, was included in this Figure).

Figure 2

Kaplan-Meier estimates of treatment outcomes for patients randomized to IM400 (1) or IM800 (2). Tickmarks indicate censored observations. Number of patients remaining at risk are shown beneath each plot. (A) Overall survival; (B) Progression-free survival; (C) Relapse-free survival of patients who achieved complete haematologic response.

Figure 2

Kaplan-Meier estimates of treatment outcomes for patients randomized to IM400 (1) or IM800 (2). Tickmarks indicate censored observations. Number of patients remaining at risk are shown beneath each plot. (A) Overall survival; (B) Progression-free survival; (C) Relapse-free survival of patients who achieved complete haematologic response.

Figure 2

Kaplan-Meier estimates of treatment outcomes for patients randomized to IM400 (1) or IM800 (2). Tickmarks indicate censored observations. Number of patients remaining at risk are shown beneath each plot. (A) Overall survival; (B) Progression-free survival; (C) Relapse-free survival of patients who achieved complete haematologic response.