Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study

Abstract

A B S T R A C T PurposeTo evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Patients and MethodsA total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n ϭ 319) or 400 mg (n ϭ 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. ResultsAt 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P ϭ .2035; CCyR, 70% v 66%; P ϭ .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P ϭ .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P ϭ .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. ConclusionMMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib.

Nilotinib dose‐optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd

“…Notably, although high‐dose imatinib has been associated with poor tolerability (Cortes et al , 2010; Hehlmann et al , 2011), most patients who had nilotinib dose escalation in this study were able to maintain the higher dose, with 83 of 88 remaining on nilotinib 400 mg twice daily at the end of treatment. Although some of these patients (14 of 88; 15·9%) later discontinued treatment due to suboptimal response or treatment failure, the majority (63·6%) achieved MMR by 24 months.…”

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

“…Preliminary results from the study indicated that the CCyR was significantly better at 6 months with HD-IM (45% SD-IM vs 57% HD-IM; P ¼ .0146), but there was no statistical difference in CCyR at 12 months (66% SD-IM vs 70% HD-IM). 51 MMR rates were higher with HD-IM at 3 months and 6 months compared with SD-IM (12% vs 3% at 3 months, P ¼ .0011; 34% vs 17% at 6 months, P ¼ .0002) although no difference in the MMR rate at 12 months was observed (46% vs 40%; P ¼ .20). However, there was a trend toward improved MMR at 12 months in patients who had high Sokal risk scores (26% SD-IM vs 41% HD-IM; P ¼ .16).…”

“…However, there was a trend toward improved MMR at 12 months in patients who had high Sokal risk scores (26% SD-IM vs 41% HD-IM; P ¼ .16). 51 The ELN also performed a randomized study of standard-dose imatinib (400 mg daily) versus high-dose imatinib (800 mg daily) as front-line therapy for patients with high Sokal risk CML-CP in which the CCyR rate at 12 months was the primary endpoint. 52 There was no difference in the CCyR rate at 12 months in the intention-to-treat analysis.…”

“…54 For nontrial patients who have CML-CP, the recommended starting dose of imatinib should be 400 mg daily based on long-term data from the IRIS trial and on confirmatory data from the TOPS study. 24,51 It has been demonstrated that imatinib 800 mg daily is an effective strategy for overcoming resistance to imatinib 400 mg daily and can be tolerated long-term, as demonstrated in the studies of imatinib dose escalation from the IRIS and MDACC studies and from the TOPS study. 47,49,51 …”

Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: Approach to Patients with Treatment-Naive or Refractory Chronic-Phase Disease

“…At 12 months, there was no statistically significant difference in MMR (46% vs 40%, P ϭ .2035) or CCyR (70% vs 66%, P ϭ .3470), but MMR rates at 3 and 6 months were higher in patients randomly assigned to imatinib 800 mg, as was the CCyR rate at 6 months (57% vs 45%, P ϭ .0146). 12 Longer follow-up is required to determine whether the faster responses achieved with higher doses of imatinib will provide clinical benefit. Nonhematologic and hematologic adverse event rates were higher in the 800-mg arm 12 and, notably, whereas patients assigned to the 400-mg arm achieved an average daily dose of 388.4 mg, patients in the 800-mg arm achieved an average daily dose of only 662.0 mg, indicating the reduced tolerability of higher doses of imatinib.…”