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Title: High-Dose vs Standard-Dose Imatinib in Treatment-Naive Patients With Newly Diagnosed CML: Presented at EHA

"High-Dose vs Standard-Dose Imatinib in Treatment-Naive Patients With Newly Diagnosed CML: Presented at EHA"

By Emma Hitt, PhD COPENHAGEN, Denmark -- June 15, 2008 -- High-dose versus standard-dose imatinib induces rapid responses and a trend toward improvement in achieving major molecular response (MMR) at 12 months in patients with previously untreated chronic myeloid leukemia (CML), according to research. Jorge Cortes, MD, Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, reported the first findings from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial here on June 14 at the 13th Congress of the European Hematology Association (EHA). "Several phase 2 studies have explored the initial use of 600 or 800 mg of imatinib in patients with early, chronic-phase CML," noted Dr. Cortes. "And all of these results have consistently shown a higher rate and an earlier achievement of both complete cytogenetic and major molecular response." Dr. Cortes and colleagues compared the efficacy of high-dose imatinib 400 mg BID versus the standard dose of imatinib 400 mg QD in patients with newly diagnosed, previously untreated chronic-phase CML. Patients were stratified by Sokal score at diagnosis, with the majority of patients classified as low- or intermediate-risk and 24% classified as high-risk. Patients (N = 476) were randomised in a 2-to-1 ratio to receive either high-dose imatinib (n = 319) or standard-dose imatinib (n = 157). The results reported at EHA represent the first interim analysis of this 5-year study, with a median follow-up of 17 months. At 12 months, over 90% of patients remained on treatment and on study in both groups, and discontinuation of therapy was comparable between both groups. In the intention-to-treat population, there was a significantly higher rate of complete cytogenetic responses (CCR) at 6 months with the higher dose (57% vs 45%, [P = .0146). However, at 12 months, while the CCR rate remained higher with high-dose imatinib, it was not significantly different (70% vs 66%; P = .3470).

Time to MMR was significantly more rapid in the high-dose imatinib group, with a median time of 8.4 months to first MMR compared with 13.6 months for the standard-dose group (P = .0038).

On an intention-to-treat basis, MMR rates also were significantly higher among those treated with high-dose imatinib at 3 months (P = .0011) and 6 months (P = .0002); however, the significance was not maintained at 9 months (P = .0604) and 12 months (P = .2035).

When patients were assessed by Sokal risk score, there was a trend for a favourable impact of higher doses of imatinib, with 41% achieving an MMR at 12 months, compared with 26% of those in the standard-dose group (P = .1565).

In addition, a smaller proportion of patients with low plasma levels of imatinib at 1 month achieved a major molecular response.

Dr. Cortes noted that at 12 months, over 80% of patients in the standard-dose arm actually received imatinib 400 mg QD; whereas, only 60% of those in the high-dose group were receiving imatinib 800 mg QD. Dose management included dose reductions, dose escalations, and interruptions in treatment >5 days.

Rates of grade 3/4 nonhaematologic toxicity were low in both arms. There was a slightly higher rate of rash (5.7% vs 2.6%), diarrhoea (4.1% vs 1.3%), and myalgia (3.5% vs 0.6%) in the high-dose group, but most of these toxicities were manageable in both groups, Dr. Cortes said. There was a trend for a higher rate of grade 3/4 neutropenia and thrombocytopenia with the higher dose, requiring additional treatment interruptions and dose reductions in some patients.

"These results confirm the high efficacy of imatinib as the initial therapy for patients with chronic myeloid leukaemia in early chronic phase," Dr. Cortes said. "Increasing the doses can speed up the achievement of response, and this may possibly translate into a better long-term survival and disease-free duration for patients. And the majority of patients can indeed tolerate these higher doses."

[Presentation title: First Report of the TOPS Study: A Randomized Phase III Trial of 400 mg vs 800 mg Imatinib in Patients With Newly Diagnosed, Previously Untreated CML in Chronic Phase Using Molecular Endpoints. Abstract 402.]

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