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High-Dose Imatinib Followed by Maintenance Not Significantly Different Than Continuous Standard-Dose Imatinib in Patients With Previously Treated Chronic Phase Chronic Myeloid Leukaemia: Presented at EHA

By Emma Hitt, PhD

COPENHAGEN, Denmark -- June 15, 2008 -- Induction of high-dose imatinib, followed by maintenance imatinib, produces similar outcomes to that of continuous standard-dose imatinib in previously treated patients with chronic-phase chronic myeloid leukaemia (CML), according to interim findings from the Imatinib Standard Dose Versus High Dose Induction Trial (ISTAHIT) study.

Andreas L. Petzer, MD, Innsbruck and Hospital BHS Linz; Central European Leukaemia Study Group (CELSG), Innsbruck, Austria, and colleagues, reported the interim findings of this multicentre, randomised, open-label, phase 3 trial on June 15 at the 13th Congress of the European Hematology Association (EHA).

Between February 2004 and December 2006, 227 pretreated Ph+/BCR-ABL+ patients with chronic-phase CML were randomised in a 1-to-1 ratio to receive continuous standard-dose imatinib 400 mg QD (SD arm) or high-dose imatinib 800 mg QD (HD arm) for 6 months followed by a maintenance dose of imatinib 400 mg QD.

The researchers performed the first planned interim analysis after 50% of the patients had been treated for 12 months after randomisation.

All patients were imatinib-naive, although they could have received other prior treatment for at least 12 months before study entry. Pretreatment of patients included hydroxyurea, interferon, and busulfan in about 97%, 70%, and 20% of patients in both arms.

The median age of the patients was approximately 46 years, and median duration of CML was about 26 to 27 months. The median follow-up at the time of interim analysis was 12.75 months (range, 3-24 months).

Rates of major cytogenetic response (MCyR) at 48 weeks, the primary endpoint, were not significantly different between arms at 58.9% (SD arm) versus 56.5% (HD arm). However, high-dose imatinib followed by maintenance imatinib resulted in a significantly higher MCyR at 12 weeks (20.6% vs 37.3%, P = .01) and 24 weeks (33.8% vs 53.8%, P = .009).

Rates of complete haematologic remission at 48 weeks were also not significantly different between arms, with 82% in the SD arm versus 90% in the HD arm. Rates of complete cytogenetic response (CCyR) were significantly higher in the HD arm compared with the SD arm at week 12 (24.5% vs 6.2%, P < .001) and week 24 (43.8% vs 19.8%, P < .001), but not at week 48 (47.8% vs 37.3%, P = .29).

Rates of major molecular response (MMR) were significantly higher in the high-dose arm compared to the standard-dose arm at week 24 (20.3% vs 8.2%, P = .034). However, at week 48, there was no significant difference between arms with 25% (HD arm) and 17.5% (SD arm) achieving this endpoint.

Haematologic toxicity was more common in patients receiving high-dose imatinib. Anaemia was noted in 2% of the SD group versus 14% of the HD group B (P = .02), leukopenia in 24% versus 46% (P = .02) and thrombocytopenia in 15% versus 39% (P = .003).

"Despite high rate of grade 3/4 leukopenias in the high-dose arm, the incidence of grade 3/4 infections was low in both arms (2% vs 3% in the standard vs high-dose arms, respectively)," Dr. Petzer said. He added that the major cytogenetic response at 12 months was not yet statistically significantly different, "but there was still a clear trend to higher rates of CCyR and MMR in the experimental high-dose arm," Dr. Petzer concluded.

[Presentation title: High Doses of Imatinib Mesylate (800mg/day) Significantly Improve Rates of Major and Complete Cytogenetic Remissions (MCR, CCR) - Results From the First Planned Interim Analysis of a Multicenter, Randomised, 2-Arm - Phase III Study Comparing Imatinib Standard Dose (400 mg/day) With Imatinib High Dose Induction (800 mg/day) Followed by Imatinib Standard Dose Maintenance (400 mg/day) in Pretreated Ph+/BCR-Abl-, Abl+ CML Patients in Chronic Phase. Abstract 407.]

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