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High dose imatinib improves cytogenetic and molecular remissions in pretreated Ph⁺/BCR-ABL⁺ CML chronic phase patients: first results from the randomized CELSG Phase III CML 11 "ISTAHIT" Study

¹ Central European Leukemia Study Group (CELSG), Internal Medicine V, Haematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
² Internal Medicine I, Haematology and Medical Oncology; Krankenhaus Barmherzige Schwestern Linz, Linz, Austria
³ CCRI Children’s Cancer Research Institute/LabDia Labordiagnostik, Vienna, Austria
⁴ Department of Haematology, RC Radiation Medicine, Kiev, Ukraine
⁵ Institute of Blood Pathology and Transfusion Medicine, Lviv, Ukraine
⁶ Clinical Center of Serbia, Institut za Haematologiju, Belgrad, Serbia and Montenegro
⁷ Clinics of Internal, Family Medicine and Oncology, Medical Faculty, Vilnius University, Hospital Santariskiu Clinics, Vilnius, Lithuania
⁸ National Center of Haematology, Riga, Latvia
⁹ University Hospital for Active Treatment "St. George", Plovdiv, Bulgaria
¹⁰ University Hospital for Active Treatment "St. Marina", Varna, Bulgaria
¹¹ Clinic for Haematology, National Clinical Center Skopje, Skopje, Macedonia
¹² National Center of Haematology and Transfusiology, Sofia, Bulgaria
¹³ University Hospital for Active Treatment, Pleven, Bulgaria
¹⁴ Kaunas University Hospital, Kaunas, Lithuania
¹⁵ Alexandrovska University Hospital, Sofia, Bulgaria
¹⁶ Department of Medical Statistics, Informatics and Health Economics, Medical University Innsbruck
¹⁷ Novartis, Basel, Switzerland
¹⁸ Novartis, Origgio VA, Italy

Correspondence: Andreas L. Petzer, Hospital Barmherzige Schwestern Linz, Internal Medicine I, Haematology and Oncology, Seilerstaette 4 4010 Linz, Austria. Phone: international +0043/73276777345. E-mail: andreas.petzer{at}bhs.at

ABSTRACT

Background: Imatinib 400 mg/day is the standard treatment for patients with chronic phase CML. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib.

Design and Methods: This prospective international, multicentre randomized phase III study randomized 227 patients with pre-treated Ph⁺/BCR-ABL⁺ CML either into a standard dose (SD) imatinib arm A (400 mg/day) or a high dose (HD) imatinib arm B (800 mg/day for 6 months followed by 400 mg/day as maintenance). In this planned interim analysis haematologic, cytogenetic and molecular responses as well as toxicity were evaluated.

Results: HD imatinib led to higher rates of major (MCyR) and complete cytogenetic responses (CCyR) at 3 months (MCyR: 21% versus 37%, p=0.01; CCyR: 6% versus 25%, p<0.001) and at 6 months (MCyR: 34% versus 54%, p=0.009; CCyR: 20% versus 44%, p<0.001). This was paralleled by a significantly higher major molecular response (MMR) rate at 6 months in the imatinib HD arm B (11.8% versus 30.4%; p=0.003). At 12 months, rates of MCyR (the primary endpoint) were comparable between both arms (57% versus 59%). In contrast to non-haematological toxicities, grade 3/4 haematological toxicities were more common in the HD arm B. Cumulative CCyR rates were higher in patients without dose reduction in the HD arm B (61%) compared to patients with no dose reduction in arm A (36%, p=0.014).

Conclusions: This is the first randomized phase III trial in pre-treated CP-CML patients demonstrating improvement in MCyR, CCyR and MMR rates with HD imatinib therapy.

Key words: phase III study, chronic Phase CML, high dose imatinib.