CELSG CML 11 “ISTAHIT” Phase III Study – Planned Interim Analysis: High Doses of Imatinib Mesylate (800mg/day) Significantly Improve Rates of Major and Complete Cytogenetic Remissions (MCR, CCR) in PretreatedPh+/BCR-ABL+CML Patients in Chronic Phase.

We have recently reported results from the first planned interim analysis of a multicenter, randomised, 2-arm - phase III study comparing imatinib standard dose (400 mg/day; arm A) with imatinib high dose (HD) induction (800 mg/day; HD arm B) followed by imatinib standard dose maintenance (400 mg/day) in pretreatedPh+/BCRABL+CML patients in chronic phase (CP; Blood,110,1048a). The first planned interim analysis was performed after 50% of the patients had been treated for 12 months (mo) since randomisation. A total of 227 patients were randomized. Pretreatments included hydroxyurea (96%), interferon (72%), busulfan (17%) and “others” (26%; mainly AraC +/− combinations). Although rates of complete haematological responses did not differ significantly between the 2 arms at 3, 6 and 12 mo, significantly more patients achieved a major (MCR) and a complete cytogenetic response (CCR) at 3 mo (MCR: 21% arm A, 37% arm B, p=0.01; CCR: 6% arm A, 25% arm B, p<0.001) and 6 mo (MCR: 34% arm A, 54% arm B, p=0.009; CCR: 20% arm A, 44% arm B, p<0.001). At 12 mo, following dose reduction of imatinib to 400 mg/d for “maintenance” at mo 6 in the HD arm B, the rates of MCR (the primary endpoint of the study) were comparabel (59% arm A, 57% arm B). Nevertheless, there was still a clear trend to higher rates of CCR (37% arm A, 48% arm B) in the HD arm B, but at the time of the interim analysis these values did not reach statistical significance. In contrast to non-hematological toxicities, grade 3/4 hematological toxicities were significantly more common in the HD arm B (anemia: 2% arm A, 14% arm B; leukopenia: 24% arm A, 46% arm B; thrombocytopenia: 15% arm A, 39% arm B; p≤0.02). Updated results reveal, that the cumulative median doses of imatinib were 400 mg (arm A) and 767 mg (arm B), respectively. The median days of dose interruptions during the first 6 mo were not significantly different (12.5 days arm A, 13 days arm B; p=0.78). Nevertheless, significantly more patients (65.1%) remained on the initial 400mg dose of imatinib in arm A as compared to the initial 800mg dose in the HD arm B (45.6%; p=0.009). 35% of the patients that had to be dose reduced in arm B were reduced to 600mg/day, 63% to 400mg and 2% to 300mg. The cumulative rates of MCR in patients with no dose reduction/interruption were higher in the HD arm B (71%) compared to arm A (59%, p=0.232). Moreover, the cumulative rates of CCR were significantly better for patients with no dose reduction/interruption in the HD arm B (61%) compared to the patients with no dose reduction/interruption in arm A (36%, p=0.014). In addition, in the HD arm B the cumulative rates of CCR were significantly better for patients with no dose reduction/interruption (61%) compared to patients in the HD arm B with an interruption and/or dose reduction (34.9%; p=0.017).