High Dose Imatinib Induction Therapy (800 mg/day, 6 Months) In Pre-Treated Chronic Phase CML Patients Improves Cytogenetic and Molecular Responses but Does Not Improve Overall and Progression Free Survival – Final Results of the CELSG Phase III CML11 “ISTAHIT” Trial

Imatinib 400 mg/day represents the current standard treatment for de novo as well as pre-treated CML patients in chronic phase (CP). Recent randomized phase III trials revealed conflicting results concerning the potential higher efficacy of dose-increased imatinib in de novo treated CP-CML.

We here present the final analyses including response data, OS, EFS and PFS of the multicenter, randomised, 2-arm phase III CELSG “ISTAHIT” trial evaluating imatinib high dose (HD) induction (800 mg/day, 6 months) followed by 400 mg/day as maintenance (experimental arm B) compared to continuous imatinib standard dose (400mg/day; arm A) in pre-treated CP CML patients. ClinicalTrials.gov Identifier: NCT0032726.

From a total of 243 patients screened for inclusion, 16 patients were not eligible (mainly due to non sufficient numbers of metaphases obtainable from the bone marrow before the start of the study). Of the remaining 227 patients, 113 patients were randomized into arm A and 114 patients into the experimental arm B. Subsequent data are presented as per protocol. No significant differences between treatment groups were observed regarding sex (55.5% female, 44.5% male), age (median: 46.3 years, range 18 –76), Sokal scores at diagnosis (30% low, 41% intermediate, 16% Sokal high risk, 13% unknown) and different pre-treatments, which included hydroxyurea (96%), interferon (72%), busulfan (17%) and “others” (26%; mainly Ara-C). The median observation time was 673 days. Cytogenetic responses were generally higher in the experimental arm B and revealed statistically significant differences in major cytogenetic responses (MCyR) at 3 and 6 months (month 3: 25.8% arm A, 48.3% arm B, p=0.002; month 6: 41.9% arm A, 58.8% arm B, p=0.029) as well as in complete cytogenetic responses (CCyR) not only during imatinib HD therapy (month 3: 7.5% arm A, 29.9% arm B, p<0.001; month 6: 20.4% arm A, 47.4% arm B, p<0.001) but also thereafter (month 12: 31.8% arm A, 52.9% arm B, p=0.006). The primary endpoint of the study, the achievement of an improved MCyR at 12 month was, however, not significantly different (56.8% arm A, 64.4% arm B). In line with improved cytogenetic responses, major molecular response (MMR^IS) rates were also significantly better at 3, 6 and even at 24 months in the HD arm B (month 3: 3.7% arm A, 15.9% arm B, p=0.003; month 6: 9.4% arm A, 34.6% arm B, p<0.001; month 24: 26.5% arm A, 42.5% arm B, p=0.034). Surprisingly, however, this impressing improvement in cytogenetic and molecular remissions in patients achieving high dose imatinib as induction therapy did not translate into a better OS and PFS, both of which were comparable in the two treatment arms (OS: p=0.25; EFS: p=0.37). Moreover, the EFS was even significantly worsened in the experimental arm B (p=0.014). Grade 3/4 non-haematological toxicities during the first 6 months of therapy were comparable, whereas grade 3/4 haematological toxicities were significantly more common in the imatinib HD arm B.

Although high dose imatinib induction induces more rapid and higher cytogenetic and molecular remission rates in pre-treated CP CML patients, OS as well as PFS were not improved and EFS was even worsened in the high dose induction arm B. Therefore we conclude that imatinib 400mg/day remains the standard of care for pre-treated CP-CML patients.

Petzer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Imatinib 800mg is not licensed as the initial therapy of chronic phase CML. Lion: Novartis: Honoraria, Research Funding. Bogdanovic: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griskevicius: Novartis: Research Funding. Kwakkelstein: Celgene: Employment. Rancati: Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gastl: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wolf: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.