Significant Higher Rates of Undetectable Molecular Residual Disease and Molecular Responses with Pegylated Form of Interferon a2a in Combination with Imatinib (IM) for the Treatment of Newly Diagnosed Chronic Phase (CP) Chronic Myeloid Leukaemia (CML) Patients (pts): Confirmatory Results at 18 Months of Part 1 of the Spirit Phase III Randomized Trial of the French CML Group (FI LMC).

IM 400 mg daily is the front-line treatment of CP CML, but provides only 50% major molecular responses (MMR) at 18 months (Mo).

we designed a phase III randomized multicenter open-label prospective trial comparing IM 400 mg/d (n=159) with 3 experimental arms: IM 600 mg/d (n=160), IM 400 mg/d combined to s/c cytarabine (Ara-C), (20 mg/m²/d, d15-28 of 28-day cycles)(n=158) and IM 400 mg/d combined to s/c Peg-IFN2a (90 μg/wk) (n=159).

Pts were allocated at a 1.1.1.1 ratio, stratified by Sokal risk groups. Molecular assessments were centralized, blinded and calculated according to the international standardized scale (IS). The purpose of this trial was to first determine whether higher doses of IM or combining IM with interferon or Ara-C would result in higher rates of molecular responses and if so, in better survival. Thus the trial was designed to be conducted according to 2 parts. During the part 1, the increased dose of IM or a combination regimen would be considered as promising at 1 year, if it increased the 4 log reduction response rate by at least 20 percentage points, e.g. from 15% to 35%, with an acceptable tolerability A planned interim analysis of 636 pts based on an optimal molecular response (OMR = BCR-ABL/ABL ratio ≤ 0.01) (α=0.85%, β=10%) at 1 year has suggested the superiority of the combination of Peg-IFN2a and imatinib (ASH 2008). We now report the 18 months update of this planned interim analysis of part 1 of the trial.

Pts of the part 1 were recruited between 9/2003 and 10/2007, median age 51 yrs (18-82), 62% males; Sokal score was low 37%, intermediate 39% and high risk 24%. Median follow-up was 42 Mo. (range 18-73) for alive patients. MMR, OMR and undectable molecular residual disease (UMRD) rates are described in Table 1. During the first year of treatment the median dose of IM was 400 mg for the 3 arms including IM 400 and 590 mg for IM 600; the median dose for Peg IFN2a was 54 μg per week (range11-166) and was 24mg per day (range 10-40) for Ara-C. Overall, 45% of the pts discontinued Peg-IFN2a during the first 12 months. Of interest, duration of treatment with Peg-IFN2a had an impact on responses. In pts who have been treated less than 4 months as compare to more than 12 months, rate of MMR, OMR and UMRD increased from 48% to 82%, 23% to 49% and 8% to 20% respectively.

Grade 3/4 neutropenia and/or thrombocytopenia occurred during the first year in 8% IM-400, in 14% IM-600, in 41% IM-Ara-C and in 40% IM-PegIFN arms respectively. No significant infection rates were observed between the 4 arms. Grade 3/4 non-haematological toxicities occurred in 19% IM-400 (oedemas, muscle cramps), in 30% IM-600, in 27% IM-Ara-C (diarrhoea) and in 31% IM-PegIFN pts (skin rashes, asthenia).

Based on these results and as recommended by the Independent Data and Ethics Monitoring Board, the CML French Group (FI-LMC) stopped accrual into the IM 600mg and IM 400mg + Ara-C arms and is currently continuing with IM 400 mg as control arm and the combination IM400mg + Peg-IFN2a as best experimental arm. This second part of the trial aims to confirm if achieving significant higher molecular responses will translate into a better event free and overall survival.

Mahon:Amgen: Honoraria; Novartis Pharma: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria.