Pegylated Interferon a2a (PegIFN) At the Dose of 45μg Per Week in Combination with Imatinib 400mg Is the Recommended Initial Dose for Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML-CP): Results From the French SPIRIT Trial of the French CML Group (FI LMC)

The SPIRIT phase III randomized multicenter open-label prospective trial was designed to compare 4-arm, imatinib 400 mg versus imatinib 600 mg versus imatinib 400 mg + cytarabine at a dose of 20 mg/m²/day in cycles of 28 days, versus imatinib 400 mg + PegIFN at an initial dose of 90 μg/week. The planned molecular analysis after 1 year based on the outcome of 636 pts resulted in a highly significant improvement of superior molecular response (SMR) (0.01 % Bcr-Abl/Abl on IS) of the combination imatinib 400mg-PegIFN (N Engl J Med, 2010). Accrual within the imatinib 600 mg and imatinib 400 mg-cytarabine has been stopped. In the initial cohort of 171 pts who had been treated less than 4 months with the 2 combined agents, major molecular response (MMR: 0.1%) rate was 48%, SMR rate was 23%, and undetectable molecular residual disease (UMRD) was 8%. By contrast, in pts receiving the combined agents longer than 12 months, MMR, SMR and UMRD rates were 82%, 49% and 20% respectively. In order to improve tolerability of the combination, initial dose of PegIFN has been reduced to 45μg/week. The current analysis focuses on the tolerability and efficacy of the reduced dose of PegIFN as compared to the initial planned dose of 90μg/week. Patients and methods: As of December 31^st 2010, date for closing accrual, 789 pts have been included, 445 pts within the imatinib 400mg and imatinib 400mg+PegIFN arms. The high proportion of PegIFN discontinuation during the first year prompted an amendment that recommended reducing the initial dose down to 45ug/week at enrolment. For these pts the weekly dose of PegIFN was increased up to 90μg after 2 months of treatment with the combination of PegIFN 45μg plus Imatinib 400mg, if the hematological and non-hematological tolerance was acceptable. Out of the 221 pts assigned to imatinib plus PegIFN, 171 received 90μg and 50 received 45μg/week of PegIFN, both groups being similar with a median age of 51 and 48 years respectively. Molecular biology was centralized, samples being collected every 4 months, with a karyotype recommended yearly. Data of parameters of effectiveness and tolerance were collected even after stopping treatment protocol. Adverse events (AE) considered for the analysis are those which led for PegIFN dose adjustment. Results. At the time of the analysis, 30% of pts were still on PegIFN. Table 1 describes the AE which occurred during the two consecutive periods of the trial (before and after the amendment).

Hematologic toxicity was predominant within the PegIFN arm (68% pts suffering all grade including 54% with G3-4) leading to 40% of permanent discontinuation of PegIFN. However, only a small proportion of neuropsychiatric syndrome (including depression, chronic fatigue and insomnia) and flu-like syndrome were observed and no cardiac event occurred with PegIFN at the dose of 45μg/week. Rate of all grade hematologic toxicity decreased from 68% to 45% of pts after the amendment. Of interest the reduced dose of PegIFN had a significant impact on the adherence to the treatment. During the first 6 months before and after the amendment, 40% and 10% of pts discontinued PegIFN respectively. Thus after the amendment 90% received at least 6 months of PegIFN. Of note the reduced dose of 45μg/week resulted in a similar response rate as compared to the initial planned dose of 90μg. The MMR rates at 6 months were before and after the amendment 36.3% (95%CI: 29.1–49.3) and 36% (95%CI: 22.0–50.8) respectively. The corresponding number for SMR rates at 6 months were 9.9% (95%CI: 5.9–15.4) and 10% (95%CI: 3.3–21.8) respectively. Finally for 222 pts, imatinib 400mg alone resulted in less responses at 6 months with MMR and SMR rate of 19.3% (95CI: 14.3–25.0) and 5.8% (95CI:3.1–0.7) respectively. The combination of imatinib and PegIFN has been shown in this trial as an effective combination for increasing the rate of molecular responses compared to imatinib alone. The lower dose of PegIFN (45 mg/week) resulted in less early toxicity. It will allow the combination to be given together for a longer period of time and preserve the increased antitumor efficacy. An update with a minimum of 12 months of follow-up of the 50 pts will be presented.

Off Label Use: Pegylated form of interferona2a.