The advent of imatinib has considerably changed treatment in chronic myeloid leukemia (CML). Although response rate and duration of response with imatinib monotherapy continue to be impressive, the majority of patients (pts) in complete cytogenetic remission (CCR) retain BCR-ABL transcripts as markers of residual disease and potential cause of relapse. In addition rapid evolvement of blast crises from CCR has been reported. Therefore, we designed an investigator-initiated phase IV prospective trial aiming to address the role of imatinib in combination with interferon alpha (IFN) or Ara-C and treatment intensification with high dose imatinib. In July 2002, the German CML-Study Group has activated the four-armed randomized controlled trial comparing imatinib 400 mg/d with imatinib+IFN, imatinib+Ara-C and imatinib after IFN failure in newly diagnosed pts with chronic phase CML. Randomization is stratified according to prognostic risk groups and not biased by consecutive allogeneic stem cell transplantation (SCT). High risk pts are randomly assigned to primary imatinib-based therapies including a 4th treatment arm with imatinib 800 mg/d. The treatment arm imatinib after IFN failure retains the chance of an IFN-induced CCR with 10 year-survival rates of 70–80%. In case of IFN failure pts are crossed over to imatinib. Allogeneic SCT is recommended for all pts with high risk, imatinib failure and EBMT-score 0–1. By August 2004, 429 pts were randomized: imatinib 400 mg/d (n=103), imatinib+IFN (n=130), imatinib+Ara-C (n=108), imatinib after IFN failure (n=84), and imatinib 800 mg/d (n=4). According to the New CML score, 34% of patients were low risk, 56% intermediate risk, and 10% high risk. At baseline, median WBC count was 63/nl (3.5–513), median platelet count was 385/nl (49–2,799) and median hemoglobin was 12.7 g/dl (6.1–16.6). We sought to evaluate results of the first cohort of pts (n=217) with a >12 months follow-up, recruited between 7/2002 and 5/2003 (imatinib 400 mg/d, n=52; imatinib+IFN, n=70; imatinib+Ara-C, n=49; imatinib after IFN failure, n=46). Median age was 56 yrs (16–82), 62% of pts were male. Cytogenetic data are available from 117 pts (68%) randomized to primary imatinib-based therapies. At 12 months, 104 pts (89%) achieved a major cytogenetic remission (Ph+<34%), being complete in 86 pts (74%). Quantitative RT-PCR data are available from 148 pts (87%). 56 pts (38%) achieved a ratio BCR-ABL/ABL <0.12%, which is equivalent to a 3-log reduction of the tumor load. 16 pts (11%) had at least one follow-up sample with undetectable BCR-ABL by real-time RT-PCR, in one patient additional nested RT-PCR was also negative. Cytogenetic response rates were not different between imatinib-based treatment arms. Estimated rate of freedom from progression to advanced disease was 97%. The first analysis of a prospective randomized trial with imatinib and imatinib in combination for newly diagnosed pts with CML has proven feasibility of imatinib combinations in addition to high response rates. The intention of combination therapy is to delay or avoid treatment resistance. Long-term observation will demonstrate whether these promising results will be maintained and will have the potential to improve survival of CML pts.

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