Targeted therapy with the BCR-ABL tyrosine kinase inhibitor imatinib induces high response rates in chronic myeloid leukemia (CML) patients (pts). Nevertheless, residual disease remains in virtually all pts on imatinib monotherapy as a potential cause of relapse. In July 2002, the German CML-Study Group activated the four-armed randomized controlled trial comparing imatinib 400mg/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 treatment arm with 800mg/d imatinib. By 7/05, 632 pts were randomized: imatinib 400mg/d (n=129), imatinib+IFN (n=179), imatinib+Ara-C (n=156), imatinib after IFN failure (n=157), and imatinib 800mg/d (n=11). According to the Hasford score, 35% of pts were low risk, 54% intermediate risk, and 11% high risk. At baseline, median WBC count was 67/nl (3–529), median platelet count 391/nl (34–2,799) and median hemoglobin 12.6 g/dl (6.1–16.6). We sought to evaluate results of pts with a >12 months follow-up (n=416), recruited between 7/02 and 6/04 (imatinib 400mg/d, n=102; imatinib+IFN, n=126; imatinib+Ara-C, n=104; imatinib after IFN failure, n=81; imatinib 800mg/d, n=3) and of pts with a >24 months follow-up (n=232), recruited between 7/02 and 6/03 (imatinib 400mg/d, n=55; imatinib+IFN, n=74; imatinib+Ara-C, n=54; imatinib after IFN failure, n=49) with respect to response, resistance, and progression. After 12 months of treatment cytogenetic data are available from 238/335 pts (71%) randomized to primary imatinib based therapies. 209 pts (63%) achieved a major cytogenetic remission (MCR; Ph+<35%), being complete in 53%. Q-PCR data were available in 270 pts (81%). 89 pts (27%) achieved a major molecular response (MMR; ratio BCR-ABL/ABL <0.12%). After 24 months cytogenetic data are available from 141/183 pts (77%). 126 pts (69%) achieved a MCR, being complete in 60%. Q-PCR data were available in 149 pts (81%). 73 pts (40%) achieved a MMR. 12/177 pts lost CCR (7%) during the 1st year and 6/110 pts (5%) during the 2nd year of treatment. Within the 1st year 13/335 pts (6 low, 3 intermediate, 4 high risk; 4%) progressed to blast crisis, 4 of them revealed clonal evolution (complex aberrant karyotype, n=3; +8, n=1), two others BCR-ABL mutations (E355G and M244V). Within the 2nd year 3/232 pts (1 each low, intermediate, and high risk; 1%) progressed to blast crisis. During the 1st year of treatment imatinib therapy was stopped due to side effects or resistance in 6% of pts in the imatinib 400mg arm, in 2% of pts in the imatinib+IFN, and in 2% of pts in the imatinib+Ara-C arm. IFN was stopped in 21%, Ara-C in 18% of pts. This interim 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 and low progression rates. Long-term observation will demonstrate whether the promising results will be maintained and will improve survival.

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