227 patients with pretreated Ph+/BCR-ABL+ CML were randomized into this 2-arm phase III trial comparing standard dose Imatinib (400 mg/d; arm A) with high dose (HD) Imatinib (800 mg/d for 6 months) for induction followed by Imatinib 400 mg/d for maintenance (400 mg/d; arm B). The interim analysis presented here was performed on all patients after 50% of the patients had been treated for 12 months since randomisation. There were no significant differences between treatment arms regarding sex, age and different pretreatments. Rates of complete hematological responses did not differ significantly between both groups at 3, 6 and 12 months (82% arm A, 90% arm B). However, significantly* more patients achieved a major (MCR) and a complete cytogenetic response (CCR) at 3 months (MCR: 21% arm A, 37% arm B; CCR: 6% arm A, 25% arm B) and 6 months (MCR: 34% arm A, 54% arm B; CCR: 20% arm A, 44% arm B). Moreover, significantly* more patients achieved a major molecular response (MMR) at 6 months in the Imatinib HD arm B compared to arm A (20% vs 7%). At 12 months, following dose reduction of Imatinib to 400 mg/d for maintenance at month 6 in the HD arm B, the rates of MCR (the primary endpoint of the study) were comparable (57% arm A, 59% arm B). Nevertheless, there was still a clear trend to higher rates of CCR (37% arm A, 48% arm B) and MMR (16% arm A, 21% arm B) in the HD arm, but at the time of the interim analysis these values did not reach statistical significance. In contrast to non-hematological toxicities, grade 3/4 hematological toxicities were significantly* more common in the HD arm B [anemia: 2% (A), 12% (B); leukopenia: 23% (A), 41% (B), thrombopenia: 14% (A), 34% (B)]. In conclusion, this is the first randomized phase III trial demonstrating significantly* higher rates of MCR, CCR and MMR in chronic phase CML during therapy with HD Imatinib. *p<0.05

Gene expression profiling has proven useful for identification of gene sets predicting response and/or prognosis in various hematological malignancies. So far expression profiling studies in CML predicting response to imatinib therapy suffered from major flaws, as previous retrospective studies relied on various technical platforms using rather small patient populations. Here, we present the interim results of an expression profiling study performed within a prospective multicenter CML trial of the Central European Leukemia Study Group(CELSG) comparing standard (SD) with high-dose (HD) imatinib as second line treatment for chronic phase CML. Blood samples from at total of 102 CML patients with early or late chronic phase disease were collected prior to and six weeks after treatment with either 400 mg/day for 12 months or 800 mg/day for 6 months followed by 6 months of 400 mg imatinib therapy. Whole blood samples preserved by PAX gene technology were further processed and evaluated centrally at the expression profiling core facility at Innsbruck Medical University. For expression profiling samples were subjected to hemoglobin mRNA reduction before target preparation for hybridization to Affymetrix hGU133 Plus 2 genechips detecting ∼47000 transcripts thereby allowing a whole genome profiling approach. For response prediction we used both the linear discriminatory analysis (LDA) and a random Forest (RF) decision tree algorithm provided in Bioconductor software packages for the open source statistical language “R”. A 100- or 10-fold crossvalidation was performed using a robust leave-10-out setting for LDA and RF respectively. The planned interim analysis of clinical data from 76 evaluable patients undergoing 12 months of therapy with daily doses of 400 mg or 800 mg imatinib revealed 50 (66%) patients with and 26 (34%) patients without a major cytogenetic response (<35% Ph+ metaphases). We found, irrespective of imatinib dosing, a predictive gene expression signature for achieving a major cytogenetic response after 12 months of imatinib therapy. This predictive gene set comprises five genes (ENTPD4, F5, SCL22A4, AIM2, TLR5, PXK) achieving a correct prediction rate of 87% within the 6-week-treatment patient subgroup and an overall prediction rate of 76%. In conclusion, this is the first prospective gene expression profiling study in CML indicating a gene expression profile predicting major cytogenetic response, which still represents a robust response parameter for long-term outcome during imatinib therapy of patients with early or late chronic phase CML.