Maintenance of Imatinib Dose Intensity in the First Six Months of Therapy for Newly Diagnosed Patients with CML Is Predictive of Molecular Response, Independent of the Ability To Increase Dose at a Later Point.

We have conducted a Phase II trial (TIDEL) in de-novo CML patients using imatinib 600 mg initially, increasing to 800 mg if specified response criteria were not met, including: major cytogenetic response (MCR) at 6 months; complete cytogenetic response (CCR) at 9 months, and ≥4 log reduction in BCR-ABL at 12 months as determined by Real Time Quantitative PCR (RQ-PCR). We have previously shown in this cohort that the mean daily dose (MDD) of imatinib in the first 6 months was predictive for the log reduction of BCR-ABL at 12 months. A BCR-ABL reduction of ≥3 logs from the standardized baseline (major molecular response, MMR) is highly predictive for progression free survival for de-novo patients treated with 400 mg of imatinib. The aim of the current exploratory analysis was to assess the impact of MDD and cytopenias in the first and second 6 months of imatinib therapy on the molecular response at 12 and 24 months. Out of 101 accrued patients 81 were assessable for the 24 month molecular response (median age 47 years, range 21–75). Four patients were not yet assessable and 16 patients were off study, 7 for non-disease related reasons and 9 because of treatment failure, 3 of whom progressed to blast crisis. Dose increases to 800 mg for failure to achieve response criteria as mandated by the protocol were activated in 7 patients before 12 months and in most of the remaining patients after 12 months. Dose intensity through periods of neutropenia was maintained by protocol specified use of Filgrastim. By 12 months 89%, 45% and 13% had achieved CCR, ≥3 log and ≥4 log reduction respectively. By 24 months 92%, 65% and 29% achieved these response levels. MDD 1st 6 months, 2nd 6 months No. % MMR at 12 months P value % MMR at 24 months P value LR at 24 months P value LR is mean log reduction in BCR-ABL. The P values refer to paired comparisons of the [600,600] dose with each of the other 3 dose patterns 600,600 51 56 89 3.61 400–599,600 18 50 NS 61 0.02 2.94 0.006 600, 400–599 6 50 NS 67 NS 3.15 NS 400–599,400–599 10 22 0.08 43 0.009 3.1 NS The percentage of patients achieving MMR at 24 months in the [600, 600] group (89%) was also significantly different (P=0.009) from the percentage (50%) in the [500–599, 600] group. Thus even minor dose reductions in the first 6 months appears to have a strong bearing on the achievement of MMR at 24 months. Dose modifications in the second 6 months may have less impact on molecular response. Dose modifications were commonly due to cytopenia. However, thrombocytopenia and neutropenia in the first 12 months were not significantly associated with MMR at 12 or 24 months. Sokal prognostic scores were not significantly different in patients who had reduced MDD in the first 6 months. We conclude that a more dose intense approach to the treatment of newly diagnosed CML achieves better rates of MMR than lower doses, and that maintenance of dose intensity in the first 6 months of therapy is predictive of molecular response, independent of the ability to increase dose at a later point.