Higher-Dose Imatinib (600 mg/Day) with Selective Intensification in Newly Diagnosed CML Patients in Chronic Phase; Cytogenetic Response Rates at 12 Months Are Superior to IRIS.
Authors: Hughes Timothy , Branford S. , Reynolds J. , Seymour J. , Taylor K. , Guzzo-Pernell N. , Filshie R. , Arthur C. , Schwarer A. , Hertzberg M. , Rudzki Z. , Copeman M. , Lynch K. , Grigg A. 
Published: April 2020

Abstract
The IRIS trial demonstrated that imatinib at 400 mg/day was superior to alpha interferon as first line therapy for chronic phase CML. To assess the tolerability and efficacy of higher doses of imatinib in this setting we are conducting a Phase II trial (TIDEL) using imatinib 600 mg initially, increasing to 800 mg if specified response criteria are not met: complete hematologic response (CHR) at 3 Mo; major cytogenetic response (MCR) at 6 Mo; complete cytogenetic response (CCR) at 9 Mo, and &gt;4 log reduction in BCR-ABL at 12 Mo. Filgrastim was used in cases of neutropenia to maintain dose intensity. Of 103 patients enrolled, 8 came off study in the first 12 Mo (2 unrelated deaths, 3 blast crisis, 3 poor response). 80 patients are currently assessable at 12 Mo (median age 47 years, range 21–75). Protocol mandated dose increases to 800 mg for failure to achieve MCR or CCR targets were activated in 7 patients before 12 months. We made a historical comparison of the best response by 12 Mo to responses in the IRIS trial (95% confidence intervals).
Response rates at 12 Mo MCR (0–35% Ph+) CCR (0% Ph+) MMR (≥3 log reduction in BCR-ABL) 400mg - imatinib arm of IRIS n=556 84.1% (81.0 – 87.2%) 69.3% (65.3 – 73.2%) 40% (NA) 600mg - imatinib in TIDEL trial n=80 94.2% (87.3 – 97.5%) 88.5% (80.3 – 93.5%) 47.4% (37.5 – 57.6%) P-value for z-test 0.0004 &lt;0.0001 NA
Patients who had a mean daily dose (MDD) &lt;600 mg in the first 2 months (n=27) had a CCR rate at 12 months of 78%, significantly lower than the 12 month CCR rate of 93% in patients receiving a MDD of 600 mg (n=75)(P=0.0015, log-rank test). Within the subgroup of patients receiving a MDD &lt;600 mg in the first 2 Mo who subsequently received a MDD of 600 mg in months 2–6 the CCR rate at 12 Mo remained 73% (n=11) (P=0.004, log rank test). The probability of achieving MMR by 12 Mo was analysed according to the MDD of imatinib received in the first 6 Mo. Patients with a MDD of 600 mg had a probability of 58% (CI 45–71%) (n=62) of achieving MMR compared to 33% (CI 15–59%) in those with a MDD of 500 – 599 mg (n=17) and 32% in those with a MDD of &lt;500 mg (n=20). Given these marked differences even at a MDD of 500–599 mg we looked at the median Sokal score in each group to see if more poor risk patients were present in the groups receiving reduced dose. Median Sokal scores for the groups with MDD of 600mg, 500–599 mg and &lt;500 mg were no different − 0.94, 1.08; and 1.04 respectively. BCR-ABL mutations were detected in 7 patients within 12 Mo (2 had blast crisis, 1 lost CHR, 2 lost CCR and 2 maintain CCR on an increased imatinib dose). Mutation was the main cause of loss of response (5 of 8 patients). We conclude that cytogenetic response rates at 12 Mo are significantly superior to responses observed in the IRIS trial. Major molecular responses are frequent in the cohort able to tolerate a MDD of 600mg. The substantially lower rate of MMR in patients with a moderately reduced MDD was unexpected. These patients did not have less favourable CML biology based on Sokal scores. Although it is possible that other adverse prognostic factors were an influence in these patients, it suggests that dose intensity may be critically important to maximise molecular response.+