Early Optimization of Imatinib Therapy in Patients Newly Diagnosed with Chronic-Phase Chronic Myeloid Leukemia (CP-CML). A Study of the Spanish PETHEMA Group.

Abstract 1113

Poster Board I-135

Currently, imatinib (IM) 400 mg daily is the frontline therapy for patients with CP-CML. In an attempt to improve the therapeutic response to IM, the Spanish collaborative PETHEMA group undertook a study of early optimization of therapy, in which 210 adult patients newly diagnosed with CP-CML (< 3 months from diagnosis) were included. Median age was 44 (range: 18-71) years and distribution by Sokal groups: low risk 56%, intermediate risk 28%, and high risk 16%. Hydroxyurea was permitted before IM. Patients initially received IM 400 mg daily for 3 months and then those failing to achieve a complete hematologic response (CHR) had the dose increased (to 600 and then 800 mg daily), while the remainder were maintained on 400 mg daily for three more months. At 6 months, depending on cytogenetic response, patients were kept on IM 400, if they had achieved a complete cytogenetic response (CCyR), or randomized to receive higher IM doses (600 and then 800 mg) or IM 400 plus low dose interferon (IFN, 3 million units 3 times a week) in case that a CCyR had not been attained by that time. In patients already in CCyR at 6 months, the IM dose was increased if a major molecular response (MMolR) according to the international scale had not been achieved at 18 months, whereas in patients not in CCyR and randomized at 6 months, a switch to a second generation TKI (dasatinib or nilotinib) was permitted if a CCyR was not achieved at one year of randomization. At standard intervals, cytogenetic response was assessed in bone marrow by chromosome banding analysis and molecular response determined in peripheral blood by RT-Q-PCR performed in three reference laboratories. At the time of the analysis, median follow-up was 48.3 (range: 1.2-73) months. Median time from diagnosis to IM start was 0.5 (range: 0-2.8) months; 72% of patients started IM within one month from diagnosis. At 3 months of treatment, 4 patients had not achieved a CHR; two of them failed to achieve a favorable response following the increase in the IM dose. At 6 months, a CCyR was obtained in 79% of patients; of the 41 patients not in CCyR, 9 could not be randomized because of toxicity (n= 3) or withdrawal of consent (n=6), 17 were assigned to higher IM dose, and 15 to IM 400 + IFN, but only 9 of the latter actually started IFN. Due to the scarce number of patients randomized, no comparison could be established between the two arms. Overall, cumulative incidence of response at 3 years was: CHR 98.6%, CCyR 90%, and MMolR 82%. Based on an intention-to-treat analysis, CCyR was 70% at 18 months. With current follow-up, only 5 patients have died and 9 have progressed to the accelerated or blastic phases (AP/BP). At 5 years, overall survival rate is 97.5%, survival free from AP/BP 95.5%, survival free from failure (including death, progression to AP/BP and the lack of achievement or the loss of a previously obtained CHR and CCyR) 82%, and event-free survival (including the above plus the permanent IM discontinuation for any reason) 80%. Twenty-seven patients (12.8% of the overall group) had grade 3-4 hematological toxicity and 26 (12.4%) grade 3-4 nonhematological side effects, in most cases during the first year of treatment. The presentresults show the benefit of prompt institution and early optimization of IM therapy in patients with newly diagnosed CP-CML.