Interim Analysis of a Multicenter Trial of High Dose (HD) Imatinib in Newly Diagnosed Early Chronic Phase (CP) Patients (pt) with Chronic Myeloid Leukemia (CML).

While imatinib (400 mg daily) results in 12 mo complete cytogenetic responses (CCyR) in 76% of pt, complete molecular responses (CMR) at this time are in the range of 4–6%. A single center study recently showed higher 12 mo CMR when newly diagnosed CP pt were given 800 mg daily. We report here an interim analysis of similar patients treated in a Phase II single arm multicenter setting with 800 mg imatinib daily. Eligible pt. were ≥18y, had normal organ function and were newly diagnosed. Prior hydroxyurea or imatinib was allowed for ≤ 1 mo. Treatment dose was adjusted for ≥Gr3 toxicity. Peripheral blood (PB) PCR and FISH were measured every 3 mo in a central laboratory (Quest, Northridge, CA) and marrow cytogenetics and PCR was done at 1 yr in the same laboratory. The primary endpoint was molecular response at one year. Secondary endpoints included hematologic response, marrow cytogenetic response at 1 yr, progression/loss of response and safety. Accrual of 115 pt in 29 institutions was completed in April 2005 and the current report is based on 20 pt reaching 12 mo follow up by May 2005. Median follow up is 5 mo (0.2–16 mo). Median age is 51 (19–81). Sokal classification was predominantly low (73.1%) or intermediate (17.3%). To date, 11/115 patients have gone off study (4 withdrew, 4 AEs, 2 progression, 1 protocol violation). The 2 early progressing patients were withdrawn following 10 and 11 mo of treatment respectively. PB PCR showed an initial decline in both patients with a subsequent rise after 3 and 6 months respectively. Mutational analysis in these patients showed wild type (wt) bcr/abl in one and an E255V mutation identified at 6 mo in the second. Median Dose Intensity for the entire population is 98% (29–100%). By 6 mo, 24/52 pt (46%) already had a BCR-ABL/ABL ratio <0.045% (>3 log reduction from baseline). Sixteen of twenty pt (80%) have CCyR at one year with 11/20 (55%) showing non detectable levels of transcripts. The 5 pt with CCyR still showing detectable BCR-ABL/ABL ratios have a mean reduction of 3.21 (2.54–4.47) log from baseline. Two pt with MCyR have 3–15% Ph+ cells in marrow with PB FISH that is either negative or marginally positive (1.2%). PCR in these patients at 12 mo shows a 3.28 and 2.24 log reduction below the median baseline respectively. Two additional pt at 12 mo continue to have 40 and 95% PH+ metaphases in their marrow and 7% FISH positive cells in PB of both. PCR at 12 mo for these pt shows a < 2 log reduction of BCR-ABL/ABL ratio from baseline for both. Additional mutational analysis is being performed. We conclude that 800 mg daily of imatinib results in a high rate of CMR for newly diagnosed pt by 12 mo of treatment. The treatment was relatively well tolerated and could be delivered in a multicenter setting with sustained dose intensity over the entire treatment period.