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| |  Interim Analysis: First-Line Nilotinib Effective in Patients With Chronic Myeloid Leukaemia: Presented at EHA By Emma Hitt, PhD COPENHAGEN, Denmark -- June 15, 2008 -- Nilotinib as first-line treatment in patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukaemia (CML) demonstrated high response rates and appeared to be well tolerated, according to an interim analysis of an open-label, multicentre, phase 2 trial. Gianantonio Rosti, MD, Institute of Hematology Seràgnoli, Bologna, Italy, reported the findings of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) CML Working Party here on June 14 at the 13th Congress of the European Hematology Association (EHA). According to Dr. Rosti, nilotinib binds more effectively to Bcr-Abl than imatinib in Ph-positive cells and fits more tightly with its target. Nilotinib is approved in the United States and Europe for the treatment of patients with CML who have failed or are intolerant to imatinib, but its role as first-line treatment remains to be validated. In the study, 73 patients (mean age 51 years, 51% male) received nilotinib 400 mg BID with no dose escalations allowed. Patients were assessed by Sokal risk score and classified as low (53%), intermediate (34%), or high (13%) risk. The kinetics of molecular response were evaluated by quantitative polymerase chain reaction at baseline and after 1, 2, 3, and 6 months of treatment. The primary endpoint of the trial is complete cytogenetic response (CCyR) rate at 1 year. The current analysis includes data through 6 months. The median duration of nilotinib exposure was 200 days (range, 66-332). Patients received a median dose of 794 mg QD (range, 301-800). Of the patients, 48% required dose interruptions for a median duration of 7 days (cumulative). A CCyR was observed in 84% of 49 evaluable patients at 3 months and in 97% of 29 patients evaluable at 6 months. When evaluating the outcomes by Sokal risk score, the researchers found that nilotinib benefited all risk groups; although, Dr. Rosti pointed out that the numbers were too small for statistical evaluation. At 3 months, low-risk patients (n = 24) had an 88% CCyR while non-low risk patients (n = 25) had an 80% CCyR. At 6 months, the CCyR rates were 100% for the low-risk patients (n = 13) and 94% for non-low risk patients (n = 16). Patient age did not seem to influence the outcomes. At 3 months, patients aged <65 years (n = 35) had an 86% CCyR, while older patients (n = 14) had a 79% CCyR. At 6 months, the CCyR rates were 100% for patients aged <65 years (n = 19) and 90% for patients aged >=65 years (n = 10). A major molecular response (MMR) was observed in 62% of 41 evaluable patients at 3 months and in 75% of 27 evaluable patients at 6 months. Most frequent nonhaematologic adverse events (grades 1-3) were skin rash, headache, and bone/muscle pain occurring in approximately 27% to 47% of patients. The majority of adverse events were mild in nature. Common laboratory abnormalities included elevated total bilirubin occurring at an incidence of 35.6% (grade 1), 30.1% (grade 2), and 11.0% (grade 3). Other laboratory abnormalities included elevated liver enzymes and lipase. Grade 3-4 neutropenia occurred in 4% of patients; grade 3 thrombocytopenia occurred in 3% (no grade 4). No grade 3-4 anemia was observed. In addition, no evidence of QTc interval prolongation >500 ms was noted, which is notable because the United States prescribing information for nilotinib carries a Black Box warning. "These data suggest that nilotinib produces a high and early rate of CCyR," Dr. Rosti said. "Furthermore, the response was independent of age and Sokal risk score, a high-dose intensity was achieved, and adverse events were easily managed with dose adaptation." [Presentation title: Nilotinib 800 mg Daily as First Line Treatment of Chronic Myeloid Leukemia in Early Chronic Phase: Results of a Phase 2 Trial of the GIMEMA CML Working Party. Abstract 404.]
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