Pharmacy & Therapeutics - February 2008 - (Page 113)

Meeting Highlights: ASH serious adverse events. Dr. List commented that deferasirox was fairly well tolerated, most frequently causing gastrointestinal side effects, and that patients stopped therapy usually because of diarrhea or elevated serum creatinine levels. Serum creatinine increases were noted in 25% of 119 patients whose levels had been normal at baseline and in 33% of patients (n = 11) with abnormal levels at baseline. Dr. List stated: “These data indicate that deferasirox effectively reduces serum ferritin and LPI levels in a population of patients with low- and intermediate-risk MDS, with no unexpected safety concerns.” He also speculated that deferasirox might even have a beneficial effect on organ complications through sustained suppression of the labile iron. generally well tolerated, with no significant differences noted between twice-daily and once-daily schedules. Most nonhematological adverse events were grade 1 or 2; musculoskeletal pain was highest, at 50%. Grade 3 events, including fatigue, headache, skin, and infection (with normal absolute neutrophil counts) were reported in 5% or fewer patients. Grade 2 pleural effusion was observed in 13% of patients, and dose interruptions were needed for three participants. Dr. Borthakur pointed out that MMR rates were better than those reported historically with the standard imatinib dose. The MMR rates, however, were similar at 18 months: for imatinib 800 mg, the MMR rate was 52%, and for dasatinib, the MMR rate was 57%. He summarized his findings as follows: “Dasatinib induced rapid CCyRs in most patients, and most patients were able to receive the target dose.” Dasatinib (Sprycel) in Chronic Myelogenous Leukemia Presenter: Gautam Borthakur, MD, MD Anderson Cancer Center, Houston, Tex. In a clinical trial, responses to dasatinib (Sprycel, BristolMyers Squibb) were superior to those of imatinib (Gleevec, Novartis) in patients with early chronic-phase Philadelphiapositive (Ph+) chronic myelogenous leukemia (CML). Although chronic-phase CML patients receiving the standard dose of imatinib (400 mg/day) have excellent molecular improvements, polymerase chain reaction (PCR) analysis indicates that most of them have residual disease. Dr. Borthakur said that dasatinib’s more potent inhibition of tyrosine kinase (which is 300 times higher than that of imatinib) led investigators to hypothesize that “dasatinib could induce more complete and faster responses among newly diagnosed CML patients and could eventually translate to improved long-term outcomes.” Dr. Borthakur and his team enrolled 40 patients (median age, 41 years) with Ph+ CML in the early chronic phase. Patients either had undergone no previous treatment, or they had been treated for less than a month. Fifty percent of the patients were randomly assigned to receive dasatinib 100 mg once daily, and the other 50% received 50 mg twice daily. The study’s primary endpoint was a major molecular response (MMR). All patients had cytogenetic responses (CyRs); 87% achieved complete CyRs (CCyRs), 3% achieved partial CyRs, 3% achieved minor CyRs, and 7% achieved early complete CyRs. Within three months, 72% had achieved CCyRs. One patient who did not achieve a CCyR was taken off therapy at nine months. CCyRs were sustained in all patients with longer follow-up. An evaluation of molecular response (MR) rates showed that bcr-abl transcripts declined rapidly over time, with a median reduction of 2log after six months and a reduction of 3log after 18 months. These rates increased steadily over time to 57% at 18 months, including complete molecular responses (CMRs) in 5% of patients. There was a trend toward better molecular responses (MRs) in the once-daily group (MMR + CMR = 40% vs. 27% for the twice-daily group). Hematological adverse events were minimal; grade 3–4 thrombocytopenia was observed in 10% of patients, neutropenia affected 5%, and anemia occurred in 3%. Treatment was Nilotinib (Tasigna) in Chronic Myelogenous Leukemia Presenter: Philipp le Coutre, MD, Charite Campus Virchow Klinikum, Humboldt-Universität, Berlin, Germany Nilotinib (Tasigna, Novartis), the most recently approved tyrosine kinase inhibitor (in October 2007), demonstrated rapid and significant responses among patients with accelerated-phase imatinib-resistant or imatinib-intolerant Philadelphia-positive chronic myelogenous leukemia (Ph+ CML) in an open-label pivotal phase 2 study. Noting nilotinib’s greater potency than imatinib (by 30-fold), Dr. le Coutre started patients with inadequate responses with nilotinib 400 mg twice daily. If there were no safety concerns, the dose was escalated to 600 mg twice daily. The primary endpoint was hematological response (HR). The study included 136 patients with a median age of 58 years (55% were men) with a median CML duration of 71 months. Additional chromosomal abnormalities beyond Ph+ were detected in 31% of subjects. Eighty percent of patients were imatinib-resistant, and 20% were imatinib-intolerant. The HR rate among patients completing at least one nilotinib cycle was 54% (53% for imatinib-resistant patients and 56% for imatinib-intolerant patients). The rate of complete HRs was 26%. Major cytogenetic responses (mCyRs) were noted for 31% of patients (29% were imatinib-resistant, and 40% were imatinibintolerant), and complete cytogenetic responses (CCyRs) were noted in 19%. At 12 months, HRs were sustained in 82% of patients, but responses were lost in 16. The overall survival rate at 12 months was 81% (27 patients died). Dr. le Coutre commented that overall survival data for nilotinib were comparable to those seen years ago in the phase 2 trials of imatinib in CML patients who had not responded to interferon-alpha. “The fact that the dose intensity is so close to the intended dose of [400 mg/day twice daily] indicates how well tolerated this compound is,” he said. The median dose intensity was 781 mg/day, and the median duration of exposure was 210 days. For 49% of the patients, however, dose interruptions lasted a median of 22 days. The continued on page 117 Vol. 33 No. 2 • February 2008 • P&T® 113

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Pharmacy & Therapeutics - February 2008 Contents Editorial Medication Errors Prescription: Washington The Language of (Forgive Us) Change, As P&T Enters the Digital Age New Drugs/Drug News/New Medical Devices Drug Forecast Use and Outcomes of Antifibrinolytic Therapy in Patients Undergoing Cardiothoracic Surgery at 20 Academic Medical Centers in the United States Evaluation of the Management of Acute Venous Thromboembolism and Its Outcomes: One Institution's Experience American Society of Hematology, 49th Annual Meeting Pharmaceutical Approval Update

Pharmacy & Therapeutics - February 2008

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