Pharmacy & Therapeutics - February 2008 - (Page 112)

Meeting Highlights: ASH or rather low transfusion requirements.” Although normal LDH levels generally fall between 250 and 300 units/liter (U/L), PNH patients in all four strata in this study had mean baseline levels exceeding 1,000 U/L. In the most recent six months with eculizumab therapy, this level dropped to between 347 and 461 U/L. In the same time period, the mean LDH level of 2,426 U/L at baseline in patients with mild anemia (below a hemoglobin count of 10.5 g/dL) was reduced to 384 U/L, and the mean LDH level of 2,258 U/L at baseline among patients with low transfusion requirements fell to 399 U/L. In those six months of eculizumab treatment, none of the patients needed transfusions. Dr. Bessler said that improvements in the patients with milder disease suggest that it was the change in hemolysis that brought the benefit, not the milder anemia or the lower need for transfusions. She concluded that patients with low baseline levels of hemolysis and anemia and with low transfusion requirements, who might be expected to have less severe disease, did in fact bear a substantial PNH burden. Eculizumab therapy did decrease hemolysis, and it improved anemia and fatigue in these groups and in patients with evidence of bone marrow insufficiency. Benefits were sustained during long-term follow-up. Finally, eculizumab reduced the risk of thrombosis in all patients regardless of their level of baseline hemolysis or anemia severity. Commenting on eculizumab’s high cost (almost $400,000 per year) in a subsequent interview, Dr. Parker said that the pricing of orphan drugs is intended to motivate research that otherwise would not be supported. In this case, he said: “You can see PNH patients who turn around from being totally debilitated, wheelchair-bound with no quality of life, who are put on the drug and become productive people living normal lives,” he said. because of cytopenias or other toxicities. At the interim analysis in this heavily pretreated NHL population who had received a median of two cycles of RAD001 (from 1 to 16 or more), the overall response rate was 32% in 12 of the 37 patients. The investigators recorded one complete response and 11 partial responses. The response rates for DLBC and MCL were 35% and 29%, respectively. The overall time to disease progression (TTP) was 3.1 months, and the median duration of response for the 12 responders was 5.5 months. Five patients have remained free of disease progression at six months or more, and three patients have maintained a response at a median of 10.5 months (2.09 to 15.6 months or more). Incidence rates for grade 3 toxicity were 11% for anemia, 16% for neutropenia, 30% for thrombocytopenia, and 11% for hyperglycemia. Grade 4 hyperlipidemia was reported in one patient (2%). Dr. Reeder stated: “Oral RAD001 has single agent activity in relapsed aggressive NHL and is well tolerated for long periods of time.” Deferasirox (Exjade) in Chelation of Iron Overload Presenter: Alan F. List, MD, Professor of Medicine and Oncology, H. Lee Moffitt Cancer Center, Tampa, Fla. Iron accumulation secondary to chronic transfusion therapy is associated with significant morbidity and mortality. The hazard ratio for incremental decline in overall survival rates for patients with iron overload and low-risk myelodysplastic syndrome (MDS) has been reported at 1.36 for every 500-mcg/L increase in serum ferritin above 1,000 mcg/L.1 The mainstay of therapy for these patients, Dr. List explained, is supportive care, including red blood cell (RBC) transfusions to manage symptomatic anemia. Labile plasma iron (LPI) is a reactive oxidative species considered to be the main cause of toxicity in iron overload, and keeping it within normal limits at all times is a goal of iron chelation therapy, he emphasized. In his core phase 3 study, the iron chelator deferasirox (Exjade, Novartis) was given at a dose of 20 mg/kg per day over one year in patients with lower-risk MDS and who had received more than 20 units of transfused RBCs. The endpoints were changes in the levels of serum ferritin and plasma iron. The mean number of lifetime transfusions before the study was 63; the mean transfusion rate during the study year was 4.1 RBC units per month. At one year, the mean serum ferritin decrease was 859 mcg/L. About 51% of patients had serum ferritin reductions of 500 mcg/L or greater, and approximately 13% showed reductions between 200 and 499 mcg/L. The rest of the patients (10%) showed no changes or had elevations in serum ferritin (26%) that ranged from 200 to more than 500 mcg/L. Fifty-three patients with a baseline labile plasma iron level of 0.5 mcg/L or higher improved quickly. Dr. List said, “Importantly, we had sustained decreases of mean LPI and got everyone to within normal range within three months.” Among 165 patients eligible for the safety evaluation, 6% discontinued deferasirox treatment because of suspected adverse events, and 4% discontinued therapy secondary to RAD001 (Everolimus) in Lymphoma Presenter: Craig B. Reeder, MD, Mayo Clinic, Scottsdale, Ariz. RAD001 (Novartis) had single-agent activity in patients with relapsed aggressive non-Hodgkin’s lymphoma (NHL) and was well tolerated for an extended treatment interval. Dr. Reeder presented clinical trial data supporting the concept that “targeting mTOR is clinically relevant in NHL.” Mammalian target of rapamycin (mTOR) is an intracellular protein kinase that regulates cell proliferation though activating kinases, which in turn control protein synthesis. Dr. Reed and his colleagues hypothesized that everolimus, which targets mTOR, would block the signaling needed for cell cycle G1−>S progression, thereby producing tumor responses in relapsed or refractory lymphoma. A Mayo Clinic/Dana Farber Cancer Institute trial (MC048G) assessed tumor responses in patients with aggressive histological changes, including diffuse large B-cell lymphoma (DLBC), mantle-cell lymphoma (MCL), and grade 3 proliferative lymphomas. Thirty-seven enrolled patients (mean age, 72) had received a median of four prior therapies, with some patients undergoing as many as 15. They received oral RAD001 at 10 mg/day, with dose reductions or stoppages allowed 112 P&T® • February 2008 • Vol. 33 No. 2

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - February 2008

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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