Pharmacy & Therapeutics - December 2008 - (Page 713)

MEETING HIGHLIGHTS: Chemotherapy Foundation Symposium XXVI Epigenetic Therapies for Myelodysplastic Syndromes and Leukemia: Azacytidine (Vidaza) And Decitabine (Dacogen) • Hagop M. Kantarjian, MD Anderson Cancer Center, Houston, Tex. Epigenetic therapies modulate gene and protein expression. Global and site-specific DNA methylation induces suppression of regulatory genes, which promotes tumor progression and resistance. This mechanism is shared by many tumors, including hematological cancers. Protein or histone deacetylation also contributes to this process. Epigenetic therapy relies on two classes of agents that enhance hypomethylation or acetylation: • hypomethylating agents: • azacytidine (Vidaza, Pharmion) • decitabine (Dacogen, MGI Pharma/SuperGen) • histone deacetylase inhibitors: • valproic acid • depsipeptide (Romidespin, Gloucester; FK-228 [FR-901228, NSC-630176], Fujisawa) • vorinostat (Zolinza, Merck) • MGCD-0103 (Celgene) Azacitidine. Azacitidine (AZA), an older cytotoxic drug, was synthesized in 1964 and approved by the FDA in 2004 for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). In one European study, 358 patients with higher-risk MDS were randomly assigned to one of two groups; 179 patients received AZA and 179 received conventional or supportive care, low-dose cytarabine, or intensive chemotherapy. The study showed a significant survival benefit for AZA overall; median survival was 24.4 months versus 15 months with conventional care (P < 0.0001). The median number of AZA courses was nine. A survival benefit was noted not only in patients achieving complete responses but also in those achieving partial responses or showing hematological improvement. In another study, different schedules of subcutaneous (SQ) AZA showed equivalent benefits in hematological responses. Schedules consisted of 50 mg/m2 daily for 10 doses, 75 mg/m2 daily for seven doses, and 75 mg/m2 daily for five doses. No marrow studies or survival data are available. An oral formulation of AZA showed a reasonable absorption with a mean bioavailability of 17% for patients with a history of SQ exposure to AZA. Efficacy studies of oral AZA are ongoing. Decitabine. Decitabine is indicated for patients with MDS, including previously treated and untreated de novo and secondary MDS of all French–American–British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and CMML). This drug is also intended for patients in intermediate-1, intermediate-2, and high-risk MDS groups based on the International Prognostic Scoring System (IPSS). Decitabine is thought to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are essential for controlling cellular differentiation and proliferation. The complete response rate was highest with the five-day IV course, which also brought about the best degree of hypomethylation. The optimal dose of decitabine was 20 mg/m2 IV daily for five doses, although the five-day SQ schedule was also promising; decitabine in this low-dose schedule had significant anti-MDS activity in poorer-risk MDS patients. Adverse effects were acceptable, and timely and repeated courses of decitabine therapy were required for optimal response results. These findings were also confirmed in the Alternate Dosing for Outpatient Treatment (ADOPT) trial. Summar y. Hypomethylating agents (decitabine and AZA) might play a role in AML treatment, especially in elderly patients as well as in those receiving maintenance therapy after a complete response. An ongoing study is comparing decitabine with best standard therapy (supportive treatment with low-dose cytarabine) in older patients. Current studies include decitabine combinations with histone deacetylase inhibitors (valproic acid, vorinostat). Lenalidomide (Revlimid) in Relapsed or Refractory Aggressive Non-Hodgkin’s Lymphoma • Myron S. Czuczman, Roswell Park Cancer Institute, Buffalo, N.Y. Lenalidomide (Revlimid, Celgene), a thalidomide analogue, belongs to a unique class of immunoregulatory drugs. It is approved as a single agent for transfusion-dependent patients with MDS who have a 5q-deletion (with or without additional cytogenetic injuries) and in combination with dexamethasone for patients with multiple myeloma who have received at least one prior therapy. An earlier U.S.-based phase 2 study demonstrated activity of lenalidomide in relapsed or refractory aggressive NHL. To confirm the drug’s safety and efficacy, researchers undertook a larger international clinical trial using lenalidomide as a single agent in 200 patients. Patients received lenalidomide 25 mg orally once daily on days 1 to 21 every 28 days and continued treatment as tolerated or until disease progression. The median patient age was 66 years (range, from 21 to 86 years), with 71% men. The median number of prior treatment regimens was three. Ninety-six percent of the patients had received rituximab (Rituxan, Genentech); 51% of NHL cases were refractory to rituximab, and 39% were refractory to the previous treatment. The overall response rate to treatment for the first 83 patients was 24%; 5% had a complete response or an unconfirmed complete response, 19% had a partial response, and 19% had stable disease. Responses were observed for all NHL histological types treated (i.e., diffuse large B-cell lymphoma, mantle-cell lymphoma, grade 3 follicular lymphoma, and transformed NHL). It is too early to estimate a meaningful duration of Vol. 33 No. 12 • December 2008 • P&T® 713

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Pharmacy & Therapeutics - December 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Interpreting Estimates of Treatment Effects Chemotherapy Foundation Symposium XXVI: Innovative Cancer Therapy for Tomorrow Third Annual Onmark National Payor/Provider Forum Fourth Annual Ophthalmic Drug Development and Delivery Summit Classification and Pharmacological Management Of Obesity CE Test and Forms Season’s Greetings: Thanks to Our Readers and Reviewers

Pharmacy & Therapeutics - December 2008

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