First Quarter 2008 - Issues in Hematology - ION Solutions

oncologistics drug updateNEW STUDIES IN VIDAZA ®THERAPY: PROLONGED SURVIVALIN HIGHER-RISK MDS PATIENTS,ALTERNATE DOSING SCHEDULES,AND USE IN AMLby: Lewis R. Silverman, M.D.The U.S. Food and Drug Administration (FDA) approvedVidaza (azacitidine) as the fi rst treatment for themyelodysplastic syndrome (MDS) for all FAB subtypesincluding both low-risk and high-risk patients. These FABsubtypes include: refractory anemia (RA) or refractoryanemia with ringed sideroblasts (RARS) if accompaniedby severe neutropenia (< 1 x 10 9 /L) or thrombocytopenia(< 0.5 x 10 9 /L) or anemia requiring RBC transfusions;refractory anemia with excess blasts (RAEB), refractoryanemia with excess blasts in transformation (RAEB-T),and chronic myelomonocytic leukemia (CMMoL).Vidaza is a substituted cytidine nucleoside analog andis believed to exert its antineoplastic effects by causinghypomethylation of DNA and direct cytotoxicity onabnormal hematopoietic cells in the bone marrow.Vidaza is a hypomethylating agent and belongs toa new class of anti-cancer compounds known asepigenetic therapies. Epigenetics refers to normalcontrol mechanisms in the genome that regulate geneexpression, mediated in part by changes in DNAmethylation and histone acetylation, two of the morestudied epigenetic regulatory mechanisms. Epigeneticchanges in cancer cells and other states can aberrantlysilence gene expression and, unlike DNA mutations,may be reversed by targeting the mechanisms involved.Thus, an epigenetic approach to cancer therapy isdesigned to reactivate silenced genes through targetedtherapy, re-establishing the cancer cells’ naturalmechanisms to control abnormal growth resulting in areversal of the malignant phenotype. By inhibiting DNAmethyltransferase and thus reversing hypermethylation,Vidaza may restore normal expression of silenced genescritical to cell differentiation and proliferation. The drugalso appears to exhibit its effects, through directtoxicity, when cells are undergoing DNA synthesis inS phase. Because all cells are not in the same phasesimultaneously, longer treatment time will expose morerapidly dividing cells to Vidaza. Vidaza therapy alsocauses the death of rapidly dividing cancer cells nolonger responsive to normal growth control mechanisms.The benefi ts of Vidaza therapy in MDS have long beenknown, however, recent studies have shown new resultsnot previously recognized. Trials demonstrating increasedsurvival in higher-risk MDS patients as comparedto conventional regimens, effective alternate dosingschedules in MDS patients with lower risk disease, andeffectiveness in acute myeloid leukemia (AML) patientshave generated additional and increased interest inVidaza therapy throughout the oncology community.oncologistics 31