Grand Rounds: “Towards Biologically Rational Therapy for Myelodysplastic Sydrome.”

November 2, 2007

Bellevue AmphitheaterWelcome to our new Grand Rounds Series. Each week, we plan to post a summary of the week’s Medicine Grand Rounds lecture. The summaries are reviewed and approved by the grand rounds speaker prior to posting. Enjoy.

Commentary by Marshall Fordyce MD, Senior Chief Resident 

This week’s Medicine Grand Rounds guest lecturer was Dr. Steven Gore, currently Associate Professor of Oncology, and Faculty Member of Cell and Molecular Medicine, at the Johns Hopkins University School of Medicine. Dr. Gore’s research focuses on improving our understanding of the epigenetic determinants of myeloid neoplasms. Early in his career, he has had the insight and opportunity to translate bench observations to clinical trials at the bedside. Dr. Gore is the principal investigator for several multicenter Phase 1 and Phase 2 trials testing new regimens and novel therapies in the treatment of myelodysplastic syndrome, for which he has won multiple young investigator awards. His talk was entitled: “Towards Biologically Rational Therapy for Myelodysplastic Sydrome.”

Dr. Gore proposed a clear approach to the management of myelodysplastic syndrome (MDS), and described the rationale for DNA methyltransferase inhibitors in selected patients. MDS is a group of clonal bone marrow stem cell disorders characterized by hypercellular marrow and ineffective erythopoiesis. The syndrome is heterogeneous with variable natural histories. Dr. Gore emphasized that the distinction between MDS and acute myeloid leukemia by number of blasts in the bone marrow is somewhat arbitrary, and fails to appreciate the molecular similarity, and thus their response to therapy, of these diseases. Thus, he points out, acute myeloid leukemia with trilineage dysplasia (AML-TLD) is not “AML,” but MDS.

Dr. Gore defines MDS more generally as a chronic leukemia that is progressive and lethal. Currently, the only known curative therapy for MDS is allogenic bone marrow transplant. If a patient is not a candidate for transplant, a patient’s risk of progression is assessed using the International Prognostic Staging System (IPSS), which is based on percent of blasts in the bone marrow, karyotype, and cytopenia. If patients do not receive transplant, prognosis is generally poor, cytotoxic chemotherapy generally fails. A variety of medications are being used for these patients. One class of drugs that has shown promise are the DNA methyltransferase inhibitors, 5-azacytidine and decitabine, which have produced an overall response of 50% as monotherapy.

Dr. Gore presented early clinical trial data suggesting a benefit from the use of methyltransferase inhibitors in combination with histone deacetylase inhibitors in these patients. Because methyltransferase and the histone deacteylase play important roles in methylation of DNA and inducing its transcriptionally inactive form (heterochromatin), the effect of the medications are to inhibit these two steps, leading to transcriptionally active DNA and reactivation of gene expression. This attempt to target the epigenetic control of MDS holds great promise for patients.

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