Advancing Diagnostics and Therapeutics in Bone Marrow Failure

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DESCRIPTION (provided by applicant): Dr. Amy DeZern is an Assistant Professor of Oncology at The Johns Hopkins University School of Medicine with a primary appointment in the division of Hematologic Malignancies and a secondary appointment in the Division of Hematology. She has previously been supported on a K12 grant and has completed a Masters in Clinical Investigation. Her primary mentor, Dr. Robert Brodsky, is a leader in discoveries in paroxysmal nocturnal hemoglobinuria (PNH), and her co-mentor is Dr. Mary Armanios, a leading telomere biologist. Her advisory committee of Drs. Borowitz, Cooke, Rosner and Jones are all faculty experts in clinical trials and application of these paradigms to bone marrow failur. Support from the K23 award will enable Dr. DeZern to gain additional research skills and receive mentorship in authoring publications and developing research grants while performing her research project. Dr. DeZern's goal is to become an independent investigator and leader in bone marrow failure (BMF) clinical research. In this application, Dr. DeZern is studying the role of immune response in BMF, specifically aplastic anemia (AA), and then piloting a novel therapeutic approach to bone marrow transplant in patients who are not responsive to immunosuppressive therapy. PNH clones are a marker of immune-mediated AA. Short telomere length is a marker of genetic BMF. In combination, testing of these assays for patients with AA may predict who is more likely to respond to immunosuppressive therapy. For the portion of patients who do not respond to immunosuppression, we must have a therapeutic option that is available, not limited by age or availability of a donor for bone marrow transplant. Dr. DeZern has generated significant preliminary data and developed collaborations throughout the Johns Hopkins Hospital to answer these two related questions. (1) Can we explain the significance of PNH clones and telomere lengths in AA? and (2) Can we increase survival for AA patients refractory to immunosuppressive therapy? She will test these questions by (1) retrospectively analyzing the PNH clones of patients with AA and correlating it to response to immunosuppression (2) prospectively measuring telomere lengths in granulocytes and lymphocytes by the clinically validated method in patients with AA and correlating it to response to immunosuppression, and (3) piloting a clinical trial of bone marrow transplantation from haplo-identical donors in patients with refractory severe AA using post transplantation cyclophosphamide to decrease the complications of graft versus host disease. Results of this research will support future work on biological correlates to predict immunosuppressive therapy response and therapy modification, thereby reducing AA treatment-related morbidity and mortality from inappropriate treatment. This will eliminate unnecessary resource utilization in the field of hematology.