The Impact of Germline Predisposition to Myelodysplastic Syndrome on Allogeneic Hematopoietic Stem Cell Transplant Outcomes Using Related Donors
Abstract
Rationale/Objective: The aim of this study is to determine the frequency of underlying inherited mutations in patients with myelodysplastic syndrome (MDS), which is a pre-leukemic state that can transform into acute myeloid leukemia. An existing inherited mutation predisposes individuals to develop MDS, and often, at a younger age than typically expected. We plan to use material from a large cohort of 404 MDS patients and their related bone marrow donors to screen for these inherited mutations in more than 1,000 cancer-related genes. Since the patients and their donors are related, sharing a particular mutation will define that variant as inherited. Once we have established patients and their donors as carriers of a mutation, we will determine whether the patients who carry such a mutation suffer any specific complications after bone marrow transplant. This might include a longer time to recovery of their peripheral blood cells or a complete failure of the new bone marrow to function. We will also gather information about how these inherited mutations affect their related donors. This could include donors having low blood counts at baseline or requiring an unexpectedly long time to collect sufficient stem cells for the bone marrow transplant. Near-Term Impact and Applicability: This study focuses on patients with MDS who undergo a stem cell transplant, which is the only curative option known to date for this disease. The relatives of these patients often act as their bone marrow stem cell donors, since they are genetically close and “match” to the patient, which then reduces the risk of rejection by the patient’s immune system. Young patients with MDS are most often good candidates for transplant due to their overall good health and decreased risk for transplant-associated complications. However, young patients with this disease are also presumed to have a higher likelihood of an underlying genetic predisposition. Using a related donor can be problematic, especially if the mutation is also present in the donor and is thus given back to the recipient during the transplant. The first aim of this study is to determine the frequency of these mutations in MDS patients across the entire age spectrum and identify subgroups that are especially at risk for carrying such a genetic change (e.g., patients who are diagnosed at a younger age). To date, no such comprehensive study using a large cohort of patients has been performed. The results from this study will therefore change the clinical care and follow-up for these patients in the near future since we will be able to recommend genetic testing to screen for such mutations–which is the first step in optimizing treatment and transplant and avoiding a sibling-donor carrying the same mutation. The second aim of this study focuses on the clinical and transplant data of patients who carry such an inherited mutation. To date, no data are available on the outcomes of these patients after transplant and whether these individuals suffer from any specific complications that could be addressed or prevented before or during the transplant. We do not know if particular gene defects are associated with certain poor outcomes, for example. Recognizing the specific complications suffered by these patients will enable physicians to alter the clinical work-up, donor-selection, and treatments during/after bone marrow transplant. The outcomes of these patients and their donors will be immediately affected by this study, since no such work has been done before. Once published, this work will impact the clinical guidelines and provide transplant physicians with sufficient data to optimize transplantation in this patient cohort. The projected time to achieve clinical outcomes will be short, with new diagnostic and treatment strategies incorporated into clinical trials or even implemented immediately. Both the FY18 PRCRP Topic Area(s) “Blood Cancer” and “Cancer in children, adolescents, and young a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910241
Entities
People
- Lucy Godley
Organizations
- United States Army
- University of Chicago