Grant generously funded by the family and friends of Hadi Abdur Rasheed »»»
Aplastic anemia Aplastic anemia: (ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells - red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most… (AA) is a type of bone marrow failure bone marrow failure: A condition that occurs when the bone marrow stops making enough healthy blood cells. The most common of these rare diseases are aplastic anemia, myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Bone marrow failure can be acquired (begin any time in life) or can be… arising from autoimmune destruction of bone marrow bone marrow: The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow. stem cells stem cells: Cells in the body that develop into other cells. There are two main sources of stem cells. Embryonic stem cells come from human embryos and are used in medical research. Adult stem cells in the body repair and maintain the organ or tissue in which they are found. Blood-forming (hemapoietic) stem… . AA can occur at any age, however, the peak incidence is between 15-24 years. Among pediatric and adolescent/ young adult patients (aged < 40 years) with AA, somatic mutations are common, detected in ~20% of patients at diagnosis. The presence of high-risk somatic mutations in these patients have been associated with decreased responses to immunosuppressive therapy immunosuppressive therapy: Immunosuppressive drug therapy lowers your body's immune response. This prevents your immune system from attacking your bone marrow, allowing bone marrow stem cells to grow, which raises blood counts. For older patients with acquired aplastic anemia, immunosuppressive drug therapy is the… (IST), development of hematologic malignancies, and decreased overall survival (OS). Allogeneic hematopoietic cell transplantation (AlloHCT) is a potential curative approach for pediatric and AYA patients with AA; however, its use is limited by transplant-related complications, in particular graft vs. host disease, graft failure, and organ toxicity. In non-transplanted patients, the development of somatic mutations or clonal hematopoiesis hematopoiesis: (hi-mat-uh-poy-EE-suss) The process of making blood cells in the bone marrow. (CH) is associated with chronic inflammation and several age-related conditions, in particular organ dysfunction involving the heart, kidneys, lung, and liver among others. The chronic inflammation and organ toxicity associated with somatic mutations in AA may predispose AA patients to a higher risk of post-transplant complications. Although somatic mutations are enriched among patients progressing on IST, the prognostic impact of recipient somatic mutations on transplant outcomes currently unknown. As patients with AA present similarly to other types of bone marrow failure, about 5-15% of pediatric and AYA patients diagnosed with AA proceeding to alloHCT have an inherited bone marrow failure syndrome (IBMFS). In some cases, IBMFS are also associated with somatic mutations and an increased risk for transplant toxicity. Here, we will perform comprehensive sequencing on blood specimens from pediatric and AYA patients with AA collected prior to alloHCT to identify both somatic mutations and inherited gene mutations known to cause an IBMFS. The cohort of patients will predominantly include pediatric patients age < 20 years, which represent 64% of all AA recipients undergoing alloHCT. We aim to determine the type and frequency of somatic mutations and associations with AA and IBMFS disease characteristics. We also aim to determine the impact of somatic mutations on alloHCT outcomes. The findings from our proposal will directly impact patient care and enable more personalized transplant approaches, tailoring the timing, conditioning regimen, and type of GVHD regimen to mitigate the risk associated with recipient somatic mutations.