Abstract: Allogeneic hematopoietic cell transplantation (HCT) is uniquely curative for a variety of pediatric malignant and non-malignant conditions. With respect to non-malignant conditions, due to the increasing use of DNA-based screening and diagnostic testing, many of the genetic diseases that are curable by HCT are now identified early in life. Accordingly, ~35% of all pediatric HCT procedures are performed for non-malignant diseases, which is significantly higher than the proportion of non-malignant diseases for which HCT is performed for adults. HCT approaches differ significantly between patients with malignant and non-malignant diseases. Those with malignant conditions, in both children and adults, undergo extensive cytotoxic chemotherapy cycles, leading to a compromised immune system and reduced capacity to reject donor cells. In contrast, patients with non- malignant diseases, having not undergone prior chemotherapy, exhibit a spectrum of immune responses, ranging from absence to hyper-activation, depending on the specific hematopoietic cell transplantation indication. Thus, a more personalized HCT approach may benefit such patients. One of the major areas of unmet need for personalized HCT arises from the fact that the metabolism of pre-HCT chemotherapy varies significantly across individuals. This variation, in both weight-based and body surface area-based dosing, can lead to some patients receiving too much or too little chemotherapy exposure, risking either toxicity or non-engraftment. Because of this, the ideal situation might be one where pharmacokinetic modeling could be used to more accurately dose patients, which would better balance immune suppression and toxicity. These and many other variables highlight the unique needs of pediatric HCT recipients, making it a distinct discipline within the larger field of HCT. Further, at any single transplant center, the number of children and young adults undergoing HCT is relatively small, and the diseases treated are diverse, making it essential for centers to work together in a cooperative group setting. For >30 years the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) has been a pediatric clinical trials consortium focused on bringing clinical trials to children and young adults with both malignant and non-malignant diseases. The PTCTC is now the largest pediatric-focused HCT consortium in the world. In this proposal we describe our plans and desire to continue to be a core clinical consortium (CCC) of the BMT CTN. These include (A) Detailing our unique capabilities of the PTCTC within the BMT CTN; (B) Proposing a clinical trial to optimize the conditioning regimen for children and adults with Inborn Errors of Immunity (IEI); and (C) Describing the operational and scientific approach of the PTCTC to HCT trials, and how this approach could benefit the BMT CTN. Together, our unique expertise, creativity, commitment to diversity, mentorship, and innovative clinical tri...