Precision Dosing to Protect Transplants: Reducing Graft Rejection in Pediatric HCT
For children undergoing hematopoietic cell transplantation (HCT), a graft failure — where the body rejects the new cells — can collapse the hope of being cured.
"Graft rejection is a true transplant emergency that requires an urgent second transplant to rescue their bone marrow and regrow blood cells the child needs to survive, adding incredible stress and another six weeks in the hospital in the best-case scenario," says Chris Dvorak, MD, professor in the UCSF Department of Pediatrics and division chief of Allergy, Immunology, and Bone Marrow Transplantation.
For decades, clinicians viewed rejection risk as a fixed biological consequence of donor mismatch or immune biology. However, a new study led by Dvorak and Janel Long-Boyle, PharmD, PhD, proves that this risk can be reduced.
By updating how a common chemotherapy drug, fludarabine, is dosed, UCSF researchers have found a way to dramatically reduce rejection rates.
The Shift from One-Size-Fits-All to Precision Dosing
Traditionally, fludarabine has been given based on body surface area (BSA) — a "one-size-fits-all" approach that doesn't account for how differently individual children metabolize the drug.
Recently published in Transplantation and Cellular Therapy, the study analyzed 410 pediatric and young adult patients to see the impact of pharmacokinetic (PK) model-based dosing, which targets a specific drug exposure for each individual child based on body fat, kidney function, and other factors. The results were striking:
- 1.8% rejection rate for patients who received precision, model-based dosing.
- 8.5% rejection rate for patients who received traditional, BSA-based dosing.
"Conditioning chemotherapy is the root of most toxicities in HCT, and traditional dosing was adapted from adult studies,” explains Dvorak. “We can now precisely dose these agents in children, avoiding high doses that cause unnecessary harm and low doses that fail to suppress the host’s immune system.”
Expanding Access to Life-Saving Transplants
The implications of this study go far beyond a single drug. By using precision dosing to counterbalance immunologic risk, UCSF is making transplantation a safer option for patients who lack a perfect donor match.
This is particularly vital for patients from less common ancestral backgrounds, who often struggle to find well-matched donors in national registries.
"The more risk factors for rejection a child has, the more benefit that personalized dosing provides," says Dvorak. "This allows us to perform mismatched donor transplants with much greater confidence, helping everyone who needs an HCT get one."
Advancing Precision Medicine in Pediatric Transplantation
This study reinforces a growing principle in pediatric care: precision medicine is not only about discovering new therapies — it can also use existing tools more intelligently.
Because this approach uses existing drugs and straightforward modeling, it is scalable and ready for universal use in pediatric transplant centers worldwide.
"To my knowledge, UCSF is the first center in the world to completely move to personalized precision dosing," says Dvorak. "Fludarabine is just the beginning; we have been systematically studying and optimizing all the conditioning agents we use. We are already seeing benefits with less short-term toxicity and fewer relapses, and we expect fewer long-term side effects in the years to come.”
As pediatric transplant programs continue to refine conditioning strategies, this study highlights a clear opportunity to improve outcomes through personalized dosing and ensure more children get the best possible chance of being cured by an HCT transplant.
Authors: Other authors from the UCSF Department of Pediatrics include Ella Waters; Gabriel Cisneros, MD; Julia Chu, MD, MPH; Lena Winestone, MD, MPH; Christine Higham, MD; Sandhya Kharbanda, MD; Kristin Shimano, MD; Serine Avagyan, MD, PhD; Philip Pauerstein, MD, PhD; and James Huang, MD.