A potential game-changer in blood and marrow transplantation

A methodical approach
In 2016, Mielcarek, along with Paul J. Martin, MD, now professor emeritus in the Clinical Research Division and others, published a seminal study demonstrating that PTCy reduced the likelihood of developing both severe acute and chronic GVHD in transplant recipients who were HLA-matched and who received their transplants from a donor’s peripheral blood (as opposed to a direct bone marrow transplant, which comes with significant discomfort for the donor). 
The new study, which will include up to 120 patients divided into two cohorts, builds on these findings. One cohort is made up of HLA-matched donors and patients, and the other is made up of haploidentical (half-matched) donors and patients. All recipients in the current study will receive the same chemotherapy and radiation treatment before transplant and the graft will be sourced from a donor’s peripheral blood. 
“Our study is somewhat unique because our PTCy dose de-escalation approach is more systematic,” Mielcarek said. 
The Phase I study (a step in which a treatment is evaluated for safety and ideal dosage) began in 2024 when Mielcarek and his collaborators at the NCI and City of Hope used institutional funds to launch the project. One group of patients received the standard-of-care dose of PTCy on days 3 and 4 after their transplant. They were monitored for 100 days to look for signs of acute GVHD and graft rejection. The second cohort received a reduced dosage of 35 mg/kg/dose of PTCy on the same time schedule, with the same 100 days of supervision and laboratory studies. Further cohorts received 25 mg/kg/dose or 15 mg/kg/dose of PTCy.
The U01 award will allow the investigators to complete the Phase I study and move on to Phase II, a step where the effectiveness of the treatment will be evaluated in more detail. In this step, the researchers will choose the most effective dosage of PTCy based on data from Phase I and will widen the study to include more patients. 
In tandem, corresponding laboratory studies will aim to describe in detail how the reduction in PTCy dosage affects a number of the body’s functions as it recovers from the transplant, including immune recovery, relapse risk, sensitivity to infection and subsequent GVHD development. The researchers will monitor pharmacokinetic markers such as cyclophosphamide metabolites in the blood to understand how PTCy exposure affects the body’s ability to recover, as well as assess the recipient’s ability to fight off infections and re-populate the immune system with the transplanted stem cells.
The study will help inform future work to definitively identify the optimal dose of PTCy for GVHD prevention according to the HLA-match status of the patient and donor, as well as the source of the stem cells (peripheral blood versus bone marrow, for example).
Mielcarek hopes that this study will pave the way for new protocols in patient care for the use of PTCy in GVHD prevention after BMT. It’s a critical part of transplant care, particularly since the safer that transplants eventually become for recipients, including those who cannot find fully HLA-matched donors, the more people will be able to benefit from transplantation.
“It’s a game-changer,” Mielcarek said.

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