read-more
Read more about Fred Hutch achievements and accolades.
Blood and marrow transplantation, or BMT, for blood cancers is a medical miracle, but it comes with significant risks. Fred Hutch hematologist Marco Mielcarek, MD, PhD, has received a five-year, $3.5 million National Institutes of Health (NIH) U01 collaborative research grant to complete a clinical trial and related laboratory research projects to determine the optimal dosage for a drug used to prevent one of the most common illnesses associated with transplanting stem cells sourced from a donor’s bone marrow or peripheral (circulating) blood: graft-vs.-host-disease, or GVHD.
The funding will allow Mielcarek and his collaborators at the National Cancer Institute (NCI) in Bethesda, Maryland, and at City of Hope in Duarte, California, to complete a dose de-escalation study for post-transplantation cyclophosphamide, or PTCy, (pronounced “p-t-sigh”). The Phase I/II clinical trial aims to identify whether lower doses of PTCy, currently administered at a dosage of 50 milligrams per kilogram of body weight (mg/kg) on the third and fourth days after BMT, can have the same positive impact in reducing GVHD while reducing side effects associated with the drug. The study could lead to advances in the standard of care for BMT recipients, resulting in improved quality of life and survival rates.
“The overall goal is to make [the PTCy treatment] less toxic by being able to reduce the dose,” said Mielcarek, medical director of the Fred Hutch Blood and Marrow Transplant Program. “The current dose, which has never been systematically optimized, has room for improvement in terms of organ toxicities such as mucositis [the inflammation of mucous membranes in the digestive tract] and heart failure. There is also a risk of delayed immune reconstitution and increased rates of certain infections. So, a lower dose would be great if it could be achieved without compromising cyclophosphamide’s ability to prevent GVHD.”
The grant was initially submitted as an R01, one of the most prestigious multi-year research grants awarded by the NIH. After the funding decision was made, it was converted to a U01, a classification reserved for collaborative projects in which NIH scientists will be significantly involved in the project.
PTCy and GVHD prevention: a game changer in transplant science
Cyclophosphamide is a chemotherapy drug that has been used to prevent GVHD in stem cell transplant recipients for over 15 years. A derivative of nitrogen mustards, the drug selectively attacks cells that are rapidly dividing by binding to both sides of a cell’s double-stranded DNA helix to keep it from unwinding and copying itself during the process of cell division.
The cells most likely to be dividing rapidly soon after a transplant are the donor’s T cells, the powerful immune system cells primed to identify and attack foreign invaders such as viruses and other pathogens. Patients receiving transplants rely on a tissue matching system that looks at a set of cell proteins, collectively called human leukocyte antigen (HLA) markers, to find donors with all or most of the same HLA proteins. This greatly reduces the risk that a donor’s T cells will mistakenly attack the recipient’s healthy tissues.
Many transplant recipients cannot find a fully HLA-matched donor, so they rely on haploidentical, or “half-identical” donors who share half of their HLA markers. (By definition, a parent and a child are haploidentical since we inherit half of our HLA markers from each parent.) This increases the risk that donor T cells could mistakenly identify a patient’s healthy tissues as dangerous and attack them.
When the donor’s T cells (part of the “graft” that makes up the transplant) attack the patient (the “host”), the result is acute or chronic GVHD. Acute GVHD is characterized by symptoms that appear within about three months following the stem cell transplant, while chronic GVHD symptoms can arise anywhere between three months and two years after the transplant. Chronic GVHD can share symptoms of autoimmune diseases, such as scleroderma (hardened skin due to excess collagen) and Sjögren’s syndrome (dry eyes).
When PTCy is given early after transplant to prevent GVHD, cyclophosphamide metabolites seem to both “paralyze” the types of T cells destined to later cause GVHD and allow expansion of so-called regulatory T cells that help keep GVHD at bay.
You will receive a monthly newsletter from us about our innovative research and compassionate care as well as updates on events and other helpful tools and tips.
You may unsubscribe at any time.
Despite advances in care, GVHD remains the single most common side effect of BMT, with up to 60% of transplant recipients developing acute GVHD and up to 40% of transplant recipients developing chronic GVHD, even with current prevention protocols.
Mielcarek said that the advent of PTCy usage for GVHD prevention vastly increased the number of patients who could benefit from BMT.
“Not only does PTCy reduce the risk of developing serious GVHD after transplant, but it also allows us to use HLA-mismatched donors who could not previously be used safely,” he explained. “Patients from racial and ethnic minority groups are less likely to find fully HLA-matched unrelated donors in the global volunteer donor registry. Therefore, the ability to perform HLA-mismatched donor transplants using PTCy, which substantially reduces the otherwise relatively high risk of GVHD, gives more of these patients access to this potentially life-saving treatment.”
Mielcarek noted that the PTCy methodology for preventing GVHD was developed by Leo Luznik, MD, at Johns Hopkins Medicine.
“And it was initially used mainly for HLA haploidentical stem cell transplants,” he said. “Until cyclophosphamide entered the arena, so to speak, haploidentical transplants weren’t really feasible. There was a lot of prohibitive GVHD and also graft rejection.”
Today, PTCy administered at the standard-of-care dosage of 50 mg/kg/day (given on two consecutive days) has led to remarkable reductions in the rate of acute and chronic GVHD. However, the risk of side effects remains substantial. These risks include increased infections, cardiac issues, and delayed immune system reconstitution after the transplant.
An optimized dosage scheme could reduce the side effects seen with PTCy and possibly also improve the immunologic graft-vs.-tumor (GVT) effect that helps patients keep their blood cancers in remission after transplant.
Mielcarek credited National Cancer Institute (NCI) transplant immunologist Christopher G. Kanakry, MD, one of his collaborators on the current project, for his research developing laboratory studies to understand how PTCy acts on the body to prevent GVHD, and for designing the current dose de-escalation study.
He further credited his City of Hope collaborator, Ryotaro Nakamura, MD; Fred Hutch researchers Michael Boeckh, MD, PhD, professor in the Clinical Research Division; and Paul G. Thomas, PhD, the Bezos Family Distinguished Scholar in Viruses and Vaccines, for their contributions to the current research proposal; and project statistician Tim Randolph, PhD, professor in the Clinical Research and Public Health Sciences divisions.
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.
