Novel drug regimen reduces risks of graft-versus-host disease

Picture this: you’re surviving cancer, chemotherapy, radiation, immunosuppression, and a blood stem cell transplant, and you haven’t left the hospital in weeks. Yet, somehow, you have what feels and looks like a sunburn covering much of your body.

This is the reality for many patients who undergo blood stem cell transplants (SCTs) to treat high-risk blood cancers or other genetic conditions. SCTs can be lifesaving, but they are not without serious risks—such as developing graft-versus-host disease (GVHD).

GVHD occurs when donated immune cells—the graft—attack healthy tissues in the host. It can manifest as rashes, diarrhea, or liver damage, and it can be a serious and even deadly complication of stem cell transplants. While more common in transplants from unrelated or immunologically mismatched donors, GVHD can occur even when the source of the donation is from a related matched donor.

For the past 40 years, the standard prophylaxis to prevent GVHD in matched transplantation has been a regimen of chemotherapy drugs: a calcineurin inhibitor like cyclosporin suppresses donor T cell signaling that can lead to GVHD. Cyclosporin is usually combined with an anti-metabolite such as methotrexate, which interferes with DNA replication and prevents excessive donor T cell expansion. But this standard prophylaxis regimen isn’t perfect: GVHD still occurs in 20-50% of transplant patients and is a leading cause of discomfort and death.

There’s some indication that other treatments can be helpful to prevent GVHD. Specifically, an immunosuppressive chemotherapeutic called cyclophosphamide was a game changer that allowed transplants from a donor that is not perfectly immunologically matched with the recipient (known as a haploidentical transplant). Cyclophosphamide is an alkylating agent that crosslinks DNA and prevents cell division in certain susceptible cells. Importantly, blood stem cells and anti-inflammatory subsets of T cells are resistant to cyclophosphamide, but activated alloreactive T cells—which cause many of the symptoms of GVHD—are not.

Some studies have suggested that cyclophosphamide may be useful for transplants from related matched donors as well. “Data from two randomized trials have suggested that post-transplantation cyclophosphamide (PT-Cy) can reduce the risk of GVHD after SCT from a matched donor when it is added to or replaces the antimetabolite,” says Dr. Geoff Hill, a transplant expert who directs the Fred Hutch Translational Science and Therapeutics Division.

However, these studies only looked at cyclophosphamide for GVHD prophylaxis in a subset of patients: those who received less intense—or non-myeloablative/reduced intensity—conditioning. “To date, there has been no data in patients [who] receive intensive, or myeloablative conditioning,” says Dr. Hill. This is crucial because this myeloablative conditioning “is used whenever possible,” he emphasizes. Therefore, the true potential of cyclophosphamide to help all transplant patients has not been fully explored.

To address this gap, Dr. Hill collaborated with researchers in the Australasian Leukaemia and Lymphoma Group in a phase 3, open-label, randomized clinical trial to evaluate whether cyclophosphamide can replace anti-metabolite chemotherapeutics for anti-GVHD prophylaxis. Their results, which were recently published in The New England Journal of Medicine, show that cyclophosphamide is indeed a powerful anti-GVHD drug in this setting.

The researchers enrolled 134 patients undergoing SCT. About half were randomly assigned to receive an experimental prophylaxis regimen of cyclophosphamide and cyclosporin; the other half received the standard prophylaxis consisting of the anti-metabolite methotrexate and cyclosporin. The main goal of the study was to evaluate whether there was a change in relapse-free, GVHD-free survival between the two groups.

The authors found that only 17% of the patients in the experimental prophylaxis group developed moderate-to-severe chronic GVHD, compared to 34% in the standard prophylaxis group.

There were also strikingly fewer cases of severe acute GVHD (which are designated as grade III or IV). Grade III GVHD is diagnosed when diarrhea and liver issues are effected and over half the skin on the body is impacted, which presents as something looking like a severe sunburn; grade IV GVHD is even worse and can present with severe jaundice due to liver damage. Only 6% of patients in the experimental group developed grade III acute GVHD compared to 19% in the standard prophylaxis group. No patients developed grade IV acute GVHD in the experimental prophylaxis group compared to 6% in the standard group.

Even though this study was only designed to look at GVHD rates, long-term outcomes were just as promising. “Relapse was not increased and at 2 years, 74% of patients in the experimental-prophylaxis group and 59% of those in the standard-prophylaxis group were alive and relapse-free,” Dr. Hill explains. “There was also no increase in infection or toxicity in the experimental arm in the first 100 days,” he adds.

Taken together, these results strongly suggest re-evaluating what standard prophylactic care should look like for GVHD. “This data establishes a simplified two drug calcineurin inhibitor and PT-Cy as the standard of care GVHD prophylaxis after related donor transplantation with myeloablative or reduced intensity conditioning,” says Dr. Hill.

Future work will analyze the immunological impacts of cyclophosphamide versus methotrexate in this cohort. A subsequent study will also investigate whether the calcineurin inhibitor is also necessary when cyclophosphamide is used.

Looking to the past, the authors have started to question why the standard of care was what it was for so long. “The study raises the question as to the value of an anti-metabolite in the setting of PT-Cy and whether it is responsible, at least in part, for the exaggerated infection and toxicity risks when PT-Cy is used in the unrelated and haploidentical transplant settings,” says Dr. Hill.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Geoff Hill contributed to this research.

The spotlighted research was funded by the Australian Government Medical Research Future Fund, the National Health and Medical Research Council, the Auckland Medical Research Foundation, the Cancer Society of New Zealand, and the National Institutes of Health.

Curtis DJ, Patil SS, Reynolds J, Purtill D, Lewis C, Ritchie DS, Gottlieb DJ, Yeung DT, Wong E, Tey SK, Perera T, Moore J, Koldej RM, De Abreu Lourenco R, Stubbs J, Morrissey CO, Munsef N, Arenas A, Hill GR; Australasian Leukaemia and Lymphoma Group. Graft-versus-Host Disease Prophylaxis with Cyclophosphamide and Cyclosporin. N Engl J Med. 2025 Jul 17;393(3):243-254.