New drug regimen prevents both chronic and acute graft-versus-host disease

For patients with leukemias, certain types of anemias, or specific autoimmune disorders, hematopoietic stem cell transplantation is a life-saving procedure. This treatment involves suppressing a patient’s immune system with radiation or chemotherapy before the transplant. After immune suppression, patients can receive their own healthy stem cells or, more frequently, stem cells from a donor that can expand and repopulate their blood system.

Immune suppression is a crucial step in hematopoietic stem cell transplantation. Incomplete suppression means that the transplanted donor cells (the “graft”) can go haywire and attack “host” cells, resulting in a potentially life-threatening complication called graft-versus-host disease (GVHD). GVHD can be either acute and/or chronic. Acute GVHD usually develops quickly after transplant and results in skin rashes and digestive problems like diarrhea, nausea, and vomiting. Chronic GVHD usually starts within two years of a transplant, and it can affect any organ system.  

GVHD can be managed once it develops, but the immunosuppressive steroid medications used for management can lead to further complications in transplant recipients. “Steroids can cause infections and other morbidities that can contribute to early mortality after transplant,” says Dr. Masumi Ueda Oshima, lead author of a new study in the Journal of Clinical Oncology that tests new drug combinations for preventing GVHD. For patients with chronic GVHD, treatment can take years before the symptoms are effectively managed, increasing the risk of treatment-related complications. “Even in patients who are surviving after transplant and are free of disease, this can be a longstanding issue that affects quality of life, functional status, and return to work,” says Ueda Oshima.

Preventing GVHD has long been a goal for healthcare providers. Prevention typically involves prophylaxis, or beginning a medication regimen immediately after stem cell transplantation to prevent GVHD development in the first place. One standard GVHD prophylaxis regimen is a combination of cyclosporine and mycophenolate mofetil, two drugs that suppress immune function. Recent clinical trials led by Dr. Brenda Sandmaier have demonstrated that adding the drug sirolimus to this combination reduces the rates of acute GVHD and improves survival. Sirolimus (also called rapamycin) is a mammalian target of rapamycin (mTOR) inhibitor, and it suppresses immune function by making B and T cells less sensitive to activating signals. While these results are promising for acute GVHD, sirolimus had no impact on the rates of chronic GVHD in transplant patients, leaving them vulnerable to this condition.

Recent phase III clinical trials have shown that prophylactic cyclophosphamide, another immunosuppressive drug given after donor cell infusion, can reduce rates of acute and chronic GVHD in transplant recipients when it is combined with cyclosporine. Because the addition of sirolimus reduces acute GVHD and cyclophosphamide reduces chronic GVHD, researchers thought that combining these drugs might be an effective strategy to reduce the rates of both forms of GVHD. “The thought was to combine the cyclophosphamide with sirolimus and [cyclosporine] to see if that would reduce both forms of [GVHD],” explains Ueda Oshima.

To explore this possibility, the group enrolled blood cancer patients that were eligible for stem cell transplants in a phase II clinical trial. One group of the participants received the acute GVHD-fighting combination of sirolimus, cyclosporine, and mycophenolate mofetil, and the other group received the new combination of sirolimus, cyclosporine, and cyclophosphamide. The participants were followed for several years after their transplant, and the team measured rates of GVHD-free relapse-free survival, and frequency of GVHD development.

They found that patients that received the new drug combination had a significantly higher probability of GVHD-free relapse-free survival one year after transplant when compared to those receiving the standard drug combination, meaning that they developed GVHD at lower rates without their cancer coming back. They also found that only 3% of patients that received the new drug combination developed moderate to severe chronic GVHD compared to roughly 33% of patients that received the old combination. Further, there was no difference in acute GVHD development or disease recurrence in either group. These outcomes showed exactly what the group was hoping to see: the new drug combination reduced chronic GVHD without increasing disease relapse for transplant recipients.

Despite these promising results for GVHD, patients receiving the new drug complication did have an altered immune cell balance compared to those receiving the standard combination, and this increased the frequency of certain infections in this group. “There is a little bit of a compromise with infection prevention with cyclophosphamide. Importantly, though, it doesn’t seem to impact early or late mortality,” says Ueda Oshima. In the future, the team hopes to test the new drug combination in a large, multicenter trial to get a better picture of how effective it will be across diverse transplant recipients.

This work was supported by funding from the National Institutes of Health, the National Cancer Institute, and Fred Hutch Philanthropy and Center support.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Masumi Ueda Oshima, Phuong Vo, Michael Boeckh, Paul Carpenter, Marco Mielcarek, Effie Petersdorf, Ted Gooley, and Brenda Sandmaier contributed to this work.

Ueda Oshima M, Vo PT, Boeckh M, Bouvier ME, Carpenter PA, Mielcarek M, Petersdorf EW, Storb R, Gooley T, Sandmaier BM. 2025. Sirolimus and cyclosporine with post-transplant cyclophosphamide or mycophenolate mofetil as graft-versus-host disease prophylaxis in unrelated donor hematopoietic cell transplant. J Clin Oncol. 2025 Oct 3:JCO2501283. doi: 10.1200/JCO-25-01238.