Are you a “good” bone marrow donor and if not, can you become one? There are 55,000-60,000 blood stem cell transplantations also known as bone marrow transplants performed across the globe each year. A serious complication known as graft-versus-host disease (GVHD) is diagnosed for over half of these patients and occurs due to donor cells attacking healthy cells in the recipient. GVHD can be present in an acute or chronic form. While donor cells in GVHD are in “attack” mode, there may be ways to re-program them to be better resident cells in their new host. This idea comes from a body of literature that suggests statins, a common class of cholesterol-lowering drugs, can alter immune function. To evaluate this, a handful of studies have looked at either long-term or short-term statin treatment of donors and found differing results, but even so some findings from retrospective studies indicated that treatment of donors reduced the incidence of GVHD when recipients were also taking specific types of immunosuppressive drugs. Continuing investigation of this topic, Dr. Marco Mielcarek, a Professor in the Clinical Research Division at Fred Hutchinson Cancer Center and his team performed two prospective studies. Like the previous study on long-term statin treatment, they observed a reduction in GVHD incidence for cases in which donors received long-term statin treatment and recipients were taking the specific immunosuppressant cyclosporine (CSP), but not for those recipients who did not take CSP. These studies were published recently in Transplantation Cellular Therapy.
“To prevent incidence and severity of GVHD, and thereby make allogeneic transplantation safer, transplant recipients typically receive prophylaxis consisting of several immunosuppressive medications,” commented Dr. Mielcarek. “Most of the time, these medications have to be taken for months (sometimes years).” These drugs that suppress the immune system also make the person more susceptible to infection and other toxicities. Dr. Mielcarek continued, “Therefore, using a medication that could be given to allogeneic stem cell donors for a limited time before they donate stem cell products for transplantation would be an innovative way of preventing GVHD without causing the toxicity of immunosuppressive drugs given to recipients.” Pre-clinical studies support the use of statin treatment of donors to alter T cell function and reduce inflammatory effects, both of which would be beneficial to reducing the probability of developing GVHD in the recipient. Two large retrospective studies from the Mielcarek group “suggested that donor statin use reduced the risk of severe acute GVHD in patients who were also taking CSP,” added Dr. Mielcarek. Since these studies were performed as retrospective analyses, the researchers set out to perform prospective studies to investigate the outcome of short- or long-term statin treatment of donors on the occurrence of GVHD in two recipient groups, those taking CSP and those that were not.
In the first study, short-term statin treatment was given to the donors leading up to their stem cell donation date. “This study was terminated early as we did not find any evidence that donor statin treatment (for 14 days) had the desired GVHD-preventive effect,” stated Dr. Mielcarek. For the second study, “we performed a prospective observational trial (through CIBMTR/ NMDP) where we documented whether unrelated volunteer donors happened to take a statin at the time of their stem cell donation,” explained Dr. Mielcarek. “Although the study was somewhat under-powered, we found a suggestion (not statistically significant; p-value = 0.12) that the risk of severe acute GVHD was reduced when donors were on longer-term (typically many months or longer) statin treatment.” These studies again suggest that long-term over short-term statin treatment of donors may be more effective in reducing the incidence of GVHD in stem cell graft recipients when combined with recipient CSP treatment. “Long-term donor statin treatment, however, is not a feasible approach as stem cell transplants for patients with cancer typically have to be done relatively quickly,” explained Dr. Mielcarek. Also, blood stem cell donors include relatively young individuals and a very small fraction (~3%) of all donors are taking statins explained Dr. Mielcarek. Therefore, no amount of strategic planning to select donors based on ongoing statin treatment would satisfy the urgent need of transplants.
Another critical barrier remains, “there is no biomarker that has been identified that would allow us to determine if and when a protective effect through statins has been established,” stated Dr. Mielcarek. “If we had such a biomarker, one could study different types of statins and dosages to determine if or when T cells (or the immune system in more general terms) are affected in a way that GVHD would be less likely. In the meantime, there might be other and even larger datasets than ours that will allow future analyses that could help clarify whether there may be a role for donor statin treatment for GVHD prevention.”
The spotlighted research was funded by the National Institutes of Health, the Health Resources and Services Administration, the Office of Naval Research, the National Marrow Donor Program (NMDP), and Medical College of Wisconsin.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Ted Gooley, Stephanie Lee, Paul Martin, Rainer Storb, and Marco Mielcarek contributed to this work.
Rashid N, Gooley T, Furlong T, Lee SJ, Martin PJ, Storb R, Mielcarek M. 2023. Impact of Donor Statin Treatment on Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation. Transplant Cell Ther. S2666-6367(23)01509-9.