Outcomes improving for all Fred Hutch stem cell transplant patients

Bone marrow, or hematopoietic stem cell, transplantation (HCT) is frequently used to treat patients with leukemia by replacing the diseased bone marrow with healthy bone marrow from a donor. Yet, a commonconsequence of HCT is Graft-Versus-Host Disease (GVHD), a severe complication caused from the donor’scells (graft) attacking the recipient’s cells (host) leading to organ damage and even death if left untreated. Historically, between 30-50% of people undergoing HCT will develop chronic GVHD, characterized by multi-system inflammation and fibrosis that clinically resembles an auto-immune disease. 

GVHD can be controlled by immunosuppressive drugs given both before and after HCT; however, these drugs also make HCT patients susceptible to infections. To reduce the likelihood of GVHD and the need for immunosuppression, recipients are matched to a donor with a similar HLA subtype (see here for a recent Spotlight article on HLA matching). Doctors also take into consideration other known risk factors such as ageand sex of the donor. Encouragingly, “we noticed that rates of chronic GVHD had been declining steadily in our HCT survivors since 2005 and wanted to understand why,” explains Dr. Paul Carpenter, the Medical Director of the Long-Term Follow-up Research Group at Fred Hutch and first author on a recent article in Blood Advancesexamining risk factors for chronic GVHD in Fred Hutch HCT recipients. Lower rates were observed in both adults and children, and in patients transplanted for malignant as well as other life-threatening, nonmalignant diseases. 

To better understand potential reasons, Carpenter and his team evaluated the incidence of chronic GVHD requiring systemic immunosuppression therapy among all Fred Hutch patients who underwent HCT from 2005 to 2019. Their analysis revealed that the incidence of chronic GVHD declined by ~19% for every 5-year increment post HCT date even after adjusting for anticipated cause-associated factors. Over the 15-year study period, serial advances in a variety of transplant approaches might have been responsible for the improving outcomes. “We speculated that such approaches were greater use of naive and other forms of T cell depletion, moving the pretransplant cyclophosphamide component of conditioning therapy to posttransplant days 3 and 4, as well as newer combinations of posttransplant GVHD prevention medications,” describes Dr. Carpenter. Over time, Fred Hutch has also done more HCTs for non-malignant diseases, more cord blood transplants, and more transplants in children, where chronic GVHD is lower in most cases. “As it turned out, none of our speculations could sufficiently explain the stepwise decline in chronic GVHD in all populations examined,” notes Dr. Carpenter. The analysis suggests there are yet to be determined factors that need to be considered when assessing new ways to prevent GVHD. “Contemporaneous controls are essential to avoid attributing a favorable decline in chronic GVHD to a novel approach when in reality it may simply have been relative to a control group from an earlier era, even transplanted just a few years prior.”

While it is promising that chronic GVHD rates are in decline, further work will be needed to identify new risk factors that are influencing chronic GVHD. Some suspects include the role of the microbiome and its response to antibiotics, the frequency and magnitude of cytomegalovirus viremia, and donor clonal hematopoiesis. For those patients who do still develop GVHD, “further study will be needed to better understand how more recent HCT approaches impact the incidence and response to treatment of highly morbid GVHD subtypes that affect the lung, the eye and the skin,” says Dr. Carpenter. 

The spotlighted research was funded by the National Institutes of Health.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Paul Carpenter, Theodore Gooley, Laurie Burroughs, Rachel Salit, Neel Bhatt, Elizabeth Krakow, Ann Dahlberg, Corinne Summers, Masumi Ueda Oshima, Effie Petersdorf, Phuong Vo, Laura Connelly-Smith, and Stephanie Lee contributed to this work.

Carpenter PA, Gooley TA, Boiko J, Lee CJ, Burroughs L, Mehta R, Salit RB, Bhatt NS, Krakow E, Dahlberg AE, Yeh AC, Summers CN, Ueda-Oshima M, Petersdorf EW, Vo P, Connelly-Smith L, Lee SJ. 2024.Decreasing Chronic Graft-Versus-Host Disease rates in all populations. Blood Advances. 123(3):23-28.}