The drug abatacept was shown to significantly reduce the risk of acute graft-versus-host disease (GVHD) among children and adults undergoing unrelated donor blood and marrow transplant for hematologic cancer during a seven-year, multisite trial. Led by Benjamin K. Watkins, MD, and Muna Qayed, MD, hematologists and oncologists at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, findings from the trial were published in the Journal of Clinical Oncology and led to FDA breakthrough status for the therapy.
“In severe acute GVHD, almost half the patients will die, but the incidence of severe disease dropped to only 3% in our abatacept treated group, compared to 30% for the control group – so really a striking response,” said Dr. Watkins, who also serves as assistant professor at Emory University Department of Pediatrics.
Kids with hematologic cancers such as leukemia and lymphoma have malfunctioning blood cells due to the cancer’s effects on their bone marrow and lymphatic system. A common treatment is blood and marrow transplant, or bone marrow transplant, in which a donor’s healthy stem cells are delivered intravenously over several weeks to help restore bone marrow stem cells. But for the patient’s body to accept, and not reject, the donor transplant, human leukocyte antigen (HLA) proteins, or markers the immune system uses to recognize which cells belong to your body, must match as closely as possible.
Siblings have a one in four chance of being HLA matched, resulting in less than 25% of patients having that perfect match. These individuals utilize the National Marrow Donor Program through BeTheMatch.org to identify unrelated donors.
“Some groups, such as African Americans, have a less than 20% chance of finding a perfect match,” said Dr. Watkins. “For these patients, physicians must look for mismatched unrelated donors. This comes with tremendous risks, including high rates of acute GVHD.”
Acute GVHD occurs after stem cell transplantation when the donated cells turn against the patient or host and begin attacking the patient’s organs. In the most severe forms, half of patients die.
The Phase 2 trial at Children’s, led by Dr. Watkins and Dr. Qayed, began in 2013 with funding from the National Institutes of Health. Of 186 patients enrolled with hematologic malignancies, 30% were pediatric patients under age 21. The trial involved 14 other sites in the US and Canada, including the Emory Winship Cancer Center. There were two arms of the study. One was a randomized, double-blind, placebo-controlled group with 143 perfectly-matched unrelated donors. The other included 43 patients who were mismatched unrelated donors on seven out of eight HLA proteins, all receiving abatacept.
Results showed the addition of four total doses of abatacept given within one month after transplant had a significant improvement in rates of acute GVHD. In the matched unrelated donor arm, the incidence of severe disease was 7% with abatacept compared to 15% in the placebo treated. The results were the most profound in the mismatched unrelated donor arm where the incidence of severe disease dropped to only 3% in the abatacept treated group, compared to 30% for the control group. Furthermore, the overall survival two years after transplant significantly improved with 74% of patients treated with abatacept surviving, compared to just 45% of control patients.
The striking results led to U.S. Food and Drug Administration (FDA) breakthrough therapy designation for abatacept for the prevention of GVHD in unrelated donor transplant for both matched and mismatched groups. The designation expedites the development and review of new medicines that have a potential for significant impact on patients with life-threatening illnesses.
The study led to another phase 2 trial with extended dosing of abatacept and multiple other studies using abatacept in different diseases, including two at the Aflac Cancer and Blood Disorders Center.
“Up until now there has not been a groundbreaking drug to change the risk of getting GVHD in the first place,” said Dr. Watkins. “Abatacept has the potential to save many lives by preventing this devastating disease.”
The trial was completed with support from Bristol Myers Squibb. Leslie S. Kean, MD, PhD, and John Horan, MD, MPH, of Boston Children’s are senior authors on the paper, along with Amy Langston, MD, of Winship. Muna Qayed, MD, is also an associate professor at Emory University Department of Pediatrics and is co-first author with Dr. Watkins.