In landmark study, an arthritis drug appears to prevent deadly acute graft-versus-host disease after bone marrow transplant
January 15, 2021
An immune-suppressing drug normally used to treat rheumatoid
arthritis could make bone marrow transplant safer, report researchers at
Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. In a Phase 2
multi-center trial, the drug abatacept (ORENCIA®) reduced rates of severe,
acute graft-versus-host disease (GVHD) and boosted rates of survival without acute
GVHD or relapse in patients with leukemia and other blood cancers.
The study, published today, Friday, January 15, in the Journal of Clinical Oncology, found no
increase in infections or cancer relapse, suggesting that abatacept’s immune
suppression effect may be selective for GVHD.
The findings, in the largest trial to date, could open up bone
marrow transplant as an option for many more patients with cancer or blood
disorders. Abatacept was particularly beneficial when the donors and recipients
weren’t a full tissue-type match, a particular problem for people of color and
from ethnic minority populations, for whom it is harder to find a matched donor.
The drug gained FDA Breakthrough Therapy Designation last October. Its
developer, Bristol-Myers Squibb, is pursuing formal FDA approval to expand the
label of abatacept to include acute GVHD prevention. Severe acute GVHD is fatal
in up to half of patients.
In GVHD, T cells from the bone marrow transplant donor “see”
the recipient’s healthy cells as foreign, and attack the recipient’s tissues
and organs. GVHD risk is lowest when donor and recipient match on 8 of 8 immune
factors known as human leukocyte antigens (HLA). If the match is just 7 of 8,
the risk of severe, acute GVHD and associated death go up dramatically. It is
this 7/8 group that may stand to benefit most from abatacept.
“One of the great tragedies is when a bone marrow transplant
succeeds in curing a patient’s leukemia, but the patient dies from
complications of the transplant,” says Leslie Kean, MD, PhD, the study’s corresponding author, who
directs Pediatric Stem Cell Transplant at Dana-Farber/Boston
Children’s Cancer and Blood Disorders Center.
“Abatacept has now been shown, in patients transplanted for
multiple diseases, to significantly increase the safety of what have
historically been very high-risk transplants: those between donors and
recipients that are HLA mismatched.”
Study details and
Abatacept works by suppressing certain T cells from the
donor bone marrow that trigger acute GVHD, known as effector T cells.
Activating these cells normally requires two signals; abatacept blocks the
second, or costimulatory signal (hence the technical term “T cell
The trial enrolled adults and children receiving bone marrow
transplants for leukemia, myelodysplastic syndrome, Hodgkin’s lymphoma, and
other blood cancers. In one arm, 142 patients and donors matched for 8 of 8 HLA
factors were randomized to receive either abatacept or placebo in addition to standard
GVHD prevention drugs. In the second arm, 43 patients with a donor match on 7
of 8 factors all received abatacept, and were compared with a historical control
group treated with the standard prevention regimen alone.
Both study arms tracked the occurrence of acute, severe GVHD
over the first 180 days after transplant, survival free of severe (grade 3 or
4) GVHD at 180 days, and longer-term survival endpoints.
In the 8/8 group, 6.8 percent of patients given abatacept
developed severe acute GVHD, versus 14.8 percent of the placebo group.
Severe-GVHD-free survival was significantly improved: 93.2 percent in the abatacept group versus 82 percent with
The benefit of abatacept was most pronounced in the 7/8 arm
of the study. Only 2.3 percent of the patients given abatacept developed severe
acute GVHD, versus 30.2 percent of the historical control group. Rates of
survival free of severe GVHD were 97.7 percent and 58.7 percent, respectively.
“No other approach for GVHD has shown this substantial a
difference in these very high-risk patients,” says Kean.
Leveling the playing
Although the 7/8 group was small and that study arm was not
randomized, Kean says it was important to include them. Being able to safely do
bone marrow transplants when only 7 of 8 HLA factors are matched would greatly
expand the number of patients who could be treated. That includes people of
color and most ethnic groups, who are much more likely to need a mismatched
transplant than white patients, because of the complexity of their HLA
“Patients with donors matched on 7 of 8 HLA factors have
previously had dismal outcomes,” Kean says. “Many oncologists won’t even
consider these donors, which limits or even eliminates these patients’ ability
to find the donors they need. Moreover, because of their increased risk,
patients who only have 7/8 donors are often excluded from trials of new
therapeutics. If we can make these transplants safer, we would have the ability
to offer them to many more patients. I see this as the
"democratization" of transplant: leveling the playing field.”
Inhibiting T cells,
Kean and colleagues did a detailed immunologic analysis,
repeatedly sampling patients’ blood and doing RNA sequencing to measure the
effects of abatacept on the immune response. The findings confirmed that
abatacept controlled T cell activation.
While this kind of immune suppression poses a risk of
weakening the body’s defenses against the cancer, as well as uncontrolled
infections, the study found no increase in either severe infections or relapse
in the patients with leukemia.
“We found that the T cells are prevented from attacking the
host by causing acute GVHD, but they appear to retain their ability to fight
leukemia,” says Kean. “This is impressive, given that these patients received
an additional immunosuppressive drug — it’s like having your cake and eating it
More trials underway
The positive results seen in patients with blood cancers have
led to at least six new clinical trials of abatacept in patients receiving bone
marrow transplant for severe aplastic anemia, sickle cells disease, beta
thalassemia, and other diseases.
Benjamin Watkins, MD, and Muna Qayed, MD, of Emory
University, were co-first authors on the paper. Amelia Langston MD, of Emory
University and John Horan, MD, of Dana-Farber/Boston Children’s were co-senior
authors with Kean.
The study was funded by the National Institutes of Health
(R01-FD004099), Bristol-Myers Squibb, CURE Childhood Cancer, the National
Heart, Lung and Blood Institute (K23 HL136900), the National Institute of Child
Health and Human Development (K12 HD 72245-4), the American Cancer Society
(129701-MRSG-16-153-01-CCE), and the National Center for Advancing
Translational Sciences (KL2TR000455). Watkins and Qayed report receiving grants
and/or personal fees from Bristol Myers Squibb during the course of the study
and are named on pending patents.