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Abatacept may reduce graft-versus-host disease after hematopoietic stem cell transplantation
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The addition of abatacept to standard therapy reduced the incidence of severe acute graft-versus-host disease to less than 5%, according to phase 2 study results presented at ASH Annual Meeting and Exposition.
Incidence of grade 3 or grade 4 GVHD decreased from 32% to 3% among patients who underwent mismatched unrelated donor stem cell transplants for advanced malignancies and received standard prophylaxis plus abatacept (Orencia, Bristol-Myers Squibb) in the posttransplantation setting, according to Leslie Kean, MD, associate director of the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute.
Results also showed significant survival advantages for abatacept-treated patients.
At 100 days after transplant, OS rates were 85% for abatacept-treated patients, compared with 57% for those treated with a calcineurin inhibitor plus methotrexate (CNI/MTX) and 68% for those treated with CNI/MTX plus anti-thymocyte globulin.
Rates of 100-day DFS were 79% for abatacept-treated patients, compared with 50% for those treated with CNI/MTX and 63% for those treated with CNI/MTX plus anti-thymocyte globulin.
Enrollment for a second cohort of 140 patients who received human leukocyte antigen-matched unrelated donor transplants finished in November.
HemOnc Today spoke with Kean about the risk and prevalence of GVHD in pediatric transplantation populations, the importance of the results reported so far, and whether these findings ultimately could be practice changing.
Question: Why is addressing GVHD important in this patient population ?
Answer: I am a physician-scientist and, in addition to taking care of pediatric bone marrow transplant patients, I run a research program focused on transplant immunology. In the hospital, we take care of patients every day who go through bone marrow transplant, mostly for malignancies such as leukemia or lymphoma. One of the most devastating outcomes for our patients occurs when we cure their primary cancer but they die of refractory GVHD, which is the most common life-threatening complication of this treatment. Preventing the deadliest form of GVHD is a significant unmet need in both pediatric patients and adults undergoing bone marrow transplant.
Question: Why did you decide to use abatacept in this patient population?
A: I have a longstanding research interest in T-cell immunology and immune tolerance induction, in which T-cell costimulation blockade has been a major focus. In autoimmunity, where abatacept is already approved and in solid organ transplantation, where a related compound — belatacept — is approved, there are a wealth of data supporting a role for T-cell costimulation blockade in controlling alloreactivity, with the ultimate goal of these compounds being used to induce immune tolerance. I first started work on abatacept over 10 years ago, and the results in animal models were really impressive. Other researchers had also used animal models over the years in many different model systems, and we all had shown that T-cell costimulation blockade could improve outcomes for GVHD. So, there was a wealth of preclinical rationale for this study. However, people have been thwarted by the historical difficulty in getting new therapeutics into clinical trials for GVHD. We broke through this roadblock by first doing a small feasibility study — published in 2013 — which showed that we could safely give this drug to bone marrow transplant patients. The results appeared promising, so we put together this larger study. We wanted to do a more intensive study of whether abatacept could really improve survival by reducing GVHD.
Q: Can you describe the severity of GVHD in this patient population ?
A: There are a couple of things to be aware of in this trial. First, we are looking at the ability of this drug to reduce severe acute grade 3 or grade 4 GVHD. This is the GVHD that kills patients, so we need to eliminate this for our transplant patients. The prevalence of severe acute GVHD is related to the underlying risk for alloreactivity in the patients. The trial has two different patient populations, with two different levels of alloreactivity: one with a really high risk for severe acute GVHD (ABA1), and one with a lower risk (ABA2). The lower-risk cohort received transplants from matched unrelated donors — in the ABA2, trial they are called the 8/8 cohort. In our trial, this cohort comprised part of a randomized double-blind stratum. All the patients have been enrolled and blinded, with follow-up ongoing. At ASH Annual Meeting and Exposition, we presented data from the second cohort, which represent patients at very high risk for developing severe acute GVHD. In the ABA2 trial, they are called the 7/8 cohort. One of the important characteristics of these 7/8 patients is that they are more often ethnic minorities, who represent an underserved population in fully HLA-matched bone marrow transplantation.
Q: What dosage did you use ?
A: We used the FDA-approved dose for arthritis — 10 mg/kg — given on the day before transplant and on days 5, 14 and 28 after transplant.
Q: Will this approach be practice-changing ?
A: I do think this study has the possibility to be practice changing. The rate of severe acute GVHD for the really high-risk population is above 30%, but in our cohort, we saw it go down to 3%. It really was quite stunning. The most important result we observed was the improvement in survival among these high-risk patients. This could really drive the change in practice.
Q: When will results be available for the 8/8 cohort ?
A: The 8/8 cohort completed enrollment in November. We expect unblinding of the top-line data in May.
Q: Should clinicians start using this therapy, or are more data needed?
A: As a clinical scientist, I’m always careful to have anybody use a drug off-label without a completed, published trial. There is a groundswell of interest in this therapy. One thing that clinicians should keep in mind is that, although our results in the 7/8 cohort look very promising, ABA2 only used four doses of drug, and the effect we observed in reducing GVHD was confined to acute GVHD, not chronic GVHD. The next trial will likely compare the benefit of the four-dose regimen to a longer dosing regimen. There is more work to be done in this field, but the early results are promising. – by Rob Volansky
Reference:
Watkins B, et al. Abstract 212. Presented at: ASH Annual Meeting & Exposition; Dec. 9-12, 2017; Atlanta.
For more information:
Leslie Kean, PhD, can be reached at 4800 Sand Point Way NE, Seattle, WA, 98105; email: lindsay.kurs@seattlechildrens.org.
Disclosure: Kean reports research funding from Bristol-Myers Squibb and Regeneron; and consultant roles with Bristol-Myers Squibb, Kymab Ltd., Jazz Pharmaceuticals, Calimmune, Alpine Immune Sciences and Takeda.