Chronic Graft-vs-Host Disease: Future Directions in Treatment

A Conversation With Syed A. Abutalib, MD; Steven Z. Pavletic, MD, MS; and Kirk R. Schultz, MD

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Hematopoietic stem cell transplantation (HSCT) has improved survival rates for several hematologic malignancies, but as the number of transplants continues to rise, community oncologists are evaluating more posttransplant complications in the clinics.

The ASCO Post spoke with two of the principals behind the National Institutes of Health (NIH) 3rd NIH Chronic GvHD Consensus Conference held in November about the unmet needs of patients suffering from chronic graft-vs-host disease, a major cause of long-term morbidity and mortality in survivors of HSCT. These experts further commented on the importance of community oncology engagement and realistic goals for advancing treatment in the next 5 years.

Syed A. Abutalib, MD

Syed A. Abutalib, MD

Steven Z. Pavletic, MD, MS

Steven Z. Pavletic, MD, MS

Kirk R. Schultz, MD

Kirk R. Schultz, MD

Syed A. Abutalib, MD, Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Roseland Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy, was joined by Steven Z. Pavletic, MD, MS, Head of the Graft-vs-Host Disease and Late Effects Section of the Center for Cancer Research at the National Cancer Institute, and Kirk R. Schultz, MD, Professor in the Division of Hematology, Oncology, BMT in the Department of Pediatrics at the University of British Columbia, Vancouver.

Is Graft-vs-Host Disease Inevitable?

Dr. Abutalib: What are some of the major concerns, and unmet needs, related to chronic graft-vs-host disease?

Dr. Schultz: Despite of a lot of research and effort, graft-vs-host disease is still with us today, as it was 30 plus years ago. It’s a very complex, multiorgan disease associated with high morbidity and high mortality in survivors of transplantation, and it’s the most significant determinant of posttransplant quality of life.

Although much progress has been made in treating patients with hematologic malignancies with targeted immune therapies such as chimeric antigen receptor (CAR) T cells, they are still limited in their efficacy. Consequently, many patients who receive these treatments still end up receiving a subsequent bone marrow transplant. As a field, we’ve been able to decrease the frequency of chronic graft-vs-host disease, but we have not been able to eliminate it as a side effect. It’s an off-target effect of trying to elicit an immune response to hematopoietic malignancy.

“We must try to do everything we can to minimize [cGVHD], but chronic graft-vs-host disease is a long-term complication associated with successful cancer therapy.”
— Kirk R. Schultz, MD

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We have to accept that there are side effects with the treatments we administer. Despite the risk associated with chronic graft-vs-host disease, transplants save lives, and patients who need them should not be deterred from undergoing transplant. We must try to do everything we can to minimize it, but chronic graft-vs-host disease is a long-term complication associated with successful cancer therapy.

Dr. Pavletic: The concern about graft-vs-host disease is understandable. The answer is better education and communication for all stakeholders. We also need to refine our selection of candidates for transplantation. Having mild graft-vs-host disease is actually associated with the best transplant outcomes, for example, so it’s important to find the right balance.

Dr. Schultz: We have made progress, but we need to continue to raise awareness so that oncologists are better informed. Early diagnosis and early intervention are an important part of caring for patients. With increased awareness, patients will be more likely to receive the multi-disciplinary care that they need.

Goal of NIH Conferences

Dr. Abutalib: What was the purpose of the NIH conferences in 2005, 2014, and 2020?

Dr. Pavletic: The conferences have been occurring cyclically based on the communal needs. In 2005, it was obvious that with the increasing use of peripheral blood stem cells there was increasing incidence of chronic graft-vs-host disease, but there were no standards for diagnosis, no standards for pathways to conduct clinical trials, and no standards to develop biomarkers or supportive care. That’s when the community first came together to create a framework.

The conference in 2014 was evidence-based. Every single recommendation that we made, whether to refine the staging or the response criteria, was based on reference data. The goal of the 2020 conference was not to tweak response criteria or to create a new classification system. It was to think outside the box and to ask ourselves, ‘What are we doing wrong?’ We are still using steroids as the standard frontline therapy and there is no standard second-line therapy. A lot of progress has been made since 2005, but it’s time to focus on prevention, preemption, personalized medicine, steroid-free regimens, and the optimal treatment of more severe disease.

Pressing Needs Remain

Dr. Abutalib: Compared to 2005 and 2014, where do we stand today with this disease?

Dr. Pavletic: We have advanced the field of clinical research. There are many new agents coming our way that target the disease and have the potential to be more effective with less toxicity, but we need to learn how to use them better.

The biggest problem the field is facing is that we still have corticosteroids as a frontline standard therapy even though they’re only effective in about 50% of patients. We’re also lacking other pathways and approaches to treat in the second line, and we don’t have ways of predicting which drug to use in a given patient.

“The goal of the 2020 conference was not to tweak response criteria or to create a new classification system. It was to think outside the box and to ask ourselves, ‘What are we doing wrong?’”
— Steven Z. Pavletic, MD, MS

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So, we need to move away from steroids and develop more personalized treatment approaches, and we need to find effective ways of preventing the disease. Right now, there may be effective prevention strategies, but they’re given to everybody, so we don’t know who is more or less likely to benefit. That’s where the field is today. There are a lot of opportunities and there are better options for patients, but a fundamental change just still needs to happen.

Dr. Schultz: We need to enfranchise our patients a bit better. A lot of patients with this disease feel isolated, and they’re really struggling. Chronic graft-vs-host disease affects the tendons, the skin, the mouth, and the eyes, as well as various organ systems. Pain control is still a major problem and so is psychosocial depression. We need to do a better job supporting people who are affected by this disease.

Looking Toward the Future

Dr. Abutalib: What are you most excited about in chronic graft-vs-host disease in the next few years?

Dr. Schultz: We’re going to treat patients with biological therapies, which we desperately need. The field of chronic graft-vs-host disease is like leukemia in the early 1990s. We’re just beginning to understand how to biologically classify and risk stratify the disease. When we’re able to predict which patients are going to do better or worse, we’ll be able to develop more biologically based therapies. Ibrutinib, the first FDA-approved drug in chronic graft-vs-host disease, was approved in 2017. Now, it looks like ruxolitinib may be approved too.

We’ve done a pretty good job with prevention strategies to decrease the frequency of chronic graft-vs-host disease.The next phase is preemption trials that biologically assign patients higher and lower risk and utilize targeted therapies to try and prevent the onset.

Dr. Pavletic: We need to move away from corticosteroids, and we need to start using combination therapies rather than single agents. We need to bring the pharmaceutical industry to the table to develop that paradigm and to rapidly test different drug interventions. We can’t afford to do one clinical trial in chronic graft-vs-host disease every 10 years. ν

DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca and Partner Therapeutics. Dr. Pavletic and Dr. Schultz reported no conflicts of interest.