expert roundtables

Chronic Graft-versus-Host Disease: Current Challenges and Opportunities

by Daniel R. Couriel, MD, MS; Corey Cutler, MD, MPH, FRCP(C); and Sergio A. Giralt, MD

Overview

The treatment and prevention of chronic graft-versus-host disease (cGVHD) have been unmet medical needs for some time. Renewed scientific interest in this disease, along with multiple novel therapies in development, appear to signal the beginning of a new era in cGVHD management.

Q:

What have been the major challenges in cGVHD, and what are some of the opportunities that you are excited about?

Sergio A. Giralt, MD

Deputy Division Head
Division of Hematologic Malignancies
Melvin Berlin Family Chair in Multiple Myeloma
Memorial Sloan Kettering Cancer Center
New York, NY

We know more about cGVHD today than we did 10 years ago, and there are new therapies emerging. We understand the biology of fibrosis much better than we did before, and we are actually starting to have newer therapies that we can use.”

Sergio A. Giralt, MD

This used to be an orphan disease, but now there is a cadre of dedicated physicians, clinicians, and basic scientists who are strongly invested in trying to dissect this out. We have strategies to reduce the incidence of this disease. We know more about cGVHD today than we did 10 years ago, and there are new therapies emerging. We understand the biology of fibrosis much better than we did before, and we are actually starting to have newer therapies that we can use.

Some of our current challenges are also opportunities. The best care for patients with cGVHD is provided in the large centers that have comprehensive GVHD clinics, so the challenge lies in making that expertise available to as many patients as possible. My hope is that telemedicine and some of the newer technologies will allow us to provide better care to patients.

Further, those with cGVHD require expert-provided multidisciplinary care. Most GVHD experts are not ophthalmologists, dentists, or physical therapists. Conversely, trying to train subspecialists in the unique treatment needs of patients with cGVHD is not always practical. When you send a patient with cGVHD to an ophthalmologist who is not a GVHD specialist, they will get a good assessment, but they will not receive comprehensive care. So, there needs to be more integration or you risk delivering fragmented care.

Corey Cutler, MD, MPH, FRCP(C)

Medical Director, Stem Cell Transplantation Program
Dana-Farber Cancer Institute
Associate Professor of Medicine
Harvard Medical School
Boston, MA

“As the science unfolds, we will learn how to treat our patients more effectively initially, and we will see more individuals with early responses. As a result, they will suffer less in the long-term.”

Corey Cutler, MD, MPH, FRCP(C)

I am just so excited that we have renewed interest from our pharmaceutical partners in this field, and that is only going to lead to better treatments. We have ibrutinib, which works at the level of the B-cell receptor by blocking Bruton tyrosine kinase–mediated signaling and might have independent T-cell effects through interaction with ITK. We are looking at a number of other important pathways, including the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which mediates signals for interleukin 6 and interferon gamma, as well as other mediators of inflammation. The ROCK2 inhibitor belumosudil is not only an anti-inflammatory but also is very instrumental in the final common pathway in laying down collagen fibrosis. I think that people are very optimistic for several reasons. And then we have interest in CSF1R antagonists, and a number of other targets are also in early phase trials.

One of the biggest current challenges in cGVHD is identifying the right drugs for the right patients. We need to learn whether those decisions are ideally based on patient or disease characteristics, biomarkers, or some combinations of these factors. In the next few years, to best treat our patients with the drugs that are available, we will need to learn how to choose therapeutics appropriately. Whether that will require larger databases or novel learning strategies to help us understand the evolving treatment landscape remains to be seen. I am looking forward to seeing these questions answered. As the science unfolds, we will learn how to treat our patients more effectively initially, and we will see more individuals with early responses. As a result, they will suffer less in the long-term.

Daniel R. Couriel, MD, MS

Professor of Internal Medicine
HCI Chair for Adult Leukemia Research
Director, Utah Blood and Marrow Transplant Program
Medical Director, Center for Cellular Therapy and Regenerative Medicine
Division of Hematology and Hematologic Malignancies
Huntsman Cancer Institute
University of Utah School of Medicine
Salt Lake City, UT

“With newer agents and the optimization of ancillary and supportive care, I am hopeful that we can better address the challenges of steroid-related toxicities.”

Daniel R. Couriel, MD, MS

One of the challenges is optimizing the roles of ancillary and supportive care in the treatment of cGVHD. Allowing such care to function optimally could mean that it not only alleviates symptoms and improves the patient’s quality of life but may also help spare patients from the toxicities of systemic therapies, particularly corticosteroids. There has not been much research in this area, but it is an area of interest to me. Most patients with moderate to severe forms of cGVHD receive long courses of corticosteroids, and the symptoms of corticosteroid toxicity may blend into the syndrome and sometimes become more problematic than the cGVHD itself.

Supportive and adjunctive strategies can be varied and individualized to the patient with GVHD. You have adjunctive therapy in the form of osteoporosis treatment, for instance, but you also have the treatment or prevention of infections. It has been documented, for instance, that you reduce mortality by using broad spectrum antifungals in patients with GVHD who are receiving systemic therapy.

With newer agents and the optimization of ancillary and supportive care, I am hopeful that we can better address the challenges of steroid-related toxicities. I think that we are in a new era in GVHD treatment. With the advent of novel therapies, there will be significant motivation to change our models of care.

References

Hashmi SK, Bredeson C, Duarte RF, et al. National Institutes of Health Blood and Marrow Transplant Late Effects Initiative: the Healthcare Delivery Working Group report. Biol Blood Marrow Transplant. 2017;23(5):717-725. doi:10.1016/j.bbmt.2016.09.025

Lee SJ, Wolff D, Kitko C, et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015;21(6):984-999. doi:10.1016/j.bbmt.2015.02.025

Pidala J, Kurland B, Chai X, et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood. 2011;117(17):4651-4657. doi:10.1182/blood-2010-11-319509

Saidu NEB, Bonini C, Dickinson A, et al. New approaches for the treatment of chronic graft-versus-host disease: current status and future directions. Front Immunol. 2020;11:578314. doi:10.3389/fimmu.2020.578314

Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease [published correction appears in N Engl J Med. 2007;357(4):428]. N Engl J Med. 2007;356(4):335-347. doi:10.1056/NEJMoa061098

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