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New Approvals for GVHD Expand Treatment Options
By Bob Kirsch
For years, therapeutic options for graft-versus-host disease (GVHD) had been limited. Although several recent approvals have helped, clinicians will need to determine how the new agents fit into the armamentarium for this challenging condition.
“Having three FDA-approved therapies for patients with chronic GVHD [cGVHD], a debilitating condition, is truly remarkable, given that just over five years ago there was not a single FDA-approved therapy available to these patients,” said Amin M. Alousi, MD, the director of the GVHD Clinic and Research Program, and a professor of stem cell transplantation at The University of Texas MD Anderson Cancer Center, in Houston.
Ruxolitinib (Jakafi, Incyte) received an indication in September 2021, both for the treatment of steroid-refractory acute GVHD (aGVHD) in adults and children who are 12 years of age and older and for treatment of cGVHD after
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Distributed by Infectious Disease Special Edition and CMEZone.com
Faculty
Paul E. Sax, MD
Clinical Director, Division of Infectious Diseases Professor of Medicine, Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts
Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI
Director Clinical Infectious Diseases Research Director Medical Student Research Associate Professor, University of Queensland Brisbane, Australia Department Infectious Diseases Ochsner Health System New Orleans, Louisiana
Between 20% and 70% of patients who receive an allogeneic stem cell transplant as a part of their cancer treatment will develop at least a mild case of GVHD.
failure of one or two lines of systemic therapy.
“A kinase inhibitor, ruxolitinib affects the signaling of various cytokines and growth factors while also altering signaling pathways connected to the development, proliferation and activation of multiple immune cell types relevant in GVHD,” Dr. Alousi explained.
Belumosudil (Rezurock, Kadmon/ Sanofi) was approved in July 2021 to treat patients who are 12 years of age and older with cGVHD, after failure of at least two prior lines of systemic therapy. “This novel drug inhibits a protein believed pivotal for both skewing T cells toward an inflammatory phenotype, [and it] plays a role in multiple fibrotic pathways that are aberrant in patients with chronic GVHD,” Dr. Alousi said.
These medications have a pediatric indication, “whereas ibrutinib [Imbruvica, Pharmacyclics/Janssen] is only approved for adult patients,” observed Doris M. Ponce, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, in New York City, and the lead author of the 2021 Guidelines for the Prevention and Management of Graft-Versus-Host Disease After Cord Blood Transplantation of the American Society for Transplantation and Cellular Therapy Cord Blood Special Interest Group.
Abatacept (Orencia, Bristol Myers Squibb) received an indication in December 2021 for the prophylaxis of aGVHD, with a calcineurin inhibitor and methotrexate, in adults and children who are 24 months of age and older undergoing hematopoietic stem cell transplantation from a matched or one allele–mismatched unrelated donor. Abatacept is a selective T-cell co-stimulation modulator that works by inhibiting a signal needed for T-cell activation.
Abatacept’s indication is for prophylaxis of aGVHD, Dr. Alousi pointed out. “It is important to note that this therapy is the first—and to date only— drug approved in the United States for prevention of GVHD.”
The recent approvals address a large unmet need for patients who have undergone a allogeneic stem cell transplant, according to Dr. Ponce.
During the autumn of 2020, “I was using off-label treatments for patients who had progressed or not responded to the only drug the FDA had approved at that time, ibrutinib,” she added.
Dr. Alousi noted that “enthusiasm for the first approved therapy, ibrutinib, has been limited,” due to concerns that the phase 2 trial included too few patients (n=42); that the study population poorly reflected real-world patients (most had one or two organs involved and were relatively early in the course of the disease); and that the toxicity (fatigue, diarrhea and infections) seen with the study dose was not insignificant.
Ruxolitinib
Ruxolitinib, in contrast, “has broad appeal,” Dr. Alousi said, “because there has been considerable experience with this drug in chronic GVHD, even prior to its FDA approval.”
Hematologists’ experience with this drug date back to its 2011 approval for patients with myelofibrosis.
Although anemia, neutropenia and thrombocytopenia can be seen when using ruxolitinib in the cGVHD setting, this is less of a consideration with aGVHD patients, and “can generally be managed through dose reductions or holding the drug,” Dr. Alousi said.
Cytopenias are common in the setting of aGVHD, which at times can make continuation of this drug challenging. Further, the randomized trial “failed to show a reduction in non-relapse mortality, with roughly half the patients in both arms experiencing non-relapse death by 18 months post-enrollment.”
Of note, “the fact that it has demonstrated efficacy when compared headto-head with other therapies also gives weight to the data,” he said.
Belumosudil Features High Response Rate
Describing belumosudil as “the popular new kid on the block,” Dr. Alousi explained that its “unique mechanism of action with potential to halt the fibrotic process common to chronic GVHD contributes to its appeal. Further, the high response rates in the ROCKstar study that were seen in such a high-risk, heavily treated study population along with the 60% of patients who had clinically meaningful improvement in symptom burden supports the enthusiasm for this drug” (Blood 2021;138:2278-2289).
In regard to the pivotal belumosudil study, he noted that “the impressive results with a 75% response rate and 60% improvement in symptom burden are even more significant when considering the study population had very advanced and heavily treated chronic GVHD.”
The demonstrated efficacy, high percentage of patients having improvement in symptom burden, novel mechanism of action and high safety profile have “driven enthusiasm for this therapy.”
Abatacept
The standard prophylaxis for GVHD consists of a calcineurin inhibitor [tacrolimus/cyclosporine] with methotrexate or mycophenolate, and although there are a number of additional approaches, they are off-label, Dr. Alousi explained.
These approaches may involve in vivo or ex vivo depletion of T cells. Recently, there has been a marked increase in the use of cyclophosphamide, which “when administered on the third and fourth day following the transplant, has been highly effective in reducing not only acute but also severe forms of chronic GVHD,” he said.
“I think it is very unlikely that abatacept will be widely used for GVHD prophylaxis when compared with more affordable and generally accepted forms of GVHD prophylaxis, such as cyclophosphamide-based regimens,” he said.
Discussing the trials upon which abatacept approval was founded, Dr. Alousi pointed to “a number of limitations of these trial results that will limit widespread use of the drug for GVHD prevention.”
Among the limitations, the control group did not receive any of the commonly used and available strategies to mitigate the well-detailed increased rates of aGVHD and diminished survival resulting from use of a mismatched unrelated donor, and the growing use of cyclophosphamide-based GVHD prophylaxis strategies across the world. Published results from prospective and retrospective studies have shown “significant reductions in severe acute and severe chronic GVHD across various donor types: matched, mismatched, half-matched family, etc. How abatacept would measure up against this commonly employed GVHD mitigation strategy was not studied in the trial leading to approval.”
So, what does the clinician do? Especially for cGVHD, “I do not think the relevant question is when would a prescribing provider chose therapy X over therapy Y,” Dr. Alousi said.
“Given that very few patients with steroid-refractory chronic GVHD will have a complete response to any therapy, it is likely that the majority of patients with this disease” will receive several different medications throughout their lives, both indicated and offlabel medications, he added.
“A more likely question will be one of affordability, given the price of these drugs and chronic nature of the disease,” he explained.
The pharmacists’ role in treating cGVHD is not limited to clinical recommendations and monitoring. They can be important conduits of information between doctors, patients and insurance companies, according to Nancy M. Nix, PharmD, a pharmacy oncology clinical coordinator at Ballad Health, in Johnson City, Tenn. “Patients will view the relationship with their pharmacist differently from the relationship with their oncologist,” Dr. Nix said. “They will tell you things about their medication that they won’t tell the doctor because they think doctors [focus primarily on] their physical care, and so they choose to tell the pharmacist about their drug care. But the physician really needs to know all this information before he or she makes a choice of treatment, and due to our role, we can relate this information to physicians.” —Additional reporting by Myles Starr
Dr. Alousi reported serving as an advisory board member for Incyte and Kadmon Corp. and has received research funding from Incyte. Dr. Nix reported no relevant financial disclosures. Dr. Ponce reported serving as an advisory board member for CareDx, Ceramedx, Evive Biotechnology (Shanghai) Ltd., Incyte and Kadmon Corp., and has accepted research funding from Incyte.
Amin M. Alousi, MD
