Should research efforts focus on completely preventing GVHD?
We certainly hope GVHD could one day be prevented.
Transplantation is the only curative treatment for many hematologic diseases; but, at the same time, GVHD is a major morbidity, and mortality of this procedure has been the real challenge for a successful transplant outcome. Refractory GVHD carries a bad prognosis and treatment remains a real unmet need. One bright spot on the horizon is that incidence of this complication has decreased with our deeper understanding of its etiology and pathophysiology. The knowledge of all components of immune cells — coupled with the ability to selectively expand the good T cells and selectively deplete other hyperactive T and B cells — can significantly prevent and treat GVHD. New, exciting data suggest that specific food and nutritional habit changes could change the gut microbiome, which may help prevent and improve this complication.
We know that acute GVHD and chronic GVHD have different mechanisms but are linked together, and if acute GVHD doesn’t happen at day 100 even after using a nonmyeloablative conditioning regimen, it still may happen later. Consideration for preventing or pre-emptive treatment has evolved.
It is our hope GVHD is preventable completely and will go down to 0% incidence soon. This is our motivation to evolve more research efforts in the field to make it happen. It would be so fascinating if I could tell my patient I could cure their cancer with no GVHD. However, this is a challenging goal, because we still think that a graft-versus-leukemia effect is important. We also have some studies correlating GVHD incidence with lower relapse rates. GVHD-free transplant is our new goal of transplant management, by preventing the bad GVHD and maintaining the good programmed immune cells to control the leukemia.
New therapeutic approaches can be directed more precisely to target specific immunologic mechanisms and pathways, like cytokine receptor-mediated signaling on B and T cells (eg, JAK, SYK inhibitors), methods to expand T regulatory cells, adoptive T-regulatory cellular therapy, and T-cell selective depletion ex vivo and in vivo. Using posttransplant cyclophosphamide for T-cell depletion has changed GVHD incidence and significantly improved transplant outcomes. Although results of clinical studies are promising, further studies in larger multicenter cohorts of patients are in progress and are needed to identify the most effective and least toxic regimens. It seems likely that more effective and less toxic therapies will soon be available for the prevention and treatment of GVHD.
More promising is the natural killer cellular therapy approach, which has an enhanced graft-versus-leukemia effect without affecting toxicity. I see this approach, combined with other novel strategies, as the future to zero GVHD incidence with enhanced graft-against-leukemia effects.
George Yaghmour, MD, is assistant professor of clinical medicine at Keck School of Medicine of USC. He can be reached at 1975 Zonal Ave., Los Angeles, CA 90033; email: email@example.com. Disclosure: Yaghmour reports no relevant financial disclosures.
At a cost.
Whether GVHD should be completely prevented has long been a provocative question for the field, but it’s certainly not a new concept.
I would focus on the word “completely.” GVHD is certainly preventable or reducible, a disease that either occurs acutely after HSCT — affecting the GI tract, liver and skin, often with life-threatening consequences — or subsequently in the chronic phase, affecting multiple organs with significant morbidity. Fundamentally, both phases are, at least in part, mediated by T cells, which are a predominant component of the stem cell infusion. So, with that knowledge, many studies have eliminated T cells to prevent GVHD, particularly using current methods of CD34 cell selection or antithymocyte globulin.
Both these and other methods can be highly effective in reducing the severity and rates of GVHD. Although I cannot yet point to a publication that shows data leading to a zero-sum incidence of GVHD, evidence suggests severe forms can be pushed into the single digits, and this also favorably impacts rates of the chronic form.
The nuance to this question is whether complete elimination ultimately improves long-term survival for patients. That’s the underlying question here, because GVHD is at least partially linked to the efficacy by contributing to the immunotherapeutic components of allogeneic transplant. If one is to greatly reduce the amount of GVHD, there is some concern for greater rates of recurrence, relapse or even infectious complications. So, if we completely eliminate GVHD, it is unclear whether it would lead to a net improvement for our patients.
Getting to absolute zero incidence in this landscape is not impossible, but unlikely. A lot of the research happening at University of Michigan and nationally is using our new understanding of the biology of this disease to improve the clinical approaches to prevention. Treatments that reduce the most severe forms of GVHD might produce a more manageable complication without adverse effects, like increased relapse or infection.
John Martin Magenau, MD, is assistant professor of hematology, medical oncology and internal medicine at University of Michigan. He can be reached at 500 E. Medical Center Drive, Ann Arbor, MI 48109; email: firstname.lastname@example.org. Disclosure: Magenau reports no relevant financial disclosures.