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Improved outcomes sought for post-transplant patients with chronic GVHD
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William Wood
Allogeneic stem cell transplantation holds promise as a treatment of last resort for high-risk or relapsed hematologic malignancies.
The benefits attributed to this technique beyond the provision of high-dose chemotherapy — which can also be accomplished by autologous transplantation — come from the immunologic graft vs. malignancy effect.
Unfortunately, as we know all too well, this immunologic benefit is a double-edged sword. Many of our patients experience some form of its unhelpful companion, graft-versus-host disease (GVHD), in the post-transplant period.
Although challenging to treat, particularly when steroid refractory, the acute form of this disease is reasonably well suited for the transplant clinical practice environment.
The hallmarks of the disease — skin, gastrointestinal and liver involvement — are readily identifiable. The timing is fairly predictable and occurs early after transplant, when patients are undergoing close, several-times-weekly follow-up at their primary transplant centers by providers who are quite familiar with the condition.
The pathophysiology is becoming increasingly well understood, although several gaps pertinent to treatment remain, including how best to sequence and manage prophylactic and therapeutic immunosuppressants. Nonetheless, the field is moving forward and clinical treatment algorithms — although not yet assuring uniform management of this condition across providers and centers — are at least heading in this direction.
Chronic GVHD
Chronic GVHD, however, has a pathophysiology that is more mysterious and not well understood. The timing of chronic GVHD is less predictable and usually occurs later, sometimes after patients are not being followed quite as closely at the primary transplant center. The manifestations of this disease can involve one or more of many different organ systems, and the effects within a given organ system can vary from one patient to the next.
Despite this, chronic GVHD is a leading cause of late treatment-related death among allogeneic transplant recipients. In those who survive, the disease can lead to significant quality-of-life deficits that parallel those found in systemic autoimmune diseases.
From a systems of care perspective, the disease is especially challenging for several reasons. Because of the diversity of symptomatic manifestations, and the lack of clear understanding of pathophysiology, diagnosis often poses a challenge, and treatment remains largely empiric. These same factors lead to challenges in classifying grade, severity and extent of involvement — which in turn makes it difficult to accurately prescribe therapy and gauge response. Practitioners who initially see the symptoms of this disease may not be those who are best suited to diagnose and treat it.
A refined approach
For these reasons, there has been a significant national interest in refining the approach to the diagnosis and management of chronic GVHD. Under the guidance of Stephanie Lee, MD, MPH, and others, the Chronic GVHD Consortium has been established to test the 2005 NIH working group definitions for chronic GVHD severity and to determine other prognostic measures associated with mortality and functional impairment.
There also are trials to pilot treatment approaches to some of the more challenging manifestations of this condition, including cutaneous sclerosis and bronchiolitis obliterans. To date, the group has published several interesting findings, including a confirmation of the prognostic utility of the NIH global severity score at enrollment, and the independently poor prognosis of the “overlap” subtype of chronic GVHD. Several other studies are ongoing.
Besides the NIH assessments, it is also worth mentioning an insightful and useful article published by Paul Carpenter in Blood last year, titled “How I Conduct a Comprehensive Chronic Graft Versus Host Disease Assessment.”
Clearly, there is a lot of work to be done in accurately identifying and classifying chronic GVHD in post-transplant patients and, ultimately, in improving outcomes. The inherent challenges of chronic GVHD are not unique to this disease, though, and are present in many of the diseases marked by “symptoms,” outside the realm of “precision medicine” (to borrow terms from Christensen, Grossman and Hwang in The Innovator’s Prescription).
Perhaps the Chronic Graft Versus Host Disease Consortium offers a valuable model that we can use for many diseases that share similar principles. In the meantime, my hope is that the consortium will go a long way toward advancing the field in this particularly challenging condition.
References:
- Carpenter PA. Blood. 2011;118:2679-2687.
- Lee SJ. Biol Blood Marrow Transplant. 2011;17:1114-1120.
For more information:
- William Wood, MD, is assistant professor of medicine in the division of hematology/oncology at the University of North Carolina in Chapel Hill. He may be reached at william_wood@med.unc.edu, or follow him on Twitter (@WoodBD). Disclosure: Dr. Wood reports no relevant financial disclosures.