An Overview of the Graft vs Host Disease Landscape

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EP: 1.An Overview of the Graft vs Host Disease Landscape

EP: 2.Prophylactic Strategies in Graft vs Host Disease Management

EP: 3.An Overview of Treatment Options for Chronic GVHD

EP: 4.REACH-2 Trial of Ruxolitinib in Steroid-Refractory Acute GVHD

EP: 5.REACH-3 Trial of Ruxolitinib in Steroid-Refractory Chronic GVHD

EP: 6.The Evolving Treatment Landscape of Chronic GVHD

Transcript:

Corey Cutler, MD, MPH, FRCPC: The most important part is really understanding what the diseases that we’re dealing with are. What is acute and chronic graft versus host disease [GVHD]? These are 2 distinct manifestations of alloimmunity caused by donor reactivity against the host in which it was transplanted. While the names imply temporality, acute being early or sudden, and chronic being later and long-standing, they actually refer to 2 very distinct clinical syndromes. Acute graft versus host disease does tend to happen earlier, usually within the first 100 to 180 days after transplant, and chronic GVHD tends to happen later, 4 to 6 months at the earliest usually. That being said, you can have late acute graft versus host disease, which occurs later, generally in the context of a taper of immune suppression, and chronic GVHD can happen earlier, as early as 70 to 90 days after transplant. We really define the 2 diseases by the clinical manifestations that they present with. So acute graft vs host disease is an inflammatory process involving 3 organs only; those are the skin, the gastrointestinal [GI] tract, and the liver. Whereas chronic graft versus host disease is a much more pleomorphic process involving numerous organ systems, but most commonly the skin, the mouth, the eye, the liver, the GI tract, the joints and muscles, and the fascia. It really is a much more diverse disease in terms of presentation. The names, as they are currently, do not accurately reflect the temporal nature of their relationship to transplant, but really reflect a historic vignette of how we used to call acute and chronic graft versus host disease.

GVHD does come with a little bit of a silver lining. The entire purpose of doing allogeneic transplant as opposed to autologous transplant is really to induce this graft vs leukemia, or graft vs tumor effect. Now graft versus host disease is an unwanted adverse effect of that process. We cannot yet, in humans, direct the alloimmune response specifically against tumor cells or leukemia cells and not against normal host antigens that might be disparate between the donor and recipient pair. This has been separated in animal models on several occasions, but we haven’t found the tricks quite yet to do this routinely and regularly in humans. The reason there’s a little bit of a silver lining to graft versus host disease is that several studies have indicated that those individuals who do get some amount of acute or chronic GVHD actually have a slightly lower rate of relapse of their original malignancy. That being said, we don’t try to induce graft versus host disease, either acute or chronic, early after transplant in the hopes of using this as a preventive measure against malignancy. Very often, if relapses do occur and we rapidly taper immune suppression or add donor lymphocytes, GVHD is an unwanted consequence of this very sudden and abrupt immune manipulation of the donor system.

The risk factors for GVHD are actually very well known. Far and away, the most important risk and often the one that we can’t control the best is HLA [human leukocyte antigen] disparity. We know from years and years of study that the closer the donor and the recipient pair are matched at HLA loci, the lower the risk of both acute and chronic graft versus host disease. Sometimes we don’t have a choice in donors and there’s only 1 donor available for a given recipient, in which case, we have to deal with the consequences of what that HLA disparity is. There are several other factors that can influence the rate of graft versus host disease. Both donor and recipient age are important in terms of the rates of GVHD. Donor parity, particularly multiparous females, are at a higher risk of causing GVHD than women who have not carried pregnancies. We also can look at things like CMV [cytomegalovirus] serology, which historically has been a risk factor for GVHD. Then the stem cell source, which is something that we actually do control to some degree, is a very well-known and understood risk factor. For example, in unrelated donor transplantation, we know very clearly that a peripheral blood stem cell graft is associated with a higher rate of chronic graft versus host disease in particular. Overall, peripheral blood grafts are associated with a slightly higher rate of acute GVHD as well.

Umbilical cord blood is associated, in general, with the lowest rates of chronic GVHD in particular. The one other thing that we can control is the conditioning intensity prior to transplantation, with higher intensity conditioning regimens being associated with higher rates of GVHD because they cause more tissue injury. We know that tissue injury and expression of injury antigens might actually be one of the inciting causes of GVHD. So reduced intensity or reduced toxicity transplant conditioning regimens are associated with lower rates of acute and chronic graft versus host disease as well.

Transcript edited for clarity.