Graft vs. host: The battle rages on
By: Silvia Mosher, MD | December 08, 2015
In attending the annual American Society of Hematology (ASH) conference this week, I have been thinking a lot about the advances we have made in hematopoietic cell transplants (HCT), and the challenges we continue to face. The advent of HCT in the mid-1970s gave oncologists and hematologists a powerful weapon against leukemia, lymphomas and immune system diseases. But this treatment comes with a dangerous and sometimes deadly complication – acute graft versus host disease (aGVHD). aGVHD is a frequent result of HCT, especially when using allogeneic cells – those that come from a relative or other donor – which account for roughly 65% of all graft sources. Since 1980, more than 125,000 allogenic transplants have taken place.
As its name implies, aGVHD is the result of graft cells identifying the host’s body as a foreign object, which causes it to attack the patient’s organs. In acute cases, this occurs before day 100 post-transplant and the damage is mainly targeted against the liver, gut and skin which can cause rash, nausea and vomiting, diarrhea, jaundice and other symptoms.
Despite more than five decades of research into methods to prevent aGVHD, this complication continues to be a significant cause of illness and death among transplanted patients. Each year more than 8,000 patients undergo HCT and the majority will suffer some manifestations of graft versus host disease, particularly if the donor’s Human leukocyte antigen (HLA) is not a perfect match.
The standard treatment for aGVHD include high dose of corticosteroids as first line of treatment, which can have long term side-effects; and immunosuppressants that make the cells less reactive, which weakens the body’s immune system making the patient more vulnerable to infections. Resolution of inflammation and facilitation of rapid immune reconstitution in those with only a limited response to corticosteroids is a research arena that remains rife with opportunity and urgent clinical need.
We need more research
There is still no cure on the horizon, however several advancements have led to novel aGVHD detection, prophylaxis and treatment methods in the past five years. Currently, researchers are investigating new modalities, including small molecules that target different checkpoints in the aGVHD cascade, cytokine/growth factor milieu-based therapies, cell-based therapies, alteration of host microbia, infusion of T-regs or other suppressor populations, as well as new approaches to modify the graft. Several clinical trials are also available for the treatment of steroid-refractory aGVHD that include a combination of basiliximab plus infliximab (combined targeting of the IL-2 receptor and TNFα, NCT01485055); tocilizumab (targeting the IL-6 receptor, NCT01475162, NCT01757197), α1 antitrypsin (NCT01523821, NCT01700036); and brentuximab vedotin (NCT01596218).
This is an area of research that has been core to my work, and over the past five years many novel approaches to early diagnosis, prevention, and treatment of aGVHD have moved forward. Many of the researchers responsible for these efforts will be present at the ASH conference to discuss the latest efforts to treat and cure malignant & non-malignant hematology diseases. While none of the presentations specifically touch on aGVHD, it will be an underlying issue on everyone’s mind. Whether these experts are exploring new gene therapies to potentially avoid transfusions leading to aGVHD, or conducting research into preventing this disease, we are all keenly focused on the impact aGVHD has on patients, and the direct need to focus more research efforts into overcoming its impact worldwide.