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Graft vs. Host Disease (GvHD) is one of the chief complications following allogeneic stem cell transplant for blood cancers and disorders like leukemia and anemia.
Here, we take a deep dive into what causes GvHD, how it is diagnosed and treated, and the latest research about how to prevent it.
Graft vs. host disease is a life-threatening condition that may occur after an allogeneic stem cell transplant when the donor’s stem cells (graft) attack the patient’s (host’s) blood cells as foreign.
Around half of those undergoing hematopoietic stem cell transplants need to be treated for GvHD afterward, and roughly 10% ultimately die from it [*].
Broadly speaking, the treatments for GvHD focus on suppressing the patient’s immune response to the attack. But doctors want to ensure they don’t suppress the graft-versus-tumor (GvT) effect that comes from the donor’s stem cells fighting the disease the patient had the transplant for in the first place. In fact, patients who experience some GvHD are less likely to see their cancer return following a stem cell transplant [*].
At the same time, while GvHD can often be treated, it doesn’t guarantee that the transplant will succeed in treating the disease.
Graft versus Host Disease is categorized as acute or chronic by the patient’s symptoms and diagnostic tests, in tandem with the timing of when the symptoms arose after the transplant.
aGvHD is usually seen within the first 100 days after transplant and most often affects the skin, gastrointestinal (GI) tract, and liver. When these organs are affected later than 100 days, it may be categorized as late AGvHD.
cGvHD is usually seen within 1-2 years after transplant and, like aGvHD, can affect the skin, GI tract, liver as well as mouth, eyes, muscles, joints, and genitals.
Overlap Chronic GvHD (or Overlap syndrome) may occur at any time after transplant. It is diagnosed when the patient’s symptoms and tests indicate that they have both acute and chronic graft-versus-host disease [*].
The symptoms of GvHD can vary widely based on the severity of the disease. Chronic GvHD affects more organs than acute, but the acute symptoms can be more intense.
About half of the patients who have experienced Acute GvHD will develop Chronic GvHD [*].
Early detection and treatment can limit the severity of GvHD and improve long-term outcomes. Patients who have had stem cell transplants should talk to their transplant team immediately if they are experiencing any of these symptoms commonly seen in patients with GvHD [*][*]:
GvHD is caused by the donor’s stem cells attacking the host’s cells as foreign invaders. This occurs because of a protein on the surface of nearly all cells called human leukocyte antigen (HLA). HLAs are programmed to recognize compatible proteins and attack foreign ones. They help identify bacteria and viruses and signal your immune system to take action to destroy invaders and not your own healthy cells.
After the stem cell transplant, when the donor’s stem cells proliferate into new blood cells in the patient’s body, they carry the donor’s HLAs. When the patient’s HLA type isn’t close enough to the donor’s, the donor’s cells will go on the attack against the recipient’s immunocompromised system.
Each person’s HLA is unique, except for identical twins. HLA typing is far more complicated than blood typing, though it is performed with a simple blood draw or cheek swab. There are six major antigens essential for immune responses, and 1-1,543 alleles for each of these six loci [*]. Transplant research studies have identified 10 alleles in 5 HLA loci — HLA-A, -B, -C, -DRB1, and -DQB1 — as the most important ones to match to avoid GvHD.
The gold standard for most stem cell transplants is a perfect match from a twin but the level of matching is determined by the transplant team. They will also consider the risk factors for GvHD.
Anywhere from 35-50% of stem cell transplant recipients will develop GvHD depending on risk factors such as these [*]:
GvHD, whether acute or chronic, is diagnosed based on the symptoms, the timing of the onset, lab tests, and imaging tests. These tests are used to rule out other diseases that mimic GvHD, such as viral infection or drug reaction, and include:
Acute GvHD is staged and graded 0-IV based on the number of organs involved and the extent of the damage. The skin is staged based on the amount of body area affected, the GI tract is staged based on the amount of diarrhea passed per day, and the liver is staged based on the elevated bilirubin in the blood.
Patients with grade III/IV aGvHD have poorer outcomes and are less likely to survive [*].
Chronic GvHD is categorized as mild, moderate, or severe based on symptoms across eight organs (skin, eyes, mouth, joints, liver, gut, lungs, connective tissue), with each organ graded 0-3 [*]. About 5,000 patients in the U.S. develop cGvHD each year. It can take 3-5 years to resolve, if at all [*].
These standardized grading and staging protocols help researchers better understand how to treat GvHD.
Treatment for GvHD depends on what organs are affected and how severe it is. There is no standard regimen, however; Drugs are administered by the transplant care team based on their own protocols and what works for each patient. Failure to treat GvHD increases the risk of serious complications, lowers quality of life, and can lead to death.
Medications that suppress the patient’s immune response and reduce inflammation are currently the first line standard of care for both acute and chronic GvHD. These include oral, topical, and intravenous corticosteroids like prednisone.
However, long-term steroid use is not good for anyone.
While steroids are effective in 36-60% of patients, they have their own side effects, not the least of which is opening the patient up to secondary infections or a recurrence of their cancer [*]. One expert believes that the typical steroid regimen in the first 100 days post-transplant ages the patient’s bones by 17 years [*].
In children, steroids can negatively impact bone density, vascular systems supporting bone health (osteonecrosis), growth, and organ development [*].
Skin issues may be treated with topical ointments, light therapy, and wound treatments to mitigate risk of infection.
Gut issues are typically treated with medications to mitigate nausea, increase appetite, and treat diarrhea. However, half of patients with GI GvHD do not respond well to the first-line therapy of glucocorticoids; The survival of patients with acute GI GvHD treated with the standard steroid regimen is only 5-30% [*].
Patients who do not respond to steroids are called steroid-refractory and a second line treatment is indicated for these patients.
The FDA has approved three drugs for steroid-refractory GvHD which target the immune system response in other ways: Imbrutinib (Imbruvica®) for cGvHD, Ruxolitinib (Jakafi®) for aGvHD, and Belumosudi (Rezurock®) for cGvHD.
A GvHD patient who is steroid-refractory may also have photopheresis treatment post-transplant, having their blood filtered through a machine and returned to their body with altered T Cells, sort of like dialysis [*]. This treatment may be needed several times a week for months.
There is no one-size-fits-all cure for GvHD. Some patients never get it and only 36%-60% of those who do manage to get rid of it with a first-line steroid treatment.
Chronic GvHD, with the multitude of organs it can affect, is particularly challenging. It can take years to resolve chronic GvHD. Sometimes patients sustain organ damage before it is even diagnosed because liver damage may not present obvious symptoms [*].
That said, the outlook is not all doom and gloom, thanks to less toxic, novel therapies to treat and prevent GvHD.
GvHD research is moving away from broadly prescribed immune-suppression drugs and toward more targeted prevention strategies, as well as treatments specific to the patient’s blood markers and the organs involved, according to Fred Hutch Cancer Center [*]. Here are a few of the most promising treatments from recent clinical trials.
T cells, a white blood cell (lymphocyte) that has been shown to be a trigger for GvHD, are one target for researchers. There are two types of T cells: Memory T cells, which remember exposure to certain pathogens, and naive T cells, which have never encountered a protein or other molecule to provoke an immune response. Naive T cells are the problem in GvHD, for reasons researchers don’t fully understand.
Researchers tried removing both types of T cells from donated cells, called T cell depletion, but this led to some patients developing severe or fatal infections post-transplant.
By removing only naive T cells from donated cells before they are transplanted, researchers have seen cases of chronic GvHD drop significantly — from 40-45% down to 7% in one study [*]. None of the cases developed by the 7% were severe. And there was no difference in the rate of relapse — about 1 in 5 — which suggests that this therapy does not take away the graft-vs-tumor effect.
The T cell filtering work can be done using magnets or by processing the donor stem cells with UVA light, a form of photopheresis performed outside the body [*][*].
As an added bonus, the transplant team doctors were also able to reduce the intensity of the conditioning regimen, which included chemotherapy and radiation, and help older patients (60) as well [*]. About 80% of blood cancers occur in patients older than 60; Stem cell transplants are rarely performed in patients over 75 [*].
Reducing the pre-transplant conditioning, which is designed to essentially destroy the patient’s immune system, is also a major target for researchers.
The toxicity of chemotherapy has a deleterious effect on the intestinal tract, giving transplant patients only a limited ability to repair tissue ahead of transplant. Scientists know that gut health is linked to GvHD. In addition to tissue damage, high-dose chemotherapy increases the amount of cytokines circulating in the bloodstream and can lead to a cytokine storm [*].
Researchers are getting much more adept at predicting who will go on to develop GvHD based on certain biomarkers. For example, they have been able to correlate specific gut bacteria to GvHD mortality using cell-free DNA testing to analyze the patient’s plasma [*].
By better understanding which patients are most likely to develop GvHD, they can target prevention therapies that come with serious side effects only to those patients [*].
As we noted earlier, the lack of diversity in a patient’s gut microbiome is linked to an increased risk of getting GvHD and to their outcomes generally. Several clinical trials have shown promise using fecal microbiota transplantation (FMT) to treat GI GvHD.
FMT is a procedure in which a fecal suspension from a healthy donor is infused into the recipient’s GI tract. It may be used to enhance the patient’s gut microbiome before a stem cell transplant in a novel treatment, or post-transplant, as a second-line treatment for steroid-refractory GI GvHD, where it can help repair tissues damaged by steroid medications as well as resolve the immune and inflammatory response [*][*].
The survival rates for aGvHD and cGvHD are improving thanks to earlier treatment with novel therapies [*]. Historically, survival after second-line treatment has been poor — around 50% [*].
Patients who developed severe aGvHD between 2016-2017 had a 1-year survival rate of 86% and a 2-year survival rate of 79%; In the 10 years preceding, the survival rates were 55% and 41%, respectively [*].
Among those patients who developed severe chronic GvHD, the 1-year survival rate in 2016-2017 was 87% and the 2-year survival rate was 74%. In 2011-2013, survival rates for severe chronic GvHD were as low as 53% and 41%, respectively [*].
GvHD is caused by the donor’s cells (the graft) attacking the patient’s (the host’s) cells as foreign due to certain proteins on the cells called HLAs. This can arise from stem cell transplants and certain organ transplants as well.
GvHD left untreated can result in significant health issues, reduced quality of life, and in severe cases, death [*].
GvHD can be life-threatening in both acute and chronic forms when it begins to permanently damage organs or otherwise impair their function.
Yes, chronic GvHD can occur years after transplant and can recur. Most cases start within 2 years.
The skin is the organ most frequently affected [*].
If GvHD is affecting your intestinal tract, experts recommend foods that reduce symptoms, prevent weight loss, and help you recover. A liquid diet and easily digestible foods like bananas, applesauce, and toast may be a good start [*].
Using cord blood for stem cell transplants, in lieu of bone marrow or peripheral blood, has three main advantages: The incidence of GvHD is lower with cord blood, it does not require a painful surgical procedure to procure, and requires a lower degree of HLA matching than bone marrow [*].
In diseases where one’s own stem cells can be used, there is no risk of GvHD. For diseases with a genetic basis like anemia or leukemia, a sibling’s cord blood could be a lifesaver. In the case of the new treatment for sickle cell anemia, the patient’s own cells can now be genetically modified and transplanted [*].
MiracleCord provides the industry’s most advanced cord blood and cord tissue banking at prices affordable to families on a budget. Discover why we were awarded Best U.S. Cord Blood Bank by Global Health and Pharma, and download our Free Info Kit to learn more.
GvHD is one of the biggest obstacles to successful stem cell transplantation, and a great deal of research and clinical trials continue to be dedicated to creating more targeted treatments and prevention.
The last decade has seen remarkable progress and novel therapies will continue to improve outcomes.
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