Graft-Versus-Host-Disease prevention after Bone Marrow Transplant

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Summary

Graft Versus Host Disease (GVHD) is one of the common complications when Bone Marrow Transplant (BMT) is undertaken to treat certain cancers and conditions in the body. In many cases, GVHD itself can be as fatal as the condition for which BMT was undertaken as treatment. Nevertheless, BMT is important as it reduces the risk of relapse (of the original condition) in most patients. That is why; preventing GVHD or targeting it with various medications is an important aspect of treating conditions that require BMT. In this article, we will learn more.

Introduction to AHCT

Allogeneic Hematopoietic Cell Transplantation (AHCT) is an important treatment given to cure certain malignant and non-malignant conditions like blood and bone-marrow cancers (called hematologic conditions), certain metabolic diseases, some inherited deficiencies of the immune system and bone-marrow failure syndromes. In this procedure, hematopoietic stem cells which are basically immature blood-cells are harvested from the bone-marrow of a donor (who is related or unrelated to recipient) and injected into the body of the recipient. The process is also called Bone Marrow Transplant or BMT.

We have covered BMT in earlier articles. Radiation or chemotherapy done under cancer treatment can damage some quantum of bone marrow, which is responsible for producing new blood-cells. As a result, there is a shortage of blood-cells in the body which can lead to various complications. When stem cells are transplanted from another healthy person’s body, the process of blood-cell production by the host body gets a boost. Further, the new stem-cells can attack the cancer-cells directly and kill them.

While BMT is a great relief for people suffering from nearly 15 different conditions, one of the consequences or side-effects is a condition called GVHD. In this, the new stem-cells from the donor, called ‘graft’ see the cells of the ‘host’ body as a foreign threat and start attacking them. There is a ‘graft versus host’ conflict or battle happening in the recipient’s body. In the process, some of the healthy cells in the recipient’s body get destroyed. This creates new complications in a person who is already suffering from some condition for which BMT was undertaken.

Types of GVHD

GVHD is of 2 types primarily. Earlier, GVHD was classified by doctors purely based on when symptoms start showing. In recent times, GVHD is classified based on symptoms, diagnostic or image-test results and on when the symptoms started showing. Accordingly, we have:

• Acute GVHD: Symptoms onset shortly after BMT, generally within the hundred days, while in some people, it can take longer. Acute GVHD affects the liver, digestive or GI tract and the skin.
• Chronic GVHD: Symptoms onset anytime from the date of BMT, up to two years. Chronic GVHD affects liver, digestive (GI) tract and skin like in acute GVHD, the mouth, joints, lungs and genitals.

Interestingly, patients who have had a BMT can develop either of the above types, or neither of them, or even both of them.

Risk Factors for GVHD

• Huge mismatch in HLA between donor and recipient: Human Leukocyte Antigen (HLA) is a protein that identifies a person’s body-cells uniquely. Other than identical twins, everyone has a unique HLA. After BMT is done, the recipient’s body starts producing blood-cells that have HLA which are similar to the donor’s cells’ HLA. If the difference in HLA between the two types is not significant, GVHD will be mild or not even develop. However, if the difference is significant, GVHD is inevitable. That is why, matching the HLAs between donor and recipient is an important preventive step before BMT is done. It is one of the primary factors on the basis of which donors are shortlisted.
• The donor has been pregnant in the recent past
• Both donor and recipient are in their middle-age or old-age
• The donor and recipient are of opposite genders
• The stem cells have been harvested from the blood-stream of the donor and not bone-marrow, for some reason

Symptoms of GVHD

Acute GVHD

• Rash or redness on the skin similar to a sunburn
• Itching or irritable skin
• Diarrhoea, nausea and vomiting
• Cramps in the abdomen
• Jaundice

Chronic GVHD

Symptoms of Acute GVHD, and more:

• Rash or redness on the skin similar to a sunburn
• Itching or irritable skin
• Diarrhoea, nausea and vomiting
• Cramps in the abdomen
• Jaundice
• Swelling and tightness in the skin
• Hair loss on both head and body
• Dry mouth, mouth ulcers and gum disease such as gingivitis
• Dry or tight feeling in the eyes, vision problems
• Dyspnoea or shortness of breath
• Dry and persistent cough
• Constant fatigue
• Pain, weakness, soreness and cramps in the muscles
• Joints feel stiff or there is decreased movement in them
• Women have dryness, pain or itching in the vagina after intercourse
• Men have dryness, pain or itching in the penis or scrotum, after intercourse

Treatment strategies

In the past, GVHD was targeted using certain prophylactic (preventive) medication, but morbidity and mortality rates were still high. Nearly 40% of the patients did not respond favourably to corticosteroids given as a part of this treatment. That is why, new drugs and new medication have emerged over the years which target different bio-chemical processes in the body, that either prevent the onset of GVHD or minimize its consequences or stop it altogether. Newer drugs will emerge with time which may do a better job of the task at hand. Some of the strategies and drugs used today are as below. Some of these terms are highly technical, but it gives an idea of how seriously the condition is taken. (Source: Hematology, ASH Education Program, ASH Publications)

To prevent onset of GVHD

• Tocilizumab: This is one of the types (monoclonal) of antibodies produced by the body against IL-6R
• JAK inhibitors (itacitinib, ruxolitinib): Reduction of proinflammatory cytokines, T-cell activation and function, preserves Tregs, GVL effect
• Abatacept: This helps in co-stimulating the blockage of CD28:CD80/86 which helps inhibit T-cell production
• Manipulation of the microbiome: Association of loss of diversity with increased GVHD and TRM; mediate anti-inflammatory cytokines and Tregs
• Tregs (regulatory T-cells): regulates the self-tolerance mechanism in the immune system, limits GVHD symptoms and maintains GVL effect (graft versus leukaemia effect, that is important to prevent relapse of leukaemia)
• Statins: Inhibit proinflammatory Th-1 differentiation, induce Treg expansion, and downregulate APCs
• T-cell depletion (more specifically, the selection of CD34 and selective depletion of ex-vivo T-cells): basically, the depletion of allo-reactive T cells and selective depletion of αβ T-cells, while preserving NK cells and γδ T cells
• Vorinostat: This is a kind of histone deacetylase inhibitor that reduces inflammatory cytokines in the body, enhances Treg (regulatory T-cells) function, minimizes GVHD symptoms and helps preserve GVL effect

To cure GVHD once it has developed

• Sirolimus: Inhibition of mTOR impairs T-cell signaling
• Fecal microbiota transplant: This helps tackle the loss of diversity in gut microbiome as a result of GVHD, reduces TRM (transplant-related mortality) and mediates anti-inflammatory cytokines as well as Treg response
• JAK inhibitors (ruxolitinib, itacitinib): They help reduce proinflammatory cytokines, activate T-cell production and function, preserve Tregs and preserve GVL effect
• Mesenchymal stromal cells: Inhibition of B- and T-cell activation, APCs, NK cells and increase Tregs
• α-1 antitrypsin: This is a kind of serine protease inhibitor that regulates the immune-system response, and regulates inflammation function using cytokine profiles
• Extracorporeal photopheresis: Induction of Tregs possibly
• Monoclonal antibodies (natalizumab, vedolizumab): Targeting α4-integrins on activated lymphocytes mediating adhesion and trafficking
• IL-22: These are found in the intestine and acts on intestinal stem cells. They boost the epithelial-barrier function and help in tissue repair

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Frequently Asked Questions

1.  What is Graft-Versus-Host-Disease (GVHD)?

GVHD is a complication that can happen after a bone marrow transplant (BMT). It occurs when the donated stem cells (graft) attack the recipient’s body (host) as if it were foreign.

2. Are there different types of GVHD?

Yes, there are two main types: Acute GVHD (symptoms start within 100 days of BMT) and Chronic GVHD (symptoms can appear any time after BMT, even years later).

3. What are the risk factors for GVHD?

A big risk factor is a mismatch between the donor and recipient’s HLA (protein that identifies cells). Other factors include donor age, pregnancy history, and stem cell source (blood vs. bone marrow).

4. What are the symptoms of GVHD?

Symptoms can vary depending on the type of GVHD, but common ones include skin rash, nausea, diarrhea, jaundice, dry mouth, and fatigue.

5. How do doctors prevent GVHD?

Doctors try to match HLA closely and use medications to suppress the immune system before and after BMT. Newer drugs target specific processes to prevent GVHD.

6. How is GVHD treated?

Corticosteroids are a first-line treatment, but newer medications like JAK inhibitors and T-cell depletion are showing promise. In some cases, fecal transplants can help restore gut health.

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