Graft versus Host Disease (GVHD)

GvHD is the most frequent post allogeneic stem cell transplant complication and is a major cause of morbidity and mortality. GvHD is a consequence of activation of donor T lymphocytes by recipient antigen presenting cells. It requires three conditions, transplantation of immunocompetent donor cells, histo-incompatibility between recipient and donor and immunocompromised recipient such that the recipient cannot mount an adequate immune response against the donor cells. A number of randomised controlled trials have compared the incidence of GvHD in bone marrow and peripheral blood stem cell transplants in the related and unrelated setting. In allogeneic sibling transplantation, the incidence of acute GvHD was the same in the majority of studies. There was however an increased incidence of chronic GvHD with PBSC compared to BM. In the unrelated setting, matched cohort comparison of BM and PBSC transplants report no difference in the incidence of acute and chronic GvHD. These were not however randomised controlled trials.

 

GvHD develops in a three phase process. In Phase 1 the effects of the conditioning regimen leads to tissue damage and the generation of pro inflammatory cytokines including TNFα and IL-1. In Phase 2, donor T lymphocytes are activated by host antigen presenting cells. The activated T cells produce cytokines including IL-2, leading to T cell expansion. Phase 3 is a cytokine storm in which a positive feedback loop of cytokine production leads to activation of effector cells such as CTLs and NK cells, which produce more pro inflammatory cytokines such as TNFα and IL-1.

 

GvHD has traditionally been classified into acute and chronic based mainly on the time to onset. GvHD arising before day 100 post transplant was classified as acute and onset after day 100 classified as chronic. The current definition sets no time limits but is rather based on the presence of specific symptoms, though in practice, the use of the 100 day limits continues.

 

The two main mechanisms used to prevent GvHD are pre transplant T cell depletion of the stem cells and post transplant immunosuppression of the patients.  T cell depletion may be undertaken with for instance the use of alemtuzumab or Anti-Thymocyte Globulin (ATG). T cell depletion is not very popular in the UK where patient immunosuppression appears to be the preferred method of GvHD prophylaxis. A common approach is to use a calcineurin inhibitor such as Cyclosporin-A (CsA) or Tacrolimus, in combination with short course Methotrexate (MTX). Another option is Sirolimus in combination with Tacrolimus and short course MTX. In reduced intensity transplants (RIC) Mycophenolate mofetil (MMF) has been used in combination with CsA.

 

 

The organs primarily affected by GvHD are the skin, the gut and the liver. Skin GvHD manifests as a rash often affecting the palms and soles first, before spreading to the entire body surface. Gut involvement manifests as nausea and a watery diarrhoea, which in advanced disease can be bloody. Liver involvement can manifest as jaundice and is usually measured by the level of Bilirubin production.

 

Acute GvHD is traditionally classified in grades I to IV depending on the level of organ involvement. A new international classification of grades A to D is also in use. The traditional I – IV classification however continues to be the one most widely used. In brief, it classifies GvHD with only mild skin involvement as Grade I. Mild to moderate skin involvement with mild gut and/or liver involvement is classified as Grade II. Moderate to severe skin involvement with mild to moderate gut and/or liver involvement is classified as Grade III and Moderate to very severe skin involvement with moderate to severe gut and/or liver involvement is classified as Grade IV.

 

Initial GvHD therapy consists of a dose of Methyl-prednisolone.  Patients refractory to this primary treatment have a poorer prognosis. Secondary treatment is with higher doses of Methylprednisolone or other immunosuppressive drugs not already used as induction therapy, including Tacrolimus, MMF or Sirolimus, ATG, monoclonal antibodies.

 

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