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Graft-versus-host disease: prevention and treatment

Tiene Bauters
2 June, 2014  
In this article, pharmacological and non-pharmacological prevention and treatment strategies of graft-versus-host disease are reviewed
Tiene Bauters PharmD PhD
Clinical Pharmacist,
Department of Pediatric Hematology-Oncology and
Stem Cell Transplantation,
Ghent University Hospital, Belgium
Previously known as bone marrow transplantation, haematopoietic stem cell transplantation (HSCT)has evolved as a central treatment modality in the management of different diseases. HSCT was primarily used for haematopoietic and lymphoid disorders and oncological malignancies. 
However, many other diseases such as immunodeficiency, metabolic syndromes or disorders and blood disorders are now commonly treated with HSCT. Sources of donor stem cells available are bone marrow, peripheral blood stem cells and cord blood.(1–3)
Classification of HSCT
Classification of HSCT is traditionally based on the relationship of the donor to the patient. 
In autologous transplantation, patients’ stem cells are harvested from their own marrow or peripheral blood cells. A syngeneic transplant uses stem cells from an identical twin, whereas an allogeneic transplant uses stem cells from a human leucocyte antigen (HLA) identical of closely matched sibling or unrelated donor.(1–4)
Graft-versus-host disease
Graft-versus-host disease (GvHD) occurs when immune cells transplanted from a non-identical donor recognise the transplant recipient as being foreign. Hence, an immune reaction is initiated that causes disease in the transplant recipient.(2–5) In allogeneic grafts, the immune reaction is related to histocompatibility and the severity of the reactions depends on the degree of incompatibility, which is determined by HLA cell surface glycoproteins. Recipient T-cells recognise foreign donor antigens and can reject the graft: donor T-cells recognise recipient antigens and can cause GvHD.
A literature review by Pallera and colleagues revealed that, despite intensive prophylaxis with immunosuppressive agents, significant GvHD occurs in 25–70% of HLA-matched allogeneic (related or unrelated) transplant recipients. GvHD is less likely to occur, or symptoms will be milder, when the match is close.(3–5)
The possibility of GvHD is very low in patients receiving bone marrow or peripheral blood stem cells from an identical twin. When the donor and the recipient are related, the possibility of GvHD is 30–40% whereas it approximately 60–80% when the donor and recipient are not related. In addition, the incidence of GvHD increases with age.3–5 Other predictors of GvHD are HLA disparities, age, donor age, source and dose of stem cells, intensity of conditioning, GvHD prophylaxis and gender mismatch.
Classification of GvHD
GvHD has been historically divided into acute and chronic GvHD, based upon the time of onset of disease with acute GvHD defined to occur within the first 100 days of HSCT, whereas chronic GvHD had an onset of disease after the first 100 days. 
However, as this definition was artificial and far from satisfactory, the National Institutes of Health (NIH) Consensus Conference proposed two subcategories for chronic GvHD: classic and overlap syndrome. Classical features of chronic GvHD can occur within 100 days of transplant.(2,7,8)
The classification for acute GvHD now includes classic acute GvHD (acute GvHD features, no chronic GvHD features with time of manifestation ≤ 100 days), persistent, recurrent and late-onset acute GvHD (acute GvHD features, no chronic GvHD features with time of manifestation > 100 days).(8)
Chronic GvHD includes classic chronic GvHD (no acute GvHD features but chronic GvHD features, no time limit), and overlap syndrome with acute GvHD features and chronic GvHD features (no time limit for time of manifestation).(6–8)
Diagnostic (that is, clinical features establishing the diagnosis of chronic GvHD without need for further investigation) and distinctive features (that is, clinical features not associated with acute GvHD but being insufficient to make the diagnosis of chronic GvHD unless supported by positive biopsy or laboratory findings) of chronic GvHD and acute GvHD could appear together.(2,6–8)
Clinical manifestation
Acute GvHD
Acute GvHD predominantly affects the skin, the upper and lower gastrointestinal tract, the liver, hematopoietic system and occasionally the eyes and oral mucosa.(2,7–11)
The skin is most commonly affected in acute GvHD. It is usually the first organ that is involved. It manifests as macopapular rash that might be pruritic or painful. Initially, the rash typically affects palms and soles and later spreads throughout the body involving the cheeks, ears, neck, trunk while sparing the scalp. It can be described as sunburn.(2–5) In severe cases, the skin involvement is erythrodermic and occasionally can demonstrate formation of bullous lesions with toxic epidermal necrolysis.(2–5)
Gastrointestinal tract involvement of acute GvHD is often severe and usually presents as diarrhoea, with or without upper gastrointestinal symptoms such as vomiting, anorexia, nausea and/or abdominal pain and food intolerance. GvHD-associated diarrhoea is secretory and often voluminous, occasionally exceeding 10l per day in adults. For these patients, it might be a challenge to maintain adequate fluid balance. Occasionally, bleeding can occur as a result of mucosal ulceration(3,5) and ultimately ileus.
Involvement of the liver manifests as abnormal liver function tests, most commonly being an increase in serum levels of conjugated bilirubin and alkaline phosphatase, indicating the damage to the bile canaliculi, leading to cholestasis. However, liver disease caused by GvHD may be difficult to distinguish from other causes of liver dysfunction (for example, veno-occlusive disease following HSCT, drug toxicity, including drugs used for GvHD prophylaxis, effects from the conditioning regimen and viral infection among others).(2,3,5)
The incidence of severity of acute GvHD is determined by the extent of involvement of these three principal target organs. Overall grades are classified as I (mild), II (moderate), III (severe) and IV (very severe). An overview of acute GvHD classification is presented in Table 1.
Chronic GvHD
Most survivors of HSCT are active and healthy. However, some delayed complications are feared, particularly chronic GvHD. Chronic GvHD may develop as an extension of acute GvHD (progressive onset), after resolution of acute GvHD (quiescent onset) or without previous manifestation of acute GvHD (de novo onset). 
According to the NIH consensus criteria, chronic GvHD is graded as no involvement (0), mild involvement (1, no significant impairment of daily living), moderate involvement (2, significant impairment of daily living) and severe (3, major disability) based on clinical and pathologic presentation.(7) Chronic GvHD may then be classified as mild, moderate or severe.
Calcineurin inhibitors
The primary pharmacologic strategy to prevent GvHD is the use of calcineurin inhibitors, calcineurin being critical for the activation of T-cells. Currently, most centres use the calcineurin inhibitors cyclosporine and tacrolimus. They have a similar action mechanism, clinical effectiveness and toxicity profile (including nephrotoxicity, hyperkalaemia, hypertension) and are used in combination with other immunosuppresives such as methotrexate (given at a low dose, short course in the early post-transplant period). Although many other regimens are explored, this combination therapy has been repeatedly shown to result in a balance of GvHD and graft versus leukaemia effect in matched sibling transplant after myeloablative conditioning regimens.(5,8)
Mycophenolate mofetil (MMF)
MMF is a prodrug of mycophenolate acid and is a selective inhibitor of inosine monophosphate dehydrogenase. MMF inhibits T-cell proliferation and is commonly used in GvHD prophylaxis schedules in combination with a calcineurin inhibitor because of less mucositis and overall good tolerance.(8) 
Sirolimus or mTOR is an inhibitor of activated T-cells that may also expand and maintain of regulatory T-cells. It may also inhibit functions of dendritic cells, important in the initiation of GvHD. Combination of sirolimus and tacrolimus has resulted in rapid engraftment, a low incidence of acute GvHD, reduced transplant-related toxicity and improved survival.(9) However, reports of sinusoidal obstruction syndrome have been associated with the use of sirolimus.(9) 
Antithymocyte globulin (ATG), rabbit or equine antibodies against T-cells and alemtuzumab (humanised monoclonal antibody to CD52) have been used to reduce acute GvHD. However, they increase the incidence of infection owing to delayed reconstitution of the immune system and the incidence of relapse.(8,9)
Treatment of acute GvHD
First-line therapy
The most important predictor of long-term survival is the primary response of GvHD to therapy. High-dose methylprednisolone, typically starting at 2mg/kg/day, is the best initial therapy for acute GvHD.(8) Therapy often continues for 7–14 days or more, and is then tapered progressively over eight weeks or longer in function of the clinical response. Complete responses occur in 25–40% of patients with grade II–IV GvHD.(5–10) 
For skin involvement (grade I), many centres use topical creams with triamcinolone to affected areas and hydrocortisone ointment to affected facial lesion.(3,4,9)
For gastrointestinal GvHD, oral non-absorbable corticosteroids have been used in the treatment as monotherapy or in combination with systemic corticosteroids. The two most-studied drugs were oral budesonide and beclomethasone diproprionate.(11)
Second-line therapy
This will be applied to patients in whom initial therapy has failed. Numerous agents are available including: 
  • Methylprednisolone  (2–5mg/kg/day)
  • Immunosuppressives: tacrolimus, MMF, sirolimus (if not used for prophylaxis)
  • ATG
  • Non-absorbable steroids in cases of gastrointestinal involvement
  • Targeted therapy: monoclonal antibodies (infliximab, alemtuzumab, basiliximab, OKT3)
  • Pentostatin (inhibitor of adenosine deaminase).
Overall, the rates of partial and complete response have been disappointing. In addition, there is a high incidence of infectious complications or recurrence of GvHD.(2,8–10)
Treatment of chronic GvHD
In contrast to acute GvHD, chronic GvHD is treated with a variety of immunosuppressives. The response of chronic GvHD is unpredictable.(5,7,9,12)
Primary treatment involves the use of corticosteroids (initial starting dose of 1–1.5mg/kg/day prednisolone for at least two weeks). Then, the dose is slowly tapered according to the response. Morbidity associated with chronic steroid therapy includes avascular necrosis, glucose intolerance requiring administration of insulin, infections and hypertension.
Calcineurin inhibitors may be helpful in the initial treatment of GvHD as a steroid taper. Topical steroids can be used in combination with systemic steroids and may allow dose reduction in patients with GvHD limited to the skin.
Agents suggested as second-line treatment are pentostatin, rituximab (in refractory cutaneous or musculoskeletal chronic GvHD) and imatinib (refractory pulmonary or sclerodermatous chronic GvHD). There is no real salvage therapy for patients who have failed second-line treatment. 
MMF, methotrexate and pulsed corticosteroids may be considered as third-line treatment options in refractory chronic GvHD.(7,8,12)
Other agents that have been investigated in relation to the management of chronic GvHD include hydroxychloroquine, cyclophosphamide, alemtuzumab, thalidomide, alefacept and retinoids. However, at present, their use is not recommended, owing to insufficient evidence and/or significant toxicity.(7,8,12)
Other molecules are being investigated in phase II and III clinical trials for their role in the prophylaxis or treatment of GvHD (for example, rituximab in preventing acute GvHD in patients undergoing HSCT for haematological cancer; carfilzomib for the prevention of GvHD; infliximab and basiliximab for treatment of steroid refractory acute GvHD; alemtuzumab and glucocorticoids in treating newly diagnosed acute GvHD; ofatumumab as primary therapy of chronic GvHD; tocilizumab for treatment of steroid refractory acute GvHD). 
Non-pharmacological options
Extracorporeal photopheresis (ECP) is increasingly used in chronic GvHD. In some centres, it is used as an adjunct therapy for acute GvHD in order to minimise steroid exposure. ECP involves the exposure of peripheral blood cells to photoactivated 8-methoxypsoralen and ultraviolet A radiation. This covalently binds and cross-links DNA, thereby initiating apoptosis.(13)
As allogeneic HSCT becomes an attractive therapeutic option and the number of HSCTs increase, the need for novel approaches for GvHD becomes necessary. Despite improvements in the understanding of the pathophysiology as well as the new generation of monoclonal antibodies, immunomodulatory chemotherapy and enhanced supportive care, GvHD remains a major cause of morbidity and mortality after allogeneic HSCT. Several lines of investigation with cellular therapeutics and immunomodulating agents are under investigation and might become promising therapies.
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