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Stem cell transplant

Managing transplant patients with acute graft-versus-host disease

Graft-versus-host disease (GvHD) can be acute or chronic — their symptoms and management can overlap but may also vary considerably. Here, we discuss acute GvHD and its treatment.

Arm of a patient with graft-versus-host disease (Biophoto Associates/Science Photo Library)

Graft-versus-host disease (GvHD) remains the most frequent complication of allogeneic stem cell transplant (SCT) — the transplant of stem cells from one person to another. GvHD is caused by interactions between the recipient’s antigen-presenting cells and mature T-cells from the donor marrow and is the leading cause of morbidity and mortality among SCT recipients.

Despite optimal tissue matching and the use of prophylactic immunosuppressive medicines, GvHD can affect up to 80% of patients receiving an SCT from an unrelated donor[3].

GvHD can be acute or chronic — their symptoms and management can overlap but may also vary considerably. Only acute GvHD is discussed here.

Organs affected

The skin, liver and gastrointestinal (GI) tract are most commonly affected by GvHD. The skin tends to be more involved at the onset.2 The condition typically manifests as a maculopapular rash that eventually spreads over the entire body with lesions that become painful.2

Acute GvHD in the liver typically presents with jaundice and a cholestatic pattern of liver injury — including raised transaminases.1,2 GI involvement presents as secretory diarrhoea, and nausea, vomiting, weight loss and abdominal pain can also occur. In severe cases, bleeding as a result of mucosal ulceration can develop and cause ileus. When acute GI involvement occurs, immunosuppressants should be given intravenously because absorption may be impaired. Oral administration can be restarted when absorption problems resolve.

Grading

Unfortunately, there are no validated diagnostic and predictive blood biomarkers for GvHD in clinical use; therefore, diagnosis is based on clinical findings. In practice, most centres in the UK use the modified Seattle Glucksberg criteria for grading disease severity (see Box 1).

 Box 1: Modified Seattle Glucksberg grading criteria

 Stage

Skin

Liver (Serum bilirubin)

Gastrointestinal tract
(Fluid loss from gut)

 IRash covering <25% of the body34–50µmol/L 500–1,000ml/day
 IIRash covering 25–50% of the body51–102µmol/L 1,000–1,500ml/day
 IIIGeneralised erythroderma103–255µmol/L >1,500ml/day
 IVBullae formation and desquamation of skin>255µmol/L>255µmol/L
>2,500ml/day (or ileus)


Since there are few randomised, controlled trials investigating the management of acute GvHD, there is no consensus on its optimal management. The aim of treatment is to ensure maximum control of the disease while minimising the risk of toxicity and relapse.

First-line treatment

Corticosteroids Corticosteroids are the standard first-line treatment for acute GvHD[2].2 Patients with grade I disease are unlikely to require systemic treatment and most will respond to topical corticosteroids. The potency of treatment required depends on the extent, location and severity of the rash.
As the disease progresses to grade II, oral prednisolone should be initiated at 1mg/kg/day. This can be increased to 2mg/kg/day in grade III–IV disease and switched to intravenous methylprednisolone if no response is seen. If the condition responds to corticosteroids, clinicians will look to taper the dose down slowly after seven to 14 days — with a view to stopping it altogether.1

Complete response occurs in 25–40% of patients with grade II­–IV GvHD.1

Calcineurin inhibitors Unless the patient is already taking one, a calcineurin inhibitor (usually ciclosporin) should be started alongside corticosteroids for grade II disease and above. The recommended starting dose is 3–5mg/kg twice a day orally (rounded to the nearest 25mg) or 3–5mg/kg once daily intravenously. The dose should be titrated to achieve blood levels of 150–300ng/ml — measured weekly for the first few weeks of treatment.

Calcineurin inhibitors work by blocking the activation of T-cells. Although they are the mainstay of treatment in GvHD, they are associated with side effects and drug interactions — which must be considered when selecting medicines.

Drug levels must be monitored closely when interacting medicines cannot be avoided. In particular, the dose of ciclosporin should be reduced before starting voriconazole or posaconazole concomitantly, and increased accordingly when the antifungal is stopped.

Nephrotoxicity is the major adverse effect of ciclosporin — it is usually reversible when the dose is reduced. Other side effects include central nervous system toxicity (eg, tremor, headaches, encephalitis), hirsutism, gum hyperplasia, fluid retention and micro-angiopathic haemolytic anaemia. Ciclosporin toxicity should be suspected if the patient feels dizzy or lightheaded, is shaking or vomiting, or has developed anaemia. The drug can also cause hypomagnesaemia, hyperkalaemia and hypertension — these are usually manageable and do not warrant discontinuation of treatment.

Tacrolimus has similar side effects to ciclosporin. For patients already receiving ciclosporin, switching to tacrolimus has only been found to be helpful for those experiencing neurotoxicity.2 The recommended therapeutic range for tacrolimus is 5–10ng/ml.

Second-line treatment

Refractory treatment is considered when patients fail to respond to a 2mg/kg dose of corticosteroids in combination with ciclosporin or tacrolimus after five days, or they show progressive symptoms after 72 hours.2 There are other immunosuppressants available — mycophenolate mofetil and sirolimus — but there are no defined criteria or robust evidence to suggest which particular approach is preferred over the other. Choice will depend predominantly on the patient’s clinical status and the clinician’s preference.

Mycophenolate mofetil Mycophenolate mofetil can be prescribed alongside corticosteroids for patients who are intolerant of calcineurin inhibitors, or can be used as triple therapy with high-dose corticosteroids and calcineurin inhibitors. Serum drug levels are not routinely measured but may be warranted occasionally. Mycophenolate is associated with GI disturbances, particularly diarrhoea and vomiting.

Sirolimus The mammalian target of rapamycin pathway inhibitor sirolimus can be used in combination with:

  •  Mycophenolate mofetil and corticosteroids as an alternative to calcineurin inhibitors
  •  Corticosteroids and calcineurin inhibitors for patients who experience no response to mycophenolate mofetil

However, in view of the risk of sirolimus causing haemolytic uraemic syndrome and hyperlipidaemia, it should be used cautiously in combination with calcineurin inhibitors.2 Sirolimus is only available as an oral preparation so is not appropriate where GvHD causes problems with GI absorption.

Concomitant use of azole antifungals can cause a considerable increase in sirolimus levels. Manufacturers recommend that the sirolimus can continue at a reduced dose, yet some transplant centres suggest that these antifungals should be avoided altogether.

Side effects include abdominal pain, nausea, oedema and hypertension. Monitoring of drug levels is recommended to avoid toxicity (the recommended level is 3–12ng/ml).

Third-line treatment

Third-line treatments may be considered when all second-line options have been exhausted. These include infliximab, etanercept or extracorporeal photopheresis (a form of photodynamic therapy). However, there are few data to support these approaches.

The role of the pharmacist

The nature of GvHD requires the use of highly toxic medicines. Pharmacists should help ensure that any side effects are monitored and patients are appropriately counselled.

Pharmacists can offer advice on drug level monitoring and on managing interactions, and should ensure that appropriate supportive medicines (eg, antifungals, antivirals) are co-prescribed.

 

Objectives

Studying this article will help you gain a better understanding of:

  • Graft-versus-host disease (GvHD) and its presenting symptoms
  • The main treatment options for acute GvHD
  • The main side effects and main interactions involved with the immunosuppressants used

For Discussion 

  • Given that mycophenolate mofetil has fewer side effects and interactions than ciclosporin and tacrolimus, why are the latter used first line?
  • Should azole antifungals ever be prescribed for patients taking sirolimus?
  • What supportive therapies might be required by patients post-transplant?

Citation: Clinical Pharmacist DOI: 10.1211/CP.2014.11133493

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