Canterbury DHB

Management

• Chronic GvHD should be graded mild, moderate or severe as defined by the NIH consensus criteria. The extent and severity of any organ involvement should be carefully recorded in the clinical notes.
• All patients with signs and symptoms of cGvHD in one organ should be assessed for evidence of GvHD in other organs.
• cGvHD has variable manifestations and response to therapy. Some cGvHD tissue damage may be irreversible even with the appropriate treatment. There is a lack of well designed trials of management, making it difficult to choose between the various treatment options.

Localised cGvHD

This typically involves the skin, mouth or eyes.

• Skin involvement is managed topically by steroid creams eg 1% Hydrocortisone, although their use should be held to a minimum to reduce the risk of skin atrophy. Avoidance of skin damage eg sunlight is essential. Dermatology consultation if required.
• Mouth involvement can be severe and lead to significant dental caries. Avoid foods causing discomfort, regular mouth washes, Chlorhexidine may need to be diluted. Bonjela may help. Topical steroids may also be used especially if there is ulceration eg triamcinolone in emollient dental paste (Kenalog). Prednisolone liquid 5 mg/ml can also be used for generalised mouth GvHD. Diprosone OV 0.05% and nystatin cream TDS. Dental consultation is essential unless the symptoms are mild.
• Eye involvement usually leads to a failure of tear production and should be assessed and managed in conjunction with the Ophthalmologist.

Significant involvement of other organs, e.g. liver or lungs, is usually seen in association with extensive cGvHD.

1st line therapy of cGvHD

Corticosteroids are the recommended 1st line treatment of cGvHD. Calcineurin inhibitors may be useful in initial treatment and as steroid-sparing agents.

• Prednisone 1 mg/kg in divided doses. Maintain infectious prophylaxis and start osteoporosis prevention measures.
• Cyclosporin orally to maintain a level in the upper therapeutic range( 95-205 mcg/L), monitor blood pressure and creatinine.
• Mycophenolate Mofetil (MMF) can be added if the clinical situation warrants it and/or a poor response is seen to prednisone and cyclosporin. Give MMF 2 g daily in divided doses PO for an adult patient.

Monitor the response to this initial treatment. If response is not adequate there are a range of other treatment available. None of these are very effective and some are not readily available in New Zealand.

2nd line and beyond therapy of chronic GvHD

General principles

The “trial and error” system remains the commonest approach because no predictors of response exist. General principles adopted are:

• A comprehensive NIH-style comprehensive organ assessment should be made at baseline for comparison at future evaluations.
• Choose treatments with the least toxicity first.
  • Avoid CNI in renal toxicity
  • Avoid pentostatin and thoraco-abdominal radiation in marrow suppression
• Initiate one treatment at a time to identify the active component if possible (rapid progression may not allow this)
• In the presence of lack of response continuation of at least one drug in the change period
• If no response to salvage therapy after 8-12 weeks switch to 3rd line (may require considerably longer for scleroderma)
• If progressive GHVD after 4 weeks at adequate drug levels switch to 3rd line
• Agents identified as ineffective should be discontinued to minimise immunosuppression

BCSH guidelines recommendations:

• ECP schedule should be fortnightly paired treatments for a minimum assessment period of 3 months. (1C)
• M-TOR inhibitors are suggested as a second line treatment option in refractory chronic GvHD. (2C) but are not currently available in NZ.
• Pentostatin is suggested as a second line treatment option in refractory chronic GvHD. (2B)
• Rituximab is suggested as a second line treatment option in refractory cutaneous or musculoskeletal chronic GvHD. (2B)
• Extra-corporeal photopheresis (ECP) may be considered as a second line treatment in skin, oral or liver chronic GvHD. (1B) It is available at the Peter MacCallum Institute, Melbourne, Australia and must be applied for through the high costs medicines process.
• Imatinib is suggested as a second line treatment option in refractory pulmonary or sclerodermatous chronic GvHD. (2C) It is not funded for this purpose in NZ but may be applied for through the NPPA process.
• The following agents are suggested as third line treatment options in refractory chronic GvHD: mycophenolate mofetil, methotrexate, pulsed corticosteroids. (2C)
• There was insufficient evidence, at present, to support recommendations to use the following agents in the management of chronic GvHD: cyclophosphamide, MSCs, thalidomide, retinoids, alemtuzumab, infliximab, etanercept, clofazimine, alefacept, daclizumab, basiliximab, hydroxychloroquine, thoraco-abdominal irradiation. (1C)
• Azathioprine is not recommended in the management of chronic GvHD due to the risk or oral malignancy. (1C)

Results of an EBMT survey on 1st and 2nd line therapy of chronic GvHD

• In patients on no current therapy steroids alone (60%) or steroids + CNI (34%) were the commonest regimens. In patients on CNI centres increased steroids (71%), increased CNI (3%) or both (25%). If the patient was on steroids and CNI 73% added MMF. ECP was available in 10% of centres.
• 52% continued treatment for up to 1 month before evaluation. 75% continued for up to 1.5 months. Only 25% waited longer than 6 weeks.
• There was no consensus on 2nd line treatment. It was common to base 2nd line treatment on site of disease. Agents included ECP (53%), MMF (36%), rituximab (12%), mTOR (9%), steroids (8%), CNI (12%) and TKI (6%). Topical tacrolimus was used in 41% of centres.

Notes:

• Infection. Ensure that prophylaxis against bacterial, fungal, and viral infections is continued. Reinstitute a pre-emptive approach to the early detection of CMV with weekly PCR tests for CMV viral antigen.
• Extensive skin involvement with subcutaneous fibrosis resembles scleroderma. Underlying joint and muscle fibrosis may lead to limitation of movement even immobilisation. Advice from Rheumatology is essential. Refer to physiotherapy for maintenance of range of movement.
• Pulmonary involvement. The bronchiolitis obliterans syndrome may develop abruptly. More often it is of gradual onset with progressive shortness of breath. Baseline lung function studies will have been done pre transplant and are essential for early diagnosis and to provide some guideline as to the rate of progression. Patients need to be aware that lung damage may develop and to report any symptoms that could reflect this.
• Liver involvement. This is primarily cholestatic resembling primary biliary cirrhosis, the main target of hepatic GvHD being the biliary tract.

Topic Code: 9081