GvHD prophylaxis

In vitro T-cell depletion of graft or in vivo T-cell depletion with Campath-1H or anti-lymphocyte globulin (ALG) are successful in reducing both the incidence and severity of GvHD in graft recipients. The former is associated with an increased risk of relapse. Both are used in MUD and hap-loidentical grafts where the risk of severe GvHD is increased. The 'Seattle protocol' is most commonly used post graft infusion: consists of a combination of stat pulses of IV methotrexate (MTX) with bd infusions of cyclosporin:

Methotrexate MTX (IV bolus) 15mg/m2 on day +1, then 10mg/m2 days +3, +6 and +11. Folinic acid rescue 15mg/m2 IV tds may be given 24 hours after each MTX injection for 24 hours (rescue protocol designed to reduce mucositis).

Dosage reductions

• If renal/hepatic impairment 5 MTX dose as follows:

<145 100

320 146-165 50

166-180 25

>180 omit dose

<35 100

36-50 50

51-85 25

>85 omit dose

Side effects although reduced by folinic acid rescue mucositis may remain severe and require IV diamorphine.

Cyclosporin administration

Powerful immunosuppressant with profound effects on T-cell suppressor function. Available for IV and oral use.

Intravenous regimen—commence on day -1 at 1.5mg/kg IV bd as IVI in 100mL 0.9% saline/2h. If flushing, nausea or pronounced tremor, slow infusion rate 4-6h/dose. Following loading, on day +3 onwards, adjust cyclosporin dosage based on plasma cyclosporin A level together with renal and hepatic function.

Oral regimen—switch intravenous—»oral when patient can tolerate oral medication and is eating (usually day +10 to +20). Dosage on conversion is ~1.5-2.0 x IV dose (still bd).

Monitoring cyclosporin levels

• Cyclosporin is toxic and renal impairment is the most frequent dose limiting toxicity.

• Cyclosporin A levels should be monitored at least twice weekly.

• Never take blood for cyclosporin A levels from the central catheter through which cyclosporin has been given as cyclosporin adheres to plastic and falsely high levels will be obtained. One lumen should be marked for cyclosporin administration and another lumen marked for blood levels testing. • 12h pre-dose trough whole blood levels are measured.

Instruct patient to delay the morning dose of cyclosporin until after the blood level has been taken. The optimum blood cyclosporin level is not known. Target range: 100-300ng/mL. Aim towards the top of the therapeutic range in the early post-transplant period and lower part of the range at other times. In practice, the dose is often limited by a rise in serum creatinine. If serum creatinine >130|jmol/L—adjust dose. Do not give cyclosporin if serum creatinine >180jmol/L.

Dosage adjustment—cyclosporin has a very long tj^ so dosage adjustment similar to warfarin adjustment.

1. To 5 cyclosporin level omit 1-2 doses and make a 25-50% reduction in ongoing maintenance dose, recheck levels at 48h.

2. To 4 levels, give 1 additional dose, increase maintenance dose by 25-50%, recheck level in 48h.

3. Monitor renal function and LFTs daily. Check serum calcium and magnesium twice weekly.

Cyclosporin toxicity

• Nephrotoxicity (see above). Worse with concurrent use of aminoglyco-sides, vancomycin and amphotericin.

• Hypertension—often associated with fluid retention and potentiated by steroids. Treat initially with diuretic to baseline weight and then nifedipine if persists. Sub-lingual nifedipine useful where emergency reduction of blood pressure is required.

• Neurological syndromes, esp. grand mal seizures (usually if untreated hypertension/fluid retention).

• Anorexia, nausea, vomiting, tremor (almost always occurs—if severe suggests overdosage).

• Hirsutism and gum hypertrophy with prolonged usage.

• Hepatotoxicity—less common than nephrotoxicity. Usually intrahepatic cholestatic picture on LFTs. Potentiated by concurrent drug administration e.g. macrolide antibiotics, norethisterone and the azole antifungals.

• Hypomagnesaemia commonly occurs. Potentiated by combination with amphotericin. Give 20mmol IVI if levels <0.5jmol/L or if symptoms develop.

Note: only one orally absorbed preparation of magnesium. For hypomag-

nesaemia persisting on cyclosporin post-discharge, consider magnesium glycerophosphate tablets qds.

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