| Prevention of GVHD |
| GVHD prophylaxis: myeloablative conditioning |
- The standard prophylaxis is cyclosporine plus a short course of methotrexate. Tacrolimus plus methotrexate is regarded as equivalent, but experience in Europe is too limited to support recommendations. Institutions using tacrolimus plus methotrexate should establish institutional guidelines* and follow them.
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- Antithymocyte globulin has been shown to reduce chronic GVHD and improve the quality of life in transplantations from an unrelated donor. Therefore, antithymocyte globulin can be included in the prophylaxis regimen for unrelated donor transplantations. Institutions using antithymocyte globulin should follow the EBMT/ELN recommendations or establish institutional guidelines and follow them.
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| Cyclosporine |
- The initial dose is 3 mg/kg/day.
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- The administration is initiated on the day preceding the infusion of the graft (day –1). In case of two or more graft products given on more than one day, the day of the first product is counted as day 0.
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- The drug is given as short intravenous (IV) bolus infusion in two daily doses.
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- The administration is changed to oral route when oral intake is possible.
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- The first oral dose is twice the IV dose, administered in two daily doses.
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- The dose is adapted according to whole blood cyclosporine concentration or toxicity (renal insufficiency, microangiopathy, neurological problems) necessitating change of dosage.
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- The cyclosporine target concentration is 200 to 300 micrograms/L during the first three to four weeks, then 100 to 200 micrograms/L until three months after transplantation if there is no GVHD or toxicity.
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- Cyclosporine concentrations are measured from whole blood at 12 hours after a dose (trough level before the next infusion/dose).
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- The duration of cyclosporine prophylaxis is six months in the absence of GVHD.
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- The dose is tapered from three months onwards if no GVHD is present. The dose is not tapered as long as there are signs of acute GVHD or signs of chronic GVHD exceeding mild skin disease.
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| Methotrexate |
- The initial dose is 15 mg/m2 given on day +1.
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- Three additional doses of 10 mg/m2 are given, on days +3, +6 and +11. The day +11 dose is omitted in case of any toxicity of WHO grade II or higher.
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- The drug is given as bolus IV injection.
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- No dose adaptation is made except for possible omission of day +11 dose (see above).
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- Leucovorin rescue is given to all patients.
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- Leucovorin administration is started 24 hours after each methotrexate dose. The dosage is 15 mg × 3 given every six hours after methotrexate administration on day +1, the same dose × 4 given every six hours after methotrexate doses on days +3, +6 and +11.
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- Leucovorin is administered orally, in case of severe mucositis IV route is used.
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| Antithymocyte globulin (rabbit) |
- The brand of antithymocyte globulin is ATG-Fresenius (ATG-F) or Thymoglobulin.
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- The dose of ATG-F is 10 mg/kg on three days (total 30 mg/kg) and that of Thymoglobulin is 2.5 mg/kg on three days (total 7.5 mg/kg).
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- Antithymocyte globulin is administered on days –3, –2 and –1.
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| GVHD prophylaxis: reduced intensity conditioning |
- The standard prophylaxis is cyclosporine plus mycophenolate mofetil.
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- Antithymocyte globulin has been shown to reduce chronic GVHD and improve the quality of life in transplantations from an unrelated donor. Therefore, antithymocyte globulin can be included in the regimen for unrelated donor transplantations. Institutions using antithymocyte globulin should follow the EBMT/ELN recommendations or establish institutional guidelines and follow them.
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| Cyclosporine |
- Depending on the intensity of conditioning, the prophylaxis can be given either IV or PO. If the IV route is used, the recommendation for the initial dosing of cyclosporine is the same as for transplantations with myeloablative conditioning.
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- If the oral route is used, the initial dose is 12 mg/kg/day.
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- The administration is started on day –1.
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- The daily dose is given in two doses with a 12-hour interval.
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- The doses are adapted according to whole blood cyclosporine concentrations, toxicity (renal insufficiency, microangiopathy, neurological problems) necessitating change of dosage or decreasing chimerism.
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- The target concentrations are 200 to 300 micrograms/L during the first three to four weeks, then 100 to 200 micrograms/L until three months (if no GVHD, toxicity or decrease in chimerism).
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- The cyclosporine concentrations are measured from whole blood at 12 hours after a cyclosporine dose (trough levels before next infusion/dose).
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- The duration of prevention is six months, if there are no signs of GVHD. In case of persistent disease or relapse (sub-population chimerism or other sensitive method) prevention should be reduced earlier.
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- The dose is tapered from three months onwards if there are no signs of GVHD. The dose is not tapered as long as there are signs of acute GVHD or signs of chronic GVHD exceeding mild skin disease.
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| Mycophenolate mofetil |
- The dose is 30 mg/kg/day¶, given orally in two doses.
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- The administration is started on day +1.
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- The dose is adapted according to toxicity.
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- The duration of mycophenolate mofetil prophylaxis is one month in sibling transplantations, three months in transplantations from unrelated or mismatched donor.
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- In case of persistent disease or relapse (sub-population chimerism or other sensitive method) prevention should be reduced earlier.
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| Antithymocyte globulin (rabbit) |
- The brand is ATG-F or Thymoglobulin.
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- The dose of ATG-F is 10 mg/kg on three days (total 30 mg/kg) and that of Thymoglobulin is 2.5 mg/kg on three days (total 7.5 mg/kg).
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- Antithymocyte globulin is administered on days –3, –2 and –1.
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| Prophylaxis in cord blood transplantation |
- The recommended prophylaxis is cyclosporine plus mycophenolate mofetil, with dosing and duration of administration as described above for transplantations with reduced intensity conditioning.
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| Treatment of GVHD |
| Treatment of acute GVHD |
| First-line treatment |
- The first-line treatment of acute GVHD is methylprednisolone.
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- Treatment is initiated for acute GVHD of grade II or higher.
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- The initial methylprednisolone dose is 2 mg/kg/day.
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- Methylprednisolone is given in two divided doses per day.
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- The initial dose is continued for seven days. Treatment can be changed in case of clear progression after five days, but there is no evidence that change in treatment will affect the outcome.
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- No reduction of the dose is done during the first seven days.
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- Tapering of the dose is done slowly and depending on the response. No marked dose reductions are done in the early phase. Methylprednisolone is not discontinued before all signs of GVHD have disappeared.
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- Failure of treatment (corticosteroid resistance) is defined as no response after seven days of treatment or clear progression after five days.
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- Non-absorbable oral steroid (budesonide) is given, along with systemic corticosteroid, for GI GVHD in the dose of 9 mg/kg/day in one daily dose orally.
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- Topical steroids are used for skin GVHD according to center policy.
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- The decision to initiate treatment is based on clinical signs. Skin biopsy before initiation of treatment is recommended, but the decision to treat should not depend on the biopsy result. The same recommendation applies to upper GI or sigmoid biopsy if GI manifestation is suspected.
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| Second-line treatment |
- The indication for second-line treatment is failure of methylprednisolone treatment as defined above.
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- There is no standard second-line treatment for acute GVHD. Widely used components are mycophenolate mofetil, anti-TNF-antibodies, other monoclonal antibodies, antithymocyte globulin, extracorporeal photopheresis, methotrexate and mesenchymal stem cells. Continuation of calcineurin inhibitors and corticosteroids with optimal supportive care is considered a valid option. Centers should have and follow their institutional guidelines, and the patients should be treated in trials as far as possible.
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| Treatment of chronic GVHD |
- Indication for starting treatment of chronic GVHD depends on the type and severity of symptoms and the speed of symptom progression in the context of other relevant variables, such as disease risk, chimerism, and minimal residual disease results.
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- Evaluation of chronic GVHD according to the NIH consensus guidelines is recommended.
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- The first-line treatment of newly diagnosed chronic GVHD in patients not on any immunosuppressive drug, or receiving cyclosporine (or tacrolimus) only, is corticosteroid.
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- If the patient is already on corticosteroid treatment (for example, following treatment of acute GVHD), cyclosporine is added to the treatment and the dose of corticosteroid is increased.
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- If the patient is already receiving corticosteroid and cyclosporine at the time of the onset of chronic GVHD, no standard treatment is available.
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- Continuation of corticosteroid and cyclosporine with optimal supportive measures is a valid option. Alternatively, the patient should be treated in a clinical trial if possible.
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- The time needed to preliminarily assess the efficacy of the first-line treatment of chronic GVHD is at least one month.
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- There is no standard second-line treatment for chronic GVHD. The most widely used components of second-line treatment, in addition to corticosteroids, are extracorporeal photopheresis, mycophenolate mofetil, rituximab, calcineurin inhibitors and mTOR inhibitors. Centers should have and follow their institutional guidelines, and the patients should be treated in trials as far as possible.
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