Canterbury DHB

Initial Management of Acute GvHD

• At diagnosis the extent of individual organ involvement and overall grade of aGvHD, taking into account all organ involvement should be documented (using the modified Seattle Glucksberg criteria), as this has prognostic significance (1A) and clearly documented in the patient’s clinical record.
• The response to treatment should be systematically assessed and documented and the start and stop dates of therapy recorded.
• Grade 1 disease should be treated with topical therapy and optimising levels of calcineurin inhibitors without systemic therapy (1C).
• 2 mg/kg/d methylprednisolone (x1.25 for prednisone) is recommended for grades III-IV GvHD (1A).
• 1 mg/kg/d methylprednisolone is recommended for patients with grade II GvHD (2B).
• Non-absorbable steroids can be considered for acute intestinal GvHD (2B).
• Start omeprazole 40 mg PO daily at the same time.
• Prophylaxis for opportunistic infections, CMV and EBV surveillance in at-risk patients (refer to patient’s transplant protocol) and mould prophylaxis should be instituted. Standard prophylaxis is with cotrimoxazole 480 mg once daily, valaciclovir 500 mg BD, and posaconazole tablets 300 mg once daily.

Steroid tapering

• Begin steroid taper as soon as a major improvement is seen.
• Reduce by 0.2 mg/kg every 3-5 days and less frequently below 20 mg daily.
• This assumes that control of GvHD is maintained while the dose of Prednisone is being reduced.
• A single randomized study compared a taper over 86 and 147 days with no difference seen in re-activation of GvHD, cGvHD, infectious or non-infectious complications, hospital days or survival.

What dose of steroid?

There is debate and uncertainty about the optimal dose of glucocorticoids for acute GvHD.

• The British Committee for Standards in Haematology (BCSH) continue to recommend 2 mg/kg/d methylprednisolone (multiply by 1.25 for oral prednisone equivalent) for grades III-IV acute GvHD and 1 mg/kg/d for lower grades.
• The American Society for Blood and Marrow Transplantation (ASBMT) recommend 2 mg/kg/d prednisone except for grade II GvHD or GvHD confined to the upper GIT.
• A single retrospective study from the Fred Hutchinson Cancer Centre reported no difference in outcome between patients receiving low (1 mg/kg/d) and standard (2 mg/kg/d) prednisone-equivalent doses. However, it should be noted that this was a retrospective study and patients received steroids according to physician preference. The group receiving standard dosing at 2 mg/kg contained more patients with mis-matched donors, grades III and IV GvHD and fewer patients with single organ GvHD. It is therefore possible that physicians chose a higher dose of steroids for patients with more severe disease.
• In a survey of EBMT transplant centres the initial dose of steroids was >2 mg/kg in 69% and the route was intravenous in 92%.
• In a recent survey of transplant physicians in the German-Austrian-Swiss consortium of transplant centres 84% used a dose of 1-2.5 mg/kg/d for grade III aGvHD of the skin and liver and 90% used a dose of 1-2.5 mg/kg/d for grade III aGvHD of the skin with severe diarrhoea.

When to start 2nd line treatment

2nd line therapy should be started earlier for more severe GvHD.

The following is intended as a guide only:

• At day 3 for progressive GvHD.
• At day 7 for persistent, non-reponsive grade III-IV GvHD.
• At day 14 for persistent, non-responsive grade II GvHD.

Management of steroid-refractory acute GvHD

There are no uniform criteria of SR-GvHD but generally accepted definitions are:

• Progression on prednisone 1 mg/kg/d for 2 weeks
• Stable disease on >0.5 mg/kg/d for 4-8 weeks
• Inability to taper below 0.5 mg/kg/d

The management of patients with grade II-IV GvHD unresponsive to prednisone 1 mg/kg PO daily is difficult, and guidelines appropriate for all patients in this situation cannot be given. The outcome for these patients is poor with a mortality rate of approximately 70%.

The best management will now reflect the:

• Exact pattern and severity of GvHD.
• Presence of any co-morbidities.
• Underlying condition that required allografting.

Consultation within the Haematology Service, other Christchurch specialists and overseas experts may all be required.

Treatments to consider

• Increase dose of prednisone to 2 mg/kg and add mycophenolate mofetil (MMF) 20 mg/kg BD
• High dose pulsed IV steroids eg methylprednisolone 1 g/m2 IV daily for 3 days.
• Anti Thymocyte Globulin
• Change cyclosporin to tacrolimus

Which 2nd line treatment to choose

Choice of 2nd line should take into account effects of previous therapy, toxicity, and interaction with other drugs, convenience, expense, and familiarity. No treatment has been shown either to be better than another or detrimental.

• 29 phase II studies enrolling at least 10 patients using commercially available products have been reported. The 6 month overall survival across all trials was 49%. The largest study by MacMillan et al using horse ATG in 79 patients reported 44% OS at 6 months and serves as a reference point.
• In a survey of EBMT transplant centres the following treatments were used for 2nd line therapy: MMF (33%), anti-TNF (31%), ATG (24%), alemtuzumab (7%), other monoclonals (16%), pentostatin (5%).
• The following agents are suggested by the BCSH for 2nd line treatment of steroid-refractory acute GvHD: ECP, anti-TNF antibodies, mTOR inhibitors, MMF, IL-2 receptor antibodies (2C).
• The following are suggested by the BCSH as 3rd line treatment options in acute steroid refractory GvHD: alemtuzumab, pentostatin, MSC and methotrexate (2C).
• Agents not recommended for acute GHVD are: rituximab, thalidomide, azathiaprine.
• Corticosteroid therapy should be continued but tapered as soon as possible.

  2nd and 3rd line treatments
  Polyclonal anti T Cell Antibodies	ATG
  Anti cytokine agents	Infliximab 10 mg/kg over 1 hour once weekly
  	Etanercept up to 25 mg 2 x weekly for 8 weeks.
  Cytotoxic agents	Pentostatin 1.5 mg/m2 day 1-3 and 15-17.
  Macrolides	Sirolimus, Tacrolimus
  Anti T cell fusion proteins	Denileukin Diftitox
  Monoclonal anti T cell Abs	Daclizumab, Visilizumab
  Monoclonal anti T & B cell Abs	Alemtuzumab
  Photophoresis	ECP PUVA

Note: The agents in bold type are available in New Zealand.

Further reading

Alousi, A. M., et al. (2009). "Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network." Blood 114(3): 511-517.

Dignan, F. L., et al. (2012). "Diagnosis and management of acute graft-versus-host disease." Br J Haematol 158(1): 30-45.

Dignan, F. L., et al. (2012). "Organ-specific management and supportive care in chronic graft-versus-host disease." Br J Haematol 158(1): 62-78.

Levine et al, Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood 2008;111;4;2470-2475.

MacMillan, M. L., D. J. Weisdorf, S. M. Davies, T. E. DeFor, L. J. Burns, N. K. Ramsay, J. E. Wagner and B. R. Blazar (2002). "Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease." Biol Blood Marrow Transplant 8(1): 40-46.

Martin, P. J., J. D. Rizzo, J. R. Wingard, K. Ballen, P. T. Curtin, C. Cutler, M. R. Litzow, Y. Nieto, B. N. Savani, J. R. Schriber, P. J. Shaughnessy, D. A. Wall and P. A. Carpenter (2012). "First- and Second-Line Systemic Treatment of Acute Graft-versus-Host Disease: Recommendations of the American Society of Blood and Marrow Transplantation." Biol Blood Marrow Transplant 18(8): 1150-1163.

Topic Code: 9073