Graft versus host disease

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Aric C. Hall, MD
Madison, WI

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7 regimens on this page
11 variants on this page

Note: most of these regimens include complex dose adjustments based on therapeutic troughs, concomitant medications, and other factors. Therefore, the focus on this page will be inclusion of drug names and references, but not necessarily drug dosages.

Contents


Guidelines

"How we treat"

Prevention

This is very basic for now, to expand in the future. Information can also be found under individual regimens on the allogeneic HSCT page.

Cyclophosphamide, Mycophenolate mofetil, Tacrolimus

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Regimen

Study Evidence
Luznik et al. 2008 Non-randomized
Solomon et al. 2012 Phase II

Immunosuppressive therapy

References

  1. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolaños-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. link to SD article link to PMC article PubMed
  2. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012 Dec;18(12):1859-66. Epub 2012 Aug 1. link to SD article PubMed

Cyclosporine & Methotrexate

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Ratanatharathorn et al. 1998 Phase III (C) Methotrexate & Tacrolimus Inferior aGVHD rate
Finke et al. 2009 Phase III (C) Cyclosporine, MTX, ATG Seems not superior Similar NRM

Note: while Finke et al. 2009 did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.

Immunosuppressive therapy

References

  1. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14. link to original article PubMed
  2. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009 Sep;10(9):855-64. Epub 2009 Aug 18. link to original article PubMed
    1. Update: Socié G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Finke J; ATG-Fresenius Trial Group. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011 Jun 9;117(23):6375-82. Epub 2011 Apr 5. link to original article PubMed

Cyclosporine, Methotrexate, ATG

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Finke et al. 2009 Phase III (E) Cyclosporine & MTX Seems not superior Similar NRM

Note: while the study did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.

Immunosuppressive therapy

References

  1. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009 Sep;10(9):855-64. Epub 2009 Aug 18. link to original article PubMed
    1. Update: Socié G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Finke J; ATG-Fresenius Trial Group. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011 Jun 9;117(23):6375-82. Epub 2011 Apr 5. link to original article PubMed

Cyclosporine, Methotrexate, Methylprednisolone

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Regimen

Study Evidence Comparator Comparative Efficacy
Ruutu et al. 2000 Phase III (E) Cyclosporine & MTX Lower rate of aGVHD

Immunosuppressive therapy

References

  1. Ruutu T, Volin L, Parkkali T, Juvonen E, Elonen E. Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graft-versus-host disease in bone marrow transplantation from HLA-identical sibling donor: a prospective randomized study. Blood. 2000 Oct 1;96(7):2391-8. link to original article PubMed
    1. Update: Ruutu T, Nihtinen A, Niittyvuopio R, Juvonen E, Volin L. A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis. Cancer. 2018 Feb 15;124(4):727-733. Epub 2017 Nov 7. link to original article PubMed

Cyclosporine, Methotrexate, Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Chao et al. 1993 Phase III (E) Cyclosporine & Prednisone Seems to have lower rate of grade II to IV aGVHD

Immunosuppressive therapy

References

  1. Chao NJ, Schmidt GM, Niland JC, Amylon MD, Dagis AC, Long GD, Nademanee AP, Negrin RS, O'Donnell MR, Parker PM, Smith EP, Snyder DS, Stein AS, Wong RM, Blume KG, Forman SJ. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease. N Engl J Med. 1993 Oct 21;329(17):1225-30. link to original article PubMed

Cyclosporine & Mycophenolate mofetil

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Regimen

Study Evidence Comparator Comparative Efficacy
Sandmaier et al. 2019 (FH 2448.00) Phase III (C) Cyclosporine, MMF, Sirolimus Higher rate of grade II to IV aGVHD

Immunosuppressive therapy

References

  1. FH 2448.00: Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, Gutman JA, Petersen SL, Chauncey TR, Bethge WA, Pulsipher MA, Woolfrey AE, Mielcarek M, Martin PJ, Appelbaum FR, Flowers MED, Maloney DG, Storb R. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019 Aug;6(8):e409-e418. Epub 2019 Jun 24. link to original article PubMed

Cyclosporine, Mycophenolate mofetil, Sirolimus

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Sandmaier et al. 2019 (FH 2448.00) Phase III (E) Cyclosporine & MMF Lower rate of grade II to IV aGVHD

Immunosuppressive therapy

References

  1. FH 2448.00: Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, Gutman JA, Petersen SL, Chauncey TR, Bethge WA, Pulsipher MA, Woolfrey AE, Mielcarek M, Martin PJ, Appelbaum FR, Flowers MED, Maloney DG, Storb R. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019 Aug;6(8):e409-e418. Epub 2019 Jun 24. link to original article PubMed

Methotrexate & Tacrolimus

Regimen

Study Evidence Comparator Comparative Efficacy
Ratanatharathorn et al. 1998 Phase III (C) Cyclosporine & Methotrexate Superior aGVHD rate

Immunosuppressive therapy

References

  1. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14. link to original article PubMed

Methotrexate, Tacrolimus, Tocilizumab

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Regimen

Study Evidence
Drobyski et al. 2018 Phase II

Immunosuppressive therapy

References

  1. Drobyski WR, Szabo A, Zhu F, Keever-Taylor C, Hebert KM, Dunn R, Yim S, Johnson B, D'Souza A, Eapen M, Fenske TS, Hari P, Hamadani M, Horowitz MM, Rizzo JD, Saber W, Shah N, Shaw B, Pasquini M. Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease. Haematologica. 2018 Apr;103(4):717-727. Epub 2018 Jan 19. link to original article linkt o PMC article PubMed

Methotrexate, Tacrolimus, Vorinostat

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Regimen

Study Evidence
Choi et al. 2017 Phase II

Immunosuppressive therapy

  • Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6, +11
  • Tacrolimus (Prograf) by one of the following routes, starting on day -3:
    • IV: 0.03 mg/kg/day
    • PO: 0.045 mg/kg/day
    • Goal trough level of 8 to 12 ng/mL
    • In absence of GVHD, tapering begins on day +100 and completes on day +180
  • Vorinostat (Zolinza) 100 mg PO twice per day on days -10 to +100

References

  1. Choi SW, Braun T, Henig I, Gatza E, Magenau J, Parkin B, Pawarode A, Riwes M, Yanik G, Dinarello CA, Reddy P. Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT. Blood. 2017 Oct 12;130(15):1760-1767. Epub 2017 Aug 7. link to original article contains verified protocol PubMed

Rabbit ATG

Immunosuppressive therapy

References

  1. Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, Gallagher G, Kerr H, Kuruvilla J, Lee SJ, Moore J, Nevill T, Popradi G, Roy J, Schultz KR, Szwajcer D, Toze C, Foley R; Canadian Blood and Marrow Transplant Group. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016 Feb;17(2):164-173. Epub 2015 Dec 24. PubMed
  2. Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, Nagler A, Selleri C, Risitano A, Messina G, Bethge W, Pérez de Oteiza J, Duarte R, Carella AM, Cimminiello M, Guidi S, Finke J, Mordini N, Ferra C, Sierra J, Russo D, Petrini M, Milone G, Benedetti F, Heinzelmann M, Pastore D, Jurado M, Terruzzi E, Narni F, Völp A, Ayuk F, Ruutu T, Bonifazi F. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016 Jan 7;374(1):43-53. link to original article PubMed
  3. Locatelli F, Bernardo ME, Bertaina A, Rognoni C, Comoli P, Rovelli A, Pession A, Fagioli F, Favre C, Lanino E, Giorgiani G, Merli P, Pagliara D, Prete A, Zecca M. Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1126-1136. Epub 2017 Jul 10. PubMed

Treatment, aGVHD, all lines of therapy

Treatment, cGVHD, all lines of therapy

Cyclosporine & Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Arora et al. 2001 Randomized (C) Cyclosporine, Prednisone, Thalidomide Seems not superior

Immunosuppressive therapy

References

  1. Arora M, Wagner JE, Davies SM, Blazar BR, Defor T, Enright H, Miller WJ, Weisdorf DF. Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2001;7(5):265-73. link to original article PubMed

Cyclosporine, Corticosteroids, Rituximab

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Regimen

Study Evidence Efficacy
Malard et al. 2017 Phase II ORR at 12 mo: 83%

Immunosuppressive therapy

Rituximab given as a 4-week course, repeated one month later if PR or better. Corticosteroids and CsA tapered per standard of care.

References

  1. Malard F, Labopin M, Yakoub-Agha I, Chantepie S, Guillaume T, Blaise D, Tabrizi R, Magro L, Vanhove B, Blancho G, Moreau P, Gaugler B, Chevallier P, Mohty M. Rituximab-based first-line treatment of cGVHD after allogeneic SCT: results of a phase 2 study. Blood. 2017 Nov 16;130(20):2186-2195. Epub 2017 Sep 1. link to original article contains verified protocol PubMed

Cyclosporine, Sirolimus, Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Carpenter et al. 2018 (BMT CTN 0801) Phase II/III (C) Sirolimus & Prednisone Seems not superior

Immunosuppressive therapy

References

  1. BMT CTN 0801: Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolaños-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. Epub 2018 Jun 28. link to original article PubMed

Ibrutinib monotherapy

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Regimen

FDA-recommended dose
Study Evidence Efficacy
Miklos et al. 2017 Phase 1b/2 Best ORR: 67%

Immunosuppressive therapy

References

  1. Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, Flowers ME, Logan AC, Nakamura R, Blazar BR, Li Y, Chang S, Lal I, Dubovsky J, James DF, Styles L, Jaglowski S. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017 Nov 23;130(21):2243-2250. Epub 2017 Sep 18. link to original article contains verified protocol PubMed

Sirolimus, Tacrolimus, Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Carpenter et al. 2018 (BMT CTN 0801) Phase II/III (C) Sirolimus & Prednisone Seems not superior

Immunosuppressive therapy

References

  1. BMT CTN 0801: Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolaños-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. Epub 2018 Jun 28. link to original article PubMed

Response criteria

2005 NIH cGVHD Consensus Panel

References

  1. Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW, Turner ML, Akpek G, Gilman A, McDonald G, Schubert M, Berger A, Bross P, Chien JW, Couriel D, Dunn JP, Fall-Dickson J, Farrell A, Flowers ME, Greinix H, Hirschfeld S, Gerber L, Kim S, Knobler R, Lachenbruch PA, Miller FW, Mittleman B, Papadopoulos E, Parsons SK, Przepiorka D, Robinson M, Ward M, Reeve B, Rider LG, Shulman H, Schultz KR, Weisdorf D, Vogelsang GB; Response Criteria Working Group. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006 Mar;12(3):252-66. link to original article PubMed

2014 NIH Response Criteria

References

  1. Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, Pidala J, Olivieri A, Martin PJ, Przepiorka D, Pusic I, Dignan F, Mitchell SA, Lawitschka A, Jacobsohn D, Hall AM, Flowers ME, Schultz KR, Vogelsang G, Pavletic S. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015 Jun;21(6):984-99. Epub 2015 Mar 19. link to PMC article

Scoring

Glucksberg acute graft versus host (GVHD) scores

Skin

  • Stage 0: No rash
  • Stage 1: Maculopapular rash <25% of body surface area
  • Stage 2: Maculopapular rash on 25-50% of body surface area
  • Stage 3: Generalized erythroderma
  • Stage 4: Generalized erythroderma with bullous formation and desquamation

Liver

  • Stage 0: Bilirubin <2 mg/dL
  • Stage 1: Bilirubin 2-3 mg/dL
  • Stage 2: Bilirubin 3.01-6 mg/dL
  • Stage 3: Bilirubin 6.01-15.0 mg/dL
  • Stage 4: Bilirubin >15 mg/dL

GI

  • Stage 0: No diarrhea, or diarrhea <500 mL/day
  • Stage 1: Diarrhea 500-999 mL/day
  • Stage 2: Diarrhea 1000-1499 mL/day
  • Stage 3: Diarrhea >1500 mL/day
  • Stage 4: Severe abdominal pain, with or without ileus

Glucksberg grade

Overall grade I II III IV
Skin 1-2 1-3 2-3 2-4
GI 0 1 2-3 2-4
Liver 0 1 2-4 2-4
Karnofsky performance scale 90-100% 70-80% 50-60% 30-40%

IBMTR severity index

The severity is the highest level which the patient reaches based on separate skin, liver, and GI staging.

Overall grade A B C D
Skin 1 2 3 4
GI 0 1-2 3 4
Liver 0 1-2 3 4

Chronic GVHD

Localized

  • Localized skin and/or liver dysfunction due to chronic GVHD

Extensive

  • Generalized skin involvement or localized skin and/or liver dysfunction due to chronic GVHD plus at least one of the following:
    • Liver biopsy showing cirrhosis, chronic aggressive hepatitis, bridging necrosis
    • Eye involvement, defined as Schirmer's test with <5 mm wetting
    • Involvement of oral mucosa on lip biopsy or minor salivary glands
    • Other organ involvement
  • Overall severity categories: mild/moderate/severe

References

  1. Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD. Bone-marrow transplantation (first of two parts). N Engl J Med. 1975 Apr 17;292(16):832-43 link to original article PubMed
  2. Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, Lerner KG, Glucksberg H, Buckner CD. Bone-marrow transplantation (second of two parts). N Engl J Med. 1975 Apr 24;292(17):895-902 link to original article (contains staging scale) PubMed
  3. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, Cahn JY, Calderwood S, Gratwohl A, Socié G, Abecasis MM, Sobocinski KA, Zhang MJ, Horowitz MM. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997 Jun;97(4):855-64. link to original article PubMed