Graft versus host disease
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.
- We have moved How I Treat articles to a dedicated page.
Section editor | |
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Talal Hilal, MD Mayo Clinic Phoenix, AZ, USA |
Last updated on 2024-07-23: 22 regimens on this page
24 variants on this page
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Guidelines
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
ASBMT
EBMT/ELN
ERS/EBMT
ESBMT
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.
ATG (Rabbit) monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kröger et al. 2016 (ATGFamilyStudy) | 2006-12 to 2012-02 | Phase 3 (E-esc) | No ATG | Superior cGVHD rate (primary endpoint) |
Immunosuppressive therapy
- Antithymocyte globulin, rabbit ATG (Thymoglobulin) 10 mg/kg IV once per day on days -3 to -1
One course
References
- CBMTG 0801: 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. link to original article PubMed NCT01217723
- ATGFamilyStudy: 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00678275
- ProfGVHD1: 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. link to original article PubMed NCT00934557
Cyclophosphamide, Mycophenolate mofetil, Tacrolimus
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Luznik et al. 2008 (J9966) | 1999-2006 | Non-randomized | ||
Luznik et al. 2008 (FHCRC 1667) | 1999-2006 | Non-randomized | ||
Solomon et al. 2012 | 2009-01 to 2011-03 | Phase 2 | ||
Bolaños-Meade et al. 2023 (BMT CTN 1703) | 2019-06-25 to 2021-06-18 | Phase 3 (E-esc) | MTX & Tacrolimus | Superior GVHD-free RFS (primary endpoint) GVHD-free RFS12: 52.7% vs 34.9% (HR 0.64, 95% CI 0.49-0.83) |
Immunosuppressive therapy
References
- J9966: 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 original article link to PMC article PubMed NCT00006042
- FHCRC 1667: 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 original article link to PMC article PubMed
- 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 original article PubMed
- BMT CTN 1703: Bolaños-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, Elmariah H, Rezvani AR, Gooptu M, Larkin KT, Shaffer BC, El Jurdi N, Loren AW, Solh M, Hall AC, Alousi AM, Jamy OH, Perales MA, Yao JM, Applegate K, Bhatt AS, Kean LS, Efebera YA, Reshef R, Clark W, DiFronzo NL, Leifer E, Horowitz MM, Jones RJ, Holtan SG; BMT CTN 1703 Investigators. Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. N Engl J Med. 2023 Jun 22;388(25):2338-2348. link to original article link to PMC article PubMed NCT03959241
Cyclophosphamide & Cyclosporine
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Broers et al. 2022 (HOVON-96) | 2013-2018 | Phase 3 (E-switch-ic) | CsA & MPA | Superior GRFS (primary endpoint) |
Immunosuppressive therapy
References
- HOVON-96: Broers AEC, de Jong CN, Bakunina K, Hazenberg MD, van Marwijk Kooy M, de Groot MR, van Gelder M, Kuball J, van der Holt B, Meijer E, Cornelissen JJ. Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial. Blood Adv. 2022 Jun 14;6(11):3378-3385. link to original article link to PMC article PubMed NL2128
Cyclosporine & Methotrexate
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Ratanatharathorn et al. 1998 | 1993-05 to 1994-11 | Phase 3 (C) | Methotrexate & Tacrolimus | Inferior aGVHD rate | |
Finke et al. 2009 (AP-AS-21-DE) | 2003-05-26 to 2007-02-08 | Phase 3 (C) | Cyclosporine, MTX, ATG | Did not meet primary endpoint of severe aGVHD or death within 100 days of transplantation | Similar NRM |
Kennedy et al. 2021 | 2014-07 to 2017-09 | Phase 3 (C) | Cyclosporine, MTX, Tocilizumab | Did not meet primary endpoint | Similar NRM |
Note: while AP-AS-21-DE did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.
Immunosuppressive therapy
- Cyclosporine 3 mg/kg/day IV continuous infusion, started on day -1
- Methotrexate (MTX) 15 mg/m2 IV once on day +1, then 10 mg/m2 IV once per day on days +3, +6, +11
One course
References
- 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 dosing details in manuscript have been reviewed by our editors PubMed
- 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 dosing details in manuscript have been reviewed by our editors PubMed
- 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
- AP-AS-21-DE: 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 NCT00655343
- 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
- Update: Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, Heim D, Bertz H, Grishina O, Socie G. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017 Jun;4(6):e293-e301. link to original article PubMed
- Kennedy GA, Tey SK, Buizen L, Varelias A, Gartlan KH, Curley C, Olver SD, Chang K, Butler JP, Misra A, Subramoniapillai E, Morton AJ, Durrant S, Henden AS, Moore J, Ritchie D, Gottlieb D, Cooney J, Paul SK, Hill GR. A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis. Blood. 2021 Apr 8;137(14):1970-1979. link to original article PubMed ACTRN12614000266662
Cyclosporine, Methotrexate, ATG
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Finke et al. 2009 (AP-AS-21-DE) | 2003-05-26 to 2007-02-08 | Phase 3 (E-esc) | Cyclosporine & MTX | Did not meet primary endpoint of severe aGVHD or death within 100 days of transplantation | Similar NRM |
Walker et al. 2020 (CBMTG 0801) | 2010-06-09 to 2013-07-08 | Phase 3 (E-esc) | Cyclosporine & MTX | Seems to have superior OS (secondary endpoint) | Similar NRM |
Note: while AP-AS-21-DE did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.
Immunosuppressive therapy
References
- AP-AS-21-DE: 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 NCT00655343
- 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
- Update: Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, Heim D, Bertz H, Grishina O, Socie G. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017 Jun;4(6):e293-e301. link to original article PubMed
- CBMTG 0801: 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; Cell Therapy Transplant Canada. Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2020 Feb;7(2):e100-e111. Epub 2020 Jan 17. link to original article PubMed NCT01217723
Cyclosporine, Methotrexate, Methylprednisolone
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ruutu et al. 2000 | 1989-1994 | Phase 3 (E-esc) | Cyclosporine & MTX | Lower rate of aGVHD |
Immunosuppressive therapy
- Cyclosporine 3 mg/kg/day IV continuous infusion over 15 days, started on day -1, then 1.5 mg/kg PO twice per day on days +16 to +365, then tapered off over the next 6 weeks
- Methotrexate (MTX) 15 mg/m2 IV once on day +1, then 10 mg/m2 IV once per day on days +3, +6, +11
- Methylprednisolone (Solumedrol) 0.25 mg/kg PO twice per day on days +14 to +20, then 0.5 mg/kg PO twice per day on days +21 to +34, then 0.25 mg/kg PO twice per day on days +35 to +48, then 0.125 mg/kg PO twice per day on days +49 to +69, then 0.12 mg/kg PO once per day on days +70 to +89, then 0.12 mg/kg PO once every other day on days +90, +92, +94, +96, +98, then 0.06 mg/kg PO once every other day on days +100, +102, +104, +106, +108, +110
Supportive therapy
- Leucovorin (Folinic acid) 15 mg/m2 IV once on day +1, then 10 mg/m2 IV once per day on days +3, +6, +11, given 6 hours after each dose of MTX
One course
Dose and schedule modifications
- Cyclosporine dose was modified to maintain levels less than 200 mcg/L
References
- 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 dosing details in manuscript have been reviewed by our editors PubMed
- 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
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chao et al. 1993 | 1986-12 to 1991-12 | Phase 3 (E-esc) | Cyclosporine & Prednisone | Seems to have lower rate of grade II to IV aGVHD |
Immunosuppressive therapy
References
- 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
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sandmaier et al. 2019 (FH 2448.00) | 2010-11-01 to 2016-07-27 | Phase 3 (C) | Cyclosporine, MMF, Sirolimus | Higher rate of grade II to IV aGVHD at d+100 |
Immunosuppressive therapy
- Cyclosporine 5 mg/kg PO twice per day from day -3 to day +96, then tapered off by day +150 in the absence of GVHD
- Mycophenolate mofetil (CellCept) 15 mg/kg PO three times per day from day 0 to day +30, then 15 mg/kg PO twice per day from day +31 to day +150, then tapered off by day +180 in the absence of GVHD
One course
References
- 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01231412
Cyclosporine, Mycophenolate mofetil, Sirolimus
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sandmaier et al. 2019 (FH 2448.00) | 2010-11-01 to 2016-07-27 | Phase 3 (E-esc) | Cyclosporine & MMF | Lower rate of grade II to IV aGVHD at d+100 (primary endpoint) |
Immunosuppressive therapy
- Cyclosporine 5 mg/kg PO twice per day from day -3 to day +96, then tapered off by day +150 in the absence of GVHD
- Mycophenolate mofetil (CellCept) 15 mg/kg PO three times per day from day 0 to day +30, then 15 mg/kg PO twice per day from day +31 to day +150, then tapered off by day +180 in the absence of GVHD
- Sirolimus (Rapamune) 2 mg PO once per day from day -3 to day +150, then tapered off by day +180 in the absence of GVHD
One course
Dose and schedule modifications
- Sirolimus dose adjusted to maintain trough level of 3 to 12 ng/mL
References
- 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01231412
Methotrexate & Tacrolimus
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ratanatharathorn et al. 1998 | 1993-05 to 1994-11 | Phase 3 (E-switch-ic) | Cyclosporine & Methotrexate | Superior aGVHD rate |
Cutler et al. 2014 (BMT CTN 0402) | 2006-11 to 2011-10 | Phase 3 (C) | Sirolimus & Tacrolimus | Did not meet primary endpoint of day +114 grade 2-4 aGVHD |
Pulsipher et al. 2014 (COG ASCT0431) | 2007-03 to 2011-05 | Phase 3 (C) | Methotrexate, Sirolimus, Tacrolimus | Did not meet primary endpoint of EFS24 |
Luznik et al. 2021 (BMT CTN 1301) | 2015-09 to 2018-06 | Phase 3 (C) | 1. PTCy 2. CD34 selected T-cell–depleted PBSC graft without additional immunosuppression |
Did not meet co-primary endpoint of CRFS |
Bolaños-Meade et al. 2023 (BMT CTN 1703) | 2019-06-25 to 2021-06-18 | Phase 3 (C) | Cyclophosphamide, Mycophenolate mofetil, Tacrolimus | Inferior GVHD-free RFS |
Immunosuppressive therapy
- Methotrexate (MTX) 15 mg/m2 IV once on day +1, then 10 mg/m2 IV once per day on days +3, +6, +11
- Tacrolimus (Prograf) starting on day -3 until at least day +90
- Goal trough level of 5 to 15 ng/mL
One course
References
- 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
- COG ASCT0431: Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, Raetz E, Gardner S, Gastier-Foster JM, Howrie D, Goyal RK, Douglas JG, Borowitz M, Barnes Y, Teachey DT, Taylor C, Grupp SA. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014 Mar 27;123(13):2017-25. Epub 2014 Feb 4. link to original article link to PMC article PubMed NCT00382109
- BMT CTN 0402: Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D, Hogan WJ, Pasquini M, MacMillan ML, Hsu JW, Waller EK, Grupp S, McCarthy P, Wu J, Hu ZH, Carter SL, Horowitz MM, Antin JH. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014 Aug 21;124(8):1372-7. Epub 2014 Jun 30. link to original article link to PMC article PubMed NCT00406393
- BMT CTN 1301: Luznik L, Pasquini MC, Logan B, Soiffer RJ, Wu J, Devine SM, Geller N, Giralt S, Heslop HE, Horowitz MM, Jones RJ, Litzow MR, Mendizabal A, Muffly L, Nemecek ER, O'Donnell L, O'Reilly RJ, Palencia R, Schetelig J, Shune L, Solomon SR, Vasu S, Ho VT, Perales MA. Randomized Phase III BMT CTN Trial of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions in Myeloablative Hematopoietic Cell Transplantation for Hematologic Malignancies. J Clin Oncol. 2022 Feb 1;40(4):356-368. Epub 2021 Dec 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02345850
- BMT CTN 1703: Bolaños-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, Elmariah H, Rezvani AR, Gooptu M, Larkin KT, Shaffer BC, El Jurdi N, Loren AW, Solh M, Hall AC, Alousi AM, Jamy OH, Perales MA, Yao JM, Applegate K, Bhatt AS, Kean LS, Efebera YA, Reshef R, Clark W, DiFronzo NL, Leifer E, Horowitz MM, Jones RJ, Holtan SG; BMT CTN 1703 Investigators. Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. N Engl J Med. 2023 Jun 22;388(25):2338-2348. link to original article link to PMC article PubMed NCT03959241
Methotrexate, Tacrolimus, Tocilizumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Drobyski et al. 2018 | 2015-01 to 2016-06 | Phase 2 |
Immunosuppressive therapy
- Methotrexate (MTX) 15 mg/m2 IV once on day +1, then 10 mg/m2 IV once per day on days +3, +6, +11
- Tacrolimus (Prograf) 0.03 mg/kg/day IV from day -3 onwards
- Tocilizumab (Actemra) 8 mg/kg (maximum dose of 800 mg) IV once on day -1, approximately 24 hours before HSCT infusion
One course
Dose and schedule modifications
- Tacrolimus adjusted to maintain tacrolimus levels between 5 to 15 ng/mL
References
- 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 dosing details in manuscript have been reviewed by our editors PubMed
Methotrexate, Tacrolimus, Vorinostat
Regimen variant #1, IV tacrolimus
Study | Dates of enrollment | Evidence |
---|---|---|
Choi et al. 2017 (UMCC 2012.047) | 2013-06-01 to 2016-07-31 | Phase 2 |
Immunosuppressive therapy
- Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6, +11
- Tacrolimus (Prograf) 0.03 mg/kg/day IV, starting on day -3, then in absence of GVHD, tapering begins on day +100 and completes on day +180
- Goal trough level of 8 to 12 ng/mL
- Vorinostat (Zolinza) 100 mg PO twice per day on days -10 to +100
Regimen variant #2, PO tacrolimus
Study | Dates of enrollment | Evidence |
---|---|---|
Choi et al. 2017 (UMCC 2012.047) | 2013-06-01 to 2016-07-31 | Phase 2 |
Immunosuppressive therapy
- Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6, +11
- Tacrolimus (Prograf) 0.045 mg/kg/day PO, starting on day -3, then in absence of GVHD, tapering begins on day +100 and completes on day +180
- Goal trough level of 8 to 12 ng/mL
- Vorinostat (Zolinza) 100 mg PO twice per day on days -10 to +100
References
- UMCC 2012.047: 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01790568
Sitagliptin, Sirolimus, Tacrolimus
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Farag et al. 2021 (IUSCC-0522) | 2016-2018 | Phase 2 |
Immunosuppressive therapy
References
- IUSCC-0522: Farag SS, Abu Zaid M, Schwartz JE, Thakrar TC, Blakley AJ, Abonour R, Robertson MJ, Broxmeyer HE, Zhang S. Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease. N Engl J Med. 2021 Jan 7;384(1):11-19. link to original article link to PMC article PubMed NCT02683525
Treatment, aGVHD, steroid-refractory
Ruxolitinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jagasia et al. 2020 (REACH1) | 2016-2018 | Phase 2 (RT) | ||
Zeiser et al. 2020 (REACH2) | 2017-2019 | Phase 3 (E-switch-ooc) | Investigator's choice | Superior ORR at day 28 (primary endpoint) |
Immunosuppressive therapy
- Ruxolitinib (Jakafi) 10 mg PO twice per day
Continued for at least 56 days, tapered thereafter
References
- REACH2: Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socié G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. Epub 2020 Apr 22. link to original article PubMed NCT02913261
- REACH1: Jagasia M, Perales MA, Schroeder MA, Ali H, Shah NN, Chen YB, Fazal S, Dawkins FW, Arbushites MC, Tian C, Connelly-Smith L, Howell MD, Khoury HJ. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020 May 14;135(20):1739-1749. link to original article link to PMC article PubMed NCT02953678
Treatment, cGVHD, initial therapy
Cyclosporine & Prednisone
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Arora et al. 2001 | 1993-09 to 1999-04 | Randomized (C) | Cyclosporine, Prednisone, Thalidomide | Did not meet endpoint |
Immunosuppressive therapy
References
- 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
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Malard et al. 2017 (R-GVHD) | 2008-2012 | Phase 2 | ORR at 12 mo: 83% |
Note: Rituximab was repeated if PR or better after the first cycle.
Immunosuppressive therapy
- Cyclosporine 6 mg/kg PO twice per day, tapered per standard of care
- Or, continued at the dose at time of study entry
- Corticosteroids equivalent to 1 mg/kg/day of Prednisone (Sterapred), tapered per standard of care
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
8-week cycle for 1 to 2 cycles
Dose and schedule modifications
- Cyclosporine goal level 200 to 400 ng/mL
References
- R-GVHD: 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01135641
Cyclosporine, Sirolimus, Prednisone
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Carpenter et al. 2018 (BMT CTN 0801) | Not reported | Phase 2/3 (C) | Sirolimus & Prednisone | Did not meet primary endpoint of CR at 2 years |
Immunosuppressive therapy
References
- 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 link to PMC article PubMed NCT01106833
Ibrutinib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Carpenter et al. 2022 (iMAGINE) | Not reported | Phase 1/2 (RT) |
Immunosuppressive therapy
- Ibrutinib (Imbruvica) 240 mg/m2 PO once per day on days 1 to 28
28-day cycles
References
- iMAGINE: Carpenter PA, Kang HJ, Yoo KH, Zecca M, Cho B, Lucchini G, Nemecek ER, Schultz KR, Stepensky P, Chaudhury S, Oshrine B, Khaw SL, Harris AC, Verna M, Zubarovskaya L, Lee Y, Wahlstrom J, Styles L, Shaw PJ, Dalle JH. Ibrutinib Treatment of Pediatric Chronic Graft-versus-Host Disease: Primary Results from the Phase 1/2 iMAGINE Study. Transplant Cell Ther. 2022 Nov;28(11):771.e1-771.e10. Epub 2022 Aug 28. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03790332
Prednisone monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miklos et al. 2023 (iNTEGRATE) | Not reported | Phase 3 (C) | Ibrutinib & Prednisone | Did not meet primary endpoint of RR at 48 weeks |
Immunosuppressive therapy
- Prednisone (Sterapred) 1 mg/kg PO once per day, adjusted as necessary
Continued indefinitely, with a suggested 6-month taper (see supplement for details)
References
- iNTEGRATE: Miklos DB, Abu Zaid M, Cooney JP, Albring JC, Flowers M, Skarbnik AP, Yakoub-Agha I, Ko BS, Bruno B, Waller EK, Yared J, Sohn SK, Bulabois CE, Teshima T, Jacobsohn D, Greinix H, Mokatrin A, Lee Y, Wahlstrom JT, Styles L, Socie G. Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study. J Clin Oncol. 2023 Apr 1;41(10):1876-1887. Epub 2023 Jan 6. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02959944
Sirolimus, Tacrolimus, Prednisone
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Carpenter et al. 2018 (BMT CTN 0801) | Not reported | Phase 2/3 (C) | Sirolimus & Prednisone | Did not meet primary endpoint of CR at 2 years |
Immunosuppressive therapy
References
- 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 link to PMC article PubMed NCT01106833
Treatment, cGVHD, recurrent or refractory therapy
Axatilimab monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence |
---|---|---|
Wolff et al. 2024 (AGAVE-201) | 2021-03 to 2022-08 | Phase 2 (RT) |
Note: Three dosing levels were studied; this is the FDA-recommended dose.
Immunosuppressive therapy
- Axatilimab (Niktimvo) 0.3 mg/kg IV over 30 minutes once on day 1
14-day cylces
References
- AGAVE-201: Wolff D, Cutler C, Lee SJ, Pusic I, Bittencourt H, White J, Hamadani M, Arai S, Salhotra A, Perez-Simon JA, Alousi A, Choe H, Kwon M, Bermúdez A, Kim I, Socié G, Chhabra S, Radojcic V, O'Toole T, Tian C, Ordentlich P, DeFilipp Z, Kitko CL; AGAVE-201 Investigators. Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2024 Sep 19;391(11):1002-1014. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT04710576
Belumosudil monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Cutler et al. 2021 (ROCKstar) | 2018-10 to 2019-08 | Phase 2 (RT) |
Note: Two dosing levels were studied; this was the reported preferred dosage.
References
- ROCKstar: Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, Ramakrishnan A, DeFilipp Z, Salhotra A, Chai-Ho W, Mehta R, Wang T, Arora M, Pusic I, Saad A, Shah NN, Abhyankar S, Bachier C, Galvin J, Im A, Langston A, Liesveld J, Juckett M, Logan A, Schachter L, Alavi A, Howard D, Waksal HW, Ryan J, Eiznhamer D, Aggarwal SK, Ieyoub J, Schueller O, Green L, Yang Z, Krenz H, Jagasia M, Blazar BR, Pavletic S. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021 Dec 2;138(22):2278-2289. Erratum in: Blood. 2022 Mar 17;139(11):1772. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT03640481
Ibrutinib monotherapy
Regimen variant #1, adult dosing
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Miklos et al. 2017 (PCYC-1129-CA) | 2014-07-14 to not reported | Phase 1b/2 (RT) | Best ORR: 67% |
Immunosuppressive therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
28-day cycles
Regimen variant #2, pediatric dosing
FDA-recommended dose |
Study | Dates of enrollment | Evidence |
---|---|---|
Carpenter et al. 2022 (iMAGINE) | Not reported | Phase 1/2 (RT) |
Immunosuppressive therapy
- Ibrutinib (Imbruvica) 240 mg/m2 PO once per day on days 1 to 28
28-day cycles
References
- PCYC-1129-CA: 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02195869
- iMAGINE: Carpenter PA, Kang HJ, Yoo KH, Zecca M, Cho B, Lucchini G, Nemecek ER, Schultz KR, Stepensky P, Chaudhury S, Oshrine B, Khaw SL, Harris AC, Verna M, Zubarovskaya L, Lee Y, Wahlstrom J, Styles L, Shaw PJ, Dalle JH. Ibrutinib Treatment of Pediatric Chronic Graft-versus-Host Disease: Primary Results from the Phase 1/2 iMAGINE Study. Transplant Cell Ther. 2022 Nov;28(11):771.e1-771.e10. Epub 2022 Aug 28. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03790332
Ruxolitinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zeiser et al. 2021 (REACH3) | 2017-2019 | Phase 3 (E-RT-switch-ooc) | Best available therapy | Superior ORR at week 24 (primary endpoint) |
Immunosuppressive therapy
- Ruxolitinib (Jakafi) 10 mg PO twice per day
28-day cycle for at least 6 cycles
References
- REACH3: Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, Musso M, Giebel S, Uzay A, Langmuir P, Hollaender N, Gowda M, Stefanelli T, Lee SJ, Teshima T, Locatelli F; REACH3 Investigators. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2021 Jul 15;385(3):228-238. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03112603
Response criteria
2005 NIH cGVHD Consensus Panel
References
- 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
- 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 mg/dL
- Stage 4: Bilirubin >15 mg/dL
GI
- Stage 0: No diarrhea, or diarrhea less than 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 less than 5 mm wetting
- Involvement of oral mucosa on lip biopsy or minor salivary glands
- Other organ involvement
- Overall severity categories: mild/moderate/severe
References
- 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
- 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
- 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