aGvHD,   GvHD Prophylaxis

IACH 2018 | Management of acute graft-versus-host disease

At the 1st Annual Meeting of the International Academy for Clinical Hematology (IACH), Paris, France, Professor Florent Malard, a member of the GvHD Hub Steering Committee, presented an educational talk on acute graft-versus-host disease management.1

Acute graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). To date, corticosteroids are the accepted first-line therapy. Salvage therapy is administered in patients with acute GvHD not responding to corticosteroids.

Prophylaxis of acute GvHD

Professor Malard took the podium and outlined a retrospective, single-center study that evaluated changes after transplantation, graft characteristics, and outcomes in 827 patients who underwent their first allo-HSCT at the University Hospital of Nantes between 1983 and 2010. The findings of this study indicate that acute GvHD incidence remained stable over a decade (whereas chronic GvHD was significantly increased).2

To date, cyclosporine plus methotrexate is the gold standard for acute GvHD prophylaxis. Storb and colleagues studied acute GvHD prophylaxis in a sequential, prospective, randomized trial that evaluated whether the combination of methotrexate and cyclosporine (n = 43) is more effective than cyclosporine alone (n = 50) in patients who previously received allo-HSCT. They found that the combination of methotrexate plus cyclosporine is more efficient than cyclosporine alone in the prevention of GvHD. The study was updated with a 3.0 to 4.5 year follow-up report. It was found that methotrexate plus cyclosporine did not affect hematopoietic engraftment, however, granulocyte recovery to 1,000/µL was delayed by 5 days.3,4 In an open-label, randomized, multicenter, phase III trial, the combination of tacrolimus plus methotrexate was compared to cyclosporine plus methotrexate for GvHD prophylaxis. This study showed that tacrolimus and methotrexate were superior compared to cyclosporine plus methotrexate in the prevention of GvHD.5

Hoyt and colleagues added prednisolone to cyclosporine plus methotrexate for 107 recipients with peripheral blood progenitor cell transplants in order to potentially prevent acute GvHD. These patients were compared to 65 in a control group who received cyclosporine plus methotrexate alone. By day +180, the incidence of acute GvHD was similar between the two cohorts, indicating that prophylactic prednisolone only delayed acute GvHD onset rather than preventing its incidence.6 Professor Malard concluded that there is no benefit in adding corticosteroids to the prophylaxis regimen of acute GvHD.

Professor Malard then focused on the use of mycophenolate mofetil. In a retrospective analysis, immunosuppressive therapy and survival were assessed in 44 patients who underwent non-myeloablative HSCT and in 52 patients who received myeloablative HSCT. This study found that cyclosporine plus mycophenolate mofetil is effective for the prevention of acute GvHD after non-myeloablative allo-HSCT.7 Several other studies found that the combination of cyclosporine plus mycophenolate mofetil is effective for the prevention of acute GvHD after myeloablative conditioning allo-HSCT.8,9,10,11

The next acute GvHD prophylactic agent discussed was antithymocyte globulin, which was found to be associated with a lower incidence of severe acute GvHD according to a systematic review. This included randomized controlled, phase III trials evaluating antithymocyte globulin versus control for acute GvHD prophylaxis.12 A prospective, randomized, multicenter, open-label, phase III trial compared standard GvHD prophylaxis with cyclosporine plus methotrexate with or without anti-Jurkat ATG-Fresenius. Antithymocyte globulin therapy showed a lower incidence of acute GvHD.13

Florent Malard concluded the topic of acute GvHD prophylaxis by stating that patients given peripheral blood stem cells from human leukocyte antigen-matched related donors (MRD) or matched-unrelated donors (MUD) should receive 5 mg/kg ATG total dose plus cyclosporine, whilst recipients of grafts from human leukocyte antigen haploidentical donors should receive ATG plus post-transplant cyclophosphamide plus cyclosporine and mycophenolate mofetil. The role of post-transplant cyclophosphamide for GvHD prophylaxis in the reduced intensity conditioning setting is being evaluated in an ongoing phase II clinical trial assessing antithymocyte globulin versus post-transplant cyclophosphamide in MRD and MUD (NCT02876679).

First-line treatment of acute GvHD

Corticosteroids remain the accepted first-line therapy for acute GvHD. A prospective, multicenter, randomized trial evaluated 95 patients with acute GvHD who were randomized 1:1 to low-dose intravenous 6-methylprednisolone (2 mg/kg/d; n = 47) or high-dose 6-methylprednisolone (10 mg/kg/d; n = 48) for 5 days. Data showed that early treatment with higher dose of steroids for grade ≥ II acute GvHD does not improve response rates.14

A retrospective study analyzed 733 patients who underwent allo-HSCT and received systemic glucocorticoids either low-dose (n=347) or standard-dose (n=386). It was found that initial treatment with low-dose steroids for grade I-II acute GvHD did not compromise disease control.15 A further, phase III trial assessed whether initial treatment with "lower dose" prednisolone is effective and safe for patients with newly diagnosed acute GvHD. In this study, low-dose systemic steroid therapy showed superior safety and efficacy in patients with grade IIa acute GvHD.16

How we can improve first-line treatment of acute GvHD?

A randomized, four-arm, phase II trial aimed to identify the most promising therapy options for initial therapy for patients with acute GvHD. In this study, 180 patients were randomized to receive methylprednisolone (2 mg/kg/d) plus etanercept, mycophenolate mofetil, denileukin diftitox, or pentostatin. Day 28 complete response rates were the following: etanercept 26%, mycophenolate mofetil 60%, denileukin 53%, and pentostatin 38%. Corresponding 9-month overall survival were:  47%, 64%, 49%, and 47%, respectively. Cumulative incidences of severe infections were as follows: etanercept 48%, mycophenolate mofetil 44%, denileukin 62%, and pentostatin 57%. Based on this data, mycophenolate mofetil seems to be the most promising treatment option in this patient population.17 However, a phase III, multicenter, randomized, double-blind trial evaluating mycophenolate mofetil plus corticosteroids showed that the addition of mycophenolate mofetil to corticosteroids as initial therapy for the treatment of acute GvHD does not improve acute GvHD-free survival compared to corticosteroids alone.18

Professor Malard stated that stage 1-2 cutaneous acute GvHD (grade I) should be treated with topical steroids; if there is no improvement, then patients should receive corticosteroids at a dose of 1 mg/kg/d. In the case of grade II acute GvHD, corticosteroids should be given at a dose of 1–2 mg/kg/d. Corticosteroids at a dose of 2 mg/kg/d should be administered for patients with grade III–IV acute GvHD. Professor Malard highlighted that “supportive care is critical” in patients with acute GvHD.

There is a randomized, double-blind, phase III trial underway comparing the efficacy of the addition of methotrexate to current standard acute GvHD first-line treatment with corticosteroids for acute GvHD. The primary endpoint of the study is a composite endpoint of GvHD-free and corticosteroid-free survival at 12 months after randomization (NCT03371667).

Second-line treatment of acute GvHD

Patients who are refractory to corticosteroids have poor prognosis. There is no standard second-line treatment for these patients, however, studies have assessed several treatment strategies in the last couple of years including additional immunosuppressive/chemotherapeutic interventions, polyclonal and monoclonal antibodies, immunotoxins, and extracorporeal photopheresis.

In a retrospective survey, 19 stem cell transplant centers in Europe and the United States reported findings from 95 patients who previously received ruxolitinib as salvage therapy for steroid-refractory GvHD (SR-GvHD). In this study by Zeiser et al., overall response rate was 81.5%, complete remission was 46.3%, GvHD relapse was 6.8%, and the 6-month survival was 79% in patients who received rituximab salvage therapy. Main side-effects included cytopenia (55.6%) and cytomegalovirus reactivation (33.3%). This data indicates that ruxolitinib may be a promising treatment option for acute GvHD patients.19 Ruxolitinib is currently being evaluated in a prospective, phase III trial: ruxolitinib versus best available therapy for SR-acute GvHD, grades II–IV (REACH-3 trial).

Professor Malard’s suggested treatment strategy for patients with SR-GvHD was to enroll them in the REACH-3 clinical trial or to administer best available therapy. Patients with skin prednisolone predominant SR-GvHD should receive extracorporeal photopheresis or methotrexate, and for patients with gastrointestinal predominant SR-GvHD, methotrexate should be administered. Additionally, fecal microbiota transplantation seems a promising treatment option for SR-GvHD of the gut.

References
  1. Malard F. Management of acute GvHD. 1st Annual Meeting of the International Academy for Clinical Hematology (IACH). 2018 September 27–29.
  2. Malard F. et al. Continuous reduced non-relapse mortality after allogeneic hematopoietic stem cell transplantation: a single-institution's three decade experience. Biol Blood Marrow Transplant. 2014 August. DOI: 10.1016/j.bbmt.2014.04.021. Epub 2014 Apr 23.
  3. Storb R. et al. Methotrexatee and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986 Mar 20;314(12):729–35.
  4. Storb R. et al. Methotrexatee and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood. 1989 May 1;73(6):1729–34.
  5. Ratanatharathorn V. et al. Phase III study comparing methotrexatee and tacrolimus (prograf, FK506) with methotrexatee and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303–14.
  6. Hoyt R. et al. Cyclosporin, methotrexatee and prednisolonenisolone for graft-versus-host disease prophylaxis in allogeneic peripheral blood progenitor cell transplants. Bone Marrow Transplant. 2008 Apr;41(7):651–8. DOI: 10.1038/sj.bmt.1705955. Epub 2008 Jan 7.
  7. Mielcarek M. et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003 Jul 15;102(2):756–62. Epub 2003 Mar 27.
  8. Bolwell B. et al. A prospective randomized trial comparing cyclosporine and short course methotrexateewith cyclosporine and mycophenolate mofetil for GvHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004 Oct;34(7):621–5.
  9. Neumann F. et al. Cyclosporine A and mycophenolate mofetil vs cyclosporine A and methotrexatee for graft-versus-host disease prophylaxis after stem cell transplantation from HLA-identical siblings. Bone Marrow Transplant. 2005 Jun;35(11):1089–93.
  10. Piñana JL. et al. METHOTREXATE or mycophenolate mofetil with Cyclosporine as GVHD prophylaxis after reduced-intensity conditioning PBSCT from HLA-identical siblings. Bone Marrow Transplant. 2010 Sep;45(9):1449–56. DOI: 10.1038/bmt.2009.362. Epub 2010 Feb 8.
  11. Gupta S. et al. Transfusion-associated graft-versus-host disease with a non-fatal course. Indian J Hematol Blood Transfus. 2016 Jun; 32(Suppl 1): 326–328. DOI:  10.1007/s12288-016-0677-8. Published online 2016 Apr 12.
  12. Kumar A. et al. Antithymocyte globulin for acute-graft-versus-host-disease prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation: a systematic review. Leukemia. 2012 Apr;26(4):582–8. DOI: 10.1038/leu.2011.349. Epub 2011 Dec 20.
  13. Finke J. et al. 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. DOI: 10.1016/S1470-2045(09)70225-6. Epub 2009 Aug 18.
  14. Van Lint MT. et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolonenisolone: A multicenter randomized trial from the Italian group for bone marrow transplantation. Blood. 1998;92:2288–93.
  15. Mielcarek M. et al. Initial therapy of acute graft-versus-host disease with low-dose prednisolonenisone does not compromise patient outcomes. Blood. 2009 Mar 26;113(13):2888–94. DOI: 10.1182/blood-2008-07-168401. Epub 2008 Nov 10.
  16. Mielcarek M. et al. Effectiveness and safety of lower dose prednisolonenisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial. Haematologica. 2015 Jun;100(6):842–8. DOI: 10.3324/haematol.2014.118471. Epub 2015 Feb 14.
  17. Alousi AM. et al. 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. 2009 Jul 16;114(3):511–7. DOI: 10.1182/blood-2009-03-212290. Epub 2009 May 14.
  18. Bolaños-Meade J. et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014 Nov 20;124(22):3221–7; quiz 3335. DOI: 10.1182/blood-2014-06-577023. Epub 2014 Aug 28.
  19. Zeiser R. et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015 Oct;29(10):2062–8. DOI: 10.1038/leu.2015.212. Epub 2015 Jul 31.

Expert Opinion

Take-home messages from Florent Malard
  • Acute GvHD prophylaxis and treatment have remained the same for more than one decade
  • Development of innovative strategies is required to lower the incidence of acute GvHD
  • Use of PT-Cy outside the haplo setting
  • New first-line treatment for acute GvHD: MTX?
  • Role of fecal microbiota transplantation and microbiota manipulation
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