Abstract

Allogeneic hematopoietic cell transplantation is a potentially curative therapy for many malignant and nonmalignant hematologic diseases. Graft-versus-host disease (GVHD) is a common complication after transplantation and remains a major cause of morbidity and mortality, limiting the success of a potentially curative transplant. This paper reviews the current and emerging strategies in GVHD prevention and treatment. New insights are leading the way to the development of novel targeted approaches to minimize the risk of disease relapse and infection. Continued collaborative efforts to conduct high-quality, multicenter clinical trials with standard end points and risk stratification are needed to determine the optimal approach to minimize GVHD and limit toxicities.

Learning Objectives
  • Review current standard graft-versus-host disease (GVHD) prophylaxis regimens and treatment

  • Describe novel approaches and biologic insights currently under investigation for GVHD prevention

  • Understand the need for high-quality, multicenter, randomized trials with standard end points and risk stratification to determine the optimal GVHD prevention and treatment strategies

Introduction

Graft-versus-host disease (GVHD) remains a challenge after allogeneic hematopoietic cell transplantation (HCT). GVHD occurs when immunocompetent donor T cells recognize the recipient host as foreign and mount an immune response to allogeneic antigen-bearing cells with subsequent destruction of host tissues. Despite current prophylactic strategies, morbidity and mortality remain high, and treatment of established GVHD can be difficult, with only about 40% of patients having a durable response to corticosteroid therapy.1  Recent experimental models and biologic insights, however, have greatly improved the understanding of the pathogenesis of GVHD, and newer approaches targeting different components of immune dysregulation are currently being used and further investigated in improving GVHD outcomes. This paper reviews the current and novel approaches in GVHD prevention and treatment (Figure 1).

Figure 1.

Mechanisms of action of current and novel approaches to prevent and treat GVHD. APC, antigen-presenting cell; ATG, antithymocyte globulin; CSA, cyclosporine; CTLA4, cytotoxic T lymphocyte antigen 4; ECP, extracorporeal photopheresis; IL, interleukin; IL-6R, interleukin-6 receptor; ITAM, immunoreceptor tyrosine-based activation motif; JAK, janus kinase; LPS, lipopolysaccharides; MHC II, major histocompatibility complex II; MMF, mycophenolate; MSC, mesenchymal stem cell; mTOR, mammalian target of rapamycin complex; MTX, methotrexate; NFAT, nuclear factor of activated T cell; STAT, signal transducer and activator of transcription protein; Tac, tacrolimus; TCR, T-cell receptor; TNFα, tumor necrosis factor-α; Treg, regulatory T cell.

Figure 1.

Mechanisms of action of current and novel approaches to prevent and treat GVHD. APC, antigen-presenting cell; ATG, antithymocyte globulin; CSA, cyclosporine; CTLA4, cytotoxic T lymphocyte antigen 4; ECP, extracorporeal photopheresis; IL, interleukin; IL-6R, interleukin-6 receptor; ITAM, immunoreceptor tyrosine-based activation motif; JAK, janus kinase; LPS, lipopolysaccharides; MHC II, major histocompatibility complex II; MMF, mycophenolate; MSC, mesenchymal stem cell; mTOR, mammalian target of rapamycin complex; MTX, methotrexate; NFAT, nuclear factor of activated T cell; STAT, signal transducer and activator of transcription protein; Tac, tacrolimus; TCR, T-cell receptor; TNFα, tumor necrosis factor-α; Treg, regulatory T cell.

Prevention

The most common GVHD prophylaxis has historically been based on a calcineurin inhibitor and a short course of methotrexate (MTX). MTX, an antimetabolite and folate antagonist, attenuates T-cell activation at low noncytotoxic doses and has had a long history in the prevention of GVHD. The first calcineurin inhibitor, cyclosporine (CSA), was introduced, and studies showed that the combination of CSA and a short course of MTX was significantly better at preventing GVHD, improving survival compared with either drug alone.2  Tacrolimus (Tac) subsequently was also found to be effective in combination with a short course of MTX for prevention of GVHD.3  Although structurally distinct, both CSA and Tac have similar mechanism of actions—CSA complexes with cyclophilin and Tac complexes with FKBP12 to inhibit calcineurin and block the dephosphorylation, nuclear translocation, and transcriptional function of nuclear factor of activated T cells, thus reducing T-cell function. Two large multicenter phase 3 prospective trials were performed to compare CSA in combination with MTX and Tac with MTX.4,5  These trials showed superiority of Tac in reducing acute GVHD but no difference in overall and relapse-free survival rates compared with CSA and MTX. Therefore, both regimens are considered standard backbones to most GVHD prevention strategies for patients undergoing allogeneic HCT.

Mycophenolate mofetil (MMF) is an ester prodrug of the immunosuppressant mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase that is a key enzyme in the de novo synthesis of guanine nucleotides. T and B lymphocytes are extremely dependent on this pathway, and thus, MPA has a potent cytostatic effect on lymphocytes. Given its favorable toxicity profile, the combination of a calcineurin inhibitor and MMF is also commonly used in patients undergoing allogeneic HCT6 ; however, several studies have raised the question of MMF’s efficacy compared with MTX with findings of more severe acute GVHD and higher nonrelapse mortality.7  A recent Center for International Blood and Marrow Transplant Research study of 3979 matched sibling donors and 4163 unrelated donors showed significantly inferior GVHD and survival outcomes with CSA + MMF compared with Tac + MTX, CSA + MTX, and Tac + MMF in myeloablative transplantation,8  suggesting an advantage of MTX over MMF for GVHD prevention.

Other current approaches to GVHD prophylaxis

Sirolimus binds to FKBP12 and inhibits the mammalian target of the rapamycin inhibitor to block interleukin-2 (IL-2)–mediated signal transduction, leading to cell cycle arrest in naïve T cells. Its immunomodulatory properties include inhibition of antigen presentation and dendritic cell maturation as well as preservation of regulatory T-cell (Treg) subsets after transplantation. A phase 3 multicenter, prospective, randomized clinical trial conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) comparing Tac + sirolimus with Tac + MTX showed no difference in rates of grades 2 to 4 acute GVHD or GVHD-free survival.9  Hematopoietic recovery was more rapid with less mucositis in the Tac + sirolimus arm, although it was also associated with increased rates of endothelial injury syndromes, elevations in cholesterol and triglycerides, and increase in creatinine. Tac + sirolimus is thus considered an important alternative for patients undergoing total body irradiation-based transplantation, particularly for those who may be at higher risk for developing severe mucositis or require faster engraftment for risk of infection.

Posttransplant cyclophosphamide (PTCy) alone or in combination with other immunosuppressive agents has also emerged as an effective pharmacologic approach to GVHD prevention. This strategy was pioneered by investigators at Johns Hopkins in the haploidentical setting based on experimental models showing cyclophosphamide’s potent and selective activity against alloreactive donor T cells, resulting in low incidences of GVHD and transplant-related mortality (TRM). This approach has revolutionized our ability to cross the human leukocyte antigen (HLA) barrier by performing mismatched transplants, greatly expanding donor availability. The success and widespread use of PTCy in T cell–replete haploidentical and mismatched transplants have now prompted its use as a single agent in recipients of transplant from matched sibling or unrelated donors. Although initial reports using bone marrow showed encouraging results with comparable rates of GVHD,10  subsequent studies using peripheral blood stem cells reported higher rates of GVHD and poor outcomes.11  The addition of a calcineurin inhibitor or other immunosuppressive drugs to PTCy seems to further mitigate GVHD, and it is a viable prophylactic strategy to promote tolerance and minimize longer-term immunosuppressive therapy in high-risk patients.12  Results from the BMT-CTN trial evaluating novel approaches for GVHD prevention using reduced intensity conditioning (PROGRESS I trial NCT02208037) have shown that PTCy + Tac + MMF is associated with lower rates of severe acute GVHD and chronic GVHD requiring immunosuppression without a significant impact on overall survival or relapse compared with Tac + MTX.13 

T-cell depletion as an approach to GVHD prophylaxis

In vivo T-cell depletion with antithymocyte globulin (ATG) products has been associated with decreased GVHD but also, still debated effects on relapse, infection risk, and overall survival. ATGs are polyclonal immunoglobulins directed against antigens expressed on human T lymphocytes. Several randomized trials have reported a significant benefit of ATG for the prevention of GVHD, in particular chronic GVHD, with subsequent superior quality of life and survival free of immunosuppression and GVHD.14-17  Although 2 prospective, randomized studies from Canada and Europe demonstrated significantly lower rates of chronic GVHD and similar survival and relapse with ATG compared with non-ATG groups,16,17  a subsequent prospective, randomized, double-blind trial comparing ATG with no ATG conducted in the United States showed inferior progression-free and overall survival due to increase in relapse and nonrelapse mortality.18  The discrepancies in these findings are not completely clear, but findings in the latter study suggest that ATG effects may be dependent on lymphocyte count at the time of ATG administration. Differences in dosages and formulations of ATG also remain unknown factors. Although it is clear that the use of ATG as GVHD prophylaxis leads to significantly decreased acute and chronic GVHD, it remains to be seen whether it is the optimal approach compared with other strategies given increased infection as well as possibly relapse-related deaths.

Ex vivo T-cell depletion has been investigated since the 1980s by a variety of methods.19,20  Initial trials using pan–T-cell depletion showed significant reduction in risk of GVHD even without the use of standard posttransplant pharmacologic GVHD prophylaxis; however, it was also associated with an increased incidence of disease relapse, rejection, and infections.21  Additional exploration of T-cell depletion and graft manipulation includes CD34+ selection,22  T-cell depletion with subsequent T-cell add back,23,24  and selective CD3+ (αβ T cell) and CD19+ B-cell depletion.25  Selective elimination of αβ T cells, which are implicated in GVHD, with preservation of γδ T cells and natural killer (NK) cells, which mediate antitumor activity and immune reconstitution, is an area of ongoing active investigation (NCT02323867, NCT02600208, NCT03301168, and NCT03047746). Studies investigating selective T-cell depletion via CD34+ cell selection without other GVHD pharmacologic prophylaxis have also shown promise, with successful engraftment, improved chronic GVHD, and no differences in relapse mortality, nonrelapse mortality, or overall survival.22  Given the success of these recent strategies, an ongoing BMT-CTN trial is further evaluating calcineurin inhibitor-free GVHD prophylaxis with a 3-arm trial comparing PTCy using bone marrow grafts, mobilized CD34-selected peripheral blood stem cell graft, and a control cohort of Tac + MTX (PROGRESS 2; NCT02345850).

Development of novel end points

The evaluation of novel GVHD prophylactic approaches is complex. As reviewed above, although many current GVHD prevention strategies that either increase immunosuppression or manipulate the graft may reduce GVHD, they also have an effect on disease relapse, infection, or graft failure. The success of allogeneic HCT is thus dependent not only on the development of GVHD but also on the risk of disease relapse and infection. In addition, not all GVHD is considered to be a detriment—the development of grade 2 GVHD has been shown to be not predictive of treatment failure (death or relapse),26  and can be associated with improved outcomes.27  In contrast, the development of grades 3 and 4 GVHD is significantly associated with treatment failure, and it may be a more appropriate end point to consider in evaluating GVHD prophylaxis. Given additional effects on relapse and infection, however, evaluating the true effectiveness of GVHD prophylaxis ideally incorporates multiple outcomes. The BMT-CTN has thus developed composite GVHD end points to better characterize posttransplant recovery and the effectiveness of different GVHD prophylactic strategies.26  In an analysis of 6 different promising GVHD prophylactic approaches, the BMT-CTN evaluated several composite GVHD end points: graft-versus-host disease relapse-free survival (GRFS)—survival without acute grades 3 to 4 GVHD plus chronic GVHD plus disease relapse or progression or death; off immunosuppression relapse-free survival—withdrawal of all immunosuppression or other systemic intervention for treatment or prophylaxis of GVHD and without primary disease progression or death; and chronic graft-versus-host disease relapse-free survival (CRFS)—survival without development of chronic GVHD plus disease relapse, progression, or death. The results of this analysis subsequently resulted in the 2 large multicenter trials evaluating GVHD prophylaxis—PROGRESS I (BMT-CTN 1203; NCT02208037) and PROGRESS 2 (BMT-CTN 1301; NCT02345850)—using GRFS and CRFS as the primary outcomes, respectively. GRFS has thus become a popular primary end point in many studies to better reflect HCT recovery without ongoing morbidity. It is important to consider, however, that the evaluation of novel GVHD prophylaxis strategies remains complex. In using GRFS as a primary end point in evaluating novel approaches, severe GVHD consequently represents the smallest proportion of this composite end point.28 

Other experimental approaches to acute GVHD prevention

Many novel GVHD prophylaxis approaches (including agents such as bortezomib, maraviroc,13  etancercept,29  infliximab,30  and daclizumab and basiliximab31 ) have shown promise in preclinical and single-institution studies; however, they have subsequently shown no benefit in larger multicenter clinical trials. Smaller numbers, selective patient population, differences in GVHD scoring, and end points analyzed account for some of the lack of reproducibility, and they underscore the importance of large multicenter clinical trials using uniform and standard end points. Several newer approaches, many of which move away from a broad-based immunosuppressive approach, are being evaluated in early studies, and they are further reviewed here and summarized in Figure 1 and Table 1.

Table 1.

Novel approaches to GVHD

TherapiesMechanisms of actionDataOngoing clinical trials
Prevention    
 Tocilizumab Human monoclonal antibody against IL-6R Phase 2 study of tocilizumab + Tac + MTX: 14% grade 2-4 acute GVHD, 3% grades 3 and 4 acute GVHD at 100 d39  NCT03434730 
 Abatacept Costimulation blockade of CD28:CD80/86 to inhibit T cells 2 of 10 patients with grade 2-4 acute GVHD, no day 100 TRM40  NCT01743131 
NCT02867800 
 Tregs Regulate self-tolerance, limit GVHD while maintaining GVL effect Modified expanded umbilical cord blood–derived Tregs: grade 2-4 acute GVHD 9% at 100 d42  NCT01660607 
NCT00602693 
NCT01818479 
NCT01795573 
 T-cell depletion (CD34 selection and selective ex vivo T-cell depletion) Depletion of alloreactive T cells and selective αβ T-cell depletion, with preservation of γδ T cells and NK cells CD34+ selection: grade 2-4 acute GVHD 22.7%, chronic GVHD 6.8%29  NCT02323867 
NCT02600208 
NCT03301168 
NCT03047746 
NCT02345850 
 Statins Inhibit proinflammatory Th-1 differentiation, induce Treg expansion, and downregulate APCs Phase 2 study of statin to both donors and recipients with Tac + MTX—grade 2-4 3.3%; chronic GVHD 52.3%46  NCT03066466 
 Vorinostat Histone deacetylase inhibitor decreases inflammatory cytokines, enhances Treg function, and reduces GVHD while preserving GVL Phase 2 study of vorinostat + Tac + MTX: grade 2-4 acute GVHD 22%, grades 3 and 4 acute GVHD 8%; chronic GVHD 29%51  NCT01790568 
 JAK inhibitors (itacitinib, ruxolitinib) Reduction of proinflammatory cytokines, T-cell activation and function, preserves Tregs, GVL effect Preclinical studies and use in treatment setting NCT03320642 
 Manipulation of the microbiome Association of loss of diversity with increased GVHD and TRM; mediate anti-inflammatory cytokines and Tregs Pilot study of fecal microbiota transfer early posttransplant: 2 of 13 developed acute GI GVHD66  NCT02763033 
NCT02641236 
NCT03102060 
NCT03529825 
Treatment    
 Sirolimus Inhibition of mTOR impairs T-cell signaling Retrospective study of sirolimus as primary therapy for acute GVHD: 50% achieved CR vs 59% (matched historical control using 1 mg/kg prednisone)67  NCT02806947 
 JAK inhibitors (ruxolitinib, itacitinib) Reduction of proinflammatory cytokines, T-cell activation and function, preserves Tregs, GVL effect Retrospective study of steroid refractory acute GVHD with ruxolitinib, ORR 81.5%, and CR 46.3%68  NCT03139604 
Phase 1 study of itacitinib in acute GVHD, ORR 88.3% first line and 64.7% steroid-refractory GVHD69  
 α-1 antitrypsin Serine protease inhibitor that modulates immune and inflammatory function through cytokine profiles Phase 1/2 study of 12 patients with steroid-refractory GVHD: ORR 8 of 12, CR 4 of 1270  NCT01700036 
NCT02953122 
NCT03172455 
 IL-22 Acts on intestinal stem cells to strengthen epithelial barrier function; tissue repair Preclinical murine models show reduced mortality and improved intestinal pathology from GVHD with in vivo IL-2271  NCT02406651 
 Monoclonal antibodies (natalizumab, vedolizumab) Targeting α4-integrins on activated lymphocytes mediating adhesion and trafficking Used in inflammatory bowel diseases; case series of 5 patients with grade 4 GI GVHD, with responses in all patients72  NCT02176031 
NCT02133924 
NCT02993783 
 Extracorporeal photopheresis Induction of Tregs(?), unknown Retrospective studies of steroid refractory acute GHVD, ORR of ∼60%73  NCT02524847 
NCT02151539 
 Mesenchymal stromal cells Inhibition of B- and T-cell activation, APCs, NK cells and increase Tregs Several early phase studies with ORR 60-75%74 NCT00603330 
NCT02687646 
NCT02336230 
NCT02770430 
NCT02359929 
 Fecal microbiota transplant Association of loss of diversity with increased GVHD and TRM; mediate anti-inflammatory cytokines and Tregs Case series of fecal microbiota transplant: 3 out of 4 patients with CR48 NCT03359980 
NCT03214289 
NCT03148743 
TherapiesMechanisms of actionDataOngoing clinical trials
Prevention    
 Tocilizumab Human monoclonal antibody against IL-6R Phase 2 study of tocilizumab + Tac + MTX: 14% grade 2-4 acute GVHD, 3% grades 3 and 4 acute GVHD at 100 d39  NCT03434730 
 Abatacept Costimulation blockade of CD28:CD80/86 to inhibit T cells 2 of 10 patients with grade 2-4 acute GVHD, no day 100 TRM40  NCT01743131 
NCT02867800 
 Tregs Regulate self-tolerance, limit GVHD while maintaining GVL effect Modified expanded umbilical cord blood–derived Tregs: grade 2-4 acute GVHD 9% at 100 d42  NCT01660607 
NCT00602693 
NCT01818479 
NCT01795573 
 T-cell depletion (CD34 selection and selective ex vivo T-cell depletion) Depletion of alloreactive T cells and selective αβ T-cell depletion, with preservation of γδ T cells and NK cells CD34+ selection: grade 2-4 acute GVHD 22.7%, chronic GVHD 6.8%29  NCT02323867 
NCT02600208 
NCT03301168 
NCT03047746 
NCT02345850 
 Statins Inhibit proinflammatory Th-1 differentiation, induce Treg expansion, and downregulate APCs Phase 2 study of statin to both donors and recipients with Tac + MTX—grade 2-4 3.3%; chronic GVHD 52.3%46  NCT03066466 
 Vorinostat Histone deacetylase inhibitor decreases inflammatory cytokines, enhances Treg function, and reduces GVHD while preserving GVL Phase 2 study of vorinostat + Tac + MTX: grade 2-4 acute GVHD 22%, grades 3 and 4 acute GVHD 8%; chronic GVHD 29%51  NCT01790568 
 JAK inhibitors (itacitinib, ruxolitinib) Reduction of proinflammatory cytokines, T-cell activation and function, preserves Tregs, GVL effect Preclinical studies and use in treatment setting NCT03320642 
 Manipulation of the microbiome Association of loss of diversity with increased GVHD and TRM; mediate anti-inflammatory cytokines and Tregs Pilot study of fecal microbiota transfer early posttransplant: 2 of 13 developed acute GI GVHD66  NCT02763033 
NCT02641236 
NCT03102060 
NCT03529825 
Treatment    
 Sirolimus Inhibition of mTOR impairs T-cell signaling Retrospective study of sirolimus as primary therapy for acute GVHD: 50% achieved CR vs 59% (matched historical control using 1 mg/kg prednisone)67  NCT02806947 
 JAK inhibitors (ruxolitinib, itacitinib) Reduction of proinflammatory cytokines, T-cell activation and function, preserves Tregs, GVL effect Retrospective study of steroid refractory acute GVHD with ruxolitinib, ORR 81.5%, and CR 46.3%68  NCT03139604 
Phase 1 study of itacitinib in acute GVHD, ORR 88.3% first line and 64.7% steroid-refractory GVHD69  
 α-1 antitrypsin Serine protease inhibitor that modulates immune and inflammatory function through cytokine profiles Phase 1/2 study of 12 patients with steroid-refractory GVHD: ORR 8 of 12, CR 4 of 1270  NCT01700036 
NCT02953122 
NCT03172455 
 IL-22 Acts on intestinal stem cells to strengthen epithelial barrier function; tissue repair Preclinical murine models show reduced mortality and improved intestinal pathology from GVHD with in vivo IL-2271  NCT02406651 
 Monoclonal antibodies (natalizumab, vedolizumab) Targeting α4-integrins on activated lymphocytes mediating adhesion and trafficking Used in inflammatory bowel diseases; case series of 5 patients with grade 4 GI GVHD, with responses in all patients72  NCT02176031 
NCT02133924 
NCT02993783 
 Extracorporeal photopheresis Induction of Tregs(?), unknown Retrospective studies of steroid refractory acute GHVD, ORR of ∼60%73  NCT02524847 
NCT02151539 
 Mesenchymal stromal cells Inhibition of B- and T-cell activation, APCs, NK cells and increase Tregs Several early phase studies with ORR 60-75%74 NCT00603330 
NCT02687646 
NCT02336230 
NCT02770430 
NCT02359929 
 Fecal microbiota transplant Association of loss of diversity with increased GVHD and TRM; mediate anti-inflammatory cytokines and Tregs Case series of fecal microbiota transplant: 3 out of 4 patients with CR48 NCT03359980 
NCT03214289 
NCT03148743 

APC, antigen-presenting cell; CR, complete response; GI, gastrointestinal; GVL, graft-versus-leukemia; IL-6R, interleukin-6 receptor; JAK, janus kinase; mTOR, mammalian target of rapamycin complex; NK, natural killer; ORR, overall response rate.

IL-6 plays an important role in inflammation and immune regulation and has been implicated in a variety of immune-mediated inflammatory diseases. Experimental models show increased IL-6 receptor levels during GVHD, with reduction in GVHD with blockade of IL-6. Tocilizumab, a human monoclonal antibody against IL-6R, in combination with standard GVHD prophylaxis has resulted in encouragingly low rates of GVHD, warranting additional investigation in a randomized trial.32,33 

Studies targeting in vivo T-cell costimulation blockade as a way to inhibit T cells and prevent GVHD have identified abatacept or cytotoxic T lymphocyte antigen 4-immunoglobin, a selective inhibitor of CD28:CD80/86, as a potential strategy for GVHD prophylaxis. Abatacept is approved for the use of autoimmune arthritis, and a small first-in disease trial in GVHD has shown promising low rates of GVHD and no TRM at day 100, although higher rates of viral reactivation.34  A phase 2 multicenter, randomized, double-blind trial of abatacept in combination with standard GVHD prophylaxis is currently being conducted (NCT01743131).

Tregs are important regulators of self-tolerance and have been found in preclinical models to suppress the expansion of alloreactive donor T cells and limit GHVD while maintaining the graft-versus-leukemia effect.35  The safety and feasibility of Treg infusion were initially shown in 2 clinical trials using Tregs isolated and expanded from partially HLA-matched umbilical cord units and donor Tregs in the haploidentical setting, showing favorable GVHD outcomes.36,37  Challenges continue to remain in Treg purity and expansion on a larger scale; however, this continues to be a promising GVHD prophylaxis approach and target,38  with several ongoing studies (NCT 01660607, NCT00602693, NCT01818479, and NCT01795573).

3-Hydroxy-3-methyl-coenzyme A reductase inhibitors or “statins” have been shown to have immunomodulatory and anti-inflammatory properties by inhibiting proinflammtory TH-1 differentiation, inducing Treg expansion, and downregulating antigen-presenting cells.39  Preclinical studies of atorvastatin showed protective effects against GVHD. A prospective phase 2 clinical study modeling murine experiments of atorvastatin administration to both donors and recipients showed a promisingly low incidence of GVHD (3.3%) in matched sibling donors40 ; however, a subsequent second single-institution phase 2 study did not show any difference in incidence of GVHD but favorable overall survival compared with historical controls.41  A second study by Hamadani et al40  using atorvastatin in recipients only of matched sibling and unrelated donor transplants also showed safety and a favorably low incidence of acute GVHD.42  A randomized, open label, phase 3 study of Tac + MTX with or without atorvastatin administration in matched unrelated donor transplants is currently ongoing (NCT03066466).

Vorinostat is a histone deacetylase inhibitor used in the treatment of cutaneous T-cell lymphoma. At low and noncytotoxic concentrations, vorinostat has been shown to possess anti-inflammatory and immunoregulatory effects. Experimental GVHD models have shown that vorinostat decreases inflammatory cytokines, enhances Treg function, and reduces GVHD while preserving a graft-versus-leukemia effect.43  A phase 1/2 clinical trial of vorinostat with standard GVHD prophylaxis showed safety and feasibility and resulted in relatively low rates of GVHD in matched sibling donor transplants.44  A subsequent phase 2 trial of vorinostat with Tac + MTX in the myeloablative unrelated donor setting again showed safe administration along with encouragingly low rates of acute GVHD (22%) and favorable survival (76%).45 

Alteration in the gastrointestinal microbiome has also become an active area of study in the prevention and treatment of GVHD.46  Recent small studies have shown the success of fecal microbiota transplantation in the treatment of steroid-refractory gastrointestinal GVHD.47  Subsequently, a pilot study of third-party fecal microbiota transplantation administered early after neutrophil engraftment post-HCT has shown proof of principle for expansion of recipient microbiome diversity. Although too early to correlate with GVHD outcomes, this approach to repopulate intestinal microbiota was shown to be feasible, safe, and a potential novel strategy in GVHD prevention.48 

Novel preclinical GVHD preventative strategies

There are several novel strategies being studied in the preclinical setting for the prevention of GVHD. These approaches focus on targeting cytokine receptors, proinflammatory pathways, and the intestinal microbiome among many others. New targets include the inhibition of Aurora kinase A and the Janus Kinase/signal transducer and activator of transcription pathway,49,50  inhibition of mitogen-activated protein kinase,51  and improving the expansion and suppressive capabilities of Tregs,52,53  with the goal of suppressing GVHD without affecting the graft-versus-leukemia effect. Additional investigations into the gastrointestinal microbiome also show that dysbiosis and loss of Paneth cells have been shown to be critical in the development of GVHD. Recent murine models have shown that R-spondin-1, a Wnt agonist, protects intestinal stem cells from injury by expanding Paneth cells and enhancing secretion of antimicrobial α-defensins, preventing GVHD-mediated dysbiosis.54  Although most of these approaches remain in the laboratory, the preferential targeting of the microbiome, cytokine, and inflammatory pathways holds the promise of improved GVHD prevention, moving away from our standard broad-based immunosuppressive approaches that are often limited by increased disease relapse and infection.

Treatment

Glucocorticoids remain the only standard initial treatment of acute GVHD, despite response rates of only 40% to 60%.1,55  Studies have shown no advantage to initial treatment with corticosteroid (prednisone-equivalent) doses >2.5 mg/kg per day,56  and in patients with grade 2 GVHD, studies have shown no disadvantage to starting doses of 1 mg/kg per day.55  Patients with severe GVHD tend to be less responsive to steroids, leading to high TRM. Although several agents have been evaluated in the upfront and second-line setting, no proven therapy other than corticosteroids has been shown to be more effective or uniformly adopted to date.1,57 

Risk stratification

The identification and risk stratification of patients for treatment based on clinical staging and blood biomarkers have thus been proposed as a new treatment paradigm to identify those who are at greatest risk and require more aggressive upfront therapy while sparing those who are likely to respond from excess toxicity. The refined Minnesota acute GVHD risk score was developed to stratify patients into standard risk, which is defined as single-organ involvement (stage 1-3 skin or stage 1 or 2 gastrointestinal) or 2-organ involvement (stage 1-3 skin plus stage 1 gastrointestinal or stage 1-3 skin plus stage 1-4 liver), and high risk (all others). Patients identified as high-risk GVHD are less likely to respond to therapy and have an increased risk of TRM.58  The Ann Arbor biomarker risk score based on plasma levels of tumor necrosis factor receptor-1, regenerating islet-derived 3-α (REG3α), and suppression of tumorigenicity 2 (ST2) has also been developed and validated to identify patients less likely to respond to treatment.59  This has been further refined (MAGIC biomarkers) to include just 2 biomarkers (REG3α and ST2)60  that have prognostic utility at diagnosis as well as time of clinical response. Data on using microRNA (miRNA), which regulates proinflammatory genes and signaling,61  as a biomarker are also emerging. The detection of multiple miRNAs in the serum has been strongly associated with GVHD, and an miRNA signature may serve as a specific independent biomarker to diagnose and predict severity of GVHD.62  By evaluating novel therapies based on risk stratification models, we may be able to improve outcomes for the patients at the highest risk of treatment failure while minimizing toxicities.

Upfront GVHD therapy

Although several past studies have combined the use of immunosuppressive agents (eg, ATG,63  infliximab,64  MMF, etanercept, and pentostatin65 ) with corticosteroids as frontline therapy, no strategy has been identified to be beneficial beyond steroids alone.1,57  These studies underscore not only the importance of risk stratification approaches to identify the highest-risk patients but also, the critical need for GVHD approaches beyond blanket immunosuppression.

More recently, sirolimus as a single agent has been studied as upfront treatment in patients with newly diagnosed acute GVHD, showing safety and efficacy.66  This has led to an ongoing BMT-CTN (1501) phase 2 trial using sirolimus vs prednisone for first-line treatment of Minnesota standard risk acute GVHD, with additional stratification by the Ann Arbor biomarker risk score (NCT02806947). This study recently completed accrual, and results are eagerly awaited.

Second-line therapy for GVHD

There is no standard indication or timing for the initiation of second-line therapy for acute GVHD. Steroid-refractory GVHD is typically defined by progressive symptoms after 3 days of therapy or lack of improvement after 1 to 2 weeks, depending on severity of symptoms. Poor tolerance of high-dose steroids may also be an indication to start second-line therapy. Although many prospective and retrospective analyses have been done evaluating second-line treatments, no effective adjunctive therapy has been identified, and it is unfortunately often characterized by lack of response, significant toxicities, and subsequent high TRM.1  Given the lack of a superior second-line therapy and Food and Drug Administration–approved agent for the treatment of acute GVHD, enrollment in a well-designed clinical trial should always be encouraged. In the absence of a trial, there are several novel therapeutic options available; however, the choice of any secondary agent is acknowledged as “off label” and guided by side effect profile, cost/availability, and physician preference and discretion. Table 1 provides a brief summary of some of the current novel second-line strategies for steroid-refractory acute GVHD,47,66-73  some of which are reviewed in more detail in a subsequent accompanying paper. Novel targets for the treatment of chronic GVHD are not included and are beyond the scope of this paper. An algorithm for a proposed treatment approach is shown in Figure 2.

Figure 2.

Approach to GVHD treatment.

Figure 2.

Approach to GVHD treatment.

Summary and conclusions

GVHD remains a significant complication after allogeneic HCT, limiting its success as a curative therapy. Additional understanding of the biology and pathogenesis of GVHD has improved our approaches to safer and more targeted strategies. Continued effective translation of preclinical experimental models into clinical implementation will be needed, and as we continue to identify more therapies for prevention and treatment, planning of well-designed, multicenter, randomized clinical trials will be critical to identify the most optimal approaches to GVHD.

Correspondence

Betty Ky Hamilton, Blood and Marrow Transplant Program, Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Ave, CA60, Cleveland, OH; e-mail: hamiltb2@ccf.org.

References

References
1.
Martin
PJ
,
Rizzo
JD
,
Wingard
JR
, et al
.
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
.
2012
;
18
(
8
):
1150
-
1163
.
2.
Storb
R
,
Deeg
HJ
,
Whitehead
J
, et al
.
Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia
.
N Engl J Med
.
1986
;
314
(
12
):
729
-
735
.
3.
Storb
R
,
Raff
RF
,
Appelbaum
FR
, et al
.
FK-506 and methotrexate prevent graft-versus-host disease in dogs given 9.2 Gy total body irradiation and marrow grafts from unrelated dog leukocyte antigen-nonidentical donors
.
Transplantation
.
1993
;
56
(
4
):
800
-
807
.
4.
Ratanatharathorn
V
,
Nash
RA
,
Przepiorka
D
, et al
.
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
;
92
(
7
):
2303
-
2314
.
5.
Nash
RA
,
Antin
JH
,
Karanes
C
, et al
.
Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors
.
Blood
.
2000
;
96
(
6
):
2062
-
2068
.
6.
Sabry
W
,
Le Blanc
R
,
Labbé
AC
, et al
.
Graft-versus-host disease prophylaxis with tacrolimus and mycophenolate mofetil in HLA-matched nonmyeloablative transplant recipients is associated with very low incidence of GVHD and nonrelapse mortality
.
Biol Blood Marrow Transplant
.
2009
;
15
(
8
):
919
-
929
.
7.
Eapen
M
,
Logan
BR
,
Horowitz
MM
, et al
.
Bone marrow or peripheral blood for reduced-intensity conditioning unrelated donor transplantation
.
J Clin Oncol
.
2015
;
33
(
4
):
364
-
369
.
8.
Hamilton
BK
,
Liu
Y
,
Hemmer
M
, et al
.
Cyclosporine in combination with mycophenolate mofetil leads to increased incidence of graft-versus-host disease and inferior outcomes after myeloablative allogeneic hematopoietic cell transplantation: a CIBMTR analysis
.
Biol Blood Marrow Transplant
.
2018
;
24
(
3
):
S185
.
9.
Cutler
C
,
Logan
B
,
Nakamura
R
, et al
.
Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT
.
Blood
.
2014
;
124
(
8
):
1372
-
1377
.
10.
Kanakry
CG
,
Tsai
HL
,
Bolaños-Meade
J
, et al
.
Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS
.
Blood
.
2014
;
124
(
25
):
3817
-
3827
.
11.
Holtick
U
,
Chemnitz
JM
,
Shimabukuro-Vornhagen
A
, et al
.
OCTET-CY: a phase II study to investigate the efficacy of post-transplant cyclophosphamide as sole graft-versus-host prophylaxis after allogeneic peripheral blood stem cell transplantation
.
Eur J Haematol
.
2016
;
96
(
1
):
27
-
35
.
12.
Ruggeri
A
,
Labopin
M
,
Bacigalupo
A
, et al
.
Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT
.
J Hematol Oncol
.
2018
;
11
(
1
):
40
.
13.
Bolanos-Meade
J
,
Reshef
R
,
Fraser
R
, et al
.
LBA1: novel approaches for graft-versus-host disease (GvHD) prophylaxis: primary results of progress I multicenter trial of matched allogeneic hematopoietic cell transplantation (alloHCT) using reduced intensity conditioning (RIC) BMT CTN 1203. In: Proceedings of the 2018 Tandem Meeting; 21-25 February 2018; Salt Lake City, UT.
14.
Finke
J
,
Bethge
WA
,
Schmoor
C
, et al
;
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
;
10
(
9
):
855
-
864
.
15.
Bacigalupo
A
,
Lamparelli
T
,
Bruzzi
P
, et al
.
Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO)
.
Blood
.
2001
;
98
(
10
):
2942
-
2947
.
16.
Kröger
N
,
Solano
C
,
Wolschke
C
, et al
.
antilymphocyte globulin for prevention of chronic graft-versus-host disease
.
N Engl J Med
.
2016
;
374
(
1
):
43
-
53
.
17.
Walker
I
,
Panzarella
T
,
Couban
S
, et al
;
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
;
17
(
2
):
164
-
173
.
18.
Soiffer
RJ
,
Kim
HT
,
McGuirk
J
, et al
.
Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation
.
J Clin Oncol
.
2017
;
35
(
36
):
4003
-
4011
.
19.
Frame
JN
,
Collins
NH
,
Cartagena
T
, et al
.
T cell depletion of human bone marrow. Comparison of Campath-1 plus complement, anti-T cell ricin A chain immunotoxin, and soybean agglutinin alone or in combination with sheep erythrocytes or immunomagnetic beads
.
Transplantation
.
1989
;
47
(
6
):
984
-
988
.
20.
Filipovich
AH
,
Vallera
D
,
McGlave
P
, et al
.
T cell depletion with anti-CD5 immunotoxin in histocompatible bone marrow transplantation. The correlation between residual CD5 negative T cells and subsequent graft-versus-host disease
.
Transplantation
.
1990
;
50
(
3
):
410
-
415
.
21.
Wagner
JE
,
Thompson
JS
,
Carter
SL
,
Kernan
NA
;
Unrelated Donor Marrow Transplantation Trial
.
Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial
.
Lancet
.
2005
;
366
(
9487
):
733
-
741
.
22.
Devine
SM
,
Carter
S
,
Soiffer
RJ
, et al
.
Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303
.
Biol Blood Marrow Transplant
.
2011
;
17
(
9
):
1343
-
1351
.
23.
Geyer
MB
,
Ricci
AM
,
Jacobson
JS
, et al
.
T cell depletion utilizing CD34(+) stem cell selection and CD3(+) addback from unrelated adult donors in paediatric allogeneic stem cell transplantation recipients
.
Br J Haematol
.
2012
;
157
(
2
):
205
-
219
.
24.
Di Stasi
A
,
Tey
SK
,
Dotti
G
, et al
.
Inducible apoptosis as a safety switch for adoptive cell therapy
.
N Engl J Med
.
2011
;
365
(
18
):
1673
-
1683
.
25.
Federmann
B
,
Bornhauser
M
,
Meisner
C
, et al
.
Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study
.
Haematologica
.
2012
;
97
(
10
):
1523
-
1531
.
26.
Pasquini
MC
,
Logan
B
,
Jones
RJ
, et al
.
Blood and marrow transplant clinical trials network report on the development of novel endpoints and selection of promising approaches for graft-versus-host disease prevention trials
.
Biol Blood Marrow Transplant
.
2018
;
24
(
6
):
1274
-
1280
.
27.
McCurdy
SR
,
Kanakry
CG
,
Tsai
HL
, et al
.
Grade II acute graft-versus-host disease and higher nucleated cell graft dose improve progression-free survival after HLA-haploidentical transplant with post-transplant cyclophosphamide
.
Biol Blood Marrow Transplant
.
2018
;
24
(
2
):
343
-
352
.
28.
Martin
PJ
.
Bortezomib for prevention of acute graft-versus-host disease: a conclusion reached
.
Haematologica
.
2018
;
103
(
3
):
377
-
379
.
29.
Choi
SW
,
Stiff
P
,
Cooke
K
, et al
.
TNF-inhibition with etanercept for graft-versus-host disease prevention in high-risk HCT: lower TNFR1 levels correlate with better outcomes
.
Biol Blood Marrow Transplant
.
2012
;
18
(
10
):
1525
-
1532
.
30.
Hamadani
M
,
Hofmeister
CC
,
Jansak
B
, et al
.
Addition of infliximab to standard acute graft-versus-host disease prophylaxis following allogeneic peripheral blood cell transplantation
.
Biol Blood Marrow Transplant
.
2008
;
14
(
7
):
783
-
789
.
31.
Fang
J
,
Hu
C
,
Hong
M
, et al
.
Prophylactic effects of interleukin-2 receptor antagonists against graft-versus-host disease following unrelated donor peripheral blood stem cell transplantation
.
Biol Blood Marrow Transplant
.
2012
;
18
(
5
):
754
-
762
.
32.
Drobyski
WR
,
Szabo
A
,
Zhu
F
, et al
.
Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease
.
Haematologica
.
2018
;
103
(
4
):
717
-
727
.
33.
Kennedy
GA
,
Varelias
A
,
Vuckovic
S
, et al
.
Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial
.
Lancet Oncol
.
2014
;
15
(
13
):
1451
-
1459
.
34.
Koura
DT
,
Horan
JT
,
Langston
AA
, et al
.
In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial
.
Biol Blood Marrow Transplant
.
2013
;
19
(
11
):
1638
-
1649
.
35.
Edinger
M
,
Hoffmann
P
,
Ermann
J
, et al
.
CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation
.
Nat Med
.
2003
;
9
(
9
):
1144
-
1150
.
36.
Brunstein
CG
,
Miller
JS
,
Cao
Q
, et al
.
Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics
.
Blood
.
2011
;
117
(
3
):
1061
-
1070
.
37.
Hoffmann
P
,
Ermann
J
,
Edinger
M
,
Fathman
CG
,
Strober
S
.
Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation
.
J Exp Med
.
2002
;
196
(
3
):
389
-
399
.
38.
Brunstein
CG
,
Miller
JS
,
McKenna
DH
, et al
.
Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect
.
Blood
.
2016
;
127
(
8
):
1044
-
1051
.
39.
Zeiser
R
,
Youssef
S
,
Baker
J
,
Kambham
N
,
Steinman
L
,
Negrin
RS
.
Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity
.
Blood
.
2007
;
110
(
13
):
4588
-
4598
.
40.
Hamadani
M
,
Gibson
LF
,
Remick
SC
, et al
.
Sibling donor and recipient immune modulation with atorvastatin for the prophylaxis of acute graft-versus-host disease
.
J Clin Oncol
.
2013
;
31
(
35
):
4416
-
4423
.
41.
Efebera
YA
,
Geyer
S
,
Andritsos
L
, et al
.
Atorvastatin for the Prophylaxis of Acute Graft-versus-Host Disease in Patients Undergoing HLA-Matched Related Donor Allogeneic Hematopoietic Stem Cell Transplantation (allo-HCT)
.
Biol Blood Marrow Transplant
.
2016
;
22
(
1
):
71
-
79
.
42.
Kanate
AS
,
Hari
PN
,
Pasquini
MC
, et al
.
Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation
.
Biol Blood Marrow Transplant
.
2017
;
23
(
8
):
1295
-
1302
.
43.
Choi
S
,
Reddy
P
.
HDAC inhibition and graft versus host disease
.
Mol Med
.
2011
;
17
(
5-6
):
404
-
416
.
44.
Choi
SW
,
Braun
T
,
Chang
L
, et al
.
Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial
.
Lancet Oncol
.
2014
;
15
(
1
):
87
-
95
.
45.
Choi
SW
,
Braun
T
,
Henig
I
, et al
.
Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT
.
Blood
.
2017
;
130
(
15
):
1760
-
1767
.
46.
Jenq
RR
,
Ubeda
C
,
Taur
Y
, et al
.
Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation
.
J Exp Med
.
2012
;
209
(
5
):
903
-
911
.
47.
Kakihana
K
,
Fujioka
Y
,
Suda
W
, et al
.
Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut
.
Blood
.
2016
;
128
(
16
):
2083
-
2088
.
48.
DeFilipp
Z
,
Peled
JU
,
Li
S
, et al
.
Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity
.
Blood Adv
.
2018
;
2
(
7
):
745
-
753
.
49.
Choi
J
,
Cooper
ML
,
Staser
K
, et al
.
Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease [published online ahead of print 2 April 2018]
.
Leukemia
.
doi:10.1038/s41375-018-0123-z.
50.
Betts
BC
,
Veerapathran
A
,
Pidala
J
, et al
.
Targeting Aurora kinase A and JAK2 prevents GVHD while maintaining Treg and antitumor CTL function
.
Sci Transl Med
.
2017
;
9
(
372
):
eaai8269
.
51.
Itamura
H
,
Shindo
T
,
Tawara
I
, et al
.
The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects
.
JCI Insight
.
2016
;
1
(
10
):
e86331
.
52.
Chopra
M
,
Biehl
M
,
Steinfatt
T
, et al
.
Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion
.
J Exp Med
.
2016
;
213
(
9
):
1881
-
1900
.
53.
Nishikii
H
,
Kim
BS
,
Yokoyama
Y
, et al
.
DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease
.
Blood
.
2016
;
128
(
24
):
2846
-
2858
.
54.
Hayase
E
,
Hashimoto
D
,
Nakamura
K
, et al
.
R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease
.
J Exp Med
.
2017
;
214
(
12
):
3507
-
3518
.
55.
Mielcarek
M
,
Furlong
T
,
Storer
BE
, et al
.
Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial
.
Haematologica
.
2015
;
100
(
6
):
842
-
848
.
56.
Van Lint
MT
,
Uderzo
C
,
Locasciulli
A
, et al
.
Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation
.
Blood
.
1998
;
92
(
7
):
2288
-
2293
.
57.
Rashidi
A
,
DiPersio
JF
,
Sandmaier
BM
,
Colditz
GA
,
Weisdorf
DJ
.
Steroids versus steroids plus additional agent in frontline treatment of acute graft-versus-host disease: a systematic review and meta-analysis of randomized trials
.
Biol Blood Marrow Transplant
.
2016
;
22
(
6
):
1133
-
1137
.
58.
MacMillan
ML
,
Robin
M
,
Harris
AC
, et al
.
A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality
.
Biol Blood Marrow Transplant
.
2015
;
21
(
4
):
761
-
767
.
59.
Levine
JE
,
Braun
TM
,
Harris
AC
, et al
;
Blood and Marrow Transplant Clinical Trials Network
.
A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study
.
Lancet Haematol
.
2015
;
2
(
1
):
e21
-
e29
.
60.
Major-Monfried
H
,
Renteria
AS
,
Pawarode
A
, et al
.
MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD
.
Blood
.
2018
;
131
(
25
):
2846
-
2855
.
61.
Stickel
N
,
Hanke
K
,
Marschner
D
, et al
.
MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation
.
Leukemia
.
2017
;
31
(
12
):
2732
-
2741
.
62.
Xiao
B
,
Wang
Y
,
Li
W
, et al
.
Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease
.
Blood
.
2013
;
122
(
19
):
3365
-
3375
.
63.
Cragg
L
,
Blazar
BR
,
Defor
T
, et al
.
A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2000
;
6
(
4 4A
):
441
-
447
.
64.
Couriel
DR
,
Saliba
R
,
de Lima
M
, et al
.
A phase III study of infliximab and corticosteroids for the initial treatment of acute graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2009
;
15
(
12
):
1555
-
1562
.
65.
Alousi
AM
,
Weisdorf
DJ
,
Logan
BR
, et al
;
Blood and Marrow Transplant Clinical Trials Network
.
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
;
114
(
3
):
511
-
517
.
66.
Pidala
J
,
Tomblyn
M
,
Nishihori
T
, et al
.
Sirolimus demonstrates activity in the primary therapy of acute graft-versus-host disease without systemic glucocorticoids
.
Haematologica
.
2011
;
96
(
9
):
1351
-
1356
.
67.
Hashmi
S
,
Ahmed
M
,
Murad
MH
, et al
.
Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis
.
Lancet Haematol
.
2016
;
3
(
1
):
e45
-
e52
.
68.
Fløisand
Y
,
Lundin
KEA
,
Lazarevic
V
, et al
.
Targeting integrin α4β7 in steroid-refractory intestinal graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2017
;
23
(
1
):
172
-
175
.
69.
Zeiser
R
,
Burchert
A
,
Lengerke
C
, et al
.
Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey
.
Leukemia
.
2015
;
29
(
10
):
2062
-
2068
.
70.
Schroeder
MA
,
Khoury
HJ
,
Jagasia
M
, et al
.
A phase I trial of janus kinase (JAK) inhibition with INCB039110 in acute graft-versus-host disease (aGVHD)
.
Blood
.
2016
;
128
(
22
):390.
71.
Marcondes
AM
,
Hockenbery
D
,
Lesnikova
M
, et al
.
Response of Steroid-Refractory Acute GVHD to α1-Antitrypsin
.
Biol Blood Marrow Transplant
.
2016
;
22
(
9
):
1596
-
1601
.
72.
Lindemans
CA
,
Calafiore
M
,
Mertelsmann
AM
, et al
.
Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration
.
Nature
.
2015
;
528
(
7583
):
560
-
564
.
73.
Couriel
DR
,
Hosing
C
,
Saliba
R
, et al
.
Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD
.
Blood
.
2006
;
107
(
8
):
3074
-
3080
.

Competing Interests

Conflict-of-interest disclosure: The author declares no competing financial interests.

Author notes

Off-label drug use: None disclosed.