Pediatric Graft Versus Host Disease Treatment & Management

Updated: Aug 23, 2021
  • Author: Phillip Ruiz, Jr, MD, PhD; Chief Editor: Harumi Jyonouchi, MD  more...
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Medical Care

Prevention and treatment of acute graft versus host disease

Successful therapeutic intervention of life-threatening graft versus host disease (GVHD) is possible, although the consequence can be the development of fatal opportunistic infections. Therefore, the best approach to manage GVHD should be its prevention. Effective prevention against GVHD includes the use of histocompatible donor and recipient combinations. [19, 20, 21]

Primary prophylaxis

Interference of T-cell activation/function using immunosuppressive therapy

The calcineurin inhibitors (cyclosporine and tacrolimus) are the principal drugs used to prevent GVHD. They are not found to be very effective and have additional toxicity that reduces their use. Corticosteroids can also interfere with T-cell activation and function but are uncommonly used in prophylactic regimens because they seem to increase mortality from infection. Over the last few years, great attention has been focused on the potential of regulatory T cells (Tregs) for inhibiting the division, expansion and differentiation of donor T cells specific for host antigens. However, the potential use of this approach in humans is still not established.

Removal of T cells by T–cell depletion ex vivo or T-cell depletion in vivo

The in vivo host lymphocyte depletion has the advantage of reducing the risk of graft rejection, but both techniques are associated with a reduction in graft-versus-leukemia (GVL) effects and a concomitant increase in risk of leukemia relapse.

  • T–cell depletion ex vivo: Removing T cells from the graft is very effective in preventing GVHD without affecting the graft survival, disease-free survival, and treatment-related mortality rates. The number of infused T cells should not exceed 5 × 104 cells/kg of recipient body weight. This procedure increases a risk of graft rejection.

  • T-cell depletion in vivo: Adding T-cell antibodies to the conventional conditioning regimen has the following 2 side effects: (1) it can reduce the host response, which improves engraftment, and (2) it affects mature donor T cells in the graft. This can be accomplished with such agents as alemtuzumab (Campath) or antithymocyte globulin (ATG). These long-lived agents can be directly administered to the patient, a tactic that depletes host and donor-derived T cells. Alternatively, the T cells (in the donor bone marrow) can be eliminated in vitro using monoclonal antibodies and using physical methods such as elutriation, or using immunotoxins.

Inhibition of T-cell proliferation

Drugs often used for this therapy include methotrexate and mycophenolate (MMF). Methotrexate has been the primary drug in this indication for decades, and, although effective, it is also associated with delayed engraftment, mucositis, and transplant-associated toxicity. MMF inhibits T-cell purine salvage pathways and appears to have less toxicity than methotrexate and can be used with a calcineurin inhibitor. [22]

Interference of cytokine function

This approach is relatively new and still experimental. Agents such as corticosteroids definitely reduce inflammatory cytokine levels, but, as noted above, for the most part they have not been helpful in GVHD prophylaxis.

Removal of host antigen-presenting cells (APCs) using extracorporeal photopheresis (ECP)

ECP is pheresis of approximately 5 × 109 leukocytes that are treated with a photoactive compound 8-methoxypsoralen and ultraviolet A light and re-infused to the patients. This therapy induces lymphocytes undergoing apoptosis. Those apoptotic cells are taken up by host APCs, thereby triggering certain tolerance mechanisms, which results in lower incidence of GVHD. [23]

Increase in host immune activity using reduced-intensity conditioning regimens

This was defined as a conditioning regimen in which the dosage of chemotherapy and/or total body irradiation (TBI) was reduced to 50%. These changes may result in less toxicity and less severe GVHD due to the persistence of host T cells.

Housing the patient in a pathogen-poor protected environment can be very helpful to reduce the risk of infections.


Many different therapies have been used in the treatment of acute GVHD. Unfortunately, control of GVHD does not translate into improved survival in many patients because of the subsequent development of opportunistic infections.

First-line treatment

Steroids in conjunction with cyclosporine or tacrolimus are considered standard therapy. Treatment is required for established grades II-IV GVHD and often consists of continuation of original immunosuppressive agents used for GVHD prophylaxis and the addition of methylprednisolone at 2 mg/kg/d in divided doses for 10-14 days or until GVHD is controlled, followed by steroid taper. Patients who have not received cyclosporine or tacrolimus as part of their GVHD prophylaxis may benefit by combining it with corticosteroids. Combination triple therapy with cyclosporine, prednisone, and antithymocyte globulin has been found to be equally efficacious but more toxic in children. Successful treatment of GVHD with this initial intervention is only seen in about 25-40% of patients after donor transplantation; thus, 60-75% of patients with clinically significant GVHD require therapy in addition to corticosteroids.

Steroid-refractory GVHD

For steroid-refractory GVHD, rituximab along with other sporadically tried drugs have been studied. ATG has activity in steroid refractory GVHD, especially in the skin. Overall responses are seen in 20-60% of patients, but overall survival has not improved, and 1-year mortality rates approach 90%. 

A 2011 study noted that in patients with chronic GVHD refractory to glucocorticoid therapy, daily low-dose subcutaneous interleukin-2 was found to increase regulatory T cells in vivo, suppress clinical manifestations, and permit glucocorticoid tapering by a mean of 60%. [24, 25]

In May 2019, ruxolitinib was FDA-approved for the treatment of steroid-refractory acute GvHD in patients aged 12 years or older. Approval was based on data from REACH1, an open-label, multicenter trial, which studied ruxolitinib in combination with corticosteroids in patients with steroid-refractory acute GVHD. Patients with steroid refractory acute GVHD treated with ruxolitinib had an overall response rate was 59% and a complete response of 31%. [26]

Cytokine blockade

This has been attempted with blocking actions of IL-1 by preventing it binding to IL-1 receptor either by soluble IL-1 receptor or by IL-1 receptor antagonist, anakinra [Kineret]. This approach has not been extensively pursued. The anti-TNF alpha antibody infliximab (Remicade) has been effective in steroid-resistant GVHD but with increased subsequent infection. To date, it has shown benefit over steroids alone.

Cytotoxic therapy

MMF and the inosine monophosphate dehydrogenase (IMPDH) inhibitor, pentostatin, are cytotoxic reagents tried on acute GVHD. The latter drug appears to be highly active in acute GVHD in a single institution experience. The response rate was approximately 65%, but long-term survival was only 26%. Several small studies of MMF have shown therapeutic efficacy in the range of 40-70%, with survival rates ranging from 16-37%. As with other reagents, opportunistic infections mandate careful dosing.

Newer therapies

A murine monoclonal antibody against CD147, which is a neurothelion member of the immunoglobulin superfamily and up-regulated on activated B cells and T cells, induced 50% response in steroid-resistant acute GVHD. Moderate-to-severe myalgia occurred in 28-60% of cases and was dose limiting. Visilizumab is a humanized anti-CD3 antibody that selectively induces apoptosis of activated T-cells. A phase I study demonstrated that all patients affected by severe acute GVHD and treated with visilizumab improved. However, posttransplant lymphoproliferative disease (PTLD) was a major concern. Also, extracorporeal photopheresis has been used to treat resistant, acute GVHD; the patients who responded had a significantly better outcome.

Prevention and treatment of chronic graft versus host disease

The best prophylaxis against chronic GVHD is prevention of acute GVHD because de novo chronic GVHD is less common compared with incidence in patients with acute GVHD. Limited chronic GVHD may spontaneously resolve without specific therapy. Treatment of extensive chronic GVHD involves oral prednisone, which may be used simultaneously or on an alternate day schedule with cyclosporine or tacrolimus. Azathioprine may be used as a corticosteroid-sparing agent.

Numerous therapies, including psoralen plus ultraviolet radiation, thalidomide, and clofazimine, have been tried. MMF is an immunosuppressive agent used for prophylaxis for acute GVHD. In the treatment of steroid-refractory chronic GVHD, responses of 90% and 75% in first-line and second-line settings have been reported when MMF is added to standard tacrolimus, cyclosporine, and/or prednisone treatments. [27]

Rezurock (belumosudil),a selective Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor, is another therapy FDA-approved for the treatment of chronic GVHD in adult and pediatric patients aged 12 years and older who failed 2 prior systemic therapies.

FDA based the approval on results from the open-label, multicenter, ROCKstar trial. Sixty-five chronic GvHD patients were randomized to receive either belumosudil 200 mg oral daily or twice a day. The once-daily treated group achieved an overall response rate of 75% through Cycle 7 Day 1. Among those who achieved overall response, 6% achieved complete response and 69% achieved partial response. [28]

Supportive therapy and symptomatic management is equally important, including ursodeoxycholic acid for cholestasis, artificial tears and saliva for sicca syndrome, physiotherapy to prevent contractures, and immunoglobulin replacement and infection prophylaxis against opportunistic infections.


Surgical Care

Surgical care is restricted to insertion of a central line to aid in parental nutrition and intravenous treatments.



During acute GVHD, persistent diarrhea requires total parenteral nutrition until symptoms have subsided.



Activity is restricted depending on the patient's conditions, and isolation for infection control may be necessary.