Graft-versus-host disease medical therapy

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Graft-versus-host disease


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]


The mainstay of therapy for GvHD is corticosteroids, such as prednisone or methylprednisolone. The reason for this class of medication is that GvHD is characterized by an excessive and abnormal immune response. If these agents do not result in response, second-line treatment options include alternative immunosuppressive agents such as cyclosporine, mycophenolate, tacrolimus, or everolimus. Steroid-refractory GvHD has a poor prognosis, and treatment options are limited if there is no response to steroids. Cell-based therapy has also been studied, but this is not a currently not approved by the Food and Drug Administration (FDA). Cell-based therapies including mesenchymal stem cell (MSC) therapy and T cell depletion.

Medical Therapy


Corticosteroids, such as prednisone or methylprednisolone, are the standard of care in acute GvHD[1] and chronic GVHD. Prednisone is an oral steroids, and methylprednisolone is an intravenous steroid. Typical dose of oral prednisone is 0.5 - 1.0 mg/kg daily.[2] Typical dose of methylprednisolone is 2 to 2.5 mg/kg daily.[3] The use of these corticosteroids is designed to suppress the T cell mediated immune onslaught on the host tissues; however in high doses this immune-suppression raises the risk of infections and cancer relapse. Therefore it is desirable to taper off the post-transplant high level steroid doses to lower levels, at which point the appearance of mild GVHD may be welcome, especially in HLA-mismatched patients, as it is typically associated with a graft-versus-tumor effect. Steroids can be tapers quickly or slowly after the induction phase of steroids results in adequate response.

The response rate for steroids in GvHD is only 30-40%, suggesting that most patients will require second-line therapy.[4] If low-dose steroids were used in the first-line setting, second-line therapy can employ high-dose steroids. However, the use of steroids is associated with significant treatment-related morbidity, including systemic immunosuppression, bone loss, hyperglycemia, glaucoma, cataracts. The response rate for salvage therapy is fairly low (as low as 20%).

The median duration of treatment for patients with GvHD is 2-3 years, as the pathophysiology involves persistent, long-standing inflammation.[2] Nearly 15% of patients will continue to require treatment for 7 years or longer.[2]

Steroid-refractory GvHD

For steroid-refractory GvHD, there are a few options available, though the data is not robust. The mortality is high with steroid-refractory GvHD.[5] At best, a 30% response rate can be achieved and a 20% survival rate can be achieved.[5]

  • anti-thymocyte globulin, or ATG: This is another anti-T cell antibody. It is a mixture of antibodies produced by a rabbit with specificity for human thymocytes. For patients who developed treatment failure to prednisone, studies have shown that the complete response rate in the presence of ATG is 33% and the complete response rate in the absence of ATG is 24%.[5]
  • mTOR inhibitors: These agents inhibitor the mammalian target of rapamycin. Everolimus is an mTOR inhibitor.[6]
  • anti-TNF agents: This is a form of anti-cytokine therapy. Examples of anti-TNF agents include etanercept and adalilumab. TNF is involved in the inflammatory response, so TNF blockade results in immunosuppression.[6]
  • anti-IL-6 agents: This is also a form of anti-cytokine therapy.

Cell-based therapy

Cell-based therapy has also been attempted for GvHD.

  • Mesenchymal stem cells (MSCs), which are multipotent stem cells in the bone marrow, have been studied in the treatment of GvHD, given the immunosuppressive potential.[7] These cells also promote normal blood cell production, so it is thought that their dual role in hematopoiesis and immunosuppression offers great therapeutic potential.[7] MSCs can allow for hematopoietic stem cell engraftment. They co-localize with hematopoietic stem cells in the bone marrow, albeit in slightly different regions. The immune effector functions are that altered by MSCs include cytotoxic T cell suppression and Treg upregulation.[7] MSCs can also induce indoleamine-2,3-dioxygenase, which is an immunosuppressive cytokine.[8] The benefits of MSC therapy include:
    • Feasibility of obtaining MSCs, which are derived from a bone marrow aspirate
    • Minimal adverse effects since this is not a medication
    • Feasibility of administration, as MSCs can be given concurrently with HSCs during transplant
    • Off-the-shelf availability: No HLA matching is required


  1. Goker H, Haznedaroglu IC, Chao NJ (2001). "Acute graft-vs-host disease: pathobiology and management". Exp. Hematol. 29 (3): 259–77. PMID 11274753.
  2. 2.0 2.1 2.2 Lee SJ (2010). "Have we made progress in the management of chronic graft-vs-host disease?". Best Pract Res Clin Haematol. 23 (4): 529–35. doi:10.1016/j.beha.2010.09.016. PMC 3053022. PMID 21130418.
  3. 3.0 3.1 3.2 3.3 3.4 Jacobsohn DA, Vogelsang GB (2007). "Acute graft versus host disease". Orphanet J Rare Dis. 2: 35. doi:10.1186/1750-1172-2-35. PMC 2018687. PMID 17784964.
  4. Pidala J, Kim J, Anasetti C (2009). "Sirolimus as primary treatment of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation". Biol Blood Marrow Transplant. 15 (7): 881–5. doi:10.1016/j.bbmt.2009.03.020. PMC 4856158. PMID 19539221.
  5. 5.0 5.1 5.2 McDonald GB (2016). "How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver". Blood. 127 (12): 1544–50. doi:10.1182/blood-2015-10-612747. PMC 4807421. PMID 26729898.
  6. 6.0 6.1 6.2 6.3 6.4 Assouan D, Lebon D, Charbonnier A, Royer B, Marolleau JP, Gruson B (2017). "Ruxolitinib as a promising treatment for corticosteroid-refractory graft-versus-host disease". Br J Haematol. doi:10.1111/bjh.14679. PMID 28444730.
  7. 7.0 7.1 7.2 Stenger EO, Krishnamurti L, Galipeau J (2015). "Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation". BMC Immunol. 16: 74. doi:10.1186/s12865-015-0135-7. PMC 4681052. PMID 26674007.
  8. Patel SA, Rameshwar P (2011). "Stem Cell Transplantation for Hematological Malignancies: Prospects for Personalized Medicine and Co-therapy with Mesenchymal Stem Cells". Curr Pharmacogenomics Person Med. 9 (3): 229–239. doi:10.2174/187569211796957548. PMC 3164538. PMID 21892378.

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