Graft-versus-host disease medical therapy
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Graft-versus-host disease |
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Differentiating Graft-versus-host disease from other Diseases |
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Graft-versus-host disease medical therapy On the Web |
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Risk calculators and risk factors for Graft-versus-host disease medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]
Overview
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 like cyclosporine.
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 mis-matched 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] Furthermore, 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]
Other immunosuppressive agents that are typically used include cyclosporine and tacrolimus.[3] These are immunophilins that suppress T cell responses. Mycophenolate mofetil has been used for prophylaxis for GvHD.[3] Other modalities of therapy that have been used, besides oral or intravenous steroids or immunophilins, include ex vivo T cell depletion and in vivo T cell depletion.[3] The latter can be accomplished via anti-thymocyte globulin (ATG) or alemtuzumab.
For steroid-refractory GvHD, there are a few options available, though the data is not robust.
- Ruxolitinib: This is an inhibitor of Janus kinase 2 (JAK2), has been used.[5]
- Alemtuzumab: This is an antibody to CD52, which is found to lymphocytes. Alemtuzumab has been used in patients with chronic lymphocytic leukemia and T cell pro-lymphocytic leukemia.[5]
- mTOR inhibitors: These agents inhibitor the mammalian target of rapamycin. Everolimus is an mTOR inhibitor.[5]
- Rituximab: This is a monoclonal antibody to CD20, which is found on B cells. Rituximab is known for its immunomodulatory effects and is currently FDA-approved for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, Wegener's granulomatosis, microscopic polyangitis, and immune thrombocytopenia purpura.[5]
- Anti-TNF agents: Examples of anti-TNF agents include etanercept and adalilumab. TNF is involved in the inflammatory response, so TNF blockade results in immunosuppression.[5]
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.[6] These cells also promote normal blood cell production, so it is thought that their dual role in hematopoiesis and immunosuppression offers great therapeutic potential.[6] 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.[6] MSCs can also induce indoleamine-2,3-dioxygenase, which is an immunosuppressive cytokine.[7] The benefits of MSC therapy include:
- Off-the-shelf availability: No HLA matching is required
- Minimal adverse effects since this is not a medication
- Feasibility of administration, as MSCs can be given concurrently with HSCs during transplant
References
- ↑ Goker H, Haznedaroglu IC, Chao NJ (2001). "Acute graft-vs-host disease: pathobiology and management". Exp. Hematol. 29 (3): 259–77. PMID 11274753.
- ↑ 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.
- ↑ 3.0 3.1 3.2 3.3 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.
- ↑ 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.
- ↑ 5.0 5.1 5.2 5.3 5.4 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.
- ↑ 6.0 6.1 6.2 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.
- ↑ 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.