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==Medical Therapy== | ==Medical Therapy== | ||
[[Corticosteroids]], such as [[prednisone]] or [[methylprednisolone]], are the standard of care in acute GVHD<ref>{{cite journal |author=Goker H, Haznedaroglu IC, Chao NJ |title=Acute graft-vs-host disease: pathobiology and management |journal=Exp. Hematol. |volume=29 |issue=3 |pages=259–77 |year=2001 |pmid=11274753 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0301-472X(00)00677-9}}</ref> and chronic GVHD. Prednisone is an oral steroids, and methylprednisolone is an intravenous steroid. Typical dose of methylprednisolone is 2 to 2.5 mg/kg daily.<ref name="pmid17784964">{{cite journal| author=Jacobsohn DA, Vogelsang GB| title=Acute graft versus host disease. | journal=Orphanet J Rare Dis | year= 2007 | volume= 2 | issue= | pages= 35 | pmid=17784964 | doi=10.1186/1750-1172-2-35 | pmc=2018687 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17784964 }} </ref> 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. | [[Corticosteroids]], such as [[prednisone]] or [[methylprednisolone]], are the standard of care in acute GVHD<ref>{{cite journal |author=Goker H, Haznedaroglu IC, Chao NJ |title=Acute graft-vs-host disease: pathobiology and management |journal=Exp. Hematol. |volume=29 |issue=3 |pages=259–77 |year=2001 |pmid=11274753 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0301-472X(00)00677-9}}</ref> 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.<ref name="pmid21130418">{{cite journal| author=Lee SJ| title=Have we made progress in the management of chronic graft-vs-host disease? | journal=Best Pract Res Clin Haematol | year= 2010 | volume= 23 | issue= 4 | pages= 529-35 | pmid=21130418 | doi=10.1016/j.beha.2010.09.016 | pmc=3053022 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21130418 }} </ref> Typical dose of methylprednisolone is 2 to 2.5 mg/kg daily.<ref name="pmid17784964">{{cite journal| author=Jacobsohn DA, Vogelsang GB| title=Acute graft versus host disease. | journal=Orphanet J Rare Dis | year= 2007 | volume= 2 | issue= | pages= 35 | pmid=17784964 | doi=10.1186/1750-1172-2-35 | pmc=2018687 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17784964 }} </ref> 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.<ref name="pmid19539221">{{cite journal| author=Pidala J, Kim J, Anasetti C| title=Sirolimus as primary treatment of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation. | journal=Biol Blood Marrow Transplant | year= 2009 | volume= 15 | issue= 7 | pages= 881-5 | pmid=19539221 | doi=10.1016/j.bbmt.2009.03.020 | pmc=4856158 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19539221 }} </ref> Furthermore, the use of steroids is associated with significant treatment-related morbidity, including systemic immunosuppression, bone loss, hyperglycemia, glaucoma, cataracts. | The response rate for steroids in GvHD is only 30-40%, suggesting that most patients will require second-line therapy.<ref name="pmid19539221">{{cite journal| author=Pidala J, Kim J, Anasetti C| title=Sirolimus as primary treatment of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation. | journal=Biol Blood Marrow Transplant | year= 2009 | volume= 15 | issue= 7 | pages= 881-5 | pmid=19539221 | doi=10.1016/j.bbmt.2009.03.020 | pmc=4856158 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19539221 }} </ref> Furthermore, the use of steroids is associated with significant treatment-related morbidity, including systemic immunosuppression, bone loss, hyperglycemia, glaucoma, cataracts. | ||
The median duration of treatment for patients with GvHD is 2-3 years, as the pathophysiology involves persistent, long-standing inflammation.<ref name="pmid21130418">{{cite journal| author=Lee SJ| title=Have we made progress in the management of chronic graft-vs-host disease? | journal=Best Pract Res Clin Haematol | year= 2010 | volume= 23 | issue= 4 | pages= 529-35 | pmid=21130418 | doi=10.1016/j.beha.2010.09.016 | pmc=3053022 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21130418 }} </ref> Nearly 15% of patients will continue to require treatment for 7 years or longer.<ref name="pmid21130418">{{cite journal| author=Lee SJ| title=Have we made progress in the management of chronic graft-vs-host disease? | journal=Best Pract Res Clin Haematol | year= 2010 | volume= 23 | issue= 4 | pages= 529-35 | pmid=21130418 | doi=10.1016/j.beha.2010.09.016 | pmc=3053022 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21130418 }} </ref> | |||
Other immunosuppressive agents that are typically used include cyclosporine and tacrolimus.<ref name="pmid17784964">{{cite journal| author=Jacobsohn DA, Vogelsang GB| title=Acute graft versus host disease. | journal=Orphanet J Rare Dis | year= 2007 | volume= 2 | issue= | pages= 35 | pmid=17784964 | doi=10.1186/1750-1172-2-35 | pmc=2018687 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17784964 }} </ref> These are immunophilins that suppress T cell responses. Mycophenolate mofetil has been used for prophylaxis for GvHD.<ref name="pmid17784964">{{cite journal| author=Jacobsohn DA, Vogelsang GB| title=Acute graft versus host disease. | journal=Orphanet J Rare Dis | year= 2007 | volume= 2 | issue= | pages= 35 | pmid=17784964 | doi=10.1186/1750-1172-2-35 | pmc=2018687 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17784964 }} </ref> 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.<ref name="pmid17784964">{{cite journal| author=Jacobsohn DA, Vogelsang GB| title=Acute graft versus host disease. | journal=Orphanet J Rare Dis | year= 2007 | volume= 2 | issue= | pages= 35 | pmid=17784964 | doi=10.1186/1750-1172-2-35 | pmc=2018687 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17784964 }} </ref> The latter can be accomplished via [[anti-thymocyte globulin]] (ATG) or alemtuzumab. | Other immunosuppressive agents that are typically used include cyclosporine and tacrolimus.<ref name="pmid17784964">{{cite journal| author=Jacobsohn DA, Vogelsang GB| title=Acute graft versus host disease. | journal=Orphanet J Rare Dis | year= 2007 | volume= 2 | issue= | pages= 35 | pmid=17784964 | doi=10.1186/1750-1172-2-35 | pmc=2018687 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17784964 }} </ref> These are immunophilins that suppress T cell responses. Mycophenolate mofetil has been used for prophylaxis for GvHD.<ref name="pmid17784964">{{cite journal| author=Jacobsohn DA, Vogelsang GB| title=Acute graft versus host disease. | journal=Orphanet J Rare Dis | year= 2007 | volume= 2 | issue= | pages= 35 | pmid=17784964 | doi=10.1186/1750-1172-2-35 | pmc=2018687 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17784964 }} </ref> 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.<ref name="pmid17784964">{{cite journal| author=Jacobsohn DA, Vogelsang GB| title=Acute graft versus host disease. | journal=Orphanet J Rare Dis | year= 2007 | volume= 2 | issue= | pages= 35 | pmid=17784964 | doi=10.1186/1750-1172-2-35 | pmc=2018687 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17784964 }} </ref> The latter can be accomplished via [[anti-thymocyte globulin]] (ATG) or alemtuzumab. | ||
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*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.<ref name="pmid28444730">{{cite journal| author=Assouan D, Lebon D, Charbonnier A, Royer B, Marolleau JP, Gruson B| title=Ruxolitinib as a promising treatment for corticosteroid-refractory graft-versus-host disease. | journal=Br J Haematol | year= 2017 | volume= | issue= | pages= | pmid=28444730 | doi=10.1111/bjh.14679 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28444730 }} </ref> | *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.<ref name="pmid28444730">{{cite journal| author=Assouan D, Lebon D, Charbonnier A, Royer B, Marolleau JP, Gruson B| title=Ruxolitinib as a promising treatment for corticosteroid-refractory graft-versus-host disease. | journal=Br J Haematol | year= 2017 | volume= | issue= | pages= | pmid=28444730 | doi=10.1111/bjh.14679 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28444730 }} </ref> | ||
==References== | ==References== | ||
Revision as of 17:39, 14 June 2017
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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]
Overview
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 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]
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.