Graft-versus-host disease medical therapy: Difference between revisions

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==Overview==
==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.
The mainstay of therapy for GvHD is [[Corticosteroid|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|immunosuppressive agent]]<nowiki/>s 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==
==Medical Therapy==
'''Corticosteroids'''
'''Corticosteroids'''
[[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 salvage therapy is fairly low (as low as 20%).
[[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]]-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.<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> 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.<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>
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.
'''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.<ref name="pmid26729898">{{cite journal| author=McDonald GB| title=How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver. | journal=Blood | year= 2016 | volume= 127 | issue= 12 | pages= 1544-50 | pmid=26729898 | doi=10.1182/blood-2015-10-612747 | pmc=4807421 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26729898  }} </ref> At best, a 30% response rate can be achieved and a 20% survival rate can be achieved.<ref name="pmid26729898">{{cite journal| author=McDonald GB| title=How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver. | journal=Blood | year= 2016 | volume= 127 | issue= 12 | pages= 1544-50 | pmid=26729898 | doi=10.1182/blood-2015-10-612747 | pmc=4807421 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26729898  }} </ref>
*[[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.


For steroid-refractory GvHD, there are a few options available, though the data is not robust.
*[[mycophenolate mofetil]]: This is an inhibitor of [[IMP dehydrogenase]] and thus an inhibitor of [[T cell]] DNA synthesis. It has also 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>  
*Ruxolitinib: This is an inhibitor of Janus kinase 2 (JAK2), has been used.<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>  


*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]].<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>
*[[ruxolitinib]]: This is an inhibitor of [[Janus kinase 2]] ([[JAK2]]), has been used.<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>  


*mTOR inhibitors: These agents inhibitor the mammalian target of rapamycin. Everolimus is an mTOR inhibitor.<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>
*[[alemtuzumab]]: This is a form of anti-[[T cell]] antibody. This is an monoclonal antibody to [[CD52]], which is found on lymphocytes. Alemtuzumab has been used in patients with [[chronic lymphocytic leukemia]] and [[T cell pro-lymphocytic leukemia]].<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>


*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]].<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-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%.<ref name="pmid26729898">{{cite journal| author=McDonald GB| title=How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver. | journal=Blood | year= 2016 | volume= 127 | issue= 12 | pages= 1544-50 | pmid=26729898 | doi=10.1182/blood-2015-10-612747 | pmc=4807421 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26729898  }} </ref>
 
*[[mTOR]] inhibitors: These agents inhibitor the mammalian target of rapamycin. [[Everolimus]] is an [[mTOR]] inhibitor.<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>
 
*[[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]].<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: 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.<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-[[IL-6]] agents: This is also a form of anti-cytokine therapy.


*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>


'''Cell-based 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.<ref name="pmid26674007">{{cite journal| author=Stenger EO, Krishnamurti L, Galipeau J| title=Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation. | journal=BMC Immunol | year= 2015 | volume= 16 | issue=  | pages= 74 | pmid=26674007 | doi=10.1186/s12865-015-0135-7 | pmc=4681052 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26674007  }} </ref> These cells also promote normal blood cell production, so it is thought that their dual role in hematopoiesis and immunosuppression offers great therapeutic potential.<ref name="pmid26674007">{{cite journal| author=Stenger EO, Krishnamurti L, Galipeau J| title=Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation. | journal=BMC Immunol | year= 2015 | volume= 16 | issue=  | pages= 74 | pmid=26674007 | doi=10.1186/s12865-015-0135-7 | pmc=4681052 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26674007  }} </ref> 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.<ref name="pmid26674007">{{cite journal| author=Stenger EO, Krishnamurti L, Galipeau J| title=Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation. | journal=BMC Immunol | year= 2015 | volume= 16 | issue=  | pages= 74 | pmid=26674007 | doi=10.1186/s12865-015-0135-7 | pmc=4681052 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26674007  }} </ref> MSCs can also induce indoleamine-2,3-dioxygenase, which is an immunosuppressive cytokine.<ref name="pmid21892378">{{cite journal| author=Patel SA, Rameshwar P| title=Stem Cell Transplantation for Hematological Malignancies: Prospects for Personalized Medicine and Co-therapy with Mesenchymal Stem Cells. | journal=Curr Pharmacogenomics Person Med | year= 2011 | volume= 9 | issue= 3 | pages= 229-239 | pmid=21892378 | doi=10.2174/187569211796957548 | pmc=3164538 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21892378  }} </ref> The benefits of MSC therapy include:
 
*Off-the-shelf availability: No HLA matching is required
Cell-based therapy has also been attempted for GvHD.
*Minimal adverse effects since this is not a medication
*[[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.<ref name="pmid26674007">{{cite journal| author=Stenger EO, Krishnamurti L, Galipeau J| title=Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation. | journal=BMC Immunol | year= 2015 | volume= 16 | issue=  | pages= 74 | pmid=26674007 | doi=10.1186/s12865-015-0135-7 | pmc=4681052 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26674007  }} </ref> These cells also promote normal blood cell production, so it is thought that their dual role in [[hematopoiesis]] and immunosuppression offers great therapeutic potential.<ref name="pmid26674007">{{cite journal| author=Stenger EO, Krishnamurti L, Galipeau J| title=Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation. | journal=BMC Immunol | year= 2015 | volume= 16 | issue=  | pages= 74 | pmid=26674007 | doi=10.1186/s12865-015-0135-7 | pmc=4681052 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26674007  }} </ref> 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.<ref name="pmid26674007">{{cite journal| author=Stenger EO, Krishnamurti L, Galipeau J| title=Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation. | journal=BMC Immunol | year= 2015 | volume= 16 | issue=  | pages= 74 | pmid=26674007 | doi=10.1186/s12865-015-0135-7 | pmc=4681052 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26674007  }} </ref> MSCs can also induce indoleamine-2,3-dioxygenase, which is an immunosuppressive cytokine.<ref name="pmid21892378">{{cite journal| author=Patel SA, Rameshwar P| title=Stem Cell Transplantation for Hematological Malignancies: Prospects for Personalized Medicine and Co-therapy with Mesenchymal Stem Cells. | journal=Curr Pharmacogenomics Person Med | year= 2011 | volume= 9 | issue= 3 | pages= 229-239 | pmid=21892378 | doi=10.2174/187569211796957548 | pmc=3164538 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21892378  }} </ref> The benefits of MSC therapy include:
*Feasibility of administration, as MSCs can be given concurrently with HSCs during transplant
**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
 
*''Ex 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>
 
*''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>


==References==
==References==
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Latest revision as of 14:59, 5 July 2017

Graft-versus-host disease

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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 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

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

References

  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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