Graft-versus-host disease

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Graft-versus-host disease

James Lee Landero, Kurt W. Grelck and Carlos H. Nousari

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Graft-versus-host disease (GVHD) affects the skin, liver, and gastrointestinal tract and typically occurs in the setting of allogeneic bone marrow transplants. Host disease results from interactions between adaptive and innate immune systems of both host and donor (graft), in which host tissues are identified as foreign by the graft.

Acute GVHD (aGVHD) classically occurs 100 days after transplantation (usually several weeks) and presents as a maculopapular eruption which may progress to erythroderma, and less commonly to a toxic epidermal necrolysis-like eruption. Dermatologic findings are frequently accompanied by diarrhea and rising bilirubin levels.

Chronic GVHD (cGVHD) occurs 100 days after transplantation as a mucocutaneous lichen-planus-like eruption and/or sclerodermatous process, with hepatic, gastrointestinal, and pulmonary pathology.

Management strategy

Treatment, timing and presentation of GVHD depend on the type of transplant, pre-transplantation ablative therapy, marrow preparation, prophylactic medications, and previous treatments. Evolution of transplant strategies such as reduced-intensity conditioning, and donor lymphocyte infusion, combined with recognition of overlap phenomena, and late-onset aGVHD, have blurred the classic temporally defined division of aGVHD and cGVHD.

Prevention of GVHD is typically with a combination of methotrexate (MTX) and calcineurin inhibitor, with or without additional corticosteroids. Combinations using tacrolimus, cyclophosphamide, or mycophenolate mofetil (MMF) are also effective. Sirolimus, thalidomide, hydroxychloroquine, muromonab-CD3, alemtuzumab, suberoylanilide hydroxamic acid, keratinocyte growth factor, IL-1 receptor antibody, IL-2 receptor antibody, antithymocyte globulin, intravenous immunoglobulin, pentostatin, and extracorporeal photopheresis (ECP) have also been evaluated with mixed or preliminary results. Corticosteroids are not part of prophylaxis in spite of reductions in mild and severe aGVHD, as overall survival, disease-free survival, and incidence of relapse are not affected.

Following transplantation, 25–80% will manifest with aGVHD. For stage I aGVHD topical steroids are reasonable with or without phototherapy. For grade II-IV aGVHD first-line therapy is systemic corticosteroids, given in consultation with a transplant specialist (methylprednisolone 2 mg/kg/day, with eventual taper). If within 5 days there is no response, second-line therapy should be considered. Response to first-line therapy is the most important factor predicting long-term survival.

Second-line therapy should be initiated after non-response to high-dose steroids for 3 to 5 days, with MMF, tacrolimus, pentostatin, or antithymocyte globulin. Well designed trials do not exist to adequately compare therapies. Supportive care includes cessation of oral intake, total parenteral nutrition with hyperalimentation, antibiotic and antiviral prophylaxis, and pain control.

cGVHD treatment depends on extent of organ involvement. Skin or mucosal disease requires local therapy, whereas extensive disease (generalized cutaneous or localized cutaneous with visceral involvement) requires systemic therapy. Standard treatment is a combination of systemic corticosteroids with or without calcineurin inhibitor (prednisone 1 mg/kg/day and cyclosporine 10 mg/kg/day given as an alternating day regimen).

Refractory cGVHD has no standard therapy due to a lack of randomized controlled trials. Patients refractory to corticosteroids should be considered for clinical trials. Studies show MMF alone or in combination with cyclosporine, or tacrolimus, is beneficial in refractory disease. ECP is becoming reasonable first-line therapy in refractory cGVHD, where available. For sclerodermatous disease, salvage therapy with imatinib, or mTOR inhibitors are advocated. Lichenoid disease responds more with non-pharmacologic therapies such as 8-methoxypsoralen plus ultraviolet A irradiation (PUVA), and ECP.

Acute gvhd

Specific investigations

First-line therapies

image Corticosteroids (methylprednisolone 2 mg/kg/day) A

Second-line therapies

image Mycophenolate mofetil B
image Extracorporeal photopheresis B
image Monoclonal antibodies:  
 – Anti-IL2 receptor antibodies (daclizumab, basiliximab, inolimomab) B
 – Anti-TNF-α antibodies (infliximab, etanercept) B
image Cyclosporine B
image Tacrolimus B
image Sirolimus B

image

Third-line therapies

image Pentostatin B
image Antithymocyte globulin B
image Mesenchymal stem cells A
image Methotrexate B
image Anti-CD52 antibody (alemtuzumab) B
image Anti-CD3 antibody (visilizumab) C
image Anti-CD2 antibody (siplizumab) C
image Intra-arterial methyprednisolone B
image CD5-specific immunotoxin A
image Denileukin diftitox B
image Rituximab E
image Ustekinumab E
image Cyclophosphamide B
image PUVA B
image Narrowband UVB C
image Tocilizimab E

Chronic gvhd

Specific investigations

First-line therapies

image Systemic corticosteroids A
image Systemic corticosteroid and calcineurin inhibitor B

Second-line therapies

Systemic  
image Extracorporeal photopheresis A
image mTOR inhibitors (sirolimus, tacrolimus, everolimus) B
image Rituximab B
image Pentostatin B
Lichenoid cutaneous GVHD  
image UVB, narrow-band UVB E
image PUVA B
image Extracorporeal photopheresis A
Sclerodermatous cutaneous GVHD  
image Imatinib B
image UVA1/PUVA B
image Etretinate B
image Topical halofuginone E

Third-line therapies

Systemic  
image Mycophenolate mofetil A
image Thalidomide B
image Hydroxychloroquine B
image Cyclophosphamide C
image Pentostatin C
image Infliximab C
image Etanercept C
image Daclizumab E
image Alefacept C
image Alemtuzumab C
image Mesenchymal stromal cell therapy C
image Interleukin-2 B
image Thoracoabdominal irradiation B
image Azathioprine A
image Low-dose methotrexate C
image Pulse corticosteroids B
Lichenoid cGVHD  
image Clofazimine B
image UVA1 and mycophenolate mofetil E
Oral GVHD  
image Topical corticosteroids C
image Topical cyclosporine D
image Intraoral PUVA E
image Oral UVB E
image Topical calcineurin inhibitors D
image Topical azathioprine E

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Graft-versus-host disease

James Lee Landero, Kurt W. Grelck and Carlos H. Nousari

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Graft-versus-host disease (GVHD) affects the skin, liver, and gastrointestinal tract and typically occurs in the setting of allogeneic bone marrow transplants. Host disease results from interactions between adaptive and innate immune systems of both host and donor (graft), in which host tissues are identified as foreign by the graft.

Acute GVHD (aGVHD) classically occurs 100 days after transplantation (usually several weeks) and presents as a maculopapular eruption which may progress to erythroderma, and less commonly to a toxic epidermal necrolysis-like eruption. Dermatologic findings are frequently accompanied by diarrhea and rising bilirubin levels.

Chronic GVHD (cGVHD) occurs 100 days after transplantation as a mucocutaneous lichen-planus-like eruption and/or sclerodermatous process, with hepatic, gastrointestinal, and pulmonary pathology.

Management strategy

Treatment, timing and presentation of GVHD depend on the type of transplant, pre-transplantation ablative therapy, marrow preparation, prophylactic medications, and previous treatments. Evolution of transplant strategies such as reduced-intensity conditioning, and donor lymphocyte infusion, combined with recognition of overlap phenomena, and late-onset aGVHD, have blurred the classic temporally defined division of aGVHD and cGVHD.

Prevention of GVHD is typically with a combination of methotrexate (MTX) and calcineurin inhibitor, with or without additional corticosteroids. Combinations using tacrolimus, cyclophosphamide, or mycophenolate mofetil (MMF) are also effective. Sirolimus, thalidomide, hydroxychloroquine, muromonab-CD3, alemtuzumab, suberoylanilide hydroxamic acid, keratinocyte growth factor, IL-1 receptor antibody, IL-2 receptor antibody, antithymocyte globulin, intravenous immunoglobulin, pentostatin, and extracorporeal photopheresis (ECP) have also been evaluated with mixed or preliminary results. Corticosteroids are not part of prophylaxis in spite of reductions in mild and severe aGVHD, as overall survival, disease-free survival, and incidence of relapse are not affected.

Following transplantation, 25–80% will manifest with aGVHD. For stage I aGVHD topical steroids are reasonable with or without phototherapy. For grade II-IV aGVHD first-line therapy is systemic corticosteroids, given in consultation with a transplant specialist (methylprednisolone 2 mg/kg/day, with eventual taper). If within 5 days there is no response, second-line therapy should be considered. Response to first-line therapy is the most important factor predicting long-term survival.

Second-line therapy should be initiated after non-response to high-dose steroids for 3 to 5 days, with MMF, tacrolimus, pentostatin, or antithymocyte globulin. Well designed trials do not exist to adequately compare therapies. Supportive care includes cessation of oral intake, total parenteral nutrition with hyperalimentation, antibiotic and antiviral prophylaxis, and pain control.

cGVHD treatment depends on extent of organ involvement. Skin or mucosal disease requires local therapy, whereas extensive disease (generalized cutaneous or localized cutaneous with visceral involvement) requires systemic therapy. Standard treatment is a combination of systemic corticosteroids with or without calcineurin inhibitor (prednisone 1 mg/kg/day and cyclosporine 10 mg/kg/day given as an alternating day regimen).

Refractory cGVHD has no standard therapy due to a lack of randomized controlled trials. Patients refractory to corticosteroids should be considered for clinical trials. Studies show MMF alone or in combination with cyclosporine, or tacrolimus, is beneficial in refractory disease. ECP is becoming reasonable first-line therapy in refractory cGVHD, where available. For sclerodermatous disease, salvage therapy with imatinib, or mTOR inhibitors are advocated. Lichenoid disease responds more with non-pharmacologic therapies such as 8-methoxypsoralen plus ultraviolet A irradiation (PUVA), and ECP.

Acute gvhd

Specific investigations

First-line therapies

image Corticosteroids (methylprednisolone 2 mg/kg/day) A

Second-line therapies

image Mycophenolate mofetil B
image Extracorporeal photopheresis B
image Monoclonal antibodies:  
 – Anti-IL2 receptor antibodies (daclizumab, basiliximab, inolimomab) B
 – Anti-TNF-α antibodies (infliximab, etanercept) B
image Cyclosporine B
image Tacrolimus B
image Sirolimus B

image