Acute Graft-versus-Host Disease (agvhd) Udomsak Bunworasate Chulalongkorn University

Acute Graft-versus-Host Disease (agvhd) Udomsak Bunworasate Chulalongkorn University

Graft-versus-Host Disease (GVHD) Background GVHD is an immunologic reaction of the donor immune cells (Graft) against the Host tissues

Three Requirements for The Development of GVHD 1. Graft must contain immunologically competent cells (T cells) 2. Recipient must express tissue antigens not present in the donor (Antigenic differences) 3. Recipient incapable of mounting an effective response to reject transplanted cells Setting: AlloSCT, transfusion-associated GVHD Billingham

GVHD After disease relapse, GVHD is the most common cause of treatment failure after allosct 2 syndromes Acute GVHD (agvhd) Chronic GVHD (cgvhd) Previously defined by temporal relationship to time of transplantation (before and after 100 days) Now defined by clinical features Differences in pathophysiology

GVHD After AlloSCT Acute GVHD: Skin, GI, liver Alloreactivity Autoimmunity Immunodeficiency Classic acute Late acute Overlap Chronic GVHD: Skin, eyes, mouth, GI, liver, musculoskeletal, lungs, GU, etc. Classic chronic Day 0 50 100 180 1 yr 2 yrs 3 yrs 5 yrs Activity (inflammation) Injury Repair Damage (fibrosis)

Graft-versus-Leukemia (GVL) Horowitz et al. Blood 1990

Horowitz et al. Blood 1990

Pathophysiology of agvhd Skin GI Tract Liver Prof. Ferrara T reg T reg

Pathophysiology of agvhd N Engl J Med 2017;377:2167-79.

Acute GVHD (agvhd) Incidence: 35% after related donor transplantation 50% after unrelated donor transplantation Despite prophylaxis Current standard prophylaxis: Cyclosporine + MTX better than Cyclosporine alone No benefit in adding corticosteroid Tacrolimus + MTX may be better than cyclosporine + MTX (in unrelated transplant)

Classic Approaches to Immunosuppression

GVHD Prophylaxis REGIMENS Calcineurin inhibitor (Tacrolimus/Cyclosporine) + MTX Tacrolimus + Sirolimus Cellcept-based regimen ATG-based regimen Decrease both agvhd and cgvhd Post-transplant Cyclophosphamide In haploidentical SCT Continue calcineurin inhibitor for at least 3-6 months and taper Depends on Donor source Risk of disease relapse Occurrence of GVHD

Post-transplant Cyclophosphamide Luznik et al. Semin Oncol. 2012

Factors Donor-Recipient Factors Major HLA Disparity (HLA Class I,II) Minor HLA Disparity (mha) Sex Matching Donor Parity Donor Age ABO type Donor CMV Serostatus Cytokine Gene Polymorphisms Stem Cell Graft Factors Stem cell source Graft composition Transplantation Factors Conditioning Intensity Increase Risk of agvhd HLA mismatched donor > Matched donor Unrelated donor > Related donor Female donor to male recipient Multiparity > Nulliparity Older donor > Younger donor ABO mismatch > ABO match CMV positive > CMV negative Numerous associated with agvhd PBSC > BM > UCB Higher CD34+ count > Lower CD34+ count Higher T cell dose > Lower T cell dose Myeloablative > RIC regimens

Skin GVHD Most commonly affected organ in agvhd 75% of all GVHD patients have some skin involvement 45% have isolated skin involvement Maculopapular rash (typically palms and soles) MP rash -> Bullae -> Desquamation Median time of onset ~ 17 days Main diagnostic consideration: Drug eruption

GI GVHD Up to 50% of GVHD patients have GI involvement Upper GI: Nausea/vomiting, anorexia, weight loss Lower GI: Secretory diarrhea (may be bloody), abdominal pain, ileus Often develops during conditioning-related injury period main DDx; also must exclude infection, drug: Endoscopy and biopsy

Liver GVHD Least commonly affected organ < 20% Cholestatic jaundice +/- transaminitis as clinical features Drug reaction, TPN, infection, VOD as main alternate diagnostic criteria Biopsy standard for diagnosis (may be difficult due to concurrent thrombocytopenia)

Stage Skin BSA (%) agvhd: Staging Liver Bilirubin (mg/dl) Upper GI 1 MP rash <25% 2-3 Persistent N/V or anorexia Lower GI Stool output/day >500 ml 2 25-50% 3.1-6 >1000 ml 3 >50% 6.1-15 >1500 ml 4 Erythroderma >15 Pain++ + bullae, +/- ileus, desquamation bloody stool The European Group for Blood and Marrow Transplantation

agvhd: Consensus Grading Grade Skin Liver GI Stage Stage Stage I 1-2 0 0 II 3 1 1 5-year survival - Grade III: 25% - Grade IV: 5% III - 2-3 2-4 IV 4 4 - The European Group for Blood and Marrow Transplantation

Mount Sinai Acute Graft-versus-Host Disease International Consortium (MAGIC)

31% 5%

14% 5%

agvhd Treatment Steroid remains the standard first line therapy Methylprednisolone or prednisolone 1-2 mg/kg/day 1mg/kg might be enough for grade II disease CR rate ~ 50% Grade I skin GVHD Managed with topical treatment (0.1% TA or 0.03%/0.1% Tacrolimus cream) + optimizing immunosuppression levels Non-absorbable steroid are very useful adjuvant therapy in GI GVHD Survival correlates directly with the response to initial therapy

Advanced agvhd Long term outcome for early agvhd > 80% Much poorer for advanced: Some estimates as low as 10-20% Current 2 nd line agents effective, but too immunosuppressive->infectious death Steroid-refractory GVHD: Defined variably as: Progression after 3 days No response after 7 days Long-term survival 5-30%

Salvage Therapy for Steroid-refractory agvhd m-tor inhibitor Sirolimus (Rapamycin) Cellcept Anti-TNF antibodies Infliximab, Etanercept Extracorporeal photopheresis (ECP) T-reg (Regulatory T cells) Mesenchymal stromal cells Fecal microbiota transplantation

JAK1/2 Inhibitor in Steroid-refractory agvhd Ruxolitinib -ORR 82% (45/54 pts); CR 46% (25 pts) - Adverse events included cytopenias (56%) and CMV reactivation (33%) Zeiser R, et al. Leukemia. 2015;29:2062-2068.

agvhd Biomarkers Markers of inflammation (such as IL-2Rα, TNFR1, ST2) Products secreted when end organs are damaged (such as elafin [skin], REG3α [GI]) ST2, REG3α levels Predict the risk of agvhd Predict treatment response

CHULA HSCT Team