Graft versus Host Disease and how to report it
Daniel Weisdorf MD University of Minnesota
Transplant Events
Day-8 0 1mo 3mo 6mo
Conditioning HSCT Engraftment Mucositis Organ toxicity (VOD) Acute GVHD Chronic GVHD
Infections Bacterial ----CMV---- Varicella------Fungus------
Transplant Events
Day-8 0 1mo 3mo 6mo
Conditioning HSCT Engraftment Mucositis Organ toxicity (VOD) Acute GVHD Chronic GVHD
Infections Bacterial ----CMV---- Varicella------Fungus------
1 Acute GVHD Chronic GVHD Skin: Lichen planus, Hyper/ hypo pigmentation, Dermatitis ichthyosis, onychodystrophy, morphea, + scleroderma, hair changes. Hepatitis Oral: sicca, atrophy, lichenoid, + Hyperkeratosis GI: wasting, dysphagia, Enteritis odynophagia, strictures Eye: keratoconjunctivitis sicca Lungs: Bronchiolitis obliterans Others: myofascial, genital
Acute GVHD Chronic GVHD Dermatitis Rash + Hepatitis High bilirubin + Enteritis Nausea/vomiting/ diarrhea
Acute GVHD Chronic GVHD Skin: Lichen planus, Scaly abnormal pigmentation, Dry skin, onychodystrophy, abnormal nails scleroderma, thick skin hair changes. Oral: sicca, atrophy, lichenoid, Dry mouth
GI: wasting, dysphagia, Weight loss odynophagia, trouble swallowing Eye: keratoconjunctivitis sicca Dry eyes Lungs: Bronchiolitis obliterans Obstruction Others: myofascial, muscle stiffness Genital vaginal narrowing
2 Graft vs. Leukemia Effect
• Less leukemia relapse follows more GVHD
• Acute and particularly Chronic GVHD limit relapse
Risk Factors for GVHD Acute GVHD Chronic GVHD Increased risk Increased risk HLA mismatch Older age Older recipients Prior acute GVHD Older donors HLA mismatch High dose TBI alloimmune female donor: male recipient Reduced risk Reduced risk T cell depletion Cord blood Non-myeloablative conditioning?
Pathogenesis of GVHD
Host tissue injury: Activates or damages host APC; Augments class I & adhesion expression Inflammatory milieu
Donor T cells recognize host polypeptides as foreign. major & minor HLA plus tissue antigens
T cell recognition, activation, and host tissue injury Direct cell mediated attack, Production of inflammatory mediators (TNF IFN) Recruitment of secondary effectors
Induces cell injury and inflammation----Acute GVHD
3 Pathophysiology of chronic GVHD
• Alloreactive T cells • Donor T cells recognize foreign tissues • T cells grow in response to alloantigens or autoantigens • Attack target tissues directly, secretion of cytokines, promote B cell activation and autoantibody production
Tissue injury; Fibrosis------Chronic GVHD
Can we recognize GVHD?
GVHD grading schema
Glucksberg 1974 43 of 61 patients with GVHD Thomas et al BMT review 1975
UGI Weisdorf et al 1990
Consensus Grading 1995 accepted UGI, lessened emphasis on performance status
IBMTR 1997 A B C D narrowed B due to heterogeneity of grade II
4 Staging of Acute GVHD
Skin Lower GI Upper GI Liver Rash Diarrhea 0 -- none -- Bili <2.0 mg/dl
1 <25% <500 ml N/V 2.1-3.0 <280 ml/m2
2 25-50% 500-1000 3.1-6.0 280-555/ m2
3 >50% 1000-1500 6.1-15 generalized 556-833/ m2
4 + bullae 1500+ >15.1 desquamation >833/ m2
Record of Clinical GVHD data
Clinical GVHD Assessment Date______Karnofsky/Lansky______Stage Biopsy Differential Diagnosis 0123 4 + - E Drug TPN VOD Infect Other Skin %body rash:______Lower GI diarrhea vol:______Liver max bili:______Upper GI ______
Treatment: CSA MMF Pred/MPred TCM/HCT ATG FK506 Infliximab MPred Boluses Study______Other______Signature______
Record of Clinical GVHD data
Clinical GVHD Assessment Date______Karnofsky/Lansky______Stage Biopsy Differential Diagnosis 0123 4 + - E Drug TPN VOD Infect Other Skin %body rash:______Lower GI diarrhea vol:______Liver max bili:______Upper GI ______
Treatment: CSA MMF Pred/MPred TCM/HCT ATG FK506 Infliximab MPred Boluses Study______Other______Signature______
Data managers Dream
5 6 80% skin 6% liver at onset of 18% LGI therapy 24% UGI MacMillan et al, BBMT, 2002
MacMillan et al, BBMT, 2002
GVHD prevention
• Optimize donor selection
Incidence of AGVHD HLA identical sibling donor: 40% HLA identical unrelated donor: 50-60% Cord blood: 25-50%
Incidence of CGVHD HLA identical sibling donor: 33% HLA identical unrelated donor: 65% Cord blood: 10-30%
7 Therapeutic Interventions in GVHD
Deplete Tolerize Donor T cells Inactivate } Deplete host APCs In vivo deplete stimulated T cells
Reduce secondary inflammation
Therapeutic Interventions in GVHD
Deplete Graft modulation TCD Tolerize Donor T cells Block costimulation Add T reg Inactivate } Add NK or MSC Deplete host APCs Drug Therapy In vivo deplete stimulated T cells Immunosuppressive Blunt proliferation In vivo T cell lysis Reduce secondary inflammation Anti-cytokines Block target lysis
Drugs to prevent GVHD
Mtx CSA Tacrolimus (FK506)
MMF Sirolimus (rapamycin)
ATG Anti-TNF (infliximab, etanercept) Anti-cytokines Others…..
8 Acute GVHD--Treatment
Standard GVHD treatment—Corticosteroids Durable response 40% Sibling donors 25% Unrelated donors but
60-75% need additional therapy For steroid-refractory disease, no standard effective treatments are available
GVHD Therapy Agents
Corticosteroids + CSA/Tac
Daclizumab; Visiluzimab Infliximab, Etanercept Sirolimus MMF Pentostatin, Fludarabine ATG; Thymoglobulin Photopheresis
Corticosteroids
Used for decades lympholytic, but not tolerizing; anti-cytokine no specificity for activated T cells
Lots of toxicities infections, osteopenia, cataracts, AVN BP, DM, myopathy, skin atrophy
9 Steroid therapy of Acute GVHD PR/CR cGVHD N=443 20/35% 42%
Initial Grade (%) cGVHD % I2839 II 60 44 III/IV 13 42
MacMillan et al, BBMT, 2002
Factors predicting PR/CR to steroid therapy Variable Relative Likelihood P of CR/PR (95% CI) Type of donor Related 1.0 Matched unrelated Mismatched unrelated 0.8 (0.5 - 1.4) 0.52 0.5 (0.3 - 0.8) <0.01 GVHD prophylaxis CSA 1.0 Methotrexate alone 0.3 (0.1 - 0.6) <0.01 T-cell depletion 0.9 (0.5 - 1.6) 0.77 Tacrolimus 1.2 (0.4 - 3.8) 0.63 Initial grade of GVHD I 1.0 II 0.9 (0.6 - 1.5) 0.79 MacMillan et al, III 0.8 (0.4 - 1.7) 0.66 BBMT, 2002 IV 0.3 (0.1 - 1.9) 0.23
ATG
Active in steroid refractory GVHD, overall responses 19-56% skin responses 59-79% Randomized trials 1980s and 1990s—no benefit
1-year mortality 60-90%. Deaths typically not from GVHD opportunistic infections, EBV
10 Anti-IL2 R Antibodies
Anti-CD25 murine monoclonals B-B10 and BT563 CR 66% -73%
Daclizumab humanized IgG1 monoclonal antibody binds alpha subunit (p55 alpha, CD25, or Tac) of IL-2R inhibits IL-2 binding
Daclizumab Germany Willenbacher et al; Brit J Haem 2001 N=16; 12 steroid resistant acute (6 responded). 14 of 16 developed infections, 2 fatal
Przepiorka et al, Blood 2001 N=43 steroid refractory. Weekly (n=29) to day 42 CR 29%, 120 day survival 29% 2-3 x weekly (n=19) CR 47%, 120 day survival 53%
Wolff (ASH abstract) Daclizumab + etanercept n=12; 6 CR; 4PR; 1 early death; 1 NR
Randomized trial: Prednisone +/- Daclizumab for Initial GVHD therapy Dacliz +Pred Prednisone p GVHD control 53% 51% 0.85
100-day survival 77% 94% 0.02 Overall survival 29% 60% 0.002
Lee et al, Blood, 2004
11 Initial Systemic Treatment of Acute GVHD : A Phase II randomized trial
BMT CTN 0302
Acute/Chronic GVHD Committee D Weisdorf, B Logan, J Antin, J Ferrara, S Lee, D Couriel, R Soiffer, R Nash, M Horowitz, S Carter, R Goyal, J Klein et al
Study goal
To test new agents to treat Acute GVHD Define those promising for testing against steroids alone in a subsequent comparative, Phase III trial.
Historical control data using prednisone alone: Minnesota, Dana Farber, Seattle
Expected 35% CR at day 28 of therapy
Etanercept [25 mg sc BIW for up to 8 weeks] MMF [must be off MMF for ≥ 14 days to be eligible] Ontak [9 mcg/kg IV d 1,3,5 d 15,17,19] Pentostatin 1.5 mg/m2 qd x 3 d; day 1-3 & day 15-17
Study Agents all given with: Prednisone 2 mg/kg/d for ≥ 7 days; Taper as tolerated to not < 1 mg/kg/d at day 28
12 Prednisone + Etanercept, MMF, Ontak & Pentostatin were chosen
Plan follow-up randomized trial as this trial proceeds
Therapeutic Interventions in GVHD
Deplete Graft modulation TCD Tolerize Donor T cells Block costimulation Inactivate } Add T reg Add NK or MSC Deplete host APCs Drug Therapy In vivo deplete stimulated T cells Immunosuppressive Blunt proliferation In vivo T cell lysis Reduce secondary inflammation Anti-cytokines Block target lysis
And now the forms
• Accurate and adequate data collection for both acute and chronic GVHD. • Organ involvement. • Severity
13 Plus others………
Diagnosis of Acute GVHD
GRADE
ORGAN STAGE
14 Treatment of acute GVHD
Acute GVHD – Dermatological
• Maculo-papular rash
Apoptotic crypt cells on GI histology
Skin biopsy showing interface dermatitis
15 Chronic GVHD - Dermatological
• Same as acute GVHD • Atrophy and erythema of oral mucosa • Lichenoid lesions of skin, buccal and labial mucosa • Sclerodermatous skin thickening • Joint contractures
Sclerotic cGVHD of the lips and mucosa with restricted mouth opening
Skin involvement with cGVHD
16 Chronic GVHD
Limited skin involvement: topical steroids.
Systemic Therapy: Steroids plus CSA or tacrolimus are the mainstay of therapy for CGVHD
cGVHD requiring systemic therapy (n=159)
6 mo 1 year 2 years CR+PR 61.3% 52.7% 50.4% NR+Flare 38.7% 47.3% 49.6%
Arora et al BBMT 2003
Overall Survival and Duration of Immunosuppression
Arora et al BBMT 2003
17 Treatment of refractory CGVHD
Combination therapy
MMF Rituximab sirolimus ATG Pentostatin Pulse methylprednisolone (steroids) Hydroxychloroquine Others
ECP (extracorporeal photopheresis)
Diagnosis of cGVHD
• Traditional definition: beyond day 100 post transplant.
• Changes in transplant strategy have altered the presentation and natural history of CGVHD.
NIH consensus conference October 2005-May 2006, BBMT Diagnosis and staging Response criteria Biomarkers Supportive care
Time after aGVHD cGVHD Category HCT or DCI Symptoms Symptoms
Acute GVHD
Classic aGVHD ≤100 d Yes No Persistent, recurrent, or >100 d Yes No late-onset acute GVHD Chronic GVHD No time Classic cGVHD No Yes limit Overlap No time Yes Yes syndrome limit
18 Consensus Criteria for diagnosing cGVHD
Diagnostic signs and symptoms: establish chronic GVHD without further testing or evidence of other organ involvement.
Distinctive signs and symptoms: not ordinarily found in acute GVHD not sufficient for diagnosis of chronic GVHD without additional organ involvement.
• Other features uncommon or nonspecific features of cGVHD cannot be used to establish the diagnosis
• Common signs and symptoms are found in both chronic and acute GVHD
Organ Diagnostic features Distinctive features Skin Poikiloderma Lichen planus/ Depigmentation Sclerotic features/ Morphea- like features Nails Dystrophy. Longitudinal ridging, splitting, or brittle nails. Onycholysis Pterygium unguis. Nail loss Scalp, New onset of scarring or nonscarring hair scalp alopecia. Scaling, papulosquamous lesions Mouth Lichen-type features Xerostomia, Mucocele, Mucosal Hyperkeratotic plaques atrophy, Pseudomembranes Restriction of mouth opening Ulcers
19 Organ Diagnostic features Distinctive features
Eyes New onset dry, gritty, or painful eyes, Cicatricial conjunctivitis Keratoconjunctivitis sicca, punctate keratopathy Genitalia Lichen planus-like Erosions, Fissures, Ulcers features Vaginal scarring or stenosis GI tract Esophageal web, strictures or stenosis in the esophagus Lung BO diagnosed with lung BO diagnosed with PFTs and biopsy radiology Muscles, Fasciitis, joint stiffness or Myositis or polymyositis joints contractures
• 1 diagnostic manifestation of chronic GVHD or
• at least 1 distinctive manifestation, confirmed by pertinent biopsy, laboratory tests, or radiology
Scoring of cGVHD
• Score 0-3 to each organ based on severity of organ involvement
• Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung), • little functional impairment (maximum of score 1 in all affected organs or sites).
20 Moderate chronic GVHD • 1 organ with clinically significant but no major disability (maximum score of 2 in any affected organ or site) or • 3 or more organs or sites with no clinically significant functional impairment (maximum score of 1 in all affected organs or sites). • Lung score of 1
Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in any organ or site). Lung score of 2
Plus others
21 Duration of Chronic GVHD Therapy
Questions????
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