Chronic Graft-versus-Host Disease: Symptoms vary Utilizing the - PDF document

• Both inflammatory and fibrotic components Chronic Graft-versus-Host Disease: – Symptoms vary Utilizing the – 50% have 3 or more involved organs NIH Consensus Guidelines • Treatment is prolonged and may contribute to morbidity and mortality Stephanie J. Lee, MD MPH – Median duration of treatment is 2-3 years Fred Hutchinson Cancer Research Center – 15% still require treatment after 7 years February 3, 2012 – Infections cause 60-85% of deaths Disclosures: Astellas, research grant; All therapeutics are off-label Outline Health status • Overview of chronic GVHD • Chronic GVHD Consensus conference • Organ-specific and global severity scoring • Two clinical examples • Treatment • Information resources Fraser et al. Blood 2006;108:2867-2873 Chronic GVHD Impetus for the NIH Consensus Conference • No change in first line therapy since 1980’s • Most common long-term complication of allogeneic hematopoietic cell infusion • No standard second line therapy • No FDA approved therapies – Affects 30-70% of allogeneic recipients – Median onset 4-6 months • Literature sparse, heterogeneous – 90-95% of cases diagnosed within 1 year • Difficult to interpret clinical trials – Leading cause of non-relapse mortality – Diagnosis not standardized • 25% of deaths in 2 year survivors – Severity scale dichotomous • 11% of deaths in 5 year survivors – Response measures not defined

NIH Consensus Development Project on 2005 NIH Revision Criteria for Clinical Trials in Chronic GVHD (June 6, 2005) Chairs: Steve Pavletic & Georgia Vogelsang LATE ACUTE (15-48%) • Diagnosis and scoring (Filipovich et al) • Pathology (Shulman et al) CLASSIC ACUTE OVERLAP (20-48%) CLASSIC CHRONIC (9-60%) • Biomarkers (Schultz et al) • Response criteria (Pavletic et al) BBMT 2005; 11: 945 • Supportive care (Couriel et al) 2006; 12: 31 12: 126 Day 0 Day 100 Cho 2008; Vigorito 2009 • Clinical trials (Martin et al) 12: 252 Graft infused 12: 375 Jagasia 2007; Arora 2008 Pidala 2012 12: 491 Diagnosis and Scoring Diagnostic Manifestations SKIN GI • Criteria for chronic GVHD diagnosis • Poikiloderma • Esophageal web, stricture • Lichen-planus – 1 Diagnostic finding OR 1 Distinctive finding plus • Sclerosis Joints biopsy/test confirmation • Morphea • Fasciitis • Lichen sclerosis • Contractures • Categories of organ-specific severity (0-3) MOUTH Genital – Skin, Mouth, Eyes, Lung, GI tract, Liver, Joints and • Lichen-planus • Lichen planus Fascia, Genital Tract • Hyperkeratotic plaques • Stenosis • Sclerosis • Calculation of overall (global) severity Lung – Mild, Moderate, Severe • Bronchiolitis obliterans on bx Filipovich et al, BBMT 2005; 11: 945 Acute and Chronic GVHD Seattle 1980-2008 N>5050 100d DFS All allo Tx Clinical ext ACUTE CHRONIC chronic GVHD Day 0 Day 100 Graft infused Storer, unpublished data

NIH Skin Score NIH Lung Score 0 1 2 3 ฀ No Symptoms ฀ Mild symptoms ฀ Moderate ฀ Severe 0 1 2 3 (shortness of symptoms symptoms ฀ No ฀ < 18% ฀ 19-50% BSA ฀ >50% BSA Clinical breath after (shortness of breath (shortness of features OR involvement OR deep Symptoms BSA with climbing one flight after walking on flat breath at rest; ฀ Maculopapular rash disease with superficial sclerotic ฀ Lichen planus-like of steps) ground) requiring O 2 ) signs but sclerotic features ฀ Papulosquamous NO ฀ Ichthyosis features “not “hidebound” ฀ Hyperpigmentation sclerotic hidebound” (unable to ฀ Hypopigmentation pinch) OR features (able to pinch) ฀ Keratosis pilaris ฀ FEV1 > 80% ฀ FEV1 60-79% ฀ FEV1 40-59% OR ฀ FEV1 <39% ฀ Erythema impaired OR LFS=2 OR LFS 3-5 LFS 6-9 OR LFS 10-12 ฀ Erythroderma mobility, ฀ Poikiloderma ulceration or ฀ Sclerotic features ฀ Pruritus severe LFS = FEV1 score + DLCO score > 80% = 1 ฀ Hair involvement 70-79% = 2 pruritus ฀ Nail involvement 60-69% = 3 % BSA 50-59% = 4 involved____ 40-49% = 5 ♦ Symptoms and PFTs < 40% = 6 ♦ % BSA and degree of sclerosis NIH Eye Score Body Surface Area – Rule of 9s 0 1 2 3 ฀ No Symptoms ฀ Mild dry eye ฀ Moderate dry eye ฀ Severe dry eye symptoms not symptoms partially symptoms affecting ADL affecting ADL significantly (requiring eyedrops (requiring drops > 3 x affecting ADL < 3 x per day) OR per day or punctal (special eyeware to asymptomatic plugs) WITHOUT relieve pain) OR signs of kerato- vision impairment unable to work conjunctivitis sicca because of ocular symptoms OR loss of vision caused by kerato-conjunctivitis sicca ♦ Symptoms and interventions NIH Mouth Score Other organs • Liver 0 1 2 3 ฀ No Symptoms ฀ Mild symptoms ฀ Moderate ฀ Severe – Total bilirubin, alkaline phosphatase, ALT/AST with disease signs symptoms with symptoms • Gastrointestinal but not limiting disease signs with with disease oral intake partial limitation of signs on – Dysphagia, anorexia, nausea, vomiting, diarrhea, significantly oral intake examination abdominal pain, weight loss with major limitation of • Joint and fascia oral intake – Tightness, contractures, range of motion, ADLs • Genital ♦ Symptoms and limitation of oral intake – Physical findings, pain

NIH Eye Score Example 1 • Diane, a 36 y/o woman 0 1 2 3 ฀ No Symptoms ฀ Moderate dry eye ฀ Severe dry eye  Mild dry eye – Maculopapular rash on her face and upper chest symptoms partially symptoms symptoms not affecting ADL significantly – Food sensitivity, lichen-planus-like oral changes affecting ADL (requiring drops > 3 x affecting ADL (requiring eyedrops – Dry eyes, using eyedrops twice a day per day or punctal (special eyeware to < 3 x per day) OR plugs) WITHOUT relieve pain) OR asymptomatic vision impairment unable to work signs of kerato- because of ocular conjunctivitis sicca symptoms OR loss of vision caused by kerato-conjunctivitis Dry eyes, using eyedrops twice a day sicca ♦ Symptoms and interventions NIH Skin Score Example 2 0 1 2 3 • Mark, a 49 y/o man Clinical ฀ No  < 18% ฀ 19-50% BSA ฀ >50% BSA – Sclerosis involving his arms features OR involvement OR deep Symptoms BSA with  Maculopapular rash with superficial sclerotic disease – Oral ulcers, unable to eat spicy foods ฀ Lichen planus-like sclerotic features ฀ Papulosquamous signs but features “not “hidebound” ฀ Ichthyosis – No other organs involved NO ฀ Hyperpigmentation hidebound” (unable to sclerotic ฀ Hypopigmentation pinch) OR (able to pinch) ฀ Keratosis pilaris features ฀ Erythema impaired ฀ Erythroderma mobility, ฀ Poikiloderma ulceration or ฀ Sclerotic features ฀ Pruritus severe ฀ Hair involvement pruritus ฀ Nail involvement % BSA Maculopapular rash on her face and upper chest (10%) involved 10% ♦ % BSA and degree of sclerosis NIH Mouth Score NIH Skin Score 0 1 2 3 0 1 2 3 Clinical ฀ No ฀ < 18% ฀ 19-50% BSA  >50% BSA ฀ No Symptoms ฀ Moderate ฀ Severe  Mild symptoms features OR involvement Symptoms BSA with OR deep symptoms with symptoms with disease signs ฀ Maculopapular rash disease with superficial sclerotic disease signs with with disease ฀ Lichen planus-like but not limiting signs but sclerotic ฀ Papulosquamous features partial limitation of signs on NO oral intake features “not ฀ Ichthyosis “hidebound” oral intake examination ฀ Hyperpigmentation significantly sclerotic hidebound” (unable to with major ฀ Hypopigmentation features (able to pinch) ฀ Keratosis pilaris pinch) OR limitation of ฀ Erythema impaired oral intake Food sensitivity, lichen-planus-like oral changes ฀ Erythroderma ฀ Poikiloderma mobility,  Sclerotic features ulceration or ฀ Pruritus severe ฀ Hair involvement ♦ Symptoms and limitation of oral intake Sclerosis involving his arms (BSA 18%) ฀ Nail involvement pruritus % BSA involved 18% ♦ % BSA and degree of sclerosis