Guidelines for the Standardization of Acute Graft-Versus-Host Disease Clinical Data Collection: An International Consensus Report

Abstract

Clinical GVHD staging varies between centers and is not agreed upon by independent reviewers (Weisdorf, BBMT 2003). These inconsistencies help explain why promising GVHD treatments from single center studies have not reproduced in multicenter trials. To address this issue, our international GVHD research consortium has developed guidance that has been refined through consensus following case discussions, resulting in uniform and reproducible GVHD clinical symptom reporting.We record all raw target organ symptom data and apply staging based upon this data (Table 1). Only areas of erythema, bullae and desquamation are quantified because other skin changes are not typical of active GVHD rash. Upper GI symptoms must meet thresholds to diagnose GVHD: anorexia with associated weight loss, nausea and/or 2+ vomiting episodes/day lasting 3+ days. For lower GI GVHD we collect stool volumes excluding formed/mostly-formed stools. Unquantified episodes are counted at 200 ml per episode (3 ml/kg for children <50kg) based upon a chart review of 300 patients with post-BMT diarrhea from any cause. Non-GVHD rectal bleeding that results in flecks or streaks of blood in the stool are ignored for staging. We use the highest daily stool output in the 3 days prior to the diagnosis of lower GI GVHD to determine onset stage and, when available, a 3-day average stool volume for subsequent staging to smooth daily variability.We classify biopsy report interpretation into four standardized categories: Positive (unequivocal presence of GVHD), Equivocal (findings suggestive of GVHD, but the pathologist cannot confirm the diagnosis), Non-diagnostic (no abnormalities or subtle findings insufficient to determine etiology), and Non-GVHD etiology (definitive evidence of another diagnosis without concomitant features suggestive of GVHD). We then combine the biopsy interpretation with clinical decision making to assign an overall confidence level to the diagnosis of GVHD in each target organ (Table 2): Confirmed (positive biopsy, regardless of clinician treatment decision), Probable (GVHD diagnosis is sufficiently favored that treatment is given without a positive biopsy), Possible (symptoms present without a positive biopsy; not treated as GVHD), Negative (no symptoms or symptoms are present but a GVHD diagnosis is not entertained and a non-GVHD etiology is identified).Uniform clinical data collection is essential for future GVHD trials and requires application of clear guidance. While still subject to refinement, these guidelines, in use for 2 years by an international research consortium, are designed to be clear, easy to apply, and for clinical trial use.Table 1GVHD Target Organ StagingStageSkin (active erythema only)Liver (bilirubin)Upper GILower GI (stool output/day)0No active (erythematous) GVHD rash< 2 mg/dlNo or intermittent nausea, vomiting or anorexiaAdult: < 500 ml/day or <3 episodes/day Child: < 10 ml/kg/day or <4 episodes/day1Rash < 25% BSA2-3 mg/dlPersistent nausea, vomiting or anorexiaAdult: 500-999 ml/day or 3-4 episodes/day Child: 10 -19.9 ml/kg/day or 4-6 episodes/day2Rash 25 - 50% BSA3.1-6 mg/dl-Adult: 1000-1500 ml/day or 5-7 episodes/day Child: 20 - 30 ml/kg/day or 7-10 episodes/day3Rash > 50% BSA6.1-15 mg/dl-Adult: >1500 ml/day or >7 episodes/day Child: > 30 ml/kg/day or >10 episodes/day4Generalized rash (>50% BSA) and bullous formation or desquamation > 5% BSA>15 mg/dl-Severe abdominal pain with or without ileus, or grossly bloody stool (volume independent)Table 2Confidence LevelsPathologic evidenceClinician assessmentTreatment for acute GVHDCommentsConfirmedUnequivocal evidence of GVHDGVHD is the etiology for symptomsNot requiredGVHD is clearly present even if other etiologies co-exist simultaneouslyProbableNot required (includes equivocal and non-diagnostic biopsies)GVHD most likely etiology for symptomsYesGVHD is most likely present but other etiologies may also explain the symptoms and there insufficient evidence to make a confirmed diagnosisPossibleGVHD in differential diagnosis (but no treatment is being provided)NoGVHD may be present, but other etiologies are favoredNegativeUnequivocal evidence of a diagnosis other than GVHD (e.g., drug rash)GVHD is not considered as an explanation for the symptomsNo and the symptoms resolve without GVHD treatmentA "negative" biopsy (e.g., normal skin) is not unequivocal evidence of a diagnosis other than GVHD DisclosuresDevine:Genzyme: Research Funding. Chen:Bayer: Consultancy, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Consultancy.