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3154 Guidelines for the Standardization of Acute Graft-Versus-Host Disease Clinical Data Collection: An International Consensus Report

Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution
Program: Oral and Poster Abstracts
Session: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster II
Sunday, December 6, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Andrew C. Harris, MD1,2, Rachel Young2*, Steven M. Devine, MD3, William J Hogan, MBChB4, Francis Ayuk, M.D.5*, Udomsak Bunworasate6, Chantiya Chanswangphuwana, MD6*, Yvonne A Efebera, MD3, Ernst Holler, MD, PhD7*, Mark R Litzow, MD4, Rainer Ordemann, MD8*, Muna Qayed, MD, MSc9, Anne S. Renteria, MD10, Ran Reshef, MD11, Matthias Wölfl, MD12*, Yi-Bin Chen, MD13, Steven Goldstein, MD2*, Madan H. Jagasia14, Franco Locatelli, MD, PhD15, Stephan Mielke, MD12, David L Porter, MD16, Tal Schechter, MD17*, Zhanna Shekhovtsova, MD18*, James L.M. Ferrara, MD, DSc10 and John E. Levine, MD, MS2,19,20

1University of Utah, Primary Children's Medical Center, Salt Lake City, UT
2University of Michigan, Ann Arbor, MI
3The Ohio State University, Columbus, OH
4Division of Hematology, Mayo Clinic, Rochester, MN
5University Medical Center Hamburg-Eppendorf, Hamburg, Germany
6Chulalongkorn University, Bangkok, Thailand
7University of Regensburg, Regensburg, Germany
8University Hospital TU Dresden, Dresden, Germany
9Emory University, Atlanta, GA
10Mount Sinai Medical Center, New York, NY
11Columbia University Medical Center, New York, NY
12University of Würzburg, Würzburg, Germany
13Massachusetts General Hospital, Boston, MA
14Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN
15University of Pavia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
16Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
17The Hospital for Sick Children, Toronto, Canada
18Federal Center for Pediatric Hematology, Moscow, Russia
19Blood and Marrow Transplant Program, Mount Sinai School of Medicine, New York, NY
205303 Cancer Center, Univ. of Michigan Medical Ctr., Ann Arbor, MI

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 1: GVHD Target Organ Staging

Stage

Skin (active erythema only)

Liver (bilirubin)

Upper GI

Lower GI (stool output/day)

0

No active (erythematous) GVHD rash

< 2 mg/dl

No or intermittent nausea,

vomiting or anorexia

Adult: < 500 ml/day or <3 episodes/day

Child: < 10 ml/kg/day or <4 episodes/day

1

Rash < 25% BSA

2-3 mg/dl

Persistent nausea,

vomiting or anorexia

Adult: 500–999 ml/day or 3-4 episodes/day

Child: 10 -19.9 ml/kg/day or 4-6 episodes/day

2

Rash 25 – 50% BSA

3.1-6 mg/dl

                    -

Adult: 1000-1500 ml/day or 5-7 episodes/day

Child: 20 – 30 ml/kg/day or 7-10 episodes/day

3

Rash > 50% BSA

6.1-15 mg/dl

                    -

Adult: >1500 ml/day or >7 episodes/day

Child: > 30 ml/kg/day or >10 episodes/day

4

Generalized 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 2: Confidence Levels

 

Pathologic evidence

Clinician assessment

Treatment for

acute GVHD

Comments

Confirmed

Unequivocal evidence

of GVHD

GVHD is the etiology

for symptoms

Not required

GVHD is clearly present even if other etiologies co-exist simultaneously

Probable

Not required (includes equivocal and non-diagnostic biopsies)

 

GVHD most likely etiology for symptoms

Yes

GVHD is most likely present but other etiologies may also explain the symptoms and there insufficient evidence to make a confirmed diagnosis

Possible

GVHD in differential diagnosis (but no treatment is being provided)

No

GVHD may be present, but other etiologies are favored

Negative

 

Unequivocal evidence of a diagnosis other than GVHD (e.g., drug rash)

GVHD is not considered as an explanation for the symptoms

No and the symptoms resolve without GVHD treatment

A “negative” biopsy (e.g., normal skin) is not unequivocal evidence of a diagnosis other than GVHD

Disclosures: Devine: Genzyme: Research Funding . Chen: Regimmune: Research Funding . Levine: Novartis: Consultancy .

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