Acute GVHD Diagnosis and Adjudication in a Multicenter Trial: A Report From the BMT CTN 1202 Biorepository Study

Abstract

Purpose: Accurate and reproducible methods to diagnose, grade, and report acute graft-versus-host disease (GVHD) are critical for the evaluation of therapies and biomarkers.

Patients and methods: The Blood and Marrow Transplant Clinical Trials Network 1202 study is an observational study of 1,709 allogeneic hematopoietic cell transplantation recipients that implemented weekly data reporting and near real-time data adjudication by an end point review committee (ERC), assigning a confidence level (confirmed, probable, possible, or negative) to the diagnosis of acute GVHD at onset.

Results: During the first 100 days, symptoms consistent with GVHD developed in 90% of cases but were often determined by centers to be due to causes other than GVHD. Indeed, GVHD was under consideration in only 23% of cases at symptom onset. Diagnostic biopsies were obtained in 40% of cases, but treatment often was incongruous with biopsy findings and 10.5% of biopsies were equivocal. Importantly, more than 40% of steroid courses were started for reasons other than GVHD. The ERC modified the determination of GVHD diagnosis and/or grade in 12.3% of onset cases. The cumulative incidence of acute GVHD as reported by the centers was 62%. When the ERC adjudicated GVHD onset to be present only if the confidence level was probable or confirmed, the incidence of GVHD declined to 49%.

Conclusion: This study demonstrates that the incidence of GVHD may be overestimated at symptom onset, establishes a contemporary benchmark for acute GVHD, and suggests a structured framework for reporting and adjudication of GVHD that could be used in prospective trials.

FIG 1.

GVHD symptoms and site-reported etiologies. (A) Proportion of patients experiencing symptoms in at least one GVHD target organ. Each bar represents the prevalence of GVHD symptoms among the study population in each week following transplant. The number of evaluable patients and percentage experiencing symptoms are listed below each week. (B-E) Etiologies reported for symptoms in each GVHD target organ. Each bar shows the distribution of potential etiologies that were assigned by the reporting center. The percentages of patients reporting symptoms in the respective target organ in each week are listed below each panel. The Other category includes infection, total parenteral nutrition, engraftment syndrome, and unspecified etiologies if they were indicated as the only etiology. GVHD, graft-versus-host disease; VOD, veno-occlusive disease.

FIG 2.

(A) Proportion of patients receiving systemic steroids. Each bar represents the proportion of patients receiving steroids in each assessment week, and the colors indicate the reason for steroid therapy and whether it was a new start or ongoing therapy. This figure includes patients who received at least 10 mg/d of prednisone or equivalent (0.125 mg/kg/d in pediatric patients) in each week. (B) End point review committee (ERC) confidence level by adjudicated acute GVHD grade. Each bar represents the proportions of patients who were assigned a confirmed, probable, possible, or negative confidence level according to the acute GVHD grade assigned by the ERC at review. GVHD, graft-versus-host disease.

FIG 3.

Cumulative incidence plots of acute graft-versus-host disease (GVHD) onset by site report (A) and by end point review committee confidence level (B). All grade GVHD cases are presented together because only onset grade and not maximal grade were adjudicated for each patient, and therefore, plots of GVHD by grade will not represent the true incidence.

FIG A1.

Flow diagram of the ERC review process. ERC, end point review committee.

FIG A2.

Kaplan-Meier plots of overall survival and non-relapse mortality following transplant.

FIG A3.

Cumulative incidence plots of (A) acute GVHD grade I-IV, (B) grade II-V, and (C) grade III-IV through day 180. Death was treated as a competing risk. Data were obtained from CIBMTR and were not adjudicated by the adjudication committee. CIBMTR, Center for International Blood and Marrow Transplant Research.

FIG A4.

Cumulative incidence plots of chronic GVHD and disease relapse/progression 12 months. Death was treated as a competing risk. Data were obtained from CIBMTR and were not adjudicated by the adjudication committee. CIBMTR, Center for International Blood and Marrow Transplant Research.

FIG A5.

Proportions of equivocal biopsies in each participating center in descending order. The total number of biopsies reported from each center is displayed above each bar.

FIG A6.

Biopsy results by organ system and assessment week.

FIG A7.

Proportion of patients receiving systemic steroids. Each bar represents the proportion of patients receiving steroids in each assessment week and the colors indicate the reason for steroid therapy and whether it was a new start or ongoing therapy. This figure includes patients who received any oral or IV steroids in each week.