An early-biomarker algorithm predicts lethal graft-versus-host disease and survival

Abstract

No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set ( = 309) and validation set ( = 358). A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group ( < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, < 0.001) and the multicenter validation set (26% vs. 10%, < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.

Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy

“…The serum level of the soluble form of ST2 was reported to be an important biomarker for therapy-resistance in patients developing acute GVHD 71 . Based on this observation an early-biomarker algorithm was studied for its predictive value for lethal acute GVHD 72 . A 4-biomarker panel [ST2, TNFR1, IL-2Rα chain(CD25), regenerating islet-derived protein-3 alpha(REG3α)], released from injured tissue or activated T effs , was used to predict increased acute GVHD-related death.…”

“…A 4-biomarker panel [ST2, TNFR1, IL-2Rα chain(CD25), regenerating islet-derived protein-3 alpha(REG3α)], released from injured tissue or activated T effs , was used to predict increased acute GVHD-related death. By modeling 6-month non-relapse mortality in an independent test set and validation set, a 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month nonrelapse mortality of 28% in the high-risk and 7% in the low-risk group 72 .…”

FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease

“…The efficacy analysis population was composed largely of adults with grades 3–4 (73%) GVHD; most had undergone transplantation using peripheral blood stem cells (80%) from a matched related or unrelated donor (76%). The cohort had a median MAGIC biomarker score of 0.47, and 83% were in the MAGIC biomarker high‐risk group . The median duration of prior corticosteroid exposure at baseline was 15 days (range: 3–106 days).…”

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

“…REG3α is secreted primarily by Paneth cells and functions as an antimicrobial peptide and regulator of Gram-positive bacteria in the gut 47 . A large study ( n = 1,287) that utilized a two-biomarker signature measuring ST2 and REG3α concentrations in the blood 1 week after HSCT identified patients who were at high risk of developing lethal GVHD (~20%) and reported a cumulative incidence of 6-month non-relapse mortality (NRM) of 28% in the high-risk group compared with 7% in the low-risk group ( P < 0.001) 48 . Compared with the low-risk group, high-risk patients had a significantly greater GVHD-related mortality (4% versus 18%, P <0.001) and risk of severe gastrointestinal acute GVHD (8% versus 17%, P <0.001).…”

“…Patients who present with only skin involvement at the time of diagnosis are classified as AA3 (high risk) by their bio-marker profiles and are twice as likely to develop gastrointestinal acute GVHD compared with patients who are classified as AA1 (low risk) 49 . The two-biomarker AA algorithm is superior to the three-biomarker algorithm, as it can accurately identify more patients who are at low risk, which is perhaps a result of the adoption of a commercial enzyme-linked immunosorbent assay (ELISA) that has increased sensitivity for detection of ST2, the best single biomarker, compared with that used when the initial three-biomarker AA algorithm was developed 48 . Although promising, this algorithm is currently best used in the context of a clinical trial, as it has not yet been demonstrated that a therapeutic intervention based on the biomarker risk can change long-term outcomes.…”