Patients from MAGIC centers were enrolled at the time of HCT and all patients were monitored for 6 months for signs and symptoms of acute GVHD.
MAGIC comprises 20 international centers that monitor the clinical status of HCT patients and collect longitudinal serum samples for analysis and storage (supplemental Table 1). 17 We also evaluated the MAP in patients of all risk groups before and after treatment defined by either clinical or biomarker parameters. 17 In this study, we measured MAP before and after 4 weeks of treatment of acute GVHD to determine whether a change in MAP could serve as a response biomarker showing that a biological response had occurred after a medical intervention. 6,15,16 We have previously validated MAP as a prognostic biomarker of acute GVHD as defined by the US Food and Drug Administration and the National Institutes of Health. 15 Thus measurement in serum of REG3α and ST2 can be considered a “liquid biopsy” of the degree of damage to the lower GI tract caused by GVHD. 14 The 2 biomarkers are combined into a single algorithm developed by the Mount Sinai Acute GVHD International Consortium (MAGIC) to generate an individual patient’s estimated probability of 6-month NRM, known as the MAGIC algorithm probability (MAP).
13 Suppressor of tumorigenesis 2 (ST2), the soluble receptor for the alarmin interleukin-33 (IL-33), is shed from multiple cell types when the gastrointestinal crypt is damaged. 11,12 Regenerating islet-derived 3α (REG3α), a peptide that has antimicrobial and regenerative properties, is released into the systemic circulation from Paneth cells in the intestinal crypt that are damaged during GVHD. 10 In the past decade, 2 validated serum biomarkers have been shown to accurately measure the severity of GI GVHD.
LOW MAGIC MAPS DRIVER
GVHD in the small and large bowel is the principal driver of NRM, and patients with persistent lower GI GVHD experience an overall survival at 2 years of 25%. 6-8 Thus the change in GVHD clinical staging, or clinical response after 4 weeks of systemic treatment, has served as the primary end point in acute GVHD treatment trials for at least a decade. 4-6 Patients who do not respond to primary therapy within 4 weeks experience long-term NRM from 40% to 70%.
2,3 Systemic corticosteroids are the primary treatment of significant (grade 2-4) acute GVHD and induce clinical responses in a majority of patients. Acute GVHD, which typically occurs in 40% to 50% of HCT patients, can be lethal when severe and is graded on a clinical scale of 1 to 4 based on symptoms in the skin, liver, and gastrointestinal (GI) tract. 1 Unfortunately, graft-versus-leukemia is closely linked to the toxicity of graft-versus-host disease (GVHD), the leading cause of nonrelapse mortality (NRM) after HCT. Hematologic malignancies can be cured by hematopoietic cell transplantation (HCT) through a donor lymphocyte-mediated eradication of malignant cells, known as the graft-versus-leukemia effect. MAPs have the potential to guide therapy for acute GVHD and may function as a useful end point in clinical trials. We conclude that a MAP measured before and after treatment of acute GVHD is a response biomarker that predicts long-term outcomes more accurately than change in clinical symptoms. At the beginning of treatment, patients with a low MAP that rose above the threshold of 0.290 after 4 weeks of treatment had a significant increase in NRM, whereas patients with a high MAP at onset that fell below that threshold after treatment had a striking decrease in NRM that translated into clear differences in overall survival. MAPs successfully reclassified patients for NRM risk within every clinical grade of acute GVHD after 4 weeks of treatment. After 4 weeks of treatment, MAPs predicted NRM better than the change in clinical symptoms in all patients and identified 2 groups with significantly different NRM in both clinical responders (40% vs 12%, P <. We computed MAPs and clinical responses and compared their abilities to predict 6-month nonrelapse mortality (NRM) in the validation cohort (n = 367). We prospectively collected serum samples and clinical stages of acute GVHD from 615 patients receiving hematopoietic cell transplantation in 20 centers at initiation of first-line systemic treatment and 4 weeks later. We hypothesized that changes in MAP after treatment could validate it as a response biomarker. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP), derived from 2 serum biomarkers, measures damage to crypts in the gastrointestinal tract during graft-versus-host disease (GVHD).
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