Manhattan Plus MAGIC aGVHD Composite
About Manhattan plus MAGIC aGVHD Composite Score
The diagnosis of acute graft versus host disease (aGVHD) in allogeneic hematopoietic cell transplant (allo-HCT) patients has largely relied on clinical assessment, often in combination with biopsy. However, this approach is problematic since damage is often severe by the onset of clinical signs and biopsies are invasive, expensive and carry the risk of severe complications. Non-invasive approaches, such as the use of biomarkers to test for aGVHD have been the subject of clinical research for a number of years, but suffer from a lack of clinical validation, established Algorithmic Value cutoffs and standardization between laboratories. However, recent research has led to the development and clinical validation of an algorithm (based on ST2 and regenerating islet-derived 3 alpha (REG3α) levels) that provides prediction of risk for severe aGVHD and non-relapse mortality (NRM) in allo-HCT patients at critical times post-transplant. Use of the results may aid in treatment decisions and modifications prior to or early in the disease process, and thus improve outcomes for patients. When the Manhattan score is combined with the MAGIC biomarkers at symptomatic onset, the composite result demonstrates: An improved prognostic performance (6-month non-relapse mortality [NRM] and the ability to predict response to treatment at day 28.
This provides improved opportunities for personalized treatment strategies, potentially reducing the reliance on high-dose systemic immunosuppressive therapies that often come with significant adverse effects.
The aGVHD predictive algorithms utilize serum levels of ST2 and REG3α, and have been clinically validated to help health care professionals better predict the risk of NRM prior to the onset of aGVHD. While there are multiple clinical factors that increase the risk of NRM post-transplant include HLA mismatch, non-family donors, recipient age and GVHD prophylactic therapy, use of the predictive algorithm has been demonstrated to be more accurate. The two biomarkers used in the algorithm are both important to the pathobiology of aGVHD. ST2 is member of the Toll-interleukin 1 receptor family, and functions as a down-regulator of the pro-inflammatory cytokines IL-1, IL-6 and TNF-α. ST2 has been shown to be elevated in inflammatory conditions. REG3α, an anti-inflammatory/anti-bacterial protein expressed in Paneth cells within the epithelium of the small intestine, has been shown to be elevated in medical conditions where immune dysregulation causes damage to the mucosal epithelial barrier.
About Graft versus Host Disease (GVHD)
GVHD is one of the major causes of morbidity and mortality associated with allogeneic bone marrow, stem cell, or other kinds of hematopoietic cell transplants. GVHD occurs in 30 – 50% of HLA-matched sibling transplants and 60 – 90% of matched unrelated donors. GVHD often manifests in the skin, liver and/or gastrointestinal (GI) tract, and is caused by immune dysregulation that is initiated when allogeneic donor T cells recognize host tissues as foreign. GVHD may be either acute or chronic. Acute GVHD (aGVHD), which typically occurs in the first 3 months post-transplant, has an incidence of 19 – 66% and carries a poor prognosis if the disease is severe. The mean onset of aGVHD is around 1 month after the transplant occurs. Diagnosis of aGVHD has traditionally been based on the clinical presentation and ruling out other etiologies through differential diagnosis. In many cases biopsies of the liver, skin or GI tract are performed. Chronic GVHD (cGVHD) occurs 3 months to > 1 year post-transplant and has a pathophysiology that is distinct from aGVHD, although poorly understood. The overall incidence of cGVHD is 40 – 50%.
Pre-transplant conditioning regimens may damage host tissue, which in turn leads to inflammatory cytokine release (TNF-α, INF-γ, IL-1 and IL-6) directly from damaged tissues. The inflammatory cytokines stimulate antigen presenting cells which present host antigens to donor lymphocytes. In response, donor T cells proliferate, differentiate and undergo activation. Once donor T cells are activated, pro-inflammatory cytokines are produced in large quantities resulting in additional inflammation, recruitment of neutrophils to the site, and ultimately severe tissue damage. Administration of immunosuppressive agents are commonly used to treat cases of GVHD.
In skin, aGVHD frequently manifests as a maculopapular skin rash due to cellular/tissue damage. In the GI tract, aGVHD which frequently manifests as nausea, vomiting, anorexia, secretory diarrhea and in severe cases abdominal pain and at times hemorrhage, is caused by cellular damage to the mucosal epithelial barrier of the small intestines. The occurrence of aGVHD in the liver results in elevated bilirubin levels, indicative of liver damage.
Viracor’s Manhattan plus MAGIC aGvHD Composite test can aid in prediction of some of the most severe forms of acute graft versus host disease (aGVHD) and non-relapse mortality (NRM) before disease progression becomes serious. The aGVHD Symptomatic Onset Algorithm reports on ST2 and Regenerating islet-derived 3-alpha (REG3α) biomarkers, utilizing them to provide a clinically validated cutoff value. The Manhattan Plus MAGIC aGvHD Composite assay uses both clinical and biomarker data which has enlarged the low-risk group and has been show to most accurately predict outcomes along with response to therapy. This assay should be ordered after the patient displays symptoms of aGVHD post bone marrow, stem cell, or other kinds of hematopoietic cell transplant (HCT).
The Manhattan risk score is based only on the clinical information provided and is an assessment of risk for unfavorable outcomes. The MAGIC composite score combines the Manhattan risk score and the aGVHD Symptomatic Onset Algorithm result to yield a score of 1, 2 or 3 (1 being most favorable). Overall response rate is defined by complete or partial response at day 28 after systemic treatment. For more information see: Blood 2024, 144(9):1010-1021, PMID 38968143.
Information of the symptomology of the patient is required to determine the Manhattan Risk Score. Patient symptoms related to Skin, Liver, Upper GI, and Lower GI are graded on their presentation and severity to determine the Manhattan Risk Score in conjunction with the MAGIC Algorithm Probability (MAP) to guide Acute GvHD Therapy.
- Skin (Stage 0-4)
- Liver (Stage 0-4)
- Upper GI (Stage 0-1)
- Lower GI (Stage 0-4)
About Manhattan Plus MAGIC aGVHD Composite Testing
When the Manhattan score is combined with the MAGIC biomarkers at symptomatic onset, the composite result demonstrates: An improved prognostic performance (6-month non-relapse mortality [NRM] and the ability to predict response to treatment at day 28.
This provides improved opportunities for personalized treatment strategies, potentially reducing the reliance on high-dose systemic immunosuppressive therapies that often come with significant adverse effects.
Same day (within 24 hours of receipt of specimen)
| Specimen Type | Test Code | CPT Code | NY Approved | Volume | Assay Range | Special Instructions |
|---|---|---|---|---|---|---|
| serum | 403685P | 83006 ST2 and 83520 Reg3 | Yes | 0.5 mL (min. 100 mL) |
ST2: 1250 - 167000 pg/mL; Reg3a: 16-2000 ng/mL |
|
Ship Monday through Friday. Friday shipments must be labeled for Saturday delivery. All specimens must be labeled with patient's name and collection date. A Eurofins Viracor test requisition form must accompany each specimen. Multiple tests can be run on one specimen. Ship specimens FedEx Priority Overnight® to: Eurofins Viracor, 18000 W 99th St., Ste, #10, Lenexa, KS 66219.
Specimens are approved for testing in New York only when indicated in the Specimen Information field above.
The CPT codes provided are based on Eurofins Viracor’s interpretation of the American Medical Association's Current Procedural Terminology (CPT) codes and are provided for informational purposes only. CPT coding is the sole responsibility of the billing party. Questions regarding coding should be addressed to your local Medicare carrier. Eurofins Viracor assumes no responsibility for billing errors due to reliance on the CPT codes illustrated in this material.
References
Atkinson K. Chronic graft-versus-host disease. Bone Marrow Transplant. 1990 Feb;5(2):69-82.
Ball LM, Egeler RM, EBMT Paediatric Working Party. Acute GvHD: pathogenesis and classification. Bone Marrow Transplant. 2008 Jun;41 Suppl 2:S58-64.
Choi B, Suh Y, Kim W-H, et al. Downregulation of regenerating islet-derived 3 alpha (REG3A) in primary human gastric adenocarcinomas. Exp Mol Med. 2007 39(6):796-804.
Closa D, Motoo Y, lovanna JL. Pancreatitis-associated protein: From a lectin to an anti-inflammatory cytokine. World J Gastroenterol. 2007 13(2):170-174.
Deeg HJ, Henslee-Downey PJ. Management of acute graft-versus-host disease. Bone Marrow Transplant. 1990 Jul;6(1):1-8.
Gironella M, lovanna JL, Sans M, et al. Anti-inflammatory effects of pancreatitis associated protein in inflammatory bowel disease. Gut. 2005 54:1244-1253.
Hartwell MJ, Ozbek U, Holler E, et al. An early-biomarker algorithm predicts lethal graft-versus-host-disease and survival. JCI Insight. 2017;2(3):e89798.
Harris AC, Ferrara JLM, Levine JE. Advances in predicting acute GVHD. British J Haematol 2013, 160:288-302.
Harris AC, Levine JE, Ferrara JL. Have we made progress in the treatment of GvHD? Best Pract Res Clin Haematol. 2012 Dec;25(4):473-8.
Harris AC, Ferrara JLM, Braun TM, et al. Plasma biomarkers of lower gastrointestinal and liver acute GVHD. Blood. 2012 119:2960-2963.
Jagasia M, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012, 119(1):296–307.
Major-Monfried H, Renteria AS, Pawarode A., et al. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood 2018, 131(25):2846-2855.
Paczesny S, Krijanovski OI, Bruan TM, et al. A biomarker panel for acute graft-versus-host disease. Blood. 2009 Jan 8;113(2):273-8.
Vander Lugt MT, Braun TM, Ferrara JLM, et al. Plasma Concentration of ST2, the IL33 Receptor, AIInitiation of Graft Versus Host Disease Therapy Predicts Day 28 Response and Day 180 Survival Post-Treatment. Blood. 2011 118(21).
Vander Lugt MT, Braun TM, Ferrara JLM, et al. Plasma Concentration of Suppressor of Tumorigenicity 2 (ST2), the IL33 Receptor, at lnitiation of Graft Versus Host Disease Therapy Predicts Day 28 Response and Day 180 Survival Post-Treatment. Biol Blood Marrow Transpl. 2012 February; 18 (2):S201-S202.
Margaret L. MacMillan, Marie Robin, Andrew C. Harris et al. A refined risk score for acute GVHD that predicts response to initial therapy, survival and transplant-related mortality. Biol Blood Marrow Transplant. 2015 April ; 21(4): 761–767. doi:10.1016/j.bbmt.2015.01.001.
Yu Akahoshi,MD,PhD, Nikolaos Spyrou,MD, Daniela Weber,MD, et al. The Mount Sina iAcute Gvhd International Consortium (MAGIC) Model :An Integrated Clinical and Biomarker Grading System for Acute Graft-Versus-Host Disease(GVHD). Abstracts/Transplantation and Cellular Therapy 302S(2024)S48-S53.
Deeg HJ, Henslee-Downey PJ. Management of acute graft-versus-host disease. Bone Marrow Transplant. 1990 Jul;6(1):1-8.
Gironella M, lovanna JL, Sans M, et al. Anti-inflammatory effects of pancreatitis associated protein in inflammatory bowel disease. Gut. 2005 54:1244-1253.
Hartwell MJ, Ozbek U, Holler E, et al. An early-biomarker algorithm predicts lethal graft-versus-host-disease and survival. JCI Insight. 2017;2(3):e89798.
Harris AC, Ferrara JLM, Levine JE. Advances in predicting acute GVHD. British J Haematol. 2013, 160:288-302.
Harris AC, Levine JE, Ferrara JL. Have we made progress in the treatment of GvHD? Best Pract Res Clin Haematol. 2012 Dec;25(4):473-8.
Harris AC, Ferrara JLM, Braun TM, et al. Plasma biomarkers of lower gastrointestinal and liver acute GVHD. Blood. 2012 119:2960-3.
Jagasia M, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012, 119(1):296–307.
Major-Monfried H, Renteria AS, Pawarode A., et al. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood. 2018, 131(25):2846-55.
Paczesny S, Krijanovski OI, Bruan TM, et al. A biomarker panel for acute graft-versus-host disease. Blood. 2009 Jan 8;113(2):273-8.
Vander Lugt MT, Braun TM, Ferrara JLM, et al. Plasma Concentration of ST2, the IL33 Receptor, AIInitiation of Graft Versus Host Disease Therapy Predicts Day 28 Response and Day 180 Survival Post-Treatment. Blood. 2011 118(21).
Vander Lugt MT, Braun TM, Ferrara JLM, et al. Plasma Concentration of Suppressor of Tumorigenicity 2 (ST2), the IL33 Receptor, at lnitiation of Graft Versus Host Disease Therapy Predicts Day 28 Response and Day 180 Survival Post-Treatment. Biol Blood Marrow Transpl. 2012 February; 18 (2):S201-2.