The utility of biomarkers in acute GVHD prognostication

Spyrou, Nikolaos; Akahoshi, Yu; Ayuk, Francis; Holler, Ernst; Choe, Hannah; Etra, Aaron; Rösler, Wolf; Hexner, Elizabeth O.; DeFilipp, Zachariah; Reshef, Ran; Chanswangphuwana, Chantiya; Qayed, Muna; Kraus, Sabrina; Eder, Matthias; Javorniczky, Nora Rebeca; Grupp, Stephan A.; Kitko, Carrie L.; Merli, Pietro; Aguayo-Hiraldo, Paibel; Wölfl, Matthias; Baez, Janna; Beheshti, Rahnuma; Eng, Gilbert W; Gleich, Sigrun; Katsivelos, Nikolaos; Khan, Alina; Kowalyk, Steven; Morales, George; Young, Rachel; Nakamura, Ryotaro; Chen, Yi-Bin; Levine, John E.; Ferrara, James L.M.

doi:10.1182/bloodadvances.2023009929

Cited by 10 publications

(4 citation statements)

References 6 publications

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“…At flare onset, MAGIC biomarkers also successfully stratify patients for the risk of NRM similarly to their performance in de novo acute GVHD. 23 , 24 , 25 , 41 These findings are consistent with prior studies showing that biomarkers can predict outcomes at specified time points after initiation of treatment (eg, day 28) 13 and emphasize that the MAP reflects subclinical damage to the GI crypts when clinical symptoms are well controlled.…”

Section: Discussionsupporting

confidence: 87%

“… 21 , 22 , 23 The MAGIC algorithm probability (MAP) was calculated as a single value between 0.001 and 0.999 according to the formula: log(–log[1 – MAP]) = –11.263 + 1.844(log 10 ST2) + 0.577(log 10 REG3α) and validated thresholds for Ann Arbor (AA) scores were used (AA1 < 0.14; 0.14 ≤ AA2 < 0.29; AA3 ≥ 0.29). 18 , 21 , 22 , 24 , 25 , 26 …”

Section: Methodsmentioning

confidence: 99%

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Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis

Akahoshi,

Spyrou,

Hoepting

et al. 2024

Blood Advances

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The absence of a standardized definition for GVHD flares and data on its clinical course are significant concerns. We retrospectively evaluated 968 patients across 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of treatment. The cumulative incidence of flares within 6 months was 22% and flares were associated with a higher risk of non-relapse mortality (NRM) (adjusted Hazard Ratio [aHR] 4.84 [95% CI, 3.19-7.36], P < 0.001). Compared to the initial GVHD, flares were more severe (Grades III/IV: 41% vs. 16%, P < 0.001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs. 32%, P < 0.001). At CR/VGPR, elevated MAGIC biomarkers predicted the future occurrence of a flare, along with its severity and LGI involvement. In multivariate analyses, higher Ann Arbor (AA) biomarker scores at CR/VGPR were significant risk factors for flares (AA2 vs. AA1: aHR, 1.81 [95% CI, 1.32-2.48], P = 0.001; AA3 vs. AA1: aHR, 3.14 [95% CI, 1.98-4.98], P < 0.001), as were early response to initial treatment (aHR, 1.84 [95% CI, 1.21-2.80], P = 0.004) and HLA-mismatched unrelated donor (aHR, 1.74 [95% CI, 1.00-3.02], P = 0.049). MAGIC biomarkers also stratified the risk of NRM both at CR/VGPR and at the time of flare. We conclude that GVHD flares are common and carry a significant mortality risk. The occurrence of future flares can be predicted by serum biomarkers that may serve to guide adjustment and discontinuation of immunosuppression.

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis

Akahoshi,

Spyrou,

Hoepting

et al. 2024

Blood Advances

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“…Serum levels of ST2 14 and REG3 α 15 were measured retrospectively using enzyme-linked immunosorbent assays as previously described. 3 , 11 , 16 , 17 , 18 , 19 MAP was calculated as a single value between 0.001 and 0.999 according to the formula: log[-log(1-MAP)] = −11.263 + 1.844(log 10 ST2) + 0.577(log 10 REG3α). 16 We used a single threshold at the initiation of second-line therapy to divide MAPs into 2 groups (high, ≥0.291 vs low, <0.291), as previously described.…”

Section: Methodsmentioning

confidence: 99%

The MAGIC algorithm probability predicts treatment response and long-term outcomes to second-line therapy for acute GVHD

DeFilipp,

Kim,

Spyrou

et al. 2024

Blood Advances

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The significance of biomarkers in second-line treatment for acute graft-versus-host disease (GVHD) has not been well characterized. We analyzed clinical data and serum samples at the initiation of second-line systemic treatment of acute GVHD from 167 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC) between 2016 and 2021. Sixty-two patients received ruxolitinib-based therapy, whereas 102 received other systemic agents. In agreement with prospective trials, ruxolitinib resulted in a higher day 28 (D28) overall response Frate than nonruxolitinib therapies (55% vs 31%, P = .003) and patients who received ruxolitinib had significantly lower nonrelapse mortality (NRM) than those who received nonruxolitinib therapies (point estimates at 2-year: 35% vs 61%, P = .002). Biomarker analyses demonstrated that the benefit from ruxolitinib was observed only in patients with low MAGIC algorithm probabilities (MAPs) at the start of second-line treatment. Among patients with a low MAP, those who received ruxolitinib experienced significantly lower NRM than those who received nonruxolitinib therapies (point estimates at 2-year: 12% vs 41%, P = .016). However, patients with high MAP experienced high NRM regardless of treatment with ruxolitinib or nonruxolitinib therapies (point estimates at 2-year: 67% vs 80%, P = .65). A landmark analysis demonstrated that the relationship between the D28 response and NRM largely depends on the MAP level at the initiation of second-line therapy. In conclusion, MAP measured at second-line systemic treatment for acute GVHD predicts treatment response and NRM. The outcomes of patients with high MAP are poor regardless of treatment choice, and ruxolitinib appears to primarily benefit patients with low MAP.

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“…Although the authors have shown that 3-tier and 2-tier ST2/Reg3a categorical algorithms predict GVHD-related outcomes after hematopoietic cell transplantation, 2 , 3 , 4 , 5 , 6 no studies have yet shown that the use of these biomarkers can improve outcomes for patients. Two internally controlled open-label phase 2 studies examined whether low-risk acute GVHD, defined in part by ST2/Reg3α concentrations, could be successfully managed without corticosteroid treatment.…”

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confidence: 99%

Steroid tapering after GVHD Rx: not too fast, not too slow

Martin

2024

Blood Advances

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The utility of biomarkers in acute GVHD prognostication

Cited by 10 publications

References 6 publications

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis

The MAGIC algorithm probability predicts treatment response and long-term outcomes to second-line therapy for acute GVHD

Steroid tapering after GVHD Rx: not too fast, not too slow

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