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Multicenter Study
. 2024 Apr 23;8(8):2047-2057.
doi: 10.1182/bloodadvances.2023012091.

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

Yu Akahoshi  1   2 , Nikolaos Spyrou  1 , Matthias Hoepting  3 , Paibel Aguayo-Hiraldo  4 , Francis Ayuk  5 , Chantiya Chanswangphuwana  6 , Hannah K Choe  7 , Matthias Eder  8 , Aaron M Etra  1 , Stephan A Grupp  9   10 , Elizabeth O Hexner  11 , William J Hogan  12 , Carrie L Kitko  13 , Sabrina Kraus  14 , Monzr M Al Malki  15 , Pietro Merli  16 , Muna Qayed  17 , Ran Reshef  18 , Tal Schechter  19 , Evelyn Ullrich  20 , Ingrid Vasova  21 , Matthias Wölfl  22 , Robert Zeiser  23 , Janna Baez  1 , Rahnuma Beheshti  1 , Gilbert Eng  1 , Sigrun Gleich  3 , Stelios Kasikis  1 , Nikolaos Katsivelos  1 , Steven Kowalyk  1 , George Morales  1 , Rachel Young  1 , Zachariah DeFilipp  24 , James L M Ferrara  1 , John E Levine  1 , Ryotaro Nakamura  15
Affiliations
Multicenter Study

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

Yu Akahoshi et al. Blood Adv. .

Abstract

The absence of a standardized definition for graft-versus-host disease (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 nonrelapse mortality (NRM; adjusted hazard ratio [aHR], 4.84; 95% confidence interval [CI], 3.19-7.36; P < .001). Flares were more severe (grades 3/4, 41% vs 16%; P < .001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs 32%; P < .001) than the initial GVHD. 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 = .001]; AA3 vs AA1: aHR, 3.14 [95% CI, 1.98-4.98; P < .001]), as were early response to initial treatment (aHR, 1.84; 95% CI, 1.21-2.80; P = .004) and HLA-mismatched unrelated donor (aHR, 1.74; 95% CI, 1.00-3.02; P = .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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Conflict of interest statement

Conflict-of-interest disclosure: S.A.G. reports receiving research and/or clinical trial support from Novartis, Servier, Vertex, Cellectis, and Tmunity/Kite, and being a member of study steering committees, consulting, or scientific advisory boards for Novartis, Allogene, Adaptimmune, Juno/Bristol Myers Squibb, CRISPR/Vertex, Jazz, Kyttaro, and Cabaletta. M.W. received consulting fees from Amgen (Munich, Germany) and speaker’s fees from Novartis (Nürnberg, Germany). J.E.L. reports research support from Equillium, Incyte, MaaT Pharma, and Mesoblast, and consulting fees from bluebird bio, Editas, Equillium, Inhibrx, Kamada, Mesoblast, Sanofi, and X4 Pharmaceuticals. J.E.L. and J.L.M.F. are coinventors on a GVHD biomarker patent. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CONSORT diagram. Tx, treatments.
Figure 2.
Figure 2.
Incidence, severity, and LGI involvement of flares. (A) The cumulative incidence of flares after CR/VGPR; the cumulative incidence at 6 month was 21.6% (95% CI, 19.0-24.2). (B) The proportion of grades 3/4 acute GVHD at first onset in the entire population (n = 968, 16.3%), in patients with flare (n = 210, 18.1%), and at the time of flare (n = 210, 41.4%). (C) The proportion of LGI involvement at first onset in the entire population (n = 968, 31.6%), in patients with flare (n = 210, 32.9%), and at the time of flare (n = 210, 55.2%). P values for pairwise comparisons were adjusted using a Bonferroni method. The error bars represent standard error.
Figure 3.
Figure 3.
Association of biomarkers at CR/VGPR on GVHD flare, its severity, and NRM. (A) The cumulative incidence of flares after CR/VGPR stratified by the AA score at CR/VGPR; the cumulative incidence at 6 month was 15.8% (95% CI, 12.8-19.0) in AA1, 26.1% (95% CI, 21.4-30.9) in AA2, and 38.6% (95% CI, 28.6-48.5) in AA3. (B) The proportion of patients who developed grades 3/4 GVHD flare stratified by the AA scores at CR/VGPR (left panel); 5.4% (29/534) in AA1, 11.4% (38/334) in AA2, and 20.0% (20/100) in AA3. The proportion of patients who developed GVHD flare with stage 2-4 LGI involvement stratified by the AA scores at CR/VGPR (right panel); 4.9% (26/534) in AA1, 9.9% (33/334) in AA2, and 18.0% (18/100) in AA3. The error bars represent standard error. (C) The cumulative incidence of NRM after CR/VGPR stratified by MAP biomarkers at CR/VGPR; the cumulative incidence at 6 months was 4.7% (95% CI, 3.2-6.8) in AA1, 11.0% (95% CI, 7.9-14.7) in AA2, and 33.5% (95% CI, 24.4-43.3) in AA3. The pie chart shows the percentage of AA1 (blue), AA2 (yellow), and AA3 (red). ∗P values for pairwise comparisons were adjusted using a Bonferroni method.
Figure 4.
Figure 4.
Associations of steroid tapers on flares in all patients and patients with AA1 and AA2/3. (A) The cumulative incidence of flares was 16.5% (95% CI, 13.6-19.6) in slow tapers and 30.0% (95% CI, 25.3-34.8) in rapid tapers. (B) Only patients with AA1 at CR/VGPR. The cumulative incidence of flares was 11.9% (95% CI, 8.7-15.7) in slow tapers and 22.1% (95% CI, 16.6-28.1) in rapid tapers. (C) Only patients with AA2/3 at CR/VGPR. The cumulative incidence of flares was 22.3% (95% CI, 17.4-27.5) in slow tapers and 39.8% (95% CI, 32.1-37.4) in rapid tapers. Tapers were defined as rapid if the weekly steroid reduction rate ≥ 30% per week when the maximum steroid dose before CR/VGPR ≥1 mg/kg or ≥ 20% per week when the maximum steroid dose before CR/VGPR <1 mg/kg. The pie chart shows the percentage of patients whose steroid taper was slow (blue) and rapid (red).
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