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. 2023 Aug 22;7(16):4479-4491.
doi: 10.1182/bloodadvances.2023009885.

Incidence, clinical presentation, risk factors, outcomes, and biomarkers in de novo late acute GVHD

Yu Akahoshi  1   2 , Nikolaos Spyrou  1 , William J Hogan  3 , Francis Ayuk  4 , Zachariah DeFilipp  5 , Daniela Weber  6 , Hannah K Choe  7 , Elizabeth O Hexner  8 , Wolf Rösler  9 , Aaron M Etra  1 , Karamjeet Sandhu  10 , Gregory A Yanik  11 , Chantiya Chanswangphuwana  12 , Carrie L Kitko  13 , Ran Reshef  14 , Sabrina Kraus  15 , Matthias Wölfl  16 , Matthias Eder  17 , Hannah Bertrand  18 , Muna Qayed  19 , Pietro Merli  20 , Stephan A Grupp  21 , Paibel Aguayo-Hiraldo  22 , Tal Schechter  23 , Evelyn Ullrich  24 , Janna Baez  1 , Rahnuma Beheshti  1 , Sigrun Gleich  6 , Steven Kowalyk  1 , George Morales  1 , Rachel Young  1 , Deukwoo Kwon  25 , Ryotaro Nakamura  10 , John E Levine  1 , James L M Ferrara  1 , Yi-Bin Chen  5
Affiliations

Incidence, clinical presentation, risk factors, outcomes, and biomarkers in de novo late acute GVHD

Yu Akahoshi et al. Blood Adv. .

Abstract

Late acute graft-versus-host disease (GVHD) is defined as de novo acute GVHD presenting beyond 100 days after allogeneic hematopoietic cell transplantation (HCT) without manifestations of chronic GVHD. Data are limited regarding its characteristics, clinical course, and risk factors because of underrecognition and changes in classification. We evaluated 3542 consecutive adult recipients of first HCTs at 24 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 2014 and August 2021 to better describe the clinical evolution and outcomes of late acute GVHD. The cumulative incidence of classic acute GVHD that required systemic treatment was 35.2%, and an additional 5.7% of patients required treatment for late acute GVHD. At the onset of symptoms, late acute GVHD was more severe than classic acute GVHD based on both clinical and MAGIC algorithm probability biomarker parameters and showed a lower overall response rate on day 28. Both clinical and biomarker grading at the time of treatment stratified the risk of nonrelapse mortality (NRM) in patients with classic and late acute GVHD, respectively, but long-term NRM and overall survival did not differ between patients with classic and late acute GVHD. Advanced age, female-to-male sex mismatch, and the use of reduced intensity conditioning were associated with the development of late acute GVHD, whereas the use of posttransplant cyclophosphamide-based GVHD prevention was protective mainly because of shifts in GVHD timing. Because overall outcomes were comparable, our findings, although not definitive, suggest that similar treatment strategies, including eligibility for clinical trials, based solely on clinical presentation at onset are appropriate.

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Conflict of interest statement

Conflict-of-interest disclosure: 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.
Incidence, overall grades, and overall response of acute GVHD that required treatment. (A) Among the 3542 patients who met the criteria for inclusion, 1601 and 256 were diagnosed with classic and late acute GVHD of any grade, respectively. Of patients with classic and late acute GVHD, 1245 of 1601 (77.8%) and 193 of 256 (75.4%), respectively, received systemic GVHD treatment. (B) The cumulative incidence of classic and late acute GVHD that required systemic treatment were 35.2% (95% CI, 33.6-36.8) and 5.7% (95% CI, 4.9-6.5), respectively. (C) The rates of grades 3/4 acute GVHD were 17.7% in classic and 36.3% in late acute GVHD (P < .001). (D) Overall response rate (CR or PR) on day 28 was 72.0% in classic vs 55.4% in late acute GVHD (P < .001). CR rate on day 28 was 59.3% in classic and 46.6% in late acute GVHD (P < .001). Dx, diagnosis; CR, complete response; PR, partial response; Tx, treatment.
Figure 2.
Figure 2.
Long-term outcomes from the time of systemic treatment. (A) The cumulative incidences of NRM at 6 months were 15.2% (95% CI, 13.3-17.3) and 16.8% (95% CI, 11.8-22.6) in classic and late acute GVHD, respectively (P = .551). (B) The cumulative incidences of relapse at 6 months were 11.6% (95% CI, 9.9-13.5) and 11.9% (95% CI, 7.7-17.0) in classic and late acute GVHD, respectively (P = .869). (C) The probabilities of OS at 6 months were 79.5% (95% CI, 77.1-81.6) in classic and 78.2% (71.5-83.5) in late (P = .827). (D) The cumulative incidences of NRM at 6 months were 11.9% (95% CI, 10.0-14.0) and 30.7% (95% CI, 24.7-37.0) in grades 1/2 and grades 3/4 classic acute GVHD, respectively (P < .001). (E) The cumulative incidences of NRM at 6 months were 8.4% (95% CI, 4.3-14.3) and 32.5% (95% CI, 21.4-44.1) in grades 1/2 and grades 3/4 late acute GVHD, respectively (P < .001).
Figure 3.
Figure 3.
Association of biomarkers with NRM at treatment. (A) The proportion of patients in each risk group in classic acute GVHD at onset of treatment were AA1, 56.8% (591 of 1041) and AA2/3, 43.2% (450 of 1041). The cumulative incidences of NRM at 6 months were 7.4% (95% CI, 5.5-9.8) and 25.9% (95% CI, 22.0-30.1) in AA1 and AA2/3 groups (P < .001). (B) The proportion of patients in each risk group in late acute GVHD were 48.3% (43/89) and 51.7% (46/89) for AA1 and AA2/3 groups. The cumulative incidences of NRM at 6 months were 4.9% (95% CI, 0.9-14.7) and 42.2% (95% CI, 27.1-56.6), respectively (P < .001).
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