The Clinical Spectrum of Acute GVHD: Beyond Day 100.
Authors: Couriel Daniel R. , Saliba Rima , Gosh Shubhra , De Lima Marcos , Giralt Sergio , Khouri Issa , Andersson Borje , Mickler Kerry , Caldera Zuraima , Hsu Yvonne , Neumann Joyce , Hymes Sharon , Kim Stella , Champlin Richard 
Published: April 2020

Abstract
Objective: To assess the clinical and prognostic implications of the timing of acute GVHD (aGVHD).
Introduction: Traditionally, the syndrome of acute GVHD has been chronologically defined as GVHD occurring before day 100. It has become increasingly clear that this syndrome can occur after day 100, which raises the question of historical misclassification of aGVHD occurring after day 100 (“late aGVHD”) as chronic GVHD. On the other hand, timing of GVHD could have prognostic implications and the case in hyperacute forms of GVHD are an example. In this study, we redifine aGVHD based on clinical manifestations and we evaluate risk factors as well as clinical and prognostic differences between late aGVHD and GVHD before day 100 (“classic aGVHD”).
Methods: Retrospective evaluation of records and database on all matched sibling transplants (n= 128) performed at UT MDACC from 1/00 to 2/02.
Results: A total of 47 patients (37%) had “classic” aGVHD and another 67 (52%) were classified as chronic GVHD (cGVHD) in our database. Upon review of medical records, 30/67 patients (45%) were found to have late aGVHD, and the remainder true cGVHD. Of these 30 patients, 9 had aGVHD progressing through day 100 and were reclassified as classic aGVHD. The remainder 21 had newly diagnosed late aGVHD. We evaluated risk factors for developing late aGVHD in patients who were alive at day 100. Only a later engraftment (ANC&gt;500 beyond day 12) was associated with a higher incidence of late aGVHD, while age, gender, malignancy, disease status at transplant, type of preparative regimen (nonmyeloablative versus others), bone marrow vs peripheral blood or CD3,4 or 8 infused did not impact the incidence of late acute GVHD. Compared to classic aGVHD, the late group had a significantly higher proportion of grade 2–4 GVHD (85 vs 61%, p= 0.03) with similar grade 3–4 aGVHD (29 vs 27%, p= 0.5). Skin and GI involvement, as well as isolated elevation of the alkaline phosphatase were more common manifestations of late aGVHD. There was a trend to better response (CR/PR) to first line immunosuppression in patients with late aGVHD (81 vs 63%, p= 0.13), but this was not statistically significant. The overall survival (OS) and non-relapse mortality (NRM) since the diagnosis of GVHD were substantially better in patients with late aGVHD (OS 70 vs 29%, p= 0.01; NRM 16 vs 39%, p= 0.06). Finally, the NRM of patients with chronic GVHD prior to reclassifying patients with late aGVHD (n= 67) was 28% at 2 years. When patients with late aGVHD were excluded, the NRM at 2 years for the remainder 37 patients with chronic GVHD was 20% (p= 0.3).
Conclusions: 1- The current chronological definition of acute GVHD may lead to misclassification of late aGVHD as chronic GVHD. This could have implications in interpreting the current knowledge and literature on GVHD, 2- There was a trend to higher NRM in the chronic GVHD group prior to reclassifying cases of late aGVHD, althought the difference was not statistically significant, 3-Patients with late aGVHD share similarities with those with classic aGVHD, although there seems to be a trend to better response to therapy and better survival in patients developing aGVHD beyond day 100. Thus, timing of aGVHD may affect its outcome.