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S. Nikiforow et al.
patients with lymphoma and multiple myeloma, recipi- ents of umbilical cord or haploidentical graft sources, and those undergoing reduced-intensity conditioning. These populations have different rates and potentially different manifestations of aGvHD and merit separate analyses.
Our data can lead in two directions. One, given current non-standardized reporting and treatment patterns, reclas- sification of patients with UGI GvHD as Grade I could be considered, with Grade I aGvHD generally considered to have few prognostic implications. In our cohort, that reclassification would impact 425 (20.4%) of the 2083 patients currently graded as Grade II. While this would not impact cases of “severe” aGvHD (Grades III-IV), patients with Grades II-IV aGvHD would decrease from 44.3% to 39.9%. Whether such a shift would significantly impact perceived incidence or outcomes of patients Grades II-IV aGvHD, for example, could be investigated by retrospective reanalysis of multicenter studies with GvHD as a major outcome, such as the BMT CTN trials 0201 or 0402 (clinicaltrials.gov Identifiers: 00075816 and 00406393).31,38 Alternatively, an approach which down- grades UGI symptoms could be included in secondary analyses in the prospective PROGRESS 1 and 2 trials cur- rently testing novel aGvHD prophylaxis strategies (clinical- trials.gov Identifiers: 02208037 and 02345850), to assess impact. The implications of a change in grading include powering of future studies as well as interpretation of effi- cacy, given that major endpoints currently include seem- ingly non-informative events. Even just relabeling Stage 1 into, for example, 1a for UGI and 1b for LGI, might facili- tate the tracking of UGI and LGI symptoms in future analyses.
Alternatively, the general HSCT field could move to a more standardized approach to diagnosis using regular endoscopy biopsies and more consistent pathologic report- ing, with or without more detailed organ system reporting, such as in the Minnesota risk-adapted acute GvHD risk score.2,39 Mehta et al. recently published a retrospective sin- gle center study in which all UGI aGvHD was confirmed by biopsy and treated in a similar manner with systemic steroids.40 Patients with Grade II aGvHD consisted of 10% with iUGI, 33% with UGI + other organ involvement, and 57% with no UGI symptoms. In this study, although com- parisons with Grade I aGvHD were not performed, all sub- sets of Grade II aGvHD had similar outcomes in terms of OS, DFS, non-relapse mortality (NRM), relapse and cGvHD. In contrast to our more “real-world” data set, this highly controlled analysis supports maintaining UGI aGvHD as a Grade 2 event. Analysis of this type of con- trolled data set which includes details on kinetics of indi- vidual manifestations, response to therapy, and infectious complications of therapy would be enlightening.
In summary, we challenge the field to revisit how UGI aGvHD is diagnosed, reported, graded and treated given
that its current prognostic utility within the Consensus criteria is extremely limited. We would recommend high- ly standardized prospective trials involving endoscopic biopsies to explore whether system steroid therapy is required for these symptoms in isolation or with Grade I skin-only aGvHD. However, redefining UGI manifesta- tions, especially as currently reported across multiple insti- tutions, to a Grade I-defining entity and evaluating the impact on outcomes of large therapeutic trials of aGvHD prophylaxis and therapy should be considered.
Funding
SN was supported by ASH Fellow Scholar Award, ASBMT New Investigator Award, Jock and Bunny Adams Research and Education Fund, Farmor Fund Grant, Simberg Grant from Friends of Dana Farber. CC was supported by the Stem Cell Cyclists of the Pan-Mass Challenge. The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from Actinium Pharmaceuticals, Inc.; Alexion; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics, Inc.; Be the Match Foundation; Bluebird Bio, Inc.; Bristol Myers Squibb Oncology; Celgene Corporation; Cellular Dynamics International, Inc.; Cerus Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; Jazz Pharmaceuticals, Inc.; Jeff Gordon Children’s Foundation; The Leukemia & Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; Merck & Co, Inc.; Mesoblast; MesoScale Diagnostics, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. – Japan; PCORI; Perkin Elmer, Inc.; Pfizer, Inc; Sanofi US; Seattle Genetics; Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and Wellpoint, Inc.
The views expressed in this article do not reflect the official pol- icy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, the US Food & Drug Administration, or any other agency of the U.S. Government.
References
1. Weisdorf D, Snover D, Haake R, et al. Acute upper gastrointestinal graft-versus- host disease: clinical significance and response to immunosuppressive therapy. Blood. 1990;76(3):624-629.
2. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-
host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21(4):761-767.
3. Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow
Transplant Clinical Trials Network. Blood.
2009;114(3):511-517.
4. Snover DC, Weisdorf SA, Vercellotti GM, et
al. A histopathologic study of gastric and small intestinal graft-versus-host disease fol- lowing allogeneic bone marrow transplanta- tion. Hum Pathol. 1985;16(4):387-392.
5. Nomura K, Iizuka T, Kaji D, et al. Clinicopathological features of patients
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