Incidence and Outcome of Atypical Manifestations of Chronic Graft-versus-Host Disease: Results From a Retrospective Single-Center Analysis.

Chronic graft-versus-host disease (cGVHD) is the leading cause of late nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (alloHSCT) and defined by 8 diagnostic target organs. Recently, provisional criteria for atypical manifestations of cGVHD that include manifestations in nonclassic organs as well as atypical manifestations in National Institutes of Health (NIH)-defined organs, were proposed by a NIH task force. Little is known about the incidence, risk factors, and impact on survival of atypical cGVHD, however. The aim of the present study was to analyze these parameters in a sequential patient population. We retrospectively screened 623 patients who underwent alloHSCT at the University Medical Center Regensburg between January 2008 and December 2020 for atypical cGVHD manifestations, applying the provisional NIH taskforce criteria. A total of 102 patients (16.4%) met the criteria, representing 25% of all cGVHD cases, and 14 patients (2.2%) had only atypical cGVHD. The most frequent manifestations were immune-mediated cytopenias (24.5%), renal cGVHD (13.7%) and (poly)serositis (13.7%). Multivariate analysis identified prior acute GVHD (odds ratio [OR], 2.28 and 2.93) and infusion of donor lymphocytes (OR, 1.77 for both) as risk factors for classic cGVHD and atypical cGVHD, whereas total body irradiation was an independent risk factor for atypical cGVHD manifestations only (OR, 1.76). Compared to patients without cGVHD, those with atypical and NIH-defined cGVHD showed similarly better overall survival (P = .034 and < .001) and low relapse-related mortality (P < .001 for both). NRM was significantly increased by atypical GVHD, but not by NIH-defined cGVHD (P = .019 and .10), which was driven only by a few atypical organ manifestations (eg, renal, restrictive lung disease, peripheral neuropathy), whereas others did not contribute to NRM (eg, thyroid gland, musculoskeletal, pancreas). In summary, atypical cGVHD is more common than previously estimated and has both similarities with and differences from NIH-defined cGVHD. In particular, the increased NRM and a subset of patients with only atypical cGVHD point to the urgent need to capture these manifestations in cGVHD cohorts, including analysis of treatment outcomes.