Acute Graft-Versus-Host Disease Is Associated with Increased Bone Remodeling and Impaired B-Cell Development Suggesting Effects on the Osteoblastic Niche.
April Chiu, Yi-Bin Chen, Geraldine S Pinkus, Robert P Hasserjian. Brigham & Women's Hospital, Boston; Massachusetts General Hospital, Boston
Background: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic stem cell transplantation (allo-SCT). Recent experimental data based on murine model of acute GVHD (aGVHD) demonstrated impairment of B-lymphopoiesis, hematopoiesis, and osteoblastic function; suggesting that the bone marrow (BM) also as a target for GVHD. In this study, we aim to evaluate the effects of GVHD on hematopoiesis and BM microenvironment in patients (pts) who underwent allo-SCT.
Design: BM samples from 60 consecutive allo-SCT recipients with hematologic malignancies obtained 30-120 days after transplantation were evaluated; relapsed cases at BM examination were excluded. Pathologic data evaluated included quantitative/qualitative assessment of hematopoiesis, osteoblasts, and osteoclasts; flow cytometry BM lymphocyte percentages; and peripheral counts. The results were correlated with the presence or absence of aGVHD or chronic GVHD (cGVHD), overall (OS), and relapse-free (RFS) survival.
Results: The 60 cases included 36 male and 24 female pts (age 19-74, median 54 years). Of these, 26/60 (43%) and 27/60 (45%) clinically manifested aGVHD and cGVHD, respectively. The underlying hematologic malignancies and conditioning regimen types were similar among groups with or without GVHD. aGVHD pts showed evidence of bone remodeling manifested by increased osteoclasts (p=0.01) and more activated-appearing osteoblasts with cuboidal morphology (p=0.03). Markedly decreased hematogones (p<0.0001) and CD20+ B-cells (p=0.0004) were observed in the BM of aGVHD pts; pts with impaired platelet recovery also showed increased osteoclast activity (p=0.002) and decreased CD20+ B cells (p=0.03). BM cellular constitution, RFS, and OS were similar in pts with and without aGVHD. There were no differences in any of the pathologic and clinical parameters in the cGVHD group. However, both OS and RFS were superior in cGVHD vs. non-cGVHD groups (p=0.007 for both), consistent with graft-versus-malignancy effect.
Conclusions: Our findings demonstrate increased bone surface activity and impaired B-cell recovery in pts with aGVHD following allo-SCT. Increased bone activity was also associated with delayed platelet recovery. These observations support the notion of the BM as a target organ for aGVHD, and suggest different pathogenic mechanisms leading to aGVHD versus cGVHD. Novel therapies supporting the ostoblastic niche may aid in immune reconstitution and peripheral count recovery in allo-SCT recipients.
Tuesday, March 1, 2011 11:30 AM
Platform Session: Section B, Tuesday Morning