Impaired B Lymphopoiesis Concurrent with Marrow Infiltration By Allogeneic Donor T-Cells: Further Evidence for Bone Marrow Graft-Versus-Host Disease

Abstract Background: The recently introduced concept of bone marrow graft-versus-host disease (BM-GvHD) representing destruction of the host hematopoietic niche in the marrow by allogeneic donor T-cells is loosely defined. Otherwise unexplained B lymphocytopenia and other cytopenias of unclear etiology that frequently occur in the early post-transplant period are often attributed to BM-GvHD. B lymphocytopenia can co-exist with systemic GvHD, supporting the theory of concurrent donor T-cell-induced damage to the marrow causing suppressed B lymphopoiesis. However, demonstration of such correlations has been difficult in humans due to the lymphotoxic effect of steroids which are the frontline therapy for GvHD. The best evidence comes from a recent study showing a correlation between delayed recovery of B lymphopoiesis and donor T-cell infiltration in the marrow 3-4 weeks post-transplant. The potential confounding effect of steroids was not evaluated. The purpose of the present study was to assess whether there is significant donor T-cell infiltration in the marrow at the time of B lymphocytopenia in carefully selected, fully chimeric allo-SCT recipients on minimal or no steroids and with minimal or no systemic GvHD. Methods: A total of 11 patients who underwent allo-SCT for myeloid malignancies were retrospectively studied. Inclusion criteria were: (i) bone marrow biopsy available on days 90-100 or 170-190 post-SCT concurrent with peripheral blood B-cell count using flow cytometry, (ii) full donor chimerism at the time of bone marrow biopsy, (iii) no B lymphodepleting therapy post-SCT, (iv) not on more than 15 mg/d of prednisone on the day of measurement, (v) no GvHD other than acute stage I skin GvHD, and (vi) delayed B-cell recovery defined as Results: 11 patients (10 males) with a median (range) age of 60 (32-67) years were studied. Measurements were made between days 90-100 and 170-190 post-SCT in 4 and 7 patients, respectively. The underlying diagnosis was acute myeloid leukemia (n = 7) or myelodysplastic syndrome (n = 4). The donor was a matched sibling (n = 1), matched unrelated donor (n = 4), or haploidentical donor (n = 6). Conditioning was ablative in 5 patients. Leukopenia, anemia, and thrombocytopenia were present in 3, 9, and 11 patients, respectively. The median (range) B-cell count on days 90-100 and 180-200 was 7 (0-9) and 19 (0-65) cells/µl, respectively. All patients had ≥5% T-cells/µl in the concurrent core biopsy with one exception. This patient had zero B-cells on day 180 but no evidence of concurrent BM-GvHD while on 12 mg/d of prednisone for appetite stimulation. Conclusions: Using a carefully selected cohort of fully chimeric allo-SCT recipients with delayed B lymphopoiesis, on no or minimal amounts of steroids, and with minimal or no systemic GvHD, we demonstrated a high frequency of concurrent increased marrow T-cell infiltration. These results support the recently introduced concept of BM-GvHD and highlight its negative effect on B lymphopoiesis. We show that bone marrow damage by allogeneic T-cells can occur even in the absence of systemic GvHD. Given the difficulties in quantification of marrow T-cells on the core, a more reproducible definition for BM-GvHD is needed. Disclosures No relevant conflicts of interest to declare.