Predominant Reconstitution of B Lymphoid Precursors (Hematogones) Following Unrelated Cord Blood Stem Cell Transplantation.
Authors: Shima Takahiro , Miyamoto Toshihiro , Kikushige Yoshikane , Nagafuji Koji , Teshima Takanori , Akashi Koichi 
Published: April 2020

Abstract
Primary B lymphoid lineages development from hematopoietic stem cells occurs in the bone marrow. During their development, B lymphoid precursors progress through a series of distinct developmental stages defined by CD34+CD38+CD10+CD19−Lin− early-B cells, CD34+CD38+CD10+CD19+Lin− pro-B cells, and CD34−/loCD38+CD10−CD19+CD20+ pre-B cells. These immature B lymphoid cells are more prominent in pediatric bone marrow, and the number of B lymphoid precursors is gradually declined with aging. Benign immature B lymphoid cells, originally termed hematogones, can be observed in the bone marrows during hematopoietic recovery phase in some patients who received chemotherapy or allogeneic bone marrow transplantation (allo-BMT) for hematologic disorders. However, little is known about the mechanisms of occurrence of hematogones and no study concerning hematogones has been available following unrelated cord blood stem cell transplantation (UCBT). We retrospectively analyzed populations of B lymphoid precursors of bone marrow samples from 67 patients who received allogeneic stem cell transplantation (SCT). Patients studied included 28 women and 39 men, with a median age of 49 years (19–66 years). The underlying diseases of 67 patients varied; 26 acute myelogenous leukemia, 10 acute lymphocytic leukemia, 3 chronic myelogenous leukemia, 10 myelodysplastic syndrome, 14 malignant lymphoma, and 4 others. 46 patients underwent allo-BMT and 21 underwent UCBT. Mean number of the infused cells amounted of 2.74 x 108 cells/kg (0.92–4.02 x 108) for allo-BMT recipients and 2.66 x 107 cells/kg (1.92–5.00 x 107) for UCBT recipients. 44 patients received myeloablative conditioning regimen (total body irradiation/cyclophosphamide for 32 patients and buslfan/cyclophosphamide for 12) and 23 received reduced intensity conditioning regimen. Graft-versus-host disease (GVHD) prophylaxis included 2 cyclosporine (CSP) alone, 3 CSP and mycophenolate mofetil, 18 CSP and methotrexate, 2 tacrolimus alone, and 42 tacrolimus and methotrexate. Median time between day 0 of transplant and days performed on evaluation of hematogones by bone marrow aspiration was 31 days (15–140 days). At that time, engraftment of donor cells was confirmed by chimerism analysis using DNA amplification of polymorphic short tandem repeats of bone marrow cells, indicating that hematogones were proven to derive from donor-origins. Hematogones were identified averagely in 1.65% of bone marrow cells (0.01–12.27%) for allo-BMT recipients and 8.39% (0.15–55.56%) for UCBT recipients, respectively. Furthermore, UCBT recipients disclosed more prominent expansion of hematogones than allo-BMT recipients; 5 out of 21 (23.8%) UCBT recipients and 3 out of 46 (6.5%) allo-BMT recipients presented 5% or more of hematogones in their bone marrow cells. These results indicated that UCBT recipients presented much higher frequency and prominent reconstitution of hematogones compared with allo-BMT recipients (p=0.0035). We next analyzed the proportion of hematogones by comparing donors’ age with recipients’ age, since B lymphopoiesis is associated with aging under the physiologically condition. Donor’s age for UCBT was defined as 0-year-old for analyses. Donors for allo-BMT included 15 women and 31 men, with a median age of 36 years (17–66 years). Frequency of hematogones following SCT significantly declined with increasing the donors’ age (p=0.0014), but not with increasing the patients’ age. There was no statistically significant relationship between the number of hematogones and patients’ sex, underlying disease, infectious complications, conditioning regimen, and serum level of immunoglobulin following transplantation. In conclusion, predominant reconstitution of hematogones can be detected following UCBT much higher than allo-BMT, indicating that reconstitution of hematogones depends on donor’s age rather than recipient’s age. These findings obtained from allogeneic SCT suggest that primary lymphoid development may depend on the intrinsic property of stem cells and progenitors, especially aging, rather than bone marrow microenvironments. For the patients who underwent SCT, hematogones often can be confused with relapse of their disease. Our study indicated that prudent attention should be taken in UCBT recipients as well as BMT recipients, although clinical significance of expanded hematogones has not yet resolved.