Based on the recent progress of fluorescence-activated cell sorting technology, murine hematopoietic stem cells (HSCs) can be purified to the single cell level. The immunophenotype of murine HSCs is CD34low/−c-kit+Sca-1+Lin− (CD34low/− KSL). However, the stem cell nature of primitive human HSCs has not been fully elucidated. The biology of human HSCs is a current topic of interest that has important implications for hematopoietic stem cell transplantation (HSCT) as well as basic research on HSCs. We identified human cord blood (CB) -derived CD34− SCID-repopulating cells (SRCs) (HSCs), which seemed to be a counterpart of murine CD34low/− KSL cells, using an intra-bone marrow injection (IBMI) method. Our series of studies has elucidated the stem cell nature of these CD34− HSCs as well as CD34+ HSCs. The purpose of this review is to provide an update of the concept of the immunophenotype and functional characteristics of human primitive CD34+/− HSCs. In addition, the significance of the application of the IBMI technique in clinical HSCT is also discussed. Recent advances in the understanding of the biological nature of human HSCs may make it possible to fully characterize the most primitive class of human HSCs, and thereby clarify the human HSC hierarchy, in the near future.
Currently more than 5,000 hematopoietic cell transplantations are performed annually in Japan. Advances in transplantation technology have reduced early transplant-related mortality, and management of late effects after transplantation has become increasingly important for growing numbers of long-term survivors. Late effects include many complications such as chronic graft-versus-host disease (GVHD), recurrent malignancy, secondary malignancies, infection, lung diseases, endocrine diseases, cardiac diseases, chronic renal diseases, iron overload, bone diseases, and psychosocial distress. The leading causes of late mortality were recurrent malignancy, lung diseases, infection, secondary malignancies and chronic GVHD. International and domestic guidelines of preventive practices and management for long-term survivors have been published. Recent study results highlight the need for education of both patients and medical providers about late effects after transplantation, and demonstrate importance of dedicated long-term follow-up program for improving adherence to health care and long-term survival. This review focuses on evidences of long-term follow-up program, and diagnosis and treatment of chronic GVHD based on the 2014 National Institutes of Health criteria.
We retrospectively analyzed data from 60 patients who had relapsed after up-front autologous stem cell transplantation (ASCT). Thirteen patients received salvage ASCT, and median progression-free survival (PFS) and overall survival (OS) after salvage ASCT were 19.3 and 41.1 months, respectively. Favorable factors for PFS after salvage ASCT were as follows; achieving a partial or better response before salvage ASCT [hazard ratio (HR) =0.018, 95% confidence interval (CI): 0.005-0.64, P=0.028] and consolidation/maintenance therapy after salvage ASCT (HR=0.083, 95% CI: 0.008-0.87, P=0.038). There was no significant factor for OS after salvage ASCT. Patients without salvage ASCT had not been surveyed for PFS after relapse. Including all patients, two unfavorable factors for OS after relapse were as follows; relapsing during or after consolidation/maintenance therapy after initial ASCT and salvage therapy comprising cytotoxic agents. On the other hand, salvage ASCT was favorable for OS after relapse post initial ASCT (HR=0.30, 95% CI: 0.096-0.95, P=0.041). Confounding factors and survivor treatment selection bias do not permit definitive conclusion. We hope the current study sheds light on the salvage ASCT, but careful evaluation is needed during the approval of additional new agents.
We studied the influence of second marrow donation from Japan Marrow Donor Program on donor’s physical loads and transplant outcomes. Eight hundred and twenty donors were available. The duration between first and second donation was about 4 years. The shorter term of coordination was confirmed in second donation compared to first donation. The duration of pain and recovery to daily life in second donation were shorter than those in first donation, although the degree of pain was same in first and second donation. Harvesting time and volume of bone marrow, total cell count, cell concentration, and cell count/patient weight in first and second donation were 74 min: 78 min (P<0.001), 821 mL: 848 mL (P=0.095), 160×108 cells: 139×108 cells (P<0.001), 2.0×107 cells/mL: 1.7×107 cells/mL (P<0.001), and 3.0×108 cells/kg: 2.7×108 cells/kg (P<0.001), respectively. Delayed hematopoietic recovery and poor overall survival were observed in patients who received bone marrow transplantation from second donation. The results indicated that long-term influence is unclear, but second donation is permissible for voluntary donors. Further analysis will be necessary to clarify the impact of second marrow donation on transplant outcomes.
Calcineurin inhibitor (CI)-induced pain syndrome (CIPS) is a rare complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, because of its rarity, the optimal management of this complication remains unknown.
We analyzed the clinical features and treatment outcomes of the patients who developed CIPS after allo-HSCT. The study included patients who underwent allo-HSCT between January 2003 and December 2014 at the hospitals participating in the KSGCT. Sixteen patients developed CIPS. The most common symptom was leg pain, which was observed in 9 patients, followed by leg pain associated with pruritus in five, and pruritus only in two. The median time from allo-HSCT to CIPS was 16 days. CIPS occurred within 30 days of starting CIs in 14 patients (87.5%). CI was discontinued in four patients; the dose of CI was reduced in two patients, and seven patients were switched to another CI. The symptoms in all of those 13 patients with intervention resolved within 6 days from the onset of CIPS.
The possibility of CIPS must be considered when patients who have undergone allo-HSCT develop intolerable leg pain and/or pruritus. Our findings suggest that withdrawal/dose reduction of the CI or substitution with another CI is an effective treatment for CIPS.
A 35-year-old man developed bronchiolitis obliterans (BO) after unrelated allogeneic bone marrow transplantation (BMT) for T-cell acute lymphoblastic leukemia. He had received cadaveric lung transplantation (CLT) 4 years and 3 months after BMT. Seven months following BMT, multiple hepatic lesions were identified. Biopsy results of the lesions revealed infiltration of lymphoma cells. Immunostaining of the biopsy was positive for CD20, CD79a, and Epstein-Barr virus (EBV) encoded small RNA, and the kappa light-chain restriction was revealed by flow cytometric analysis. This analysis led to a diagnosis of EBV-associated monomorphic post-transplantation lymphoproliferative disorder (PTLD). Despite the reduction of the immunosuppressive dosage and administration of rituximab, the patient died seven days after the onset of therapy.
Recipients of lung transplantation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are more likely to develop advanced immunodeficiency than normal lung transplant recipients who have not undergone allo-HSCT. Due to the increased risk of immunodeficiency, complication associated with PTLD is a concern. Although there is potential to reduce or even terminate immunosuppression with living-donor lobar lung transplantation using the same donor as for allo-HSCT, it is difficult to achieve this with CLT. An increase in the number of cases of CLT after allo-HSCT for BO is expected; therefore, it is necessary to pay attention to the complications associated with PTLD.