Tatsuo Ichinohe

Early application of related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma.

Allogeneic hematopoietic SCT (allo-HSCT) is a curative treatment for aggressive adult T-cell leukemia/lymphoma (ATLL). Considering the dismal prognosis associated with conventional chemotherapies, early application of allo-HSCT might be beneficial for patients with ATLL. However, no previous study has addressed the optimal timing of allo-HSCT from related donors. Hence, to evaluate the impact of timing of allo-HSCT for patients with ATLL, we retrospectively analyzed data from patients with ATLL who received an allo-HSCT from a related donor. The median age was 52 years. Patients were grouped according to the interval from diagnosis to allo-HSCT: early transplant group, <100 days, n=72; late transplant group, ⩾100 days, n=428. The corresponding constituents of disease status were not statistically different between the two groups (P=0.11). The probability of OS in the early transplant group was significantly higher than that in the late transplant group (4-year OS, 49.3% vs 31.2%). Multivariate analysis revealed that late allo-HSCT was an unfavorable prognostic factor for OS (hazard ratio, 1.46; 95% confidence interval (CI), 1.01–2.11; P=0.04). Despite the limitations of a retrospective study, it might be acceptable to consider early application of allo-HSCT for ATLL.

The outcome and characteristics of patients with relapsed adult T cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation

Treatment options for patients with adult T cell leukemia/lymphoma (ATLL) who have relapsed disease after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) are limited. To clarify which patients with ATLL are likely to benefit from these treatment options and to define patient populations for novel treatments, we performed a nationwide retrospective analysis of 252 Japanese patients who had relapsed ATLL after allo‐HSCT. Some long‐term survivors remained after tapering and withdrawal of immunosuppressive agents. Thirty‐six patients who received donor lymphocyte infusion had a better overall survival (OS) in comparison to those who did not [hazard ratio (HR), 0.63; 95% confidence interval (CI), 0.43‐0.93; P = .02], suggesting the efficacy of a graft‐versus‐ATLL (GvATLL) effect even after relapse. Multivariate analysis demonstrated that skin lesions at initial relapse of ATLL were independently associated with higher OS (HR, 0.41; 95% CI, 0.22‐0.74; P = .003), indicating that the skin is a susceptible target organ of GvATLL. This study suggested that enhancement of a GvATLL effect is a potential therapeutic option for relapsed disease after allo‐HSCT. Further investigations of incorporation of immune‐based approaches with new molecular target drugs into the therapeutic options of patients with ATLL before and after transplantation are warranted.

Next-Generation Immune Repertoire Sequencing as a Clue to Elucidate the Landscape of Immune Modulation by Host–Gut Microbiome Interactions

The human immune system is a fine network consisted of the innumerable numbers of functional cells that balance the immunity and tolerance against various endogenous and environmental challenges. Although advances in modern immunology have revealed a role of many unique immune cell subsets, technologies that enable us to capture the whole landscape of immune responses against specific antigens have been not available to date. Acquired immunity against various microorganisms including host microbiome is principally founded on T cell and B cell populations, each of which expresses antigen-specific receptors that define a unique clonotype. Over the past several years, high-throughput next-generation sequencing has been developed as a powerful tool to profile T- and B-cell receptor repertoires in a given individual at the single-cell level. Sophisticated immuno-bioinformatic analyses by use of this innovative methodology have been already implemented in clinical development of antibody engineering, vaccine design, and cellular immunotherapy. In this article, we aim to discuss the possible application of high-throughput immune receptor sequencing in the field of nutritional and intestinal immunology. Although there are still unsolved caveats, this emerging technology combined with single-cell transcriptomics/proteomics provides a critical tool to unveil the previously unrecognized principle of host–microbiome immune homeostasis. Accumulation of such knowledge will lead to the development of effective ways for personalized immune modulation through deeper understanding of the mechanisms by which the intestinal environment affects our immune ecosystem.

Suppression effect on IFN‑γ of adipose tissue‑derived mesenchymal stem cells isolated from β2‑microglobulin‑deficient mice

Administration of bone marrow-derived mesenchymal stem cells (MSCs) is a possible treatment for graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation and other inflammatory conditions. To address the mechanism of immunosuppression by MSCs, in particular those derived from adipose tissue (AMSCs), AMSCs were isolated from three different mouse strains, and the suppressive capacity of the AMSCs thus obtained to suppress interferon (IFN)-γ generation in mixed lymphocyte reaction cultures serving as an in vitro model of GVHD were assessed. It was revealed that the AMSCs had a potent capacity to suppress IFN-γ production regardless of their strain of origin and that such suppression was not associated with production of interleukin-10. In addition, the results demonstrated that β2-microglobulin (β2m)-deficient AMSCs from β2m-/- mice were also potent suppressor cells, verifying the fact that the mechanism underlying the suppression by AMSCs is independent of major histocompatibility complex (MHC) class I expression or MHC compatibility. As AMSCs appear to have immunosuppressive properties, AMSCs may be a useful source of biological suppressor cells for the control of GVHD in humans.

Myeloma Cells Are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex, Which Senses Lipopolysaccharide

Multiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a noncanonical lipopolysaccharide (LPS) receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Bacterial LPS and anti-CD180 antibody, but not other Toll-like receptor ligands, enhanced the growth of MM cells via activation of MAP kinases ERK and JNK in positive correlation with expression levels of CD180. Administration of LPS significantly increased the number of CD180/CD138 double-positive cells in a murine xenograft model when MM cells were inoculated with direct attachment to BMSC. Knockdown of CD180 canceled the LPS response in vitro and in vivo Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene. Both cell adhesion and hypoxia activated transcription of the CD180 gene by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros by the immunomodulatory drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner in vitro and in vivo Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells.Significance: This study describes a novel mechanism by which myeloma cells are regulated in the bone marrow, where drug resistance and dormancy can evolve after treatment, with potential therapeutic implications for treating this often untreatable blood cancer. Cancer Res; 78(7); 1766-78. ©2018 AACR.

Allogeneic haematopoietic cell transplantation for adult acute myeloid leukaemia in second remission: a retrospective study of the Adult Acute Myeloid Leukaemia Working Group of the Japan Society for Haematopoietic Cell Transplantation (JSHCT)

To evaluate the outcomes and prognostic factors following allogeneic haematopoietic cell transplantation (HCT) for adult acute myeloid leukaemia (AML) in second complete remission (CR2), we retrospectively analysed the Japanese registration data of 1080 adult AML patients in CR2 who had received allogeneic HCT. The probability of overall survival and the cumulative incidence of relapse at 3 years was 66% and 19%, respectively. In multivariate analysis, older age, poor cytogenetics and shorter duration of first complete remission were significantly associated with a higher overall mortality. Our data demonstrated the significant efficacy of allogeneic HCT for adult AML in CR2.

Which is more important for the selection of cord blood units for haematopoietic cell transplantation: the number of CD34-positive cells or total nucleated cells?

Given that delayed neutrophil engraftment is associated with an increased risk of non-relapse mortality (NRM) (Wagner et al, 2002), cell doses should be considered when selecting cord blood (CB) units for transplantation, as well as human leucocyte antigen (HLA) matching. In general, CB units with >2 5–3 9 10 total nucleated cells (TNC)/kg are preferred to avoid the risk of graft failure (Hough et al, 2016; Ruggeri, 2016). In addition, CB units with >1 9 10 CD34 cells/kg are also associated with successful engraftment. However, if a CB unit with an optimal cell dose is not available, it is not clear whether the TNC or CD34 cell dose better predicts the clinical outcomes in single CB transplantation. Using the registry database of Japan Society for Haematopoietic Cell Transplantation (JSHCT) and the Japanese Data Centre for Haematopoietic Cell Transplantation (JDCHCT) (Atsuta et al, 2007), we retrospectively identified 1917 adult and adolescent recipients with leukaemia or lymphoma who underwent their first transplant from a single unit of CB with <2 5 9 10 TNC/kg between 2006 and 2014 (Table S1), and categorized them into 12 groups according to TNC [(1) 0 5–2 (n = 364), (2) 2–2 25 (n = 744) and (3) 2 25–2 5 (n = 809) 910/kg] and CD34 cell doses [(1) 0–0 5 (n = 392), (2) 0 5–0 75 (n = 536), (3) 0 75–1 0 (n = 458) and (4) ≥1 0 (n = 531) 910/kg] doses. Detailed methods are described in the Supporting Information. Briefly, pairwise-analyses were performed in pairs consisting of low TNC with high CD34 cells versus high TNC with low CD34 cells. Pairs such as TNC(1)CD34(1) versus TNC (3)CD34(3) were excluded because clinicians must select units with either more TNC or more CD34 cells (Figure S1). P-values <0 0028 were considered statistically significant considering the multiple comparison with the Bonferoni correction, and values between 0 0028 and 0 05 were considered to have borderline significance. This retrospective

A case of primary extranodal natural killer/T-cell lymphoma in the orbit and intraocular tissues with cerebrospinal fluid involvement

Purpose To report a rare case of primary orbital natural killer (NK)/T-cell lymphoma without nasal lesions but with cerebrospinal fluid involvement. Observations A 73-year-old woman was referred to the uveitis clinic with suspected unilateral acute uveitis in her right eye and a right orbital tumor. Epstein–Barr virus DNA was detected in the aqueous humor in her right eye, and orbital biopsy revealed the presence of extranodal NK/T-cell lymphoma (ENKTL), nasal type. Positron emission tomography showed significant 18F-fluorodeoxyglucose uptake in the right orbit, with no other signs of systemic involvement. Cerebrospinal fluid analysis demonstrated lymphoma cell infiltration. She was diagnosed with stage IV ENKTL and treated with orbital radiotherapy and systemic chemotherapy, with subsequent remission. However, the lymphoma relapsed in her left vitreous at 10 months after therapy, suggesting metastasis of lymphoma cells to the contralateral eye via the vitreous and cerebrospinal fluid. Conclusions and importance A few cases of ocular-tissue ENKTL have been reported, mostly involving invasion or dissemination of primary nasal lesions; in contrast, primary orbital and intraocular ENKTL has rarely been reported. To the best of our knowledge, this is the first report of a primary orbital ENKTL metastasizing to the vitreous of the contralateral eye. Although ENKTL is rare in the orbit and intraocular tissues, it should be considered as a possible differential diagnosis in patients with orbital tumors or intraocular inflammation resistant to steroid therapy because ENKTL has a very poor prognosis in the advanced stage.

Impact of the presence of HLA 1-locus mismatch and the use of low-dose antithymocyte globulin in unrelated bone marrow transplantation

HLA 1-locus-mismatched unrelated donors (1MMUD) have been used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. We retrospectively analyzed 3313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD between 2009 and 2014. We compared the outcomes of MUD (n=2089) and 1MMUD with antithymocyte globulin (ATG) (1MM-ATG(+); n=109) with those of 1MMUD without ATG (1MM-ATG(−); n=1115). The median total dose of ATG (thymoglobulin) was 2.5u2009mg/kg (range 1.0–11.0u2009mg/kg) in the 1MM-ATG(+) group. The rates of grade III–IV acute GvHD, non-relapse mortality (NRM) and overall mortality were significantly lower in the MUD group than in the 1MM-ATG(−) group (hazard ratio (HR) 0.77, P=0.016; HR 0.74; P<0.001; and HR 0.87, P=0.020, respectively). Likewise, the rates of grade III–IV acute GVHD, NRM and overall mortality were significantly lower in the 1MM-ATG(+) group than in the 1MM-ATG(−) group (HR 0.42, P=0.035; HR 0.35, P<0.001; and HR 0.71, P=0.042, respectively). The outcome of allo-HCT from 1MM-ATG(−) was inferior to that of allo-HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared with the use of low-dose ATG without increasing the risk of relapse.