Mitsufumi Nishio

Blastic natural killer cell lymphoma/leukemia (CD56-positive blastic tumor): prognostication and categorization according to anatomic sites of involvement.

Blastic natural killer (NK) cell lymphoma/leukemia (BNKL) is an immature CD56‐positive neoplasm, which was recognized recently and characterized by systemic proliferation of tumor cells including skin, lymph node, and bone marrow.

A Retrospective Analysis of Allogeneic Hematopoietic Stem Cell Transplantation for Adult T Cell Leukemia/Lymphoma (ATL): Clinical Impact of Graft-versus-Leukemia/Lymphoma Effect

Adult T cell leukemia/lymphoma (ATL) is a highly aggressive T cell malignancy, and has a poor prognosis. Recently, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) has been suggested to improve the outcome. We retrospectively analyzed 15 patients with ATL who had received allo-HSCT in 2 institutions in Hokkaido, Japan. The median age of the patients was 57 years. The estimated 3-year overall survival (OS) and progression-free survival (PFS) rates were 73.3% and 66.7%, respectively. Calcineurin inhibitor dosage was reduced and administration was discontinued abruptly in 6 of the 15 patients for disease control; as a result, 4 (66.7%) of the 6 patients achieved complete response (CR) or partial response. Therefore, a graft-versus-leukemia/lymphoma (GVL) effect might be induced by discontinuation of immunosuppression. Thirteen of the 15 patients were followed up by monitoring HTLV-1 proviral DNA levels. In 10 of the 11 patients with positive HTLV-1 proviral DNA before allo-HSCT, HTLV-1 proviral DNA became undetectable at least once after allo-HSCT, and only 1 of the 5 patients in whom HTLV-1 proviral DNA became detectable after allo-HSCT relapsed. Compared to the results of past studies, these results show that allo-HSCT greatly improved the prognosis of ATL and suggest a contribution of the induction of a GVL effect.

Excellent Outcome of Allogeneic Hematopoietic Stem Cell Transplantation Using a Conditioning Regimen with Medium-Dose VP-16, Cyclophosphamide and Total-Body Irradiation for Adult Patients with Acute Lymphoblastic Leukemia

We retrospectively evaluated the outcomes of 37 adult patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) conditioned with medium-dose VP-16 (VP, 30 mg/kg), cyclophosphamide (CY, 120 mg/kg), and fractionated total-body irradiation (TBI, 12 Gy) (medium-dose VP/CY/TBI). The median age of the patients was 26 years. Thirteen patients underwent transplantation from HLA-matched related donors (MRD), 18 patients underwent transplantation from HLA-matched unrelated donors (MUD), and 6 patients underwent transplantation from HLA-mismatched donors (MMD). Thirty-two patients received bone marrow and 4 patients received peripheral blood stem cells. Ten patients were Philadelphia chromosome-positive (Ph(+)) and 35 patients were in complete remission (CR) at transplantation. All of the patients achieved engraftment, and grade 3 organ toxicity before engraftment occurred in 27 patients. Grade II-III acute graft-versus-host disease (GVHD) and chronic GVHD (cGVHD) occurred in 15 and 18 patients, respectively. No patient developed grade IV acute GVHD (aGVHD) or died of GVHD. At median follow-up of 35.1 months, 32 patients were alive and all Ph(+) patients were alive. Three patients died of relapse and 2 died of transplant-related mortality (TRM). The actuarial 3-year overall survival (OS) rate, relapse rate, and TRM rate were 89.2%, 8.1%, and 5.4%, respectively. Non-CR at transplantation, MRD, and no aGVHD were significant adverse prognostic factors for survival. Medium-dose VP/CY/TBI for adult ALL patients was associated with lower relapse rate and no increase in toxicity, resulting in better survival.

Incidence and Risk of Postherpetic Neuralgia after Varicella Zoster Virus Infection in Hematopoietic Cell Transplantation Recipients: Hokkaido Hematology Study Group

To assess the incidence of and risk factors associated with postherpetic neuralgia (PHN) after hematopoietic cell transplantation (HCT) varicella zoster virus (VZV) infection, we conducted a retrospective chart review of 418 consecutive patients who underwent HCT between April 2005 and March 2007. The male/female ratio was 221/197, median age at HCT was 47 years (range: 0-69 years), and autologous/allogeneic/syngeneic HCT ratio was 154/263/1. Seventy-eight patients developed VZV infection after HCT. Sixty-two patients had localized zoster, 11 patients had disseminated zoster (rash like chicken pox), and 4 patients had visceral zoster. All cases were treated with acyclovir (ACV) or valacyclovir (VACV), and there was no VZV infection-related death. Twenty-seven (35%) of the 78 patients with VZV infection suffered PHN after resolution of VZV infection. Multivariate analysis showed that advanced age is the only risk factor in autologous HCT (P = .0075; odds ratio [OR] = 1.14; 95% confidence interval [CI], 0.97-1.33). On the other hand, advanced age (P = .0097; OR = 1.06; 95% CI, 1.01-1.12), male gender (P = .0055; OR = 12.7; 95% CI, 1.61-100.1), and graft-versus-host disease (GVHD) prophylaxis with a tacrolimus-based regimen (P = .0092; OR = 9.56; 95% CI, 1.44-63.3) were associated with increased risk of PHN in allogeneic HCT. This study for the first time clarified the risk of PHN in HCT recipients.

Effective high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in a patient with the aggressive form of cytophagic histiocytic panniculitis

A 20-year-old Japanese man developed generalized, subcutaneous, painless nodules, fever, abnormal liver function, serosal effusions, hepatosplenomegaly, lymphadenopathy and anemia. Skin biopsies revealed lobular panniculitis with a morphologically benign histiocytic infiltration and prominent phagocytosis. Atypical T lymphocytes were also present in the skin and liver. The diagnosis given was aggressive cytophagic histiocytic panniculitis (CHP) or aggressive subcutaneous panniculitic T cell lymphoma (SPTCL). He received cyclophosphamide, doxorubicin, and vincristine on day 1, prednisolone on days 1–5, and etoposide on days 1, 3 and 5 (CHOP-E), with the support of granulocyte colony-stimulating factor. This regimen was repeated every 2 weeks and complete clinical remission (CCR) was attained after three cycles of CHOP-E. As the clinical course of aggressive CHP is recurrent and often fatal, he was given high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (APBSCT), after five cycles of CHOP-E. He has remained in CCR for 12 months after APBSCT. High-dose chemotherapy followed by APBSCT is considered to be one of the most beneficial therapies for patients with aggressive CHP and aggressive phase SPTCL.

Tumor necrosis factor-α inhibits generation of glycophorin A+ cells by CD34+ cells

Abstract Objective The inhibitory effects of tumor necrosis factor-α (TNF-α) on cytokine-induced proliferation and differentiation of normal human erythroid progenitors have been characterized extensively, yet little is known about the maturation level of erythroid progenitors that are sensitive to TNF-α or of the expression of TNF receptors (TNFRs) in erythroid lineage. The aim of this study was to determine the extent to which human erythroid progenitor cells are sensitive to TNF-α, and to relate this to the expression of TNFRs in the erythroid lineage. Materials and Methods Highly purified human CD34 + cells underwent erythroid differentiation, with or without TNF-α. We used colony assay as well as a method by which colony-forming unit-erythroid (CFU-E) and glycophorin A (GPA; a specific marker for erythroid lineage) positive cells can be generated in liquid phase from purified human CD34 + cells in the presence of multiple cytokines, including stem cell factor (SCF), interleukin-3 (IL-3), and erythropoietin (EPO). During erythroid differentiation of CD34 + cells, TNFRs expression were monitored. Results TNF-α inhibited the generation of GPA + cells by CD34 + cells as well as the proliferative capacity of GPA + cells supported by EPO, IL-3, and SCF. Erythroid progenitors became resistant to the inhibitory effect of TNF-α as they matured. The detectable expression of TNFR-I was transient in the early phase of erythroid differentiation, whereas TNFR-II was expressed through the entire course of erythroid differentiation of CD34 + cells. Conclusions TNF-α suppresses erythropoiesis by inhibiting the generation of GPA + cells derived from CD34 + cells as well as by inhibiting the proliferative capacity of GPA + cells. Although the presence of TNFRs does not directly indicate that the receptor(s) mediates death signaling, altered expression of TNFRs depending on the level of maturation may imply altered sensitivities to TNF-α in various stage of erythroid progenitors.

Persistent panhypogammaglobulinemia with selected loss of memory B cells and impaired isotype expression after rituximab therapy for post-transplant EBV-associated autoimmune hemolytic anemia

To the Editor: Miles and McGratten (1) reported persistent panhypogammaglobulinemia after CHOP-rituximab for HIV-related lymphoma. Prolonged hypogammaglobulinemiawith rituximab has also been seen in patients with post-transplant Epstein–Barr virus (EBV)-associated lymphoproliferative disorder (2, 3), as well B-cell lymphoma when rituximab is used as maintenance after stem cell transplantation (4, 5). We report a case of severe persistent panhypogammaglobulinemia after treatment of a posttransplant EBV-associated autoimmune hemolytic anemia (AIHA) with rituximab. The patient is a 32-yr-old Japanese woman with severe aplastic anemia who underwent non-myeloablative allogeneic peripheral blood stem cell transplantation from her HLA-matched sister in September 2000 (6). On days 90 and 150, chronic graft versus host disease occurred, but was alleviated with tacrolimus and predonisolone. In April 2002, 19 months after transplantation, the serum immunoglobulin M (IgM) level increased and immuno-electrophresis analysis revealed monoclonality of IgM. A remarkable proliferation of EBV-DNA also occurred. Tacrolimus and predonisolone were rapidly tapered off and the IgM level and EBV-DNA decreased. At that time, the IgG level was 757 mg/ dL (normal range 870–1700); low but stable after tapering of these immunosuppressive agents. In July 2002, severe AIHA occurred (7). Due to the existence of predictive factors of post-transplant lymphoproliferative disease (PTLD), conventional immunosuppressive therapy for AIHA was not considered. We gave rituximab (Chugai Pharmaceutical, Tokyo, Japan), 375 mg/m once a week for a total of four doses. The clinical and laboratory signs of hemolysis rapidly improved and the hemoglobin level began to improve 2 wk after the start of rituximab treatment. B cells in her peripheral blood rapidly disappeared, as expected. But all serum immunoglobulin levels kept on decreasing and remained extremely low (IgG < 200 mg/dL, IgA < 10 mg/dL and IgM < 10 mg/dL) unless intravenous immunoglobulin (IVIG) was administered for more than 2 yr. She developed repeated bacterial infections, such as pneumonia and sepsis, and was treated with IVIG and antibiotics. In February 2005, 30 months after last administration of rituximab, we found her blood B-cell number reverted to a normal range (8% of total lymphocytes, 180/lL), despite the still severe hypogammaglobulinemia. Flow cytometry analysis revealed that her B cells were composed with only CD27 negative naı̈ve B cells. CD27 positive memory B cells, both IgD-positive non-switched and IgDnegative switched populations, were hardly seen (Fig. 1A). In addition, we evaluated immunoglobulin isotype production by analyzing immunoglobulin transcripts with reverse transcriptase-polymerase chain reaction as described (8). Her peripheral blood mononuclear cells (PBMC) only expressed the transcriptions of IgM, IgG1, IgA1 and IgA2, but no IgG2, IgG3 and IgG4 (Fig. 1B). Rituximab is known to induce B-cell depletion for up to 6 months post-treatment (9). Moreover, in patients treated with high dose chemotherapy and maintenance rituximab, it takes longer (18– 24 months) for B-cell recovery (4). This delay of B-cell recovery is likely to contribute to hypogammaglobulinemia, especially when rituximab is used for treatment of EBV-PTLD (2, 3, 10). But this does not seem to be the case in our patient who Eur J Haematol 2005: 75: 527–529 doi:10.1111/j.0902-4441.2005.t01-1-EJH2327.x All rights reserved Copyright Blackwell Munksgaard 2005

Professional oral health care reduces oral mucositis and febrile neutropenia in patients treated with allogeneic bone marrow transplantation

Goal of workLittle is known about the effects of professional oral health care (POHC) on the outcome of hematopoietic stem cell transplantation (HSCT). We evaluated the effects of POHC given by dentists and dental hygienists on the development of oral mucositis and febrile neutropenia (FN) after allogeneic bone marrow transplantation (BMT).Patients and methodsWe retrospectively studied 140 adult patients who had received allogeneic BMT, with or without POHC, in our hospital consecutively between February 2002 and December 2009. Oral mucositis was evaluated according to the World Health Organization scale.Main resultsThe incidence of oral mucositis was 66.7% (52/78) in the patients who had received POHC, compared to 93.5% (58/62) in the non-POHC group (P < 0.001). The incidence of FN and the maximal level of CRP were also significantly lower in the POHC group. Multivariate analysis revealed that the POHC was significantly associated with the incidence of oral mucositis (odds ratio, 7.58; 95%CI, 2.45–23.34; P < 0.001).ConclusionsWe concluded that POHC reduced the incidences of oral mucositis and FN by upgrading the overall oral hygiene during HSCT.

Therapeutic impact of human bone marrow stromal cells expanded by animal serum-free medium for cerebral infarct in rats.

BACKGROUND:The donor cell culture in animal serum-free medium is important for the clinical application of cell transplantation therapy. Recently, human-derived platelet lysate (PL) gained interest as a substitute for fetal calf serum (FCS), but there are no studies that evaluate the validity of human bone marrow stromal cells (hBMSCs) expanded with PL-containing medium for central nervous system disorders. OBJECTIVE:To test the hypothesis that hBMSCs expanded with FCS-free, PL-containing medium can promote functional recovery after cerebral infarct. METHODS:hBMSCs were cultured in the FCS- or PL-containing medium. Cell-growth kinetics were analyzed. The vehicle or hBMSCs was stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion 7 days after the insult. Motor function was assessed for 8 weeks, and the fate of transplanted hBMSCs was examined using immunohistochemistry. RESULTS:There was no significant difference in hBMSC expansion between the 2 groups. Transplantation of hBMSCs expanded with the FCS- or PL-containing medium equally promoted functional recovery compared with the vehicle group. Histological analysis revealed that there were no significant differences in their migration, survival, and neural differentiation in the infarct brain between the 2 groups. CONCLUSION:hBMSCs expanded with PL-containing medium retained their capacity of migration, survival, and differentiation and significantly promoted functional recovery when stereotactically transplanted into the infarct brain. The PL may be a clinically valuable and safe substitute for FCS in expanding hBMSCs to regenerate the infarct brain.

Bone Marrow Graft-versus-Host Disease: Evaluation of Its Clinical Impact on Disrupted Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation

Idiopathic cytopenias are frequently observed in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported the effect of graft-versus-host disease (GVHD) on bone marrow (BM) in murine models, indicating that the osteoblast injury mediated by donor T cells was associated with bone marrow suppression and delayed immune reconstitution. In this study, we prospectively evaluated the relevance of these findings in 51 patients. Patients with chronic GVHD manifested the loss of osteoblasts, contributing to cytopenic symptoms (P = .0427 compared with patients without cytopenic symptoms). The loss of osteoblasts was significantly associated with the extensive type of chronic GVHD (P = .012), and flow cytometric analyses revealed lower numbers of CD19(+) B cells and a significantly increased CD4 to CD8 ratio (P = .0002) in these patients. Our data, for the first time to our knowledge, summarize the detailed analyses of the effect of GVHD on BM in the clinical allo-HSCT patients.