Kuniko Takano

Foscarnet against human herpesvirus (HHV)-6 reactivation after allo-SCT: breakthrough HHV-6 encephalitis following antiviral prophylaxis

High incidences of human herpesvirus (HHV)-6 encephalitis have recently been reported from several Japanese SCT centers. To evaluate the effect of low-dose foscarnet (PFA) in preventing HHV-6 infection among recipients of unrelated BM or cord blood (CB), we examined consecutive cohorts without prophylaxis against HHV-6 (Cohort 1, n=51) and with PFA prophylaxis (Cohort 2, PFA 50 mg/kg/day for 10 days after engraftment, n=67). Plasma real-time PCR assay was performed weekly. High-level reactivation defined as HHV-6 DNA⩾104 copies/mL by day 70 was the primary endpoint. No significant reduction of high-level reactivation was seen in Cohort 2 (19.4%) compared with Cohort 1 (33.8%, P=0.095). A trend was identified toward fewer high-level HHV-6 reactivations in Cohort 2 among recipients of unrelated BM (P=0.067), but no difference in incidence was observed among CB recipients (P=0.75). Breakthrough HHV-6 encephalitis occurred following PFA prophylaxis in three patients, and incidence of HHV-6 encephalitis did not differ between Cohort 1 (9.9%) and Cohort 2 (4.5%, P=0.24). In conclusion, 50 mg/kg/day of PFA does not effectively suppress HHV-6 reactivation and cannot prevent all cases of HHV-6 encephalitis. To effectively prevent HHV-6 encephalitis, alternative approaches based on the pathogenesis of HHV-6 encephalitis will probably be required.

RANDOM MIGRATION OF POLYMORPHONUCLEAR LEUKOCYTES INDUCED BY GM-CSF INVOLVING A SIGNAL TRANSDUCTION PATHWAY DIFFERENT FROM THAT OF FMLP

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) Induced random migration of human polymorphonuclear leukocytes (PMNs) but not chemotaxis. Chemoattractants such as N‐formylmethionyl‐leucyl‐phenylalanine (fMLP), leukotriene B4 (LTB4), and interleukin‐8 (IL‐8) induced both random migration and chemotaxis. Other inflammatory cytokines, including granulocyte colony‐stimulating factor (G‐CSF), interleukin 1α (IL‐1α), and tumor necrosis factor α (TNF‐α), did not induce either movement. One‐minute exposure of PMNs to GM‐CSF was sufficient for the induction of random migration, whereas fMLP‐induced random migration required continued presence of fMLP. Inhibitors of phosphatidylinositol 3‐kinase (PI3‐K), protein kinase C (PKC), and protein tyrosine kinase (PTK) had no effect on random migration induced by GM‐CSF, whereas fMLP‐induced movements were partially inhibited by PTK inhibitors but not by inhibitors of PI3‐K inhibitors nor PKC inhibitors. Myosin light chain kinase inhibitors inhibited movements of PMNs induced by both GM‐CSF and fMLP. These findings also imply that some aspects of the signal transduction pathway of GM‐CSF leading to random migration is different from that of fMLP. Our findings suggest that cell movements are controlled through diverse signal transduction systems. J. Leukoc. Biol. 61: 500–506; 1997.

Pre-transplant diabetes mellitus is a risk factor for non-relapse mortality, especially infection-related mortality, after allogeneic hematopoietic SCT.

Diabetes mellitus (DM) is a factor in the hematopoietic cell transplantation-comorbidity index. However, the impact of pre-transplant DM on morbidity and cause-specific non-relapse mortality (NRM) remains unclear. We performed a retrospective study with registry data that included a total of 7626 patients who underwent their first allogeneic hematopoietic SCT (HSCT) between 2007 and 2010. The median age was 44 years (range 0–88). Compared with patients without pre-transplant DM (non-DM group, n=7248), patients with pre-transplant DM (DM group, n=378) were older and were more likely to have high-risk disease, a reduced-intensity conditioning regimen and GVHD prophylaxis using tacrolimus. Multivariate analyses showed that pre-transplant DM was associated with increased risks of NRM (hazard ratio (HR)1.46, 95% confidence interval (CI) 1.21–1.76, P<0.01) and infection-related NRM (HR 2.08, 95% CI 1.58–2.73, P<0.01). The presence of pre-transplant DM was associated with an increased risk of overall mortality in a multivariate analysis (HR 1.55, 95% CI 1.35–1.78, P<0.01). In conclusion, pre-transplant DM was a risk factor for NRM, particularly infection-related mortality, after allogeneic HSCT. To improve the clinical outcome in patients with DM, the benefits of strict infection control and appropriate glycemic control should be explored in future trials.

A retrospective analysis to estimate target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy.

BACKGROUND The target trough concentration of vancomycin in patients with febrile neutropenia has not been reported. The aim of this study was to estimate the target trough concentration for febrile neutropenia in patients with hematological malignancy. METHODS In this retrospective, single-center, observational cohort study, 63 hospitalized patients with hematological malignancy who were treated with vancomycin for febrile neutropenia due to bacteriologically documented or presumptive Gram-positive infections were analyzed. RESULTS A significant difference in the first trough concentration of vancomycin was observed between the response and non-response groups, and between the nephrotoxicity and non-nephrotoxicity groups. Multiple logistic regression analyses identified the first trough concentration as the only independent variable associated with clinical efficacy and nephrotoxicity of vancomycin. The areas under the ROC curves were 0.72 and 0.83 for clinical efficacy and nephrotoxicity, respectively. The cut-off values of the first trough concentration were 11.1 μg/ml for clinical efficacy (sensitivity 60%, specificity 87%) and 11.9 μg/ml for nephrotoxicity (sensitivity 77%, specificity 82%). CONCLUSIONS These results suggest a relationship of trough vancomycin concentration with clinical efficacy and incidence of nephrotoxicity. We propose a target trough vancomycin concentration of around 11.5 μg/ml for febrile neutropenia in patients with hematological malignancy.

Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation

In this retrospective analysis using the Transplant Registry Unified Management Program, we identified 145 patients with human herpesvirus (HHV)-6 encephalitis among 6593 recipients. The cumulative incidences of HHV-6 encephalitis at 100 days after transplantation in all patients, recipients of bone marrow or PBSCs and recipients of cord blood were 2.3%, 1.6% and 5.0%, respectively. Risk factors identified in multivariate analysis were male sex, type of transplanted cells (relative risk in cord blood transplantation, 11.09, P<0.001; relative risk in transplantation from HLA-mismatched unrelated donor, 9.48, P<0.001; vs transplantation from HLA-matched related donor) and GvHD prophylaxis by calcineurin inhibitor alone. At 100 days after transplantation, the overall survival rate was 58.3% and 80.5% among patients with and without HHV-6 encephalitis, respectively (P<0.001). Neuropsychological sequelae remained in 57% of 121 evaluated patients. With both foscarnet and ganciclovir, full-dose therapy (foscarnet ⩾180 mg/kg, ganciclovir ⩾10 mg/kg) was associated with better response rate (foscarnet, 93% vs 74%, P=0.044; ganciclovir, 84% vs 58%, P=0.047). HHV-6 encephalitis is not rare not only in cord blood transplant recipients but also in recipients of HLA-mismatched unrelated donors. In this study, development of HHV-6 encephalitis was associated with a poor survival rate, and neurological sequelae remained in many patients.

Sarcoidosis in donor-derived tissues after haematopoietic stem cell transplantation

To the Editor: This is the first case of sarcoidosis in donor-derived tissues, confirmed by fluorescence in situ hybridisation (FISH), after haematopoietic stem cell transplantation (HSCT). A 64-year-old Japanese female was diagnosed to have adult T-cell leukaemia in December 2009. She had neither any past history nor a family history of sarcoidosis. She underwent HSCT (unrelated bone marrow transplantation) in May 2010, after receiving treatment with fludarabine, busulfan, and total body irradiation, from a human leukocyte antigen (HLA)-matched male donor who had no history of sarcoidosis. Although no lung involvement was seen in the early phase after HSCT, she was complicated by cytomegalovirus viraemia and acute graft versus host disease (GVHD), which required ganciclovir, systemic steroids and tacrolimus hydrate. She had achieved a negative proviral load of human T-cell lymphocytic virus (HTLV)-1 in her peripheral blood, 3 months after the transplant. At that time, the patient did not show any skin or eye symptoms or liver dysfunction, which are symptoms that are often seen in patients with chronic GVHD. A subcutaneous mass developed on her left upper arm in September 2011 (16 months after the transplant), although the proviral load of HTLV-1 remained negative. Fluorodeoxyglucose positron emission tomography (FDG-PET) or computed tomography (CT) imaging showed FDG accumulations in the mediastinal and hilar lymphadenopathy, in addition to the mass lesion located on the left upper arm. Although …

Effects of Prophylactic Foscarnet on Human Herpesvirus-6 Reactivation and Encephalitis in Cord Blood Transplant Recipients: A Prospective Multicenter Trial with an Historical Control Group

Cord blood transplantation (CBT) is a distinct risk factor for human herpesvirus-6 (HHV-6) reactivation and HHV-6 encephalitis. In a prospective multicenter trial we investigated the effects of prophylactic foscarnet (90 mg/kg i.v. infusion from days 7 to 27 after CBT) on the occurrence of HHV-6 reactivation, HHV-6 encephalitis, and acute graft-versus-host disease (aGVHD) in CBT recipients. Between 2014 and 2016, 57 patients were included in a foscarnet-prophylaxis group. Outcomes were compared with an historical control group who received CBT between 2010 and 2014 (standard-treatment group, n = 63). The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 104 copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% versus 57.3%, P < .001). Multivariate analysis revealed that myeloablative preconditioning and standard treatment were significant risk factors for high-level HHV-6 reactivation. The cumulative incidence of HHV-6 encephalitis at 60 days after CBT was not different between the groups (foscarnet-prophylaxis group, 12.4%; standard-treatment group, 4.9%; P = .14). The cumulative incidences of grades II to IV and grades III to IV aGVHD at 60 days after CBT were not different between the groups (grades II to IV aGVHD: foscarnet-prophylaxis group, 42.0%; standard-treatment group, 40.5%; P = .96; grades III to IV aGVHD: foscarnet-prophylaxis group, 14.5%; standard-treatment group, 14.5%; P = 1.00). In the setting of this study foscarnet significantly suppressed systemic HHV-6 reactivation in CBT recipients but failed to prevent the development of HHV-6 encephalitis. Suppression of HHV-6 reactivation by foscarnet did not show any effects against the incidence of aGVHD.

Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorder, Hodgkin Type, following Epstein-Barr Viral Hepatitis in a Patient with Rheumatoid Arthritis

A 59-year-old man with an 18-year history of rheumatoid arthritis who had been treated with steroids, methotrexate, and infliximab presented with a high-grade fever, cervical lymphadenopathy, and hepatosplenomegaly. Epstein-Barr virus (EBV) hepatitis was diagnosed based on the liver histology and EBV antibody titer. The symptoms improved temporarily, but five months later, the fever, skin rash, jaundice, and thrombocytopenia relapsed. Bone marrow and liver biopsies demonstrated infiltration with Reed-Sternberg cells. Based on these findings, the patient was diagnosed with other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD), Hodgkin lymphoma type. This case followed a rare clinical course, in that acute hepatitis preceded the diagnosis of OIIA-LPD.

Clinical Outcomes after Allogeneic Stem Cell Transplantation for Adult Lymphoblastic Lymphoma.

Lymphoblastic lymphoma (LBL) is a rare subtype of non-Hodgkin lymphoma. There are limited reports on allogeneic stem cell transplantation (allo-SCT) in patients with LBL. We retrospectively analyzed the clinical outcomes of 15 adult patients with LBL who received allo-SCT at our institution. The median age at allo-SCT was 29 years (range, 18-42). Disease status at the time of transplantation was complete remission (CR), partial remission (PR), and advanced disease in 4, 4, and 7 patients, respectively. The median follow-up duration of survivors was 25 months (range, 6-106). The probabilities of overall survival (OS) and progression-free survival (PFS) at 2 years after allo-SCT were 37% and 24%, respectively. The respective 2-year OS and PFS rates of the 8 patients with CR or PR at the time of transplantation were 57% and 45%, while those with advanced disease were 14% and 0%. In conclusion, the treatment outcomes of allo-SCT in patients with LBL were unsatisfactory. Although outcomes were promising in patients with CR or PR at the time of transplantation, they were dismal in patients with progressive disease. Further advances in chemotherapy, both induction and salvage therapies, are needed to improve the clinical outcomes of patients with LBL.

A higher number of infused CD34(+) cells has a positive impact on the clinical outcome after related PBSC transplantation.

A higher number of infused CD34 + cells has a positive impact on the clinical outcome after related PBSC transplantation