Takuro Yoshimura

Reduced-intensity conditioning by fludarabine/busulfan without additional irradiation or T-cell depletion leads to low non-relapse mortality in unrelated bone marrow transplantation.

In reduced intensity, allogeneic stem cell transplantation from unrelated donors (u-RIST), graft-versus-host disease (GVHD), graft failure, and non-relapse mortality (NRM) are persistent problems. Although anti-thymocyte globulin, alemtuzumab, and total body irradiation (TBI) have been explored as conditioning modalities for u-RIST, the necessity for T-cell depletion or TBI to prevent GVHD or facilitate engraftment in u-RIST has not been determined. We here report the use of u-RIST with bone marrow grafting, following a simple conditioning regimen of 180 mg/m2 fludarabine and 8 mg/kg of oral or intravenous busulfan without TBI or T-cell depletion. The study population was exclusively Japanese patients with a history of prior chemotherapy. We retrospectively analyzed 31 consecutive patients (median age 53 years). Twenty-five patients (81%) were transplanted from HLA-A, -B, and -DRB1 allele-matched donors. In all patients, neutrophil engraftment was achieved. The cumulative incidence of grade II–IV acute GVHD was 42%. However, 77% of patients with acute GVHD improved with, and could be managed by, initial, systemic, high-dose steroid treatment alone. Two-year overall and event-free survival was 62 and 53%, respectively. The NRM of 10% at 2 years was relatively low. Our results suggest that u-RIST without TBI or T-cell depletion may improve the prognosis after u-RIST in certain patient populations.

Efficacy and safety of intra-arterial steroid infusions in patients with steroid-resistant gastrointestinal acute graft-versus-host disease

There is no established second-line treatment for steroid-resistant acute graft-versus-host disease (GVHD). We prospectively assessed the safety and efficacy of intra-arterial steroid infusions (IASIs) for steroid-resistant acute gastrointestinal (GI) GVHD and compared the outcomes with those of historical controls at our institution. Nineteen consecutive, allogeneic hematopoietic stem cell transplantation subjects aged 31-67 years (median 52) were enrolled between October, 2008, and November, 2012. Acute GVHD was confirmed by biopsy in all cases. The enrolled patients were treated with infusions of methylprednisolone into the mesenteric arteries and/or gastroduodenal and left gastric arteries. Fourteen consecutive patients who developed steroid-resistant acute GI GVHD between 2001 and 2008 were used as controls. For the primary endpoint at day 28, the overall and complete responses in the IASI group trended higher (79% vs. 42%, p = 0.066) and were significantly higher (63% vs. 21%, p = 0.033) than those in the control group. Although not statistically significant, owing to the small population, the crude day-180-nonrelapse mortality rate was about 20% lower and the day-180-overall-survival rate tended to be higher than the control (11% vs. 29%, p = 0.222; 79% vs. 50%, p = 0.109, respectively). There were no serious IASI-related complications. Our results suggest that IASI can safely provide excellent efficacy for refractory acute GI GVHD without increasing infection-related complications and may improve prognosis.

Diagnostic value of serum ferritin and the risk factors and cytokine profiles of hemophagocytic syndrome following allogeneic hematopoietic cell transplantation

Abstract To examine the diagnostic value of serum ferritin, the associated risk factors, and cytokine profiles of hemophagocytic syndrome (HPS) following allogeneic hematopoietic cell transplantation (allo-HCT), we retrospectively analyzed data from patients undergoing allo-HCT between 2006 and 2012. Of 223 eligible patients, 18 patients developed HPS. A serum ferritin level above 30,000 μg/l was highly specific for the detection of HPS (specificity, 93%). The one-year survival rate for HPS was significantly lower than that of non-HPS patients (37.5% vs. 72.9%, respectively, Log-rank p < .01). In multivariable Cox models, antigen mismatches in human leukocyte antigen (HLA) in both graft-versus-host (GVH) and host-versus-graft (HVG) directions were significantly associated with the incidence of HPS. We found a significant elevation of Th1 cytokine (IFN-γ), Th2 cytokines (IL-10), and chemokines (MCP-1 and IP-10), at the onset of HPS. Our results suggest that allo-reactivity, derived from HLA-mismatch, and possibly causing a cytokine storm, may be associated with HPS development.

Combinational approach using in situ hybridization targeting 23S ribosomal RNA genes and blood cultures for bacterial identification in patients with neutropenia and fever

BACKGROUND A new 23S ribosomal RNA genes-targeted in situ hybridization (ISH) probe to detect global bacterial genomic DNA (59 species from 35 genera; referred to as the GB probe) phagocytized in leukocytes was recently developed. This method provided early and direct evidence of bacterial infection with high sensitivity and specificity in spontaneous bacterial peritonitis ascites. However, the utility of this method in febrile neutropenia (FN) is unknown. METHODS We prospectively evaluated the utility of the ISH approach using the GB probe and previously reported probes in patients with neutropenia and fever undergoing chemotherapy at our institution between June 2011 and July 2013. Blood samples for culture analysis and ISH tests were collected simultaneously at the onset of fever; the latter were performed repeatedly. RESULTS Fifty febrile episodes were evaluated. In 24 episodes of fever of unknown origin and 15 episodes of local infection (all negative for blood cultures), ISH tests identified causal bacteria in 21% and 13% of cases, respectively, at the onset of fever. In seven sepsis cases (all positive for blood culture), positive ISH test results at fever onset were achieved in 71%; for two patients with neutrophil counts of 0/μl and 171/μl, respectively, negative results were obtained. CONCLUSIONS This new ISH approach could prove useful for early detection of bacteria in patients with neutropenia and blood culture-negative, with fever of unknown etiology after chemotherapy. Using this method in combination with blood culture, even in cases with extremely low neutrophil counts, might contribute to better management of FN.

Validation of previous prognostic models for thrombosis and exploration of modified models in patients with essential thrombocythemia

We examined the prognostic factors to validate previous prognostic models for survival and thrombosis with large‐scale data on Japanese patients with essential thrombocythemia (ET).

An Elderly Woman with Anti-neutrophil Antibody-positive Agranulocytosis Who Responded to High-dose Intravenous Methylprednisolone

Although anti-neutrophil antibodies (ANAs) often exist and immunoreaction may be involved in agranulocytosis, few reports have so far described ANA-positive cases of agranulocytosis with an unknown etiology. We herein describe the case of a 69-year-old woman who presented with ANA-positive agranulocytosis. In this case, both the withdrawal of the drugs that had possibly caused neutropenia and the use of granulocyte-colony stimulating factor (G-CSF) were ineffective treatment measures. Approximately 2 weeks after the discontinuation of the suspected drugs, we initiated corticosteroid pulse therapy; the neutrophil count recovered by day 19 of steroid therapy. High-dose methylprednisolone therapy should thus be considered for patients demonstrating ANA-positive agranulocytosis with an unknown etiology that is refractory to G-CSF treatment.

Plasma Kinetics of Th1, Th2 and Th17 Cytokines in Polymyositis Related to Chronic Graft-versus-Host Disease.

We herein describe a case of myelodysplastic syndrome with chronic graft-versus-host disease (cGVHD)-related polymyositis. On approximately day 1,570 post HLA-identical sibling bone marrow transplant, the patient presented with a fever, myalgia and liver dysfunction. A muscle biopsy revealed destruction of the muscle fibers and infiltration of CD20(+) B cells and CD4(+) and CD8(+) T cells, and a liver biopsy confirmed the findings of cGVHD. An analysis of plasma cytokine profiles indicated elevation of not only T-helper (Th)1 and Th2, but also Th17 cytokines. Increases in these cytokines in addition to the invasion of inflammatory cells might be associated with the pathophysiology of cGVHD involving the muscle and liver.

Cold autoimmune hemolytic anemia complicated with relapsed myelodysplastic syndrome after allogeneic hematopoietic cell transplantation

Myelodysplastic syndrome (MDS) is known to often be complicated by a range of autoimmune diseases. We herein present a case with MDS complicated by cold autoimmune hemolytic anemia (cold AIHA). The patient was a 51-year-old woman. She was diagnosed with MDS (refractory cytopenia with multilineage dysplasia) in May 2009. In January 2010, she underwent unrelated allogeneic bone marrow transplantation but was re-admitted in October 2010 for treatment of relapsed MDS. Despite daily transfusions of red blood cells, her anemia failed to improve. Her laboratory examinations showed a low haptoglobin level and elevation of indirect bilirubin and LDH. The direct Coombs test was positive at a low and at room temperature and cold agglutinin was negative. After confirming the diagnosis of cold AIHA, all transfusion fluids were warmed but her anemia still failed to improve. In addition to the warmed transfusion fluids, we administered corticosteroids, immunosuppressive agents and high-dose intravenous immunoglobulin infusions. This management strategy ameliorated the patients hemolytic anemia. To our knowledge, MDS cases complicated by cold AIHA are rare. Our patient thus provides a valuable contribution to medical knowledge.