Mitsuru Tsudo

Human Herpesvirus 6 (HHV-6) Reactivation and HHV-6 Encephalitis After Allogeneic Hematopoietic Cell Transplantation: A Multicenter, Prospective Study

BACKGROUND The epidemiology of human herpesvirus 6 (HHV-6) encephalitis after allogeneic hematopoietic cell transplantation (HCT) and its relationship with HHV-6 reactivation have not been sufficiently characterized. METHODS This prospective, multicenter study of 230 allogeneic HCT recipients investigated the epidemiology of HHV-6 reactivation and HHV-6 encephalitis. Plasma HHV-6 DNA load was prospectively evaluated twice weekly until 70 days after HCT. RESULTS Cumulative incidence of positive HHV-6 DNA and high-level HHV-6 reactivation (plasma HHV-6 DNA ≥10(4) copies/mL) at day 70 after HCT was 72.2% and 37.0%, respectively. Multivariate analysis identified myeloablative conditioning (hazard ratio [HR], 1.9; P = .004), umbilical cord blood transplantation (UCBT) (HR, 2.0; P = .003), and male sex (HR, 1.6; P = .04) as risk factors for displaying high-level HHV-6 reactivation. HHV-6 encephalitis occurred in 7 patients, and cumulative incidence at day 70 was 3.0%. None of the144 patients without high-level HHV-6 reactivation and 7 of 86 patients (8.1%) with high-level HHV-6 reactivation developed HHV-6 encephalitis (P = .0009). Prevalence of HHV-6 encephalitis was significantly higher among patients receiving UCBT than in patients with other sources (cumulative incidence at day 70, 7.9% vs 1.2%, P = .008). In each of 7 patients with HHV-6 encephalitis, central nervous system (CNS) symptoms developed concomitant with peak plasma HHV-6 DNA (range, 21 656-433 639 copies/mL). CONCLUSIONS High levels of plasma HHV-6 DNA are associated with higher risk of HHV-6 encephalitis. UCBT is a significant risk factor for HHV-6 encephalitis. HHV-6 encephalitis should be considered if CNS dysfunction develops concomitant to high-level plasma HHV-6 DNA after allogeneic HCT.

Interleukin‐2 Receptor β‐Chain (p70–75) Expressed on Leukemic Cells from Adult T Cell Leukemia Patients

To determine whether the interleukin‐2 receptor (IL‐2R) β‐chain (p70–75) is expressed on lenkemic cells from patients with adult T cell leukemia (ATL) as well as α‐chain (p55, Tac), we performed radiolabeled interleukin‐2 (IL‐2) binding assay, chemical crosslinking of radiolabeled IL‐2 and flow cytometric analysis using a newly‐developed anti‐IL‐2R β‐chain antibody. The results showed that leukemic cells from all the 12 ATL patients we examined expressed the IL‐2R β‐chain together with the α‐chain, whereas there was no detectable β‐chain expression on unstimulated peripheral blood CD4(+) T cells from healthy volunteers. Southern blot analysis revealed that this abnormal expression was not caused by the structural change of IL‐2R β‐chain gene. Though leukemic cells from all ATL patients examined expressed high‐affinity IL‐2Rs, leukemic cells from only 25% of all ATL patients proliferated in response to IL‐2. These results showing abnormal expression of IL‐2R β‐chain on leukemic cells from ATL patients (ATL cells) suggest a close association between HTLV‐I infection and abnormal β‐chain expression as well as α‐chain expression.

Diagnostic and clinical importance of interleukin-2 receptor alpha chain expression on non-T-cell acute leukaemia cells

The expression of interleukin‐2 receptors (IL‐2R) was examined in 328 adult patients with non‐T‐cell (non‐T) acute leukaemia and blast crisis of chronic myelocytic leukaemia (CML.BC) using two monoclonal antibodies, anti‐Tac for IL‐2R α chain (IL‐2Rα) and Mikβ1 for IL‐2R β chain (IL‐2Rβ). Leukaemic cells in the following cases were positive for anti‐Tac; 28/192 of acute myelocytic leukaemia (AML), 24/44 CML‐BC, 4/28 CD19(+)CD10(‐) acute lympho‐blastic leukaemia (ALL), and 20/64 common ALL (c‐ALL). IL‐2Rβ was not detected on leukaemic cells of any case examined. Eleven of IL‐2Rα(+) AML were derived from myelodysplastic syndrome. None of the IL‐2Rα positive leukaemic cells responded to exogenous recombinant human IL‐2 (rhIL‐2) in culture. In addition, IL‐2Rα expression on non‐T leukaemic cells was closely correlated with coexpressing different lineage markers and the presence of the Philadelphia abnormality. Marked increase of serum soluble IL‐2Rα was demonstrated in the IL‐2Rα(+) patients examined. Clinically, the IL‐2Rα(+) patients showed significantly lower response to chemotherapy and poorer prognosis than IL‐2Rα(‐) patients. Our results clearly indicate the diagnostic importance of IL‐2Rα expression in non‐T acute leukaemia with a close relation to the particular cellular characteristics and the prognosis.

Seven-year follow-up of patients receiving imatinib for the treatment of newly diagnosed chronic myelogenous leukemia by the TARGET system.

The TARGET system is an online database that can be easily accessed by physicians. The registration of ones own chronic myeloid leukemia (CML) patients in the TARGET system makes it possible to share experiences among physicians, and, thus, may facilitate appropriate treatment for patients. Patients were registered in the TARGET system from October 2003 to March 2010 in Japan. A total of 1236 patients from 176 hospitals were registered in Japan. We analyzed data from 639 CML chronic phase patients not receiving prior therapy registered in this system. After 90 months follow-up, high survival rates were demonstrated for imatinib-treated newly diagnosed CML patients, with event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) rates of 79.1, 94.8, and 95.1%, respectively. A landmark analysis of 296 patients who showed a complete cytogenetic response (CCyR) at 12 months after the initiation of imatinib treatment revealed that, at 90 months, 99% of patients (95% CI, 98-100) had not progressed to accelerated phase (AP) or blastic crisis (BC). The patients showing a CCyR and a reduction of at least 3log levels of BCR-ABL transcripts after 18 months of treatment had an estimated survival rate without CML progression of 100% at 84 months. The probability of achieving undetectable BCR-ABL in patients by 72 months with an major molecular response (MMR) at 12 months was 86.5%, compared with 64.7% for those without an MMR (p < 0.0001). There were no new safety issues. In summary, based on this 7-year TARGET analysis, imatinib showed a continual clinical benefit as first-line therapy for newly diagnosed CML. The TARGET system may represent a more practical and general feature compared with the IRIS study.

Extragastric mucosa-associated lymphoid tissue lymphoma showing the regression by Helicobacter pylori eradication therapy

Summary. A 69‐year‐old man presented with right neck tumour. Primary thyroid MALT lymphoma occurring in Hasimotos thyroiditis was diagnosed. He was also diagnosed to have gastric cancer with Helicobacter pylori infection. After subtotal gastrectomy by itself, thyroid lymphoma became smaller transiently. Then the patient was treated with H. pylori eradication therapy, resulting in the complete disappearance of lymphoma. Although H. pylori organisms were not detected in the lymphoma tissue by polymerase chain reaction (PCR), it might be implicated in the pathogenesis of extragastric MALT lymphomas.

Impact of graft-versus-host disease on allogeneic hematopoietic cell transplantation for adult T cell leukemia-lymphoma focusing on preconditioning regimens: nationwide retrospective study.

Allogeneic hematopoietic cell transplantation (HCT), but not autologous HCT, can provide long-term remission in some patients with adult T cell leukemia-lymphoma (ATL). We retrospectively analyzed the effects of acute graft-versus-host disease (GVHD) among the 616 patients with ATL who survived at least 30 days after allogeneic HCT with other than cord blood grafts. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated an association between grade I-II acute GVHD and favorable overall survival (OS) (hazard ratio [HR], 0.634; 95% confidence interval [CI], 0.477 to 0.843), whereas grade III-IV acute GVHD showed a trend toward unfavorable OS (HR, 1.380; 95% CI, 0.988 to 1.927) compared with nonacute GVHD. In subsequent multivariate analyses of patients who survived at least 100 days after HCT (n = 431), the presence of limited chronic GVHD showed a trend toward favorable OS (HR, 0.597; 95% CI, 0.354 to 1.007), and extensive chronic GVHD had a significant effect on OS (HR, 0.585; 95% CI, 0.389 to 0.880). There were no significant interactions between myeloablative conditioning or reduced-intensity conditioning with OS even when acute GVHD was absent or present at grade I-II or grade III-IV or when chronic GVHD was absent, limited, or extensive. This study demonstrates the actual existence of graft-versus-ATL effects in patients with ATL regardless of whether myeloablative conditioning or reduced-intensity conditioning is used.

Successful Treatment of TAFRO Syndrome, a Variant of Multicentric Castleman’s Disease, with Cyclosporine A: Possible Pathogenetic Contribution of Interleukin-2

Multicentric Castlemans disease is a systemic inflammatory disorder characterized by lymphadenopathy and excessive interleukin-6 production. A unique clinicopathologic variant of multicentric Castlemans disease, TAFRO (i.e., thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly) syndrome, was recently proposed in Japan. Despite the successful use of anti-interleukin-6 therapy in some patients with TAFRO syndrome, not all patients achieve remission. The pathophysiological etiology of and suitable therapeutic strategies for this variant have not been established. Here, we present our experience of a unique case of TAFRO syndrome in a 78-year-old woman whose symptoms responded differently to several therapies. Tocilizumab, an anti-interleukin-6 receptor antibody, successfully induced remission of fever and lymphadenopathy. However, severe thrombocytopenia persisted and she developed anasarca, ascites, and pleural effusion shortly thereafter. Rituximab, an anti-CD20 antibody, and glucocorticoid therapy provided no symptom relief. In contrast, cyclosporine A, an immunosuppressive agent that blocks T cell function by inhibiting interleukin-2, yielded immediate improvements in systemic fluid retention and a gradual increase in platelet count, with complete resolution of disease symptoms. Excessive serum interleukin-2, when used as an anti-cancer agent, has been reported to cause side effects such as fluid retention, thrombocytopenia, and renal failure. Our case was unique because the anti-interleukin-2 therapy successfully improved symptoms that were not relieved with anti-interleukin-6 therapy. The present report therefore provides insight into the possible role of interleukin-2, in addition to interleukin-6, in TAFRO syndrome. This report will certainly help to clarify the pathogenesis of and optimal treatment strategies for TAFRO syndrome.

Fluorodeoxyglucose-PET/CT for Diagnosis of Intravascular Large B-Cell Lymphoma

A 39-year-old woman was referred to our hospital with a 1-month history of recurrent fever. On physical examination, her spleen was palpable in the absence of peripheral lymphadenopathy and skin lesions. Laboratory studies yielded elevated values of serum lactate dehydrogenase at 1051 U/L, soluble interleukin 2 receptor at 24,500 pg/mL, and ferritin at 1019 μg/L. Blood cell counts showed a bicytopenia with a hemoglobin level of 7.0 g/dL and a platelet count of 3.7 × 109/L. Although the patient had no subjective symptoms such as dyspnea, her percutaneous oxygen saturation was low at 90%, suggesting hypoxemia. Findings on both chest radiography and computed tomography (CT) of the lungs were unremarkable. However, positron emission tomography (PET)/CT with 18F-fluorodeoxyglucose (FDG) revealed diffuse uptake in the bilateral lung, predominantly in the upper fields (Figure 1, A and B). In addition, FDG uptake was noted in the bilateral renal cortex (Figure 1, C) and vertebrae (Figure 1, A). Bone marrow aspiration yielded large atypical lymphoid cells with the appearance of hemophagocytosis. However, on bone marrow biopsy, lymphoma cells were not confirmed within the lumen of small blood vessels. Random skin biopsy specimens1 from normal-appearing skin on the patients thigh revealed CD20+ large lymphoid cells filling the small vessels in the subcutaneous tissues (Figure 1, D and E). Intravascular large B-cell lymphoma (IVLBCL) was diagnosed.

Primary large B-cell lymphoma of the bone marrow

A diagnosis of primary bone marrow lymphoma, classified as diffuse large B-cell lymphoma, was made in a 31-year-old man. He presented with persistent fever and pancytopenia and reported pain in the pelvis and femora. Computed tomography imaging showed hepatosplenomegaly but no lymphadenopathy. On magnetic resonance imaging (MRI), the right ilium and both femora demonstrated abnormal signals with low intensity on T1-weighted images and high intensity on T2weighted images (top left). A bone marrow biopsy from the right iliac crest showed diffuse infiltration by large CD20positive cells. Cytogenetic analysis of bone marrow cells was normal. A staging F-fluorodeoxyglucose positron emission tomography (PET) scan revealed striking disseminated bone marrow uptake without evidence of hepatic, splenic or lymph node involvement (top right). He underwent chemotherapy with six courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone), followed by high-dose chemotherapy combined with autologous peripheral blood stem cell transplantation. At the end of the treatment, the PET and MRI scans were repeated; while persistent bone marrow disease was suggested by MRI (bottom left), the PET scan was normal (bottom right). The patient remains in complete remission at 12 months. Although diffuse large B-cell lymphoma frequently involves the bone marrow, isolated bone marrow involvement is rare. PET scanning can be useful in diagnosis.

Lenalidomide is active in Japanese patients with symptomatic anemia in low- or intermediate-1 risk myelodysplastic syndromes with a deletion 5q abnormality

Lenalidomide is an immunomodulatory agent recently reported to be effective in the treatment of transfusion-dependent anemia due to low- or intermediate-1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q (del 5q) cytogenetic abnormality. We conducted a multicenter, single-arm clinical trial to evaluate the safety and efficacy of lenalidomide in Japanese patients with anemia in low- or intermediate-1 risk MDS associated with the del 5q cytogenetic abnormality. Eleven patients (5 with transfusion-dependent anemia; 6 with transfusion-independent symptomatic anemia) received once daily oral administrations of 10 mg of lenalidomide for 21 consecutive days in a 28-day treatment cycle. The efficacy was assessed by the IWG criteria. At an interim analysis after ≥24 weeks of therapy, hemoglobin increase was noted in all 11 patients, with a median increase of 6.0 g/dL (range, 0.9–10.9) from the baseline. All transfusion-dependent patients achieved transfusion independence. Histopathologic and cytogenetic improvement was also noted. Neutropenia and thrombocytopenia were the most common adverse events related to lenalidomide. The adverse events were manageable, and no patients experienced serious adverse events or adverse events requiring treatment discontinuation. The results indicate that lenalidomide can be a useful agent for treating Japanese patients with anemia associated with low- or intermediate-1 risk MDS with the del 5q cytogenetic abnormality.