Hidekazu Itamura

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.

Elderly Patients With Chronic Myeloid Leukemia Benefit From a Dasatinib Dose as Low as 20 mg

Micro‐Abstract A retrospective study of elderly patients with chronic myeloid leukemia aged ≥ 65 years was conducted to evaluate the efficacy and safety of low‐dose dasatinib treatment. Reducing the dose of dasatinib to < 100 mg/day (even to ≤ 20 mg/day) generated good responses in these patients. The doses were safe and induced rapid and deep molecular responses. Background: The clinical outcomes of patients with chronic myeloid leukemia (CML) treated with BCR‐ABL tyrosine kinase inhibitors has improved markedly; however, the occurrence of adverse events (AEs) means that elderly patients often cannot be administered the standard dose. Nevertheless, some patients treated with low doses of tyrosine kinase inhibitor have achieved good molecular responses. Patients and Methods: We retrospectively analyzed the efficacy and safety of low‐dose dasatinib treatment of elderly CML patients. The study enrolled 21 patients with newly diagnosed, imatinib‐resistant, or imatinib‐intolerant chronic phase CML. All the patients were aged ≥ 65 years and received dasatinib at a dose of < 100 mg/day. Of these 21 patients, 77% had newly diagnosed CML. Results: Overall, 91% and 72% of patients received a mean dasatinib dose of ≤ 50 mg and ≤ 20 mg, respectively. A molecular response of MR3 (major molecular response, indicating > 3 log reduction in the number of leukemic cells), MR4, and MR4.5 were achieved in 96%, 77%, and 62% of the patients, respectively. Of the 15 patients who received a mean dose of ≤ 20 mg, 94% achieved a major molecular response, and 74% achieved MR4. The most common nonhematologic AE was plural effusion (29%), which was controlled by diuretics and regulating the drug dose. Conclusion: Low‐dose (eg, ≤ 20 mg) dasatinib therapy generates an adequate molecular response in most elderly patients with chronic phase CML without causing severe AEs.

Rituximab-containing Chemotherapy (R-CHOP)-induced Kaposi's Sarcoma in an HIV-negative Patient with Diffuse Large B Cell Lymphoma

Rituximab treatment may cause or exacerbate Kaposis sarcoma (KS) in patients with human immunodeficiency virus (HIV)-associated multicentric Castlemans disease. Despite the widespread use of rituximab, rituximab-induced KS has not yet been reported in HIV-negative patients with diffuse large B cell lymphoma (DLBCL). We herein report a case of KS that developed after undergoing rituximab-containing chemotherapy in an HIV-negative patient with DLBCL. An 84-year-old man who received rituximab-containing chemotherapy for the treatment of DLBCL developed severe infection, and subsequently KS. Our observations indicate that serious infections under rituximab treatment may trigger KS. KS should therefore be considered when skin tumors appear in lymphoma patients receiving rituximab-containing chemotherapy.

Therapeutic management in cardiac lymphoma

1 Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, 2 Department of Medical Science Technology, School of Health Sciences at Fukuoka, International University of Health and Welfare, Fukuoka, Japan, 3 Department of Thoracic and Cardiovascular Surgery, 4 Division of Cardiology, Department of Internal Medicine 5 Department of Laboratory and Blood Transfusion Medicine, Faculty of Medicine, Saga University, Saga, Japan and 6 Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

Lenalidomide in combination with dexamethasone induced rhabdomyolysis in a multiple myeloma patient treated with pravastatin

A 77-year-old Japanese man was diagnosed with multiple myeloma (MM, IgG-j type, Durie-Salmon stage I, ISS stage I in 2007). He was additionally diagnosed with hypercholesterolemia, and had been administered pravastatin since February 2009. He was treated with a single course of melphalan plus prednisolone, intermittently administered with dexamethasone (DEX), which was followed by 12 courses of melphalan plus DEX. As his symptoms aggravated, he was treated with thalidomide plus DEX from August 2009 to August 2010. This treatment was discontinued due to peripheral neuropathy. From 8 November 2010, we began treating the patient with lenalidomide 25 mg daily plus DEX. He had additionally been on treatment regimens of allopurinol for 4 years, mecobalamin for 1 year, sulfamethoxazole trimethoprim for 1 year, brotizolam for 9 months, warfarin for 2 months, and fluconazole for 3 weeks. On the night of November 13, he developed sudden myalgic pains in both upper arms, weakness of the extremities, abasia, and fever (38.1 C), and was thus immediately admitted to our hospital. His leukocyte count was 5.0 9 10/L, hemoglobin was 7.8 g/dL, and platelets count were 14.5 9 10/L. Biochemical analysis revealed BUN 14.5 mg/dL, creatinine 1.49 mg/dL, AST 71 IU/L, ALT 47 IU/L, LDH 299 IU/L, Na 139 mEq/L, K 3.4 mEq/L, creatine kinase (CK) 3,445 IU/L. Isozymes of CK-MB, -MM, and -BB were 1, 99, and 0%, respectively. Urine myoglobin was 153,000 ng/mL (normal 0–4 ng/mL). His thyroid function was normal (TSH 2.13 lIU/ml, free T4 1.1 ng/ml). He was diagnosed with rhabdomyolysis based on the following symptoms: pain in the proximal limb muscles, faintness, CK increase, myoglobinuria, and slightly impaired renal function. Neurologic examination revealed no tetraparesis. Computed tomography of the head revealed no acute infarction or hemorrhage. We discontinued oral administration of lenalidomide and pravastatin on the day of hospitalization and initiated hydration (1.5 L/day). Although he experienced myalgic pain in both thighs on day 2 and CK increased to 16,126 IU/L, the symptoms were alleviated promptly. On day 10, both the muscular symptoms and laboratory test values returned to normal and he was discharged on day 36. Rhabdomyolysis occurs secondary to the breakdown of skeletal muscle, which leads to the release of intracellular substances into the bloodstream and can be induced by various factors, such as external injury, exercise stress, heatstroke, dehydration, hypokalemia, hypothyroidism, infectious disease, and medication. Among the latter, statins are among the best-known pharmaceutical triggers. Standard statin doses are associated with very low rates of rhabdomyolysis incidence: fewer than 1 in 10,000 patients are treated. However, when combined with other factors such as use of higher doses, concomitant drugs, age, and renal impairment, the incidence of muscle toxicity is higher [1]. It is known that rhabdomyolysis can occur in a concentration-dependent manner, especially when a patient is administered statins concomitantly with a CYP450-mediated medication [1]. Lenalidomide is an imunomodulatory drug related to thalidomide. 25 mg of lenalidomide plus DEX was given safely in Japanese patients with relapsed or refractory MM [2]. This is the first case of rhabdomyolysis among more than 1,500 registered patients according to a C. Urata M. Yoshimura (&) H. Itamura T. Hisatomi Y. Kubota N. Fukushima E. Sueoka S. Kimura Division of Hematology, Respiratory Medicine, and Oncology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: tanakam8@cc.saga-u.ac.jp

Tocilizumab for severe cytokine-release syndrome after haploidentical donor transplantation in a patient with refractory Epstein-Barr virus-positive diffuse large B-cell lymphoma

It has been well documented that patients may develop cytokine‐release syndrome (CRS) following the administration of monoclonal antibodies, such as chimeric antigen receptor‐modified T cell. Cytokine‐release syndrome is a common complication in patients who have received haploidentical donor allogeneic haematopoietic cell transplantation (haplo‐HCT). Although severe CRS after haplo‐HCT is a potentially life‐threatening toxicity, a standard treatment has not been established. Cytokine blockade with tocilizumab, an anti‐IL‐6 receptor antibody, has been effective for the treatment of patients with CRS after chimeric antigen receptor‐modified T‐cell treatment and has also improved CRS after haplo‐HCT. A 46‐year‐old man was diagnosed with haemophagocytic syndrome associated with Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma. Salvage chemotherapy was unsuccessful; consequently, he received haplo‐HCT. On day +4, he developed grade 3 CRS, subsequently high‐dose corticosteroid initiated. Nevertheless, on day +6, he developed grade 4 CRS, resulting in requirement for ventilator support and multiple vasopressors. Corticosteroid could not improve severe CRS; therefore, tocilizumab was administered on day +14. Serum C‐reactive protein level transiently decreased and weaned multiple vasopressors. Although CRS improved, he developed candidaemia; consequently, he died on day +34. Tocilizumab could transiently improve severe CRS after haplo‐HCT. Although tocilizumab may have led to the improvement of CRS, a remaining concern is whether it inhibited the patients ability to mount antifungal immunity, leading to their demise.

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.

Successful reduced-intensity umbilical cord blood transplant for fulminant hemophagocytic syndrome in an adult with pre-existing rheumatoid arthritis and autoimmune hemolytic anemia

Hemophagocytic syndrome (HPS) is a potentially fatal syndrome of dysregulated immune activation characterized by severe clinical manifestations such as pancytopenia, high fever and hepatosplenomega...

Identification of the BRAF V600E mutation in Japanese patients with hairy cell leukemia and related diseases using a quenching probe method

Hairy cell leukemia (HCL) is a rare B-cell lymphoid malignancy that is difficult to distinguish from other morphological variants. The frequency of HCL has not been determined accurately in Japan. Recent studies revealed that the BRAF V600E mutation is the causal genetic event in HCL. We assessed the BRAF mutation in Japanese patients with HCL and related diseases using the quenching probe (QP) method, a single-nucleotide polymorphism detection system, and evaluated the incidence rate of HCL among Japanese patients with chronic lymphocytic leukemia, and related diseases. We identified 18 cases (33.3%) harboring the BRAF mutation among 54 patients diagnosed with, or suspected of having HCL. Of BRAF V600E-positive patients, 7 were only detected using the QP method, not by direct sequencing, whereas 11 were positive using both tests. In a larger cohort of Japanese patients diagnosed with chronic lymphoid leukemia or related diseases, the frequency of HCL was 4%. Patients with the BRAF V600E mutation had a significantly higher frequency of neutropenia, thrombocytopenia, and elevated soluble interleukin-2 receptor and common B-cell surface markers than patients without the mutation. Our results confirm that BRAF V600E-positive HCL is a relatively rare disorder in the Japanese leukemia patient population.

Three coexisting lymphomas in a single patient: composite lymphoma derived from a common germinal center B-cell precursor and unrelated discordant lymphoma

Composite lymphoma (CL) is a rare disorder defined as the coexistence of two or more distinct lymphoma subtypes at a single anatomic site. Discordant lymphoma (DL), which is the simultaneous occurrence of two or more distinct lymphoma subtypes at different sites, is also rare. CL complicated with DL involving three distinct subtypes of lymphoma in the same patient is an extremely rare disease. Clonal relationships in CL and DL are commonly investigated by molecular analysis using mutational status with t(14;18)BCL2/IgH translocation and immunoglobulin heavy chain variable-region (IgVH) gene rearrangement. A 73-year-old woman was admitted to our hospital with systemic lymphadenopathy and was initially diagnosed with diffuse large B-cell lymphoma based on pathological features of the biopsied esophageal tumor. However, the results of inguinal lymph node biopsy led to a revised pathological diagnosis CL consisting of Hodgkin lymphoma and follicular lymphoma. Three distinct coexisting lymphomas were identified in this individual patient. Molecular analysis revealed CL derived from common germinal center B-cell precursors, while clonal relationship between CL and DL was not clarified. This case suggests a mechanism underlying B-cell lymphoma pathogenesis involving two pivotal somatic mutations, t(14;18)BCL2/IgH translocation and IgVH rearrangement.