Tadashi Yamamoto

Etanercept for the treatment of intractable hemophagocytic syndrome with systemic lupus erythematosus.

A 41-year-old woman presented with continuous fever, and her laboratory data suggested the recrudescence of systemic lupus erythematosus. She was treated with 60xa0mg/day prednisolone. With a dose reduction of prednisolone, high fever and pancytopenia were observed again. A bone marrow biopsy revealed hemophagocytosis. The effects of steroid pulse therapy, high-dose intravenous immunoglobulin, cyclosporine A, and methotrexate were insufficient. However, after four injections of etanercept (25xa0mg, twice a week) subcutaneously, her symptoms had completely resolved. In such cases, therapy with etanercept may be effective.

FLT3 internal tandem duplication is associated with a high relapse rate and central nervous system involvement in acute promyelocytic leukemia cases: single institutional analysis

To the Editor: Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is observed in 20–30% of the newly diagnosed acute myelogenous leukemia (AML) and indicates a significantly poorer prognosis in AML with normal karyotype (1). It has also been reported that a high prevalence of FLT3-ITD was observed in patients with AML who presented with central nervous system (CNS) involvement (2). In the all-trans retinoic acid era, acute promyelocytic leukemia (APL) has become the most curative subtype of AML (2); however, relapses still occur in 10–30% of patients after achieving the first complete remission (CR) (3). To improve prognosis further, risk-adapted therapy has also been utilized in APL (4). For APL, it remains under discussion whether FLT3ITD is a significant prognostic factor. Recently, it was reported that FLT3-ITD is associated with a high white blood cell (WBC) count at the onset and with poor overall and disease-free survival (5). However, there have not been any reports indicating whether FLT3-ITD is associated with CNS involvement among patients with APL. To clarify this issue, we retrospectively observed FLT3ITD and clinical outcomes of patients with APL. The institutional ethical committee approved this clinical observation, and we analyzed patients with APL who were hospitalized in our institute between November 1998 and December 2009. Patient characteristics are summarized in Table 1. Bone marrow cells were collected from informed patients, and the presence of FLT3-ITD was confirmed by the RT-PCR method (6). There were 26 patients who were screened for FLT3-ITD. Fifteen patients were men and 11 were women. FLT3-ITD was demonstrated on presentation in 6 (23%) (positive group). All patients were treated according to the Japan Adult Leukemia Study Group APL97 protocol (7). For remission induction therapy, patients received 45 mg ⁄m ⁄d of ATRA orally with or without idarubicin and cytarabine or idarubicin alone. After achieving CR, patients received three courses of consolidation chemotherapy. The first consolidation consisted of mitoxantrone on days 1–3 and Ara-C on days 1–5. The second consolidation contained Ara-C for 5 days, etoposide for 5 days, and daunorubicin on days 1 through 3. The third consolidation consisted of Ara-C for 5 days and idarubicin for 3 days. Methotrexate (15 mg), cytarabine (40 mg), and steroid were administered intrathecally for prophylaxis of CNS involvement to all patients after 1st or 2nd consolidation chemotherapy. CNS involvement was not revealed in any patients at their 1st lumabar puncture. All cases in both groups achieved CR. The relapse rates of FLT3-ITD-positive and FLT3-ITD-negative patients were 100% and 5%, respectively. Among positive patients, median duration from diagnosis to 1st relapse was 469 d (range 240–737). The rates of CNS involvement were 50% in the positive and 5% in the negative group. Among negative patients, only one patient had developed relapse. She presented with CNS relapse despite maintaining CR in the bone marrow. Thereafter, systemic relapse was demonstrated. Interest-

Colonic EBV-Associated Lymphoproliferative Disorder in a Patient Treated with Rabbit Antithymocyte Globulin for Aplastic Anemia

Epstein-Barr-virus- (EBV-) associated lymphoproliferative disorder (LPD) after immunosuppressive therapy for aplastic anemia (AA), in a nontransplant setting, has not been well described. We report one case of colonic EBV-LPD after a single course of immunosuppressive therapy for AA. The patient developed multiple colonic tumors 3 months after receiving immunosuppressive therapy, which consisted of rabbit antithymocyte globulin (ATG), cyclosporine, and methyl-predonisolone. The histological findings of biopsy specimens revealed that atypical lymphocytes had infiltrated colonic glands. Immunohistochemical staining for CD20 was positive, and in situ hybridization for EBV-encoded small RNAs was also positive. The EBV viral load in peripheral blood was slightly increased to 140/106 white blood cells. After the cessation of immunosuppressant, the colonic tumors spontaneously regressed, and the EBV viral load decreased to undetectable levels. This is the first report of the single use of rabbit ATG inducing colonic EBV-LPD. Because a single use of immunosuppressive therapy containing rabbit ATG can cause EBV-LPD, we should carefully observe patients receiving rabbit ATG for AA.

Chronic Myelogenous Leukemia Cells Contribute to the Stromal Myofibroblasts in Leukemic NOD/SCID Mouse In Vivo

We recently reported that chronic myelogenous leukemia (CML) cells converted into myofibroblasts to create a microenvironment for proliferation of CML cells in vitro. To analyze a biological contribution of CML-derived myofibroblasts in vivo, we observed the characters of leukemic nonobese diabetes/severe combined immunodeficiency (NOD/SCID) mouse. Bone marrow nonadherent mononuclear cells as well as human CD45-positive cells obtained from CML patients were injected to the irradiated NOD/SCID mice. When the chimeric BCR-ABL transcript was demonstrated in blood, human CML cells were detected in NOD/SCID murine bone marrow. And CML-derived myofibroblasts composed with the bone marrow-stroma, which produced significant amounts of human vascular endothelial growth factor A. When the parental CML cells were cultured with myofibroblasts separated from CML cell-engrafted NOD/SCID murine bone marrow, CML cells proliferated significantly. These observations indicate that CML cells make an adequate microenvironment for their own proliferation in vivo.

Vascular endothelial growth factor-C and its receptor type-3 expressed in acute lymphocytic leukemia cases with t(1;19)

The vascular endothelial growth factor (VEGF)-C system was analyzed in two cases of acute lymphocytic leukemia (ALL) with TCF3/PBX1 fusion to determine whether the VEGF-C system influences the growth of these ALL blasts. Bone marrow non-adherent mononuclear cells were prepared from the patients, and expressions of VEGFs and VEGF receptors (VEGFRs) were analyzed based on RNA and protein levels. Cell proliferation was also assayed with or without neutralizing antibodies to VEGFs. The patients’ leukemic blasts expressed a significant amount of VEGF-C and VEGFR type-3. When anti-VEGF-C antibody was added to the blast cell cultures, cell proliferation was suppressed. These observations indicate that, in our ALL cases with TCF3/PBX1 fusion, VEGF-C autocrine stimulation plays an important role in the proliferation of ALL.

Hyperuricemia in Hematologic Malignancies Is Caused by an Insufficient Urinary Excretion

In order to elucidate the mechanism of hyperuricemia in hematologic malignancies, we have retrospectively investigated the uric acid metabolism in 418 chemotherapy-naïve patients with hematologic malignancies. Hyperuricemia was present in 116 (27.8%) of these patients on initial hospitalization. Among 65 hyperuricemic patients analyzed uric acid metabolism, six (9.2%) had overproduction type, 52 (80.0%) had underexcretion type, and seven (10.8%) had a mixed type. Fourteen patients (3.3%) developed tumor lysis syndrome in 418 patients.

Remission of Refractory Ascites and Discontinuation of Hemodialysis after Additional Rituximab to Long-term Glucocorticoid Therapy in a Patient with TAFRO Syndrome

Thrombocytopenia, ascites, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a newly recognized but rare disease, and its treatment has not yet been established. We reported a 50-year-old woman with TAFRO syndrome diagnosed 2 years after the initial symptoms of a fever, fatigue, epigastric pain, edema, ascites, lymphadenopathy, thrombocytopenia and renal insufficiency. The patient showed refractory ascites and required hemodialysis under corticosteroid mono-therapy for suspected immune-mediated disease but was successfully treated with additive rituximab, resulting in improvement in her laboratory data, the withdrawal of hemodialysis and the disappearance of ascites. This case underscores the therapeutic utility of rituximab in patients with corticosteroid-resistant TAFRO syndrome, even long after the onset of the disease.