Yasuyuki Aoyama

Clinical outcome of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly in the rituximab era.

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein–Barr virus (EBV)‐positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV‐positive DLBCL is controversial. To compare the clinical outcome of EBV‐positive and EBV‐negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBV‐encoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV‐positive DLBCL patients. The median overall survival and progression‐free survival times in patients with EBV‐positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression‐free survival could not be determined in EBV‐negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV‐positive DLBCL remains poor, even in the rituximab era.

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

Association of Promyelocytic Leukemia Protein with Expression of IL-6 and Resistance to Treatment in Multiple Myeloma

Background/Aims: Promyelocytic leukemia protein (PML) was originally identified as a tumor suppressor but has been recently shown to have the ability to control stem cell function in multiple tissues including malignancies. This study aimed to evaluate the biological and clinical significance of PML in multiple myeloma (MM). Methods: We knocked down PML in myeloma cells with a lentiviral vector expressing microRNA to target PML, which were used for in vitro analyses. We also evaluated the association between PML expression in the bone marrow and patients’ clinical parameters. Results: The expression of IL-6 was decreased in myeloma cells with knocked-down PML expression. Immunohistochemical study showed that the PML expression level varied widely in the bone marrow of 48 MM patients, and that IL-6 expression correlated with PML expression in these patients. In addition, MM with high PML expression at diagnosis showed a poor prognosis regarding the 2-year survival, and PML and IL-6 positivity increased with the progression of disease in 13 sequentially analyzed cases. Conclusions: These results suggest that PML expression was positively associated with IL-6 expression in patients and was also related to tumor development and resistance to treatment in MM.

Strong effect of mogamulizumab on splenic residual disease of adult T cell leukemia/lymphoma

Dear Editor, A 54-year-old female complained of multiple subcutaneous masses. A histological study and southern blotting for HTLV1 proviral DNA led to a diagnosis of the acute type of ATLL. FDG accumulation was observed in the abdominal lymph nodes, liver, and spleen (Fig. 1, left panel). She received two cycles of multidrug chemotherapy, including vincristine, cyclophosphamide, doxorubicin, prednisone, ranimustine, vindesine, etoposide, and carboplatin (VCAP–AMP–VECP) [1]. A single residual ATLL lesion in the spleen remained following the administration of VCAP–AMP–VECP (Fig. 1, middle panel). Thereafter, the patient received intravenous infusions of mogamulizumab (1.0 mg/kg) once a week for 3 weeks and the splenic lesion completely disappeared (Fig. 1, right panel). The patient underwent umbilical cord blood transplantation (UCBT) following of cyclophosphamide (120 mg/kg) and total body irradiation (12 Gy). The HLA disparity was two loci mismatched at HLA-B and DR. The total nucleated cell and CD34-positive cell counts were 2.42× 10/kg and 0.75×10/kg, respectively. Prophylaxis for graftversus-host disease (GVHD) included tacrolimus and shortterm methotrexate. Neutrophil engraftment was achieved on day 23. STR-based chimerism testing performed on day 28 revealed BM cells to be 100 % of the donor type [2]. A skin rash emerged on day 30, and the patient was diagnosed with grade II acute GVHD. The acute GVHD immediately disappeared following the dose escalation of tacrolimus. However, after elevation of the total bilirubin level and the development of massive ascites on day 40, she died due to multiple organ failure on day 110. The autopsy results revealed widespread omission of hepatic cells and acute tubular necrosis. No findings of relapse of ATLL, GVHD, microthromboembolism, or veno-occlusive disease were observed.

Cytogenetic risk stratification may predict allogeneic hematopoietic stem cell transplantation outcomes for chronic myelomonocytic leukemia

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for chronic myelomonocytic leukemia (CMML); however, factors predicting allo-HSCT outcomes for CMML have not been well defined. This study assessed whether the existing five scoring systems for CMML prognosis could be applied for predicting allo-HSCT outcomes. We retrospectively evaluated 38 patients who underwent allo-HSCT for CMML from 2000 to 2014. At 3 years, overall survival (OS) and disease-free survival were 34.6 and 24.7%, respectively. According to the risk stratification at the time of transplantation, only the CMML-specific cytogenetic risk scoring system could successfully predict transplantation outcomes. At 3 years, OS was 56.7, 12.5, and 0% (p = .01) in the low, intermediate, and high-risk groups. Our data suggest that the CMML-specific cytogenetic risk stratification at transplant may be useful for identifying patients with CMML who may benefit from HSCT. However, further studies are warranted to confirm this observation.

Dysplastic features seen in a patient with acute myeloid leukemia harboring the KTM2A-TET1 fusion gene

Pancytopenia was noted in an apparently healthy 38-yearold woman at a regular medical checkup. Laboratory tests showed a hemoglobin level of 10.5 g/dL, 10.4 × 109/L platelets, and 1.1 × 109/L leukocytes, including 3.0% blasts. A bone marrow examination revealed 49.1% peroxidase-positive blasts with delicate nuclear chromatin and basophilic cytoplasm. Some of the blasts had Auer rods (Fig. 1 panels A, E). Flow cytometric analysis revealed positivity for CD13, CD33, CD117, HLA-DR, CD34 and CD38 among the blasts. Her bone marrow showed trilineage dysplasia, including pseudo-Pelger-Huët anomaly (Fig. 1 panels A, arrow, B, C) and hypogranular neutrophils, multi-nucleation (Fig. 1 panel D, arrow) and abnormal chromatin clumping in erythroblasts and many megakaryocytes with separated nuclei (Fig. 1 panels F–L, arrow). Paraffin sections of bone marrow aspirate showed the proliferation of dysplastic CD42b-expressing megakaryocytes (Fig. 1 panels M, N). Because dysplasia was observed in > 50% of the erythroid and megakaryocytic lineage cells, she was tentatively diagnosed with acute myeloid leukemia with myelodysplasiarelated changes (AML-MRC). A chromosomal analysis indicated 46,XX,t(10;11)(q22;q23) [7]/46,XX [1]. Reverse transcription polymerase chain reaction and sequencing analyses revealed the KMT2A (MLL)-TET1 fusion gene with KMT2A exon 9 fused to TET1 exon 9 in frame. Her final diagnosis was AML with t(10;11)(q22;q23) ; KMT2A-TET1. Among more than 120 KMT2A rearrangements, KMT2ATET1 has been reported in only 14 leukemia cases (10 AML, one therapy-related AML, two unspecified acute lymphocytic leukemia (ALL), and one T-ALL). Three patients had bone marrow-apparent dysplasia [1]. The TET1 product is

Correction to: Dysplastic features seen in a patient with acute myeloid leukemia harboring the KMT2A-TET1 fusion gene

In the original publication of the article, the title was incorrectly published as “Dysplastic features seen in a patient with acute myeloid leukemia harboring the KTM2A-TET1 fusion gene”. The correct title should be “Dysplastic features seen in a patient with acute myeloid leukemia harboring the KMT2A-TET1 fusion gene”.

Bacterial Pneumonia-induced Persistent Remission of Severe Immune Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation.

A 53-year-old woman with chronic myeloid leukemia received allogeneic hematopoietic stem cell transplantation. After neutrophil engraftment, her platelet count exceeded 100,000/μL at day 64. While she was receiving corticosteroid treatment for chronic graft versus host disease (GVHD), her platelets suddenly dropped to 6,000/μL at day 210 and she was diagnosed with immune thrombocytopenia (ITP). Corticosteroids, intravenous high-dose gamma globulin (IVIg) and a splenectomy failed to increase her platelet count. She developed bacterial pneumonia at day 599 and antibiotic therapy was initiated. Soon after, her platelet count continuously increased. Her GVHD and ITP are now in remission without any ongoing treatment.

Acknowledgements to Referees

Gregory A. Abel, Boston, USA Athanasios Aessopos, Athens, Greece Xabier Agirre, Navarra, Spain Graciela S. Alarcon, Birmingham, USA J.P. Allain, Cambridge, UK S.D. Anker, Berlin, Germany Jane F. Apperley, London, UK A. Arai, Tokyo, Japan Aderson Araújo, Recife, Brazil Luca Arcaini, Pavia, Italy Paolo Arese, Torino, Italy Maurizio Aricò, Florence, Italy Scott A. Armstrong, Boston, USA Roopen Arya, London, UK Giuseppe Avvisati, Rome, Italy Yesim Aydinok, Izmir, Turkey Ulrike Bacher, Hamburg, Germany Andrea Bacigalupo, Genoa, Italy Catherine Bagot, Glasgow, UK Carmen Baldazzi, Bologna, Italy Bernadett Balla, Budapest, Hungary David Barnett, Sheffield, UK Giovanni Barosi, Pavia, Italy Sharon L. Barrans, Leeds, UK Eva Bartova, Brno, Czech Republic Christian Bastard, Rouen, France Heiko Becker, Freiburg, Germany John M. Bennett, Rochester, USA M. Bennett, Afula, Israel J.A. Bernstein, Cincinnati, USA Erik Berntorp, Malmo, Sweden Alain Berrebi, Rehovot, Israel Caroline Besson, Le Kremlin-Bicêtre, France Wolfgang A. Bethge, Tübingen, Germany Deepa Bhojwani, Memphis, USA Janet J. Bijl, Montréal, Canada Douglas P. Blackall, Little Rock, USA Olga Blau, Berlin, Germany Dominique Bonnefont-Rousselot, Paris, France X. Bosch, Barcelona, Spain Reda Bouabdallah, Marseille, France Vassiliki A. Boussiotis, Boston, USA From September 1, 2011 to August 31, 2012 a number of additional referees assisted the editors with reviews of the submitted papers. The editors would like to thank the following colleagues: