Mitsuki Miyamoto

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.

Erratum to: Successful bypass surgery for esophageal carcinoma under adequate factor XIII/13 replacement therapy in a case of intractable autoimmune hemorrhaphilia due to anti-Factor XIII/13 antibodies

Autoimmune hemorrhaphilia due to anti-factor XIII (FXIII) antibodies (AH13) is a life-threatening disease associated with high risk of surgical bleeding. Since AH13 occurs mainly in the elderly, patients of AH13 tend to be complicated with other life-threatening diseases that may require surgical procedures. During our nation-wide survey on AH13, supported by the Japanese Ministry of Health, Labor, and Welfare, patients with unexplained bleeding were examined for FXIII-related parameters and anti-FXIII autoantibodies. A 64-year-old man had previously been tentatively diagnosed with AH13 and received immunosuppressive therapies, as FXIII inhibitor was detected by functional cross-mixing studies. About 2 years later, he was definitively diagnosed with AH13, because our immuno-chromatographic test and enzyme-linked immuno-sorbent assay detected FXIII-bound anti-FXIII-A subunit autoantibodies. Since routine endoscopic examination revealed suspected esophageal carcinoma, a preparatory FXIII pharmacokinetic (PK) analysis was performed by infusing FXIII concentrates prior to biopsy. Consequently, biopsy of this lesion was done without bleeding complications. One month later, a second PK study was carried out before surgery, and esophageal bypass surgery was completed successfully under FXIII replacement therapy. Our experience with this case suggests that operations can be performed safely and with confidence even in patients with such life-threatening hemorrhagic diseases.

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.

Refractory acute promyelocytic leukemia successfully treated with combination therapy of arsenic trioxide and tamibarotene: A case report

A 40-year-old male developed refractory acute promyelocytic leukemia (APL) after various treatments including all-trans retinoic acid, tamibarotene, arsenic trioxide (As2O3), conventional chemotherapy, and autologous peripheral blood stem cell transplantation. We attempted to use both tamibarotene and As2O3 as a combination therapy, and he achieved molecular complete remission. Grade 2 prolongation of the QTc interval on the electrocardiogram was observed during the therapy. The combination therapy of As2O3 and tamibarotene may be effective and tolerable for treating refractory APL cases who have no treatment options, even when they have previously been treated with tamibarotene and As2O3as a single agent.

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.

Noninfectious Pulmonary Complications after Stem Cell Transplantation and Induction of an Innate Immune Response

Introduction: Non-infectious pulmonary dysfunction (NIPC) represents a common and often fatal complication of hematopoietic stem cell transplantation (HSCT). Recently, bactericidal/permeability-increasing (BPI) haplotypes were associated with an increased risk of developing airflow decline after HSCT. Objective: In order to clarify whether BPI is involved in the pathogenesis of HSCT-related pulmonary complications, we performed a genetic association study. Methods: In this study, we therefore investigated the relationship between BPI and pulmonary dysfunction within an ethnic group by analyzing the incidence of NIPC based on genotype and the allelic frequency of BPI polymorphisms in 121 Japanese patients who underwent HSCT from HLA-identical sibling donors. We examined BPI-associated single nucleotide polymorphisms (SNPs) (rs5741798, rs1934917, rs5743530, rs2275954), and identified NIPC-associated polymorphisms in 20 patients (16.5%). Results: The allelic frequencies of rs1934917 and rs5743530 are significantly different between patients with and without NIPC (P=0.024 and P=0.015, respectively). For donors, the rs5743530 C allele was more frequent in the NIPC group than in the group without NIPC (P=0.038). No significant relationships were noted between each of the other gene polymorphisms and the development of NIPC. Conclusion: In this Japanese cohort study, two candidate SNPs reached statistical significance in terms of NIPC incidence and our findings suggest that BPI haplotypes contribute to the development of NIPC within an ethnic group.

Two Cases of Successful Autologous Hematopoietic Stem Cell Harvest after Treatment with Brentuximab Vedotin

with 400 μg/m 2 of filgrastim from days +10 to +14 and collected via leukapheresis within 1 day, resulting in the harvest of 2.35 × 10 7 /kg CD34+ cells. The patient complained of lumbago associated with the bone marrow recovery; however, no other complications were noted. Case 2, a 51-year-old Japanese male, complained of back pain and was found to have an abnormal chest shadow on chest X-ray. He subsequently underwent a lymph node biopsy and was diagnosed with mixed cellularity classical Hodgkin’s lymphoma. The initial clinical stage was IVB; therefore, he received six cycles of ABVD and achieved a partial response. The patient did not undergo further treatment with ABVD or other types of chemotherapy because he did not consent to continue the chemotherapy regimen. Disease progression occurred very slowly, with progressive disease diagnosed 16 months after the completion of chemotherapy. Therapy with BV at a dose of 1.8 mg/kg every 3 weeks was therefore administered, and the patient achieved complete remission after four cycles. After the fifth cycle of treatment, PBSCH was mobilized with 400 μg/m 2 of filgrastim from days +12 to +16 and collected via leukapheresis over 2 days, resulting in the harvest of 2.13 × 10 6 /kg CD34+ cells. The patient reported no complaints during the PBSCH procedure. Brentuximab vedotin (BV) is an antibody-drug conjugate that consists of the anti-CD30 monoclonal antibody conjugated with monomethyl auristatin E [1] . This agent is effective for treating CD30-positive anaplastic large cell lymphoma [2] , Hodgkin’s lymphoma [3] and other CD30-positive lymphomas [4] , even in cases of recurrence after autologous stem cell transplantation (autoSCT). However, the effects of BV on peripheral blood stem cell harvest (PBSCH) are unknown. We recently experienced 2 cases of successful stem cell harvesting after BV treatment. Case 1, a 20-year-old Japanese male, complained of neck lymph node swelling. He subsequently underwent a lymph node biopsy and was diagnosed with nodular sclerosis classical Hodgkin’s lymphoma. The initial clinical stage was IVB; therefore, he received eight cycles of multidrug chemotherapy, including the combination of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Although the patient achieved complete remission, he relapsed 21 months after the administration of chemotherapy. He, therefore, began treatment with BV at a dose of 1.8 mg/kg every 3 weeks. Again, he achieved complete remission after receiving four cycles of BV in addition to cyclophosphamide, cytarabine, etoposide, dexamethasone and rituximab. PBSCH was mobilized Received: December 8, 2014 Accepted: January 1, 2015 Published online: May 27, 2015