Search

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is widely used as a salvage therapy for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL). To investigate the safety and efficacy of regimens including high-dose MCNU followed by ASCT for DLBCL, we analyzed the data from prospective multicenter trials. Twenty-nine patients were analyzed, and the median follow-up time for survival patients was 70 months. Fifteen patients received MCVC conditioning regimen, and fourteen patients received MEAM regimen. Major toxicities associated with these conditioning regimens included nausea (69%), anorexia (66%), febrile neutropenia (62%), diarrhea (59%), and mucositis (34%). One patient who developed severe sinusoidal obstructive syndrome and acute lung injury died without disease progression, and overall therapy-related mortality at 5 years was 3%. No patient developed therapy-related hematological malignancy. At 5 years, overall survival and progression-free survival in all patients were 82.8 and 58.2%, respectively. The 5-year OS in patients treated by the MCVC and MEAM regimens were 73.3 and 92.9%, respectively. These results suggest that regimens including high-dose MCNU followed by ASCT are feasible and effective for the treatment of relapsed or high-risk DLBCL. Further investigation is needed to evaluate of these regimens.

BackgroundSuccessful recovery from acute lung injury requires inhibition of neutrophil influx and clearance of apoptotic neutrophils. However, the mechanisms underlying recovery remain unclear. We investigated the ameliorative effects of vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 (VEGFR-3) signalling in macrophages in lipopolysaccharide (LPS)-induced lung injury.MethodsLPS was intranasally injected into wild-type and transgenic mice. Gain and loss of VEGF-C/VEGFR-3 signalling function experiments employed adenovirus-mediated intranasal delivery of VEGF-C (Ad-VEGF-C vector) and soluble VEGFR-3 (sVEGFR-3) or anti-VEGFR-3 blocking antibodies and mice with a deletion of VEGFR-3 in myeloid cells.ResultsThe early phase of lung injury was significantly alleviated by the overexpression of VEGF-C with increased levels of bronchoalveolar lavage (BAL) fluid interleukin-10 (IL-10), but worsened in the later phase by VEGFR-3 inhibition upon administration of Ad-sVEGFR-3 vector. Injection of anti-VEGFR-3 antibodies to mice in the resolution phase inhibited recovery from lung injury. The VEGFR-3-deleted mice had a shorter survival time than littermates and more severe lung injury in the resolution phase. Alveolar macrophages in the resolution phase digested most of the extrinsic apoptotic neutrophils and VEGF-C/VEGFR-3 signalling increased efferocytosisviaupregulation of integrin αvin the macrophages. We also found that incubation with BAL fluid from acute respiratory distress syndrome (ARDS) patients, but not from controls, decreased VEGFR-3 expression and the efficiency of IL-10 expression and efferocytosis in human monocyte-derived macrophages.ConclusionsVEGF-C/VEGFR-3 signalling in macrophages ameliorates experimental lung injury. This mechanism may also provide an explanation for ARDS resolution.

Objectives We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study). Methods Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pre-treatment and post-treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT), and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL11m,3m) were the post-treatment factors investigated to predict the molecular response. Results The estimated major molecular response (MMR), molecular response 4.0 (MR4.0), and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4%, and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL13m was the only significant landmark for predicting DMR by multivariate analysis. Conclusions Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR-ABL13m was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR-ABL1 IS. This article is protected by copyright. All rights reserved.

Adult T-cell leukemia-lymphoma (ATL) is a mature T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Japan is the most endemic country for HTLV-1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV-1 carriers spread from endemic areas to non-endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital-based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60-75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu-Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one-third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV-1 carrier status are needed.

Summary Background A previous dasatinib discontinuation (DADI) trial showed that 31 (49%) of 63 patients with chronic-phase chronic myeloid leukaemia who were treated with second-line or subsequent dasatinib could discontinue the drug safely. However, the safety and efficacy of discontinuing first-line dasatinib remains unclear. In this trial (the first-line DADI trial) we aimed to assess molecular relapse-free survival at 6 months after discontinuation of dasatinib in patients with chronic myeloid leukaemia who had been treated with first-line dasatinib and had maintained deep molecular response for at least 1 year. Methods The first-line DADI trial was a single-arm, multicentre, phase 2 trial done at 23 hospitals in Japan. Patients with newly diagnosed chronic-phase chronic myeloid leukaemia without hepatosplenomegaly and extramedullary mass, who received at least 24-month dasatinib treatment and had a sustained deep molecular response (defined as BCR-ABL1/ABL1 international scale ≤0·0069% in at least four successive samples spanning a 12 month period) were enrolled. Other eligibility criteria were an age of 15 years or older, an Eastern Cooperative Oncology Group performance status score of 0–2, and no primary organ dysfunction. The primary outcome was molecular relapse-free survival (also known as treatment-free remission) after discontinuation of dasatinib at 6 months and was analysed in all patients who completed the 12-month consolidation phase. Safety was assessed in all patients who received treatment. This study closed early due to accrual and is registered with the UMIN Clinical Trials Registry (UMIN000011099). Findings Between Sept 20, 2013 and July 12, 2016, 68 patients who had a deep molecular response after receiving first-line dasatinib for at least 24 months were enrolled and assigned to the consolidation phase. Nine patients were excluded during the consolidation phase and one patient was excluded after study completion because of meeting exclusion criteria. 58 patients discontinued dasatinib and were assessed. 32 (55%) of 58 patients had treatment-free remission at 6 months after dasatinib discontinuation, and median follow-up was 23·3 months (IQR 11·7–31·0). Treatment-free remission at 6 months was 55·2% (95% CI 43·7–69·6). No non-haematological adverse events worse than grade 2 occurred before dasatinib discontinuation. The most common haematological adverse event was anaemia (14 [21%] of 68 treated patients); three (4%) of 68 treated patients had grade 3 neutropenia and one (1%) had grade 4 lymphopenia. Interpretation Our findings suggest that dasatinib could be safely discontinued after first-line treatment in patients with chronic myeloid leukaemia who had received at least 36 months of therapy and sustained deep molecular response; however, further confirmation in larger trials is needed. Funding Epidemiological and Clinical Research Information Network.

There have been no studies on the distribution of causes of macrocytic anemia with respect to mean corpuscular volume (MCV) cutoff values. We retrospectively investigated the causes of macrocytic anemia (MCV ≥100 fL) among 628 patients who visited the outpatient hematology clinic in Tohoku University Hospital. To ensure data validity, we also analyzed data from 307 patients in eight other hospitals in the Tohoku district. The leading causes of macrocytic anemia (number of patients, %) were myelodysplastic syndromes (121, 19.3 %), suspected bone marrow failure syndromes (BMF; 74, 11.8 %), aplastic anemia (51, 8.1 %), plasma cell dyscrasia (45, 7.2 %), and vitamin B12 deficiency (40, 6.4 %) in Tohoku University Hospital. We made three primary findings as follows. First, the most common cause of macrocytic anemia is BMF. Second, lymphoid and solid malignancies are also common causes of macrocytosis. Third, macrocytic anemia may be classified into three groups: Group 1 (megaloblastic anemia and medications), which can exceed MCV 130 fL; Group 2 (alcoholism/liver disease, BMF, myeloid malignancy, and hemolytic anemia), which can exceed MCV 114 fL; and Group 3 (lymphoid malignancy, chronic renal failure, hypothyroidism, and solid tumors), which does not exceed MCV 114 fL. These conclusions were supported by the results from eight other hospitals.

Occult hepatitis B virus (HBV) infection is a clinical challenge, but its relationship to clinicopathologic features and the risk of progression to malignant lymphoma (ML) are poorly defined. We estimated the prevalence of HBV infection of 1,358 patients with newly diagnosed ML. HBV infection was more prevalent in ML than in control patients. The occult HBV infection group had a higher median onset age, no liver or spleen involvement, and higher prevalence of diffuse large B-cell lymphoma than the other groups, indicating that occult HBV infection is a distinct clinicopathologic entity. J. Med. Virol. 88:2206-2210, 2016. © 2016 Wiley Periodicals, Inc.

Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of patients with aggressive ATL remains poor because ATL cells acquire resistance to conventional cytotoxic agents. Therefore, development of novel agents is urgently needed. We examined the effects of YM155, sepantronium bromide, on cell proliferation and survival of ATL or HTLV-1-infected T-cell lines, S1T, MT-1, and MT-2. We found that YM155 suppressed cell proliferation in these cells and induced cell death in S1T and MT-1 cells. Both real-time quantitative polymerase chain reaction and immunoblot analyses showed suppression of survivin expression in S1T, MT-1, and MT-2 cells. In addition, we observed the cleavage of caspase-3 and poly(ADP-ribose) polymerase in YM155-treated S1T and MT-1 cells, indicating that YM155 induces caspase-dependent apoptosis in these cells. To clarify the mechanism of drug tolerance of MT-2 cells in terms of YM155-induced cell death, we examined intracellular signaling status in these cells. We found that STAT3, STAT5, and AKT were constitutively phosphorylated in MT-2 cells but not in S1T and MT-1 cells. Treatment with YM155 combined with the STAT3 inhibitor S3I-201 significantly suppressed cell proliferation compared to that with either YM155 or S3I-201 in MT-2 cells, indicating that STAT3 may play a role in tolerance of MT-2 cells to YM155 and that STAT3 may therefore be a therapeutic target for YM155-resistant ATL cells. These results suggest that YM155 presents potent antiproliferative and apoptotic effects via suppression of survivin in ATL cells in which STAT3 is not constitutively phosphorylated. YM155 merits further investigation as a potential chemotherapeutic agent for ATL.

Febrile neutropenia is often observed in patients with hematologic malignancies, especially in those with acute leukemia. Meropenem has potent and broad antibacterial activity against gram-positive and gram-negative bacteria, and is recommended as first-line empiric therapy for febrile neutropenia. In contrast, the safety and efficacy of doripenem in patients with febrile neutropenia and hematologic malignancies is limited. In this randomized, prospective, cooperative, open-label trial, we compared doripenem (1.0 g every 8 h) to meropenem (1.0 g every 8 h) as first-line empiric antibacterial treatment of febrile neutropenia. To evaluate efficacy and safety, 133 hospitalized patients with acute leukemia or high-risk myelodysplastic syndrome, who developed febrile neutropenia during or after chemotherapy, were randomized to each drug. Resolution of fever within 3 to 5 days without treatment modification (i.e., the primary endpoint) did not significantly differ between the doripenem and meropenem groups (60.0% vs. 45.6%, respectively; P = 0.136). However, resolution of fever within 7 days of treatment was significantly higher in the doripenem group than in the meropenem group (78.4% vs. 60.2%, respectively; P = 0.037). Similar rates of adverse events (grades 1–2) were observed in both groups. Thus, we conclude that both drugs are safe and well-tolerated for the treatment of febrile neutropenia in patients with acute leukemia or high-risk myelodysplastic syndrome, and that the clinical efficacy of doripenem is noninferior to that of meropenem. UMIN Clinical Trial Registry number: 000006124

Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The ΔFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the ΔFRET value and molecular response, a threshold of the ΔFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with ΔFRET value ≥0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with ΔFRET value

Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients.The dasatinib concentration required to inhibit 50 % of the CrkL (CT10 regulator of kinase like) phosphorylation in bone marrow CD34+ cells (half maximal (50 %) inhibitory concentration (IC50)CD34+cells) was calculated from each patient's dose-response curve using flow cytometry. PK parameters were obtained from the population pharmacokinetic analysis of dasatinib concentrations in plasma on day 28 after administration.Early molecular responses were not significantly associated with PK or PD (IC50 CD34+cells) parameters. However, the PK/PD parameter-time above IC50 CD34+cells-significantly correlated with BCR-ABL transcript level at 3 months (correlation coefficient (CC) = -0.292, P = 0.0375) and the reduction of BCR-ABL level at 1 or 3 months (CC = -0.404, P = 0.00328 and CC = -0.356, P = 0.0104, respectively). Patients with more than 12.6 h at time above IC50 CD34+cells achieved a molecular response of 3.0 log reduction at 3 months and those more than 12.8 h achieved a deep molecular response less than 4.0 log reduction at 6 months at a significantly high rate (P = 0.013, odds ratio = 4.8 and P = 0.024, odds ratio = 4.3, respectively).These results suggest that the anti-leukemic activity of dasatinib exhibits in a time-dependent manner and that exposure for more than 12.8 h at time above IC50 CD34+cells could significantly improve prognosis.

CD56, the neural cell adhesion molecule (NCAM), is a member of the immunoglobulin superfamily and is associated with cell-to-cell adhesion and migration.1 Among haematological malignancies, CD56 expression has been described mainly in NK/T cell lymphoma, plasma cell myeloma and acute myeloid leukaemia, and rarely in B cell lymphomas, accounting for no more than 0.5% of all B lymphomas.2–8 Malignant lymphoma constitutes

Chronic hepatitis C virus (HCV) infection conditions are proposed to be an HCV syndrome of hepatic, extrahepatic or systemic disorders with malignancies such as a malignant lymphoma (ML).[1] HCV is...

Autologous stem cell transplantation (ASCT) is a treatment option for HIV-positive patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the prognosis after ASCT in HIV-positive Japanese patients remains unclear. The aim of this study was to evaluate the impact of HIV infection on transplant outcomes after ASCT in Japan. Using the national database of the Japan Society for Hematopoietic Cell Transplantation, we retrospectively evaluated patients with NHL (n = 3862) and MM (n = 2670) who underwent their first ASCT between 2001 and 2014. The presence of HIV antibody was used to diagnose HIV infection. Fifty-six patients with NHL (1.4%) and 23 with MM (.8%) were positive for HIV antibody. Among patients with NHL overall survival (OS) was lower in HIV-positive patients than in HIV-negative patients (5-year OS: HIV-positive patients, 44% versus HIV-negative patients, 65%; P .001). In a multivariate analysis HIV infection was significantly associated with an increased risk of overall mortality (hazard ratio, 2.30; P .001). The incidence of relapse was higher in HIV-positive patients (P = .036), whereas there was a similar incidence of nonrelapse mortality (P = .879). OS in patients with MM was similar between those with/without HIV infection (5-year OS: HIV-positive patients, 61% versus HIV-negative patients, 63%; P = .988). HIV infection was associated with a higher risk of overall mortality and relapse after ASCT for NHL in a Japanese population.

Approximately 70% of the ITP patients responded to high dose of intravenous immunoglobulin. The 2011 ASH guidelines recommend an initial dose of 1 g/kg as a one-time dose. This dosage may be repeated if necessary. The EU recommendations described that adult ITP patients at high risk of bleeding or prior to surgery to correct the platelet count should be indicated for the administration of intravenous immunoglobulin. Adverse events with intravenous immunoglobulin are common, but generally acceptable. High doses of immunoglobulin are thought to be involved in the Fc receptor blockade of macrophages in the reticuloendothelial system. Several other mechanisms were elucidated.

The term “platelet” whose function was the adhesive characteristic was first used by Bizzozero in 1882. The word “purpura” is the Latin derivative of the Greek word “porphyra,” which is used to designate purple fish. The pathophysiology of this disease had not been unknown until 1951. This chapter describes the history of immune thrombocytopenia.

Platelets are formed from the cytoplasm of megakaryocytes (MKs) that reside in the bone marrow (BM). MKs arise from hematopoietic stem cells in the osteoblastic niche in BM. The primary regulator of megakaryopoiesis is thrombopoietin. It is generally accepted that MKs migrate into the vascular niche and produce platelets; however, the mechanism by which platelets are formed and released from MKs remains controversial. The most prevalent proposed mechanism regarding platelet formation is the proplatelet model; in this model, MKs form long extensions (proplatelets) by remodeling their cytoplasm and release cell fragments into sinusoid vessels. Detached cell fragments in the circulating blood are heterogeneous population of cells in regard to size, shape, or structure. Large fragments (platelet progenitors) are believed to have the ability to convert into mature platelets. After leaving BM sinusoids, these platelet progenitors may convert into individual mature platelets in the bloodstream.

There are several management options for chronic refractory ITP patients. As the chance of inducing a durable remission is low, the objective of the next treatment is the achievement of adequate stable platelet levels while minimizing adverse events. This chapter includes anti-D immunoglobulin, cyclophosphamide, vincristine and vinblastine, danazol, Syk inhibitor, and other drugs (azathioprine, cyclosporine, mycophenolate mofetil, interferon, and ascorbic acid). While in the near future, several new agents might be used clinically for treating refractory ITP.

Bortezomib is a potent proteasome inhibitor that has been extensively used to treat multiple myeloma. One of the most common grade 3 adverse events is cyclic thrombocytopenia. In this study, we studied the mechanism by which bortezomib induces thrombocytopenia in a mouse model. After the intravenous administration of bortezomib (2.5 mg/kg) via tail vein, platelet counts significantly decreased on days 2-4 and recovered to the normal range on day 6. Bortezomib (2.5 mg/kg) injected into mice in vivo did not affect colony-forming unit-megakaryocytes (CFU-Mk) or megakaryocytes in the bone marrow. However, proplatelet formation (PPF) significantly decreased on days 2 and 4, after bortezomib administration to mice. Meanwhile, CFU-Mk formation and the ploidy distribution of cultured megakaryocytes in vitro were not affected by bortezomib used at concentrations of ≤ 1 ng/mL. The PPF of megakaryocytes in vitro significantly decreased with 0.1, 1, 10, and 100 ng/mL bortezomib. Considering the bortezomib concentration in clinical studies, these data strongly suggest that decreased PPF activity induces thrombocytopenia. To elucidate the mechanism behind decreased PPF, Western blot was performed. Activated Rho expression increased after the incubation of murine platelets with bortezomib. Decreased PPF activity was eliminated by the addition of Y27632, a Rho kinase inhibitor, in vitro. Given that the Rho/Rho kinase pathway is a negative regulator of PPF, bortezomib increases activated Rho, inducing decreased PPF, which results in decreased platelet count.

Progressive transformation of germinal center (PTGC) represents an asymptomatic persistent form of lymphadenopathy. We present a case of classical Hodgkin lymphoma occurring in association with PTGC. The patient was a 60-year-old woman who had noted swelling of the submandibular lymph nodes. Histopathologically, the enlarged lymph nodes appeared as multiple nodules with ill-defined and irregularly expanded germinal centers. Immunohistochemical studies indicated that the germinal center cells comprised B cells that were positive for CD10 and CD20, and negative for bcl-2. Enlarged vascular endothelial cells were present in the interfollicular areas. CD30-positive Hodgkin & Reed-Sternberg cells were seen between the interfollicular area and the mantle zone, and were surrounded by CD3-positive T-cells. In situ hybridization studies demonstrated no expression of Epstein-Barr virus-encoded small RNA in the Hodgkin & Reed-Sternberg cells. A diagnosis of classical Hodgkin lymphoma complicated by PTGC was made from the lymph node specimen.

BACKGROUND: The overall survival of patients with newly diagnosed chronic myeloid leukemia (CML) has improved significantly since the introduction of tyrosine kinase inhibitors (TKIs), and recently, some patients with CML who achieve stable deep molecular response (DMR) to TKI therapy could safely suspend treatment. In addition to European LeukemiaNet criteria (ELN), the European Society for Medical Oncology (ESMO) proposed that less than 0.01% of BCR-ABL1 transcript (MR4.0) on the International Scale (IS) after 18 months is optimal for patients to achieve treatment-free remission. Branford et al. indicated that major molecular response (MMR; less than or equal to 0.1% of BCR-ABL1 IS ; MR3.0) at three months predicts stable undetectable BCR-ABL1 transcript levels during imatinib treatment. However, second-generation TKIs induce more rapid and deeper responses at early time points compared to imatinib; however, whether early molecular response predicts MR4.0 by 18 months to second-generation TKI therapy, remains unclear. AIMS: We retrospectively analyzed BCR-ABL1 transcript levels in patients with CML in chronic phase (CML-CP) at 3, 6, 12, and 18 months after initiating dasatinib treatment to identify molecular milestones that would predict MR4.0 by 18 months. METHODS: Fifty-nine newly diagnosed patients with CML-CP were included in this study. The median age was 61 years (18-81 years), 72% of whom were males, and patients older than 65 years comprised 31% of the overall enrollment. Eighty-six percent of them had low and intermediate Sokal scores. Patients received 100 mg of dasatinib once daily. Dose interruption or reduction was allowed if drug-related grade 3 non-hematological toxicity or grade 3 or worse hematological toxicity occurred.BCR-ABL1/ ABL ratio IS (BCR-ABL1 IS) was performed at approximately 3-month intervals. To assess the kinetics of response, we calculated halving time (HT) of BCR-ABL1 IS. HT-BCR-ABL1 was calculated as described by Branford et al. We used a receiver-operating characteristic (ROC) curve to identify the cut-offs in transcript levels at three and six months. Mann-Whitney test was used to determine statistical significance. Categorical variables were compared using Fisher's exact test. Factors were subjected to multivariate analysis using Cox regression; differences with p RESULTS: The median BCR-ABL1 IS level before therapy was 82.1% (range 13.5-157.9 %). The estimated MMR by 12 months and MR4.0 by 18 months were 86.4% and 50.8%, respectively. We analyzed each into a cohort that achieved MR4.0 by 18 months (MR4.0 cohort) and a cohort that did not achieve MR4.0 (non-MR4.0 cohort). The BCR-ABL1 IS level in each cohort is indicated in the Table. Median HT-BCR-ABL1 IS 0-3 months was 10.8 days (6.5-71.3 days) in MR4.0 cohort, and 13.0 days (8.5- 169.6 days, p CONCLUSION: Even though dasatinib is highly-priced, dasatinib treatment results in higher rates of molecular responses in newly diagnosed patients with CML-CP. Assessment of molecular reduction within six months has become an important landmark to predict MR4.0 by 18 months during dasatinib treatment for patients with the aim to achieve treatment-free remission. Disclosures Oyake: Astellas: Speakers Bureau; Celgene: Honoraria; Chugai: Honoraria; Kyowa-Hakko Kirin: Honoraria. Ito:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Ono: Honoraria.

The international phase III DASISION trial demonstrated improved efficacy of dasatinib versus imatinib in treatment-naive patients with chronic myeloid leukemia in the chronic phase (CML-CP). We report efficacy and safety outcomes in a Japanese population from the final, 5-year follow-up of DASISION. At the end of the study, 77% (20/26) of dasatinib-treated and 61% (14/23) of imatinib-treated patients remained on initial therapy. Improved responses were observed in Japanese patients who received dasatinib versus imatinib (complete cytogenetic response: 96 vs 87%; major molecular response: 88 vs 74%; BCR-ABL1 ≤0.0032% International Scale [MR4.5]: 58 vs 52%). In patients who achieved BCR-ABL1 ≤10% at 3 months, 5-year progression-free survival and overall survival rates were high with dasatinib (96 and 96%) and imatinib (88 and 100%). The majority of adverse events were grade 1/2 in Japanese patients. Pleural effusion occurred more frequently in dasatinib-treated Japanese patients versus all patients (42 vs 28%), with no treatment discontinuations. Overall, in Japanese patients, dasatinib maintained its safety profile and had higher or comparable response and survival outcomes compared with imatinib or with all patients in DASISION. These findings demonstrate the long-term efficacy and tolerability of dasatinib and support frontline treatment of Japanese patients with CML-CP with dasatinib.

Recent advances in surgical corrections and supportive care for congenital heart disease have resulted in increasing numbers of adult survivors who may develop hematological malignancies. Treatments including chemotherapy for such patients may cause serious hemodynamic or cardiac complications, especially in those receiving stem cell transplantation. We present a 29-year-old woman with acute lymphoblastic leukemia and congenital heart disease. She had been diagnosed with pulmonary atresia with an intact ventricular septum at birth, and the anomaly was surgically corrected according to the Fontan technique at age 9 years. Her induction chemotherapy required modifications due to poor cardiac status with Fontan circulation. However, after surgical procedures including total cavopulmonary connection and aortic valve replacement at first complete remission, her cardiac status was significantly improved. Subsequently, she underwent cord blood stem cell transplantation at the third complete remission. She required intensive supportive care for circulatory failure as a pre-engraftment immune reaction and stage III acute graft versus host disease of the gut, but recovered from these complications. She was discharged on day 239, and remained in complete remission at 1-year post-transplantation.

Occult hepatitis B virus (HBV) infection is a clinical challenge, but its relationship to clinicopathologic features and the risk of progression to malignant lymphoma (ML) are poorly defined. We estimated the prevalence of HBV infection of 1,358 patients with newly diagnosed ML. HBV infection was more prevalent in ML than in control patients. The occult HBV infection group had a higher median onset age, no liver or spleen involvement, and higher prevalence of diffuse large B-cell lymphoma than the other groups, indicating that occult HBV infection is a distinct clinicopathologic entity. J. Med. Virol. 88:2206-2210, 2016. © 2016 Wiley Periodicals, Inc.

The overall survival of patients with multiple myeloma has significantly improved over the last decade, mainly due to the use of novel agents such as thalidomide, lenalidomide and bortezomib; however, multiple myeloma remains incurable due to its eventual relapse, necessitating urgent development of newer agents. YM155 is a novel small molecule that suppresses transactivation of survivin and induces apoptosis in various cancer cell types. However, the effects of YM155 on multiple myeloma cells have not been fully elucidated. We herein found that YM155 inhibited proliferation of and induced caspase-dependent apoptosis in myeloma cells, partially via the suppression of survivin, myeloid cell leukemia sequence-1, and X-linked inhibitor of apoptosis protein. Interestingly, YM155 suppressed c-Myc protein expression via the proteasomal degradation. Moreover, YM155 increased F-box and WD-40 domain protein 7α expression that is a component of the Skp, Cullin, F-box-like ubiquitin ligase complex, suggesting that YM155-induced c-Myc down-regulation may be due to the proteasomal degradation through ubiquitination by F-box and WD-40 domain protein 7α. These results warrant further clinical evaluation of YM155 in MM patients.

High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is widely used as a salvage therapy in the treatment of refractory malignant lymphoma. To investigate the safety and feasibility of a high-dose MCNU, carboplatin, etoposide and cyclophosphamide (MCVC) regimen, we conducted a prospective multicenter trial. Thirty patients with relapsed/refractory/poor-risk non-Hodgkin lymphoma (NHL n = 27) or Hodgkin lymphoma (HD n = 3) were uniformly treated with an MCVC regimen and underwent auto-SCT. The median follow-up duration of the surviving patients was 67 months (56-133 months). The major toxicities were anorexia (94 %), diarrhea (80 %), nausea (79 %), febrile neutropenia (70 %), alopecia (67 %) and mucositis (60 %). Three patients developed severe left ventricular dysfunction, and two patients developed severe sinusoidal obstructive syndrome (SOS). Of these patients, two died without disease progression. Treatment-related mortality was 6.6 %. Late-onset adverse events including two cases of cytomegalovirus pneumonia and one of interstitial pneumonia were observed. In DLBCL (n = 13) and transformed FL (n = 2) patients, OS and EFS at 3 years were 72 and 46 %, respectively. These results suggest that the MCVC regimen followed by auto-SCT is a feasible and tolerable therapy for relapsed/refractory malignant lymphoma. However, cardiac toxicity due to high-dose cyclophosphamide and development of SOS can occur and should be carefully monitored. Further follow-up is needed to evaluate the long-term efficacy and safety of this regimen.

Introduction We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. Patients and Methods The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. Results The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. Conclusion These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.

Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of aggressive ATL patients remains poor because of its resistance to conventional chemotherapy. We examined the effect of deguelin, a naturally occurring rotenoid, on HTLV-1-transformed T-cell lines, KUT-1 and MT-2 cells. We found that deguelin suppressed cell proliferation and induced cell death in these cells. Immunoblot analysis showed the inhibition of survivin expression and signal transducers, and activators of transcription (STAT) 3 phosphorylation of both cells. We also observed the cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP) in deguelin-treated cells, indicating that deguelin induces caspase-dependent apoptosis in these cells. Furthermore, proteasome inhibitor MG132 prevented the down-regulation of survivin expression and STAT3 dephosphorylation by deguelin, suggesting that the action mechanism of deguelin involves the degradation of survivin and phosphorylated STAT3 through the ubiquitin/proteasome pathway. Our data indicate that deguelin presents a potent anti-proliferative effect in part via the down-regulation of survivin expression and STAT3 phosphorylation in HTLV-1-transformed cells. Deguelin merits further investigation as a potential chemotherapeutic agent for ATL.

Objectives: Although rituximab therapy is not considered to be closely associated with infection, there have been reports of serious infections in patients treated with rituximab. We performed a statistical retrospective analysis to clarify the risk factors for infection in patients receiving rituximab therapy. Methods: A retrospective study of data from clinical records was performed that targeted haematology patients treated at our university hospital between April 2003 and October 2006. We selected 63 patients with CD20-positive lymphoma whose peripheral blood immunoglobulin levels had been measured within 6 months before and after rituximab therapy. Logistic regression analysis was used to investigate the risk factors for serious infection in these patients. Results: The three risk factors identified were: 1) reduction in IgM after administration of rituximab [odds ratio (OR) = 1.032, confidence interval (CI) = 1.007–1.057; P = 0.009], 2) duration of rituximab therapy [OR = 0.962, CI = 0.932–0.994; P = 0.021] and 3) G-CSF administration [OR = 4.825, CI = 1.411–16.495; P = 0.012]. Conclusions: Rituximab therapy may be associated with infection, indicating the need for sequential monitoring of IgM levels and identification of the optimal interval between rituximab cycles.

Clostridium difficile is a major cause of diarrhea in hospitalized patients. Although pseudomembranes are crucial evidence for diagnosis of C. difficile-associated diarrhea (CDAD), some cases do not show any pseudomembranes. The aim of this study was to verify the hypothesis that pseudomembranes are not generated in immunosuppressed patients because of the absence of immunoreactions.We investigated the endoscopic findings of patients with ulcerative colitis (UC) or who had received hematopoietic stem cell transplantation, and who presented with C. difficile toxin A and had undergone colonoscopy between April 2002 and July 2007 at our institutes. Results. In 4 patients the diagnosis was UC and C. difficile infection, and in another 4 patients the diagnosis was CDAD after hematopoietic stem cell transplantation. None of these cases showed pseudomembranes. Shallow ulcers were found in all four cases with UC. Only non-specific findings were obtained for the CDAD patients after hematopoietic stem cell transplantation.Pseudomembranes, the typical evidence for CDAD, were not detected in any patients using immunosuppressive agents. Additional bacterial examination is therefore essential when UC becomes exacerbated and when patients present with diarrhea after hematopoietic stem cell transplantation, even in the absence of pseudomembranes.

To review a current experience of unrelated bone marrow transplantation (BMT) with reduced-intensity conditioning (RIC) regimens, we conducted a nationwide survey with 77 patients (age, 25-68 years). The backbone RIC regimen was a combination of fludarabine or cladribine, busulfan or melphalan and total body irradiation at 2-4 Gy. Five patients died early, but 71 (92%) achieved initial neutrophil recovery. Thereafter, 36 patients (47%) died of therapy-related complications, 23 (30%) of whom died within day 100. Grades II-IV acute graft-versus-host disease (GVHD) occurred in 34 of the 68 evaluable patients (50%). In a multivariate analysis, a regimen containing antithymocyte globulin (ATG) was significantly associated with a decreased risk of acute GVHD (P = 0.041). Thirty-three patients are currently alive with a median follow-up of 439 days (28-2002 days), with an OS of 50% at 1 year. In conclusion, unrelated BMT with RIC regimens can be a curative treatment in a subset of patients.

Background We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukemia (CML). Methods From 2009 to 2011, 54 CML-chronic phase (CP) patients with resistance (n = 40) or intolerance (n = 25) to imatinib were registered to undergo dasatinib treatment. Eleven patients showed both resistance and intolerance to imatinib. Coincidentally, the resistance criteria in this study were the same as a non-optimal response to tyrosine kinase inhibitors (TKIs) as defined in the European LeukemiaNet (ELN) 2013 recommendations. Results The overall incidence rate of major molecular response (MMR) at 12 months was 62.3% (n = 47). Forty patients with resistance to imatinib who were ‘warning’ and ‘failure’ patients based on the ELN 2013 recommendations were assessed; cumulative MMR and MR4.5 rates were 62.5% (n = 39) and 21.0% (n = 40), respectively, at 12 months. Twelve patients who showed a BCR-ABL transcript level >1% on the international scale did not achieve a MMR or discontinued dasatinib treatment because of insufficient effects. With regard to safety issues, grade 3/4 non-hematologic adverse events (AEs) were infrequent. Conclusions Patients with non-optimal responses (who meet ELN 2013 warning and failure criteria) to imatinib should be switched quickly to dasatinib, which is less toxic in CML-CP patients, to improve their prognoses. A BCR-ABL1 IS of

The impact of human leucocyte antigen (HLA) incompatibility between donor and recipient on graft-versus-host disease (GVHD) and graft failure after reduced-intensity conditioning stem cell transplantation (RICT) remains to be elucidated. We retrospectively analysed outcome in 341 patients who underwent RICT from related donors for haematological malignancies. The overall cumulative incidence of grade II-IV acute GVHD (aGVHD) was 40% for all subjects; 39% in recipients with HLA-matched donors, 44% in those with one-locus-mismatched donors, and 50% in those with two- to three-loci-mismatched donors. In a Cox regression model adjusted for potential confounders, the tendency for grade II-IV aGVHD (P=0.01), chronic GVHD (cGVHD) (P=0.05) and graft failure (P=0.033) increased with HLA disparity. Use of peripheral blood grafts instead of marrow was a risk factor for cGVHD. Use of antithymocyte globulin was associated with reduced aGVHD and cGVHD. Overall survival (OS) in recipients of two- to three-loci-mismatched RICT at 2 years (18%) was significantly worse than that in patients who received one-locus-mismatched RICT (51%) and HLA-matched RICT (48%) (P

The percentage of hypochromic erythrocytes (%HYPO) and the reticulocyte hemoglobin content (CHr) have been used for the diagnosis of iron deficiency (ID). However, we found a discrepancy between %HYPO and CHr values in some hemodialysis patients. Hemodialysis patients receiving recombinant human erythropoietin (rHuEPO) with ID were defined as patients with a %HYPO value exceeding 5%. Five ID patients with a high CHr (group A) and 3 ID patients with a low CHr (group B) received 120 mg/week iron intravenously for 8 to 12 weeks. Changes in %HYPO, CHr, percentage of macrocytic erythrocytes (%MACRO), absolute reticulocyte count, immature reticulocyte fraction, and soluble transferrin receptor level were investigated over a 20-week period. CHrs were measured with 2 hematology analyzers: the Bayer HealthCare Technicon H*3 and the ADVIA 120. Patients in group A showed a significantly greater mean %MACRO (P < .01) and a lower mean red blood cell number (P < .05) than patients in group B. Even the mean CHr at baseline in group A was significantly higher than the mean CHr in the healthy subjects (P < .01), and hemoglobin levels increased in association with the reduction in rHuEPO dose following iron administration (P < .01). We found a group with high CHr, %HYPO, and %MACRO values among hemodialysis patients. Iron administration enables the rHuEPO dose to be reduced.

Periodic cell arrangements of tracheids in Cryptomeria japonica and Agathis sp., and that of wood fibers in Magnolia obovata were examined by Fourier transform image analysis (FTIA). The angular distribution functions on power spectral patterns (PSPs) transformed from the dot maps were traced. As well as this conventional method, we developed the line convolution method and domain transformation for more correct analysis of radial and tangential arrangements. Cell arrangements became clear in Cryptomeria and Agathis. Fluctuations were expressed by the standard deviation (σ) or the relative standard deviation (σr) so that we could compare the characteristics of both woods. In Cryptomeria, the most provable distance between tracheids along radial files was 36.7 µm with 17% fluctuation, whereas the tangential interval was 28.3 µm with σr of 24%. In Agathis, the radial diameter was 35.1 µm with σr of 23% and the tangential interval was 41.5 µm with σr of 23%. In Magnolia, the maximal periodicity of wood fibers was 15.8 µm and 20.5 µm along and between radial files, respectively, although the fluctuations could not be estimated because of the remarkable interruptions by numerous vessels.

Lymph node biopsies were analyzed from three patients with chronic myelogenous leukemia (CML) showing nodal blast proliferation. Immunohistochemically, the blasts from all three patients had an immature marker profile with a T-blast population (cCD3+, CD4-, CD7+, CD8-, CD99+, terminal deoxynucleotidyl transferase +) and a hematopoietic progenitor cell marker (CD34). In two patients, the blasts also expressed myeloid lineage specificity (naphthol AS-D chloroacetate esterase activity and myeloperoxidase positivity). However, it was difficult to distinguish between blast proliferation in CML and non-Hodgkin lymphoma from these immunohistopathological findings alone. Subsequently, bcr gene rearrangement and bcr/abl mRNA expression were detected by Southern blot and reverse transcription-polymerase chain reaction analysis of the lymph nodes. Fluorescence in situ hybridization (FISH) analysis of lymph node touch smears also disclosed bcr/abl gene fusion signals in the blasts of all patients, confirming that the blasts were derived from Philadelphia chromosome-positive CML. Accurate discrimination between the proliferating nodal blasts of CML and non-Hodgkin lymphoma is essential for determining subsequent therapy. FISH analysis of bcr/abl in single-cell blast preparations is an efficient tool that allows rapid, accurate cytopathological diagnosis of extramedullary blast-phase CML and its discrimination from non-Hodgkin lymphoma.

Several approaches for the detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) have shown the importance of determining the level of MRD precisely. In the present study, we tested a new real-time quantitative polymerase chain reaction (RQ-PCR) strategy with minor groove binder (MGB) technology for immunoglobulin heavy chain gene rearrangements by positioning a MGB probe at the germline JH segments and one of the primers at the downstream introns in combination with an allele-specific oligonucleotide (ASO) primer complementary to the VH-DH or DH-JH junctional region. A MGB probe forms extremely stable duplexes with single-stranded DNA targets, allowing the use of shorter probes for hybridization-based assays. Therefore, it shows positional flexibility. We have designed two novel consensus MGB JH germline probes for analyzing all of the germline rearrangements registered in the V BASE database, and demonstrated that the MRD was detectable with the probes in 17 cases of childhood ALL. The actual copy number for the targets and dynamic changes before and after treatment were almost identical between the JH MGB probe and conventional non-MGB probes in each patient. MGB technology will undoubtedly contribute to MRD-PCR studies of childhood ALL.

We describe a patient with persistent pure red cell aplasia due to human parvovirus B19 (HPVB19) infection during immunosuppressive therapy for refractory autoimmune hemolytic anemia (AIHA). The patient had been given corticosteroid (CS) and/or azathioprine for AIHA. During the course of treatment, reticulocyte count and hemoglobin levels decreased suddenly. Bone marrow aspirate showed erythroid lineage-specific aplasia with a few giant proerythroblasts, suggesting the presence of HPVB19 infection. The diagnosis of aplastic crisis due to HPVB19 infection was based on positive test results by polymerase chain reaction for HPVB19 immunoglobulin M (IgM) antibody and B19 DNA. Although splenectomy followed by administration of high-dose gamma globulin (HDIG) and plasma exchange were performed, the crisis and hemolysis recurred. Aplastic crises occurred several times when the B19 IgG result became negative and the CD4+ lymphocyte count was less than 300/microL. The patient showed complete recovery from anemia after CS was switched to cyclosporin A (CsA) and intermittent administration of HDIG. The result for B19 IgG antibody was continuously positive, and the DNA result became negative after these treatments. The results in this case indicated that concomitant administration of CsA and intermittent administration of HDIG can lead to cure of chronic anemia due to HPVB19 infection in patients with refractory AIHA.

We used 3'-minor groove binder (MGB) technology to develop consensus fluorogenically labeled probes of the immunoglobulin heavy-chain (IgH) gene for detecting minimal residual disease (MRD) in B-cell non-Hodgkin lymphoma (B-NHL). Sequence data from 59 patients with B-NHLs revealed a narrow consensus region as a result of somatic hypermutations and variable VH usage, indicating that it would be difficult to design ordinary non-MGB probes. MGB probes, characterized by shorter length but higher melting temperature, are more suitable for this situation than ordinary non-MGB probes. In fact, the present data indicated that about 20% more cases were detectable with MGB probes (34/59, 57.6%) than with the non-MGB probes (23/59, 39.0%) designed by Donovan et al. MGB technology is useful for the design of consensus fluorogenically labeled probes of the IgH gene for detecting MRD.

PURPOSE We reviewed reduced intensity stem cell transplantation (RIST) in metastatic renal cell cancer (RCC). PATIENTS AND METHODS Two cases of lung metastasis of immunotherapy invalidity. Six days of fludarabine 30 mg/m2 and 2 days of busulfan 4 mg/kg were given as conditioning for mini-SCT. CyA and short-term MTX were used as immunosuppressive agents. RESULTS Size reduction of tumor was observed with dose reduction of CyA. Following steroid therapy for the treatment of GVHD, the tumor progressed. No serious complications except for GVHD. CONCLUSION These results suggested that RIST might be considered as salvage therapy in patients metastatic RCC.