Clinical characteristics of Japanese patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries.

[A Case Report of Cancer Chemotherapy for Disseminated Carcinomatosis of the Bone Marrow Associated with Gastric Cancer Accompanied by Disseminated Intravascular Coagulation].

A 72-year-old woman was admitted to our hospital because of symptoms of bleeding diathesis such as hematuria and purpura. A blood test revealed disseminated intravascular coagulation(DIC). Upper gastrointestinal endoscopy showed advanced gastric cancer. Bone marrow aspiration cytology demonstrated diffuse hyperplasia of large atypical cells, and metastasis of the epithelial tumor was suspected on immunohistochemical examination. She was diagnosed with disseminated carcinomatosis of the bone marrow associated with gastric cancer accompanied by DIC. She was treated with weekly infusion of methotrexate 100 mg/m2 plus 5-fluorouracil 600 mg/m2 for 4 courses; and she completely recovered from DIC. She received oral tegafur/gimeracil/oteracil as an outpatient. However, DIC recurred 126 days after the initial chemotherapy, and 5-fluorouracil plus cisplatin was administered subsequently. After 1 course, she died 166 days after the initial chemotherapy. Although the prognosis of patients with disseminated carcinomatosis of the bone marrow associated with gastric cancer accompanied by DIC is extremely poor, this case shows that secession of DIC and prognostic improvement by chemotherapy could occur. Chemotherapy could be considered a potentially effective treatment in this case.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

Detection of MYD88 L265P mutation by next-generation deep sequencing in peripheral blood mononuclear cells of Waldenström's macroglobulinemia and IgM monoclonal gammopathy of undetermined significance.

We investigated the feasibility of using next-generation sequencing (NGS) technique using molecular barcoding technology to detect MYD88 L265P mutation in unselected peripheral blood mononuclear cells (PBMCs) in 52 patients with Waldenström's macroglobulinemia [1] and 21 patients with IgM-monoclonal gammopathy of undetermined significance (MGUS). The NGS technique successfully detected the MYD88 L265P in unselected PBMCs at a sensitivity of 0.02%, which was ×5 higher than that of AS-PCR. All the results between paired BM and PB samples from 2 IgM MGUS and 4 untreated WM patients matched completely. MYD88 L265P mutation was detected in 14/21 (66.7%), 14/19 (73.7%), and 10/33 (30.3%) with the median mutant allele burden of 0.36% (range, 0.06-2.85%), 0.48% (range, 0.02-32.3%), and 0.16% (range, 0.02-33.8%), in IgM-MGUS, untreated WM, and previously treated WM, respectively. Multiple linear regression analysis identified an absolute peripheral lymphocyte count as the positive predictor of PB mutant allele burden (R2 = 0,72, P<0.0001). Our non-invasive, simple NGS method has the potential to detect MYD88 L265P mutations in PBMCs of IgM MGUS and WM patients, which may especially utilized for monitoring minimal residual tumor burden after treatment.

Characteristics and Prognosis of Patients with Immunoglobulin M Monoclonal Gammopathy.

Many patients with immunoglobulin M (IgM) monoclonal gammopathy remain asymptomatic and, consequently, untreated; however, few studies have evaluated the clinical course and prognosis of these patients. Using the screening procedures at our hospital, 74 patients with IgM monoclonal gammopathy were selected. We excluded 11 patients in whom the treatment for lymphoid neoplasms had been initiated at the time of IgM monoclonal protein detection. The remaining 63 patients were considered to be the patient population with IgM MGUS and asymptomatic WM, and were analyzed. In these patients, the median overall survival was longer than 14 years. More than half of these patients died from causes other than lymphoid neoplasm. The cumulative incidence of lymphoid neoplasm requiring treatment was 17.5%. In five of eight patients requiring treatment for lymphoid neoplasms, the causes of death were related with these lymphoid neoplasms. Our study suggests that not all patients with IgM monoclonal gammopathy require uniform treatment for prolonged survival; however, most lymphoid neoplasms requiring treatment are refractory diseases. Our findings may help manage patients with macroglobulinemia.

Development of Epstein-Barr Virus-related Primary Diffuse Large B-cell Lymphoma of the Central Nervous System in a Patient with Peripheral T-cell Lymphoma, Not Otherwise Specified after Mogamulizumab Treatment.

Mogamulizumab is a defucosylated humanized anti-CC chemokine receptor type 4 (CCR4) antibody that exerts an anti-tumor immune effect against various tumors through a suppressive effect on regulatory T-cells. We herein report a patient with peripheral T-cell lymphoma who developed Epstein-Barr virus (EBV)-related primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) after mogamulizumab therapy. Our experience should alert physicians to the possibility of the development of EBV-related CNS DLBCL in patients treated for primary lymphoma and suggests that the anti-tumor immune effect of mogamulizumab is ineffective for the prophylaxis of EBV-related lymphomas.

Impact of Hematopoietic Progenitor Cell Count as an Indicator for Optimal Timing of Peripheral Stem Cell Harvest in Clinical Practice.

For optimizing CD34+ cell collection, appropriately timing peripheral blood stem cell harvest (PBSCH) initiation is crucial. Automatic cell analyzers with the immature myeloid information channel provide hematopoietic progenitor cell (HPC) count, a surrogate marker of CD34+ cells, which can be obtained within a few minutes without requiring monoclonal antibodies. The final decision on PBSCH initiation can be made using the HPC count obtained on the morning of the harvest day. Herein, we evaluated the impact of the HPC count as an indicator for the optimal timing of PBSCH in clinical practice over 9 years. One hundred and eighteen aphereses from 72 cases had a definite number of CD34+ cells/kg in the PBSC yield. A correlation was found between the HPC count in the PB and the CD34+ cell count (R = 0.563, p ＜ 0.001), whereas no correlation existed between the white blood cell and CD34+ cell counts (R = 0.0418, p = 0.65). We defined ＞ 2.0 × 106/kg of CD34+ cells in a single apheresis as good mobilization. Multivariate analysis demonstrated that an HPC count of ＞ 21/µL, myeloblast count of ＞ 12/µL, and age at PBSCH of ＜ 50 years were independently associated with good mobilization (p = 0.001, p ＜ 0.001, and p = 0.005, respectively). Our findings suggest that the HPC count is a good indicator for the optimal timing of PBSCH.

Prognostic impact of serum soluble LR11 in newly diagnosed diffuse large B-cell lymphoma: A multicenter prospective analysis.

BACKGROUND: LR11 (also called SorLA or SORL1) is a type I membrane protein, originally identified as a biomarker for atherosclerosis and Alzheimer's disease. We recently found that LR11 was specifically expressed in Diffuse Large B-cell lymphoma (DLBCL) cells, and high serum sLR11 concentrations in retrospective cohort indicated inferior survival. In this study, we prospectively validated the clinical impact of serum sLR11 in 97 patients with newly-diagnosed, untreated DLBCL. RESULTS: Serum sLR11 concentrations were increased in DLBCL patients compared to normal controls (mean±SD: 21.2±27.6 vs. 8.8±1.8ng/ml, P<0.0001), and significantly reduced at remission (mean±SD: 17.4±16.4 vs. 10.9±4.5ng/ml, P=0.02). Increased serum sLR11 concentrations were affected by tumor burden and bone marrow invasion. The 2-y OS and PFS were significantly lower in patients with high sLR11 concentrations (≤18.1ng/ml vs. >18.1ng/ml; 2-y OS: 89.0% vs. 56.4%, P<0.0001; 2-y PFS: 85.8% vs. 56.9%, P<0.0001). CONCLUSIONS: Serum sLR11 is a tumor-derived biomarker for predicting the survival of newly diagnosed patients with DLBCL.

Immune pancytopenia after chemotherapy in a patient with diffuse large B-cell lymphoma.

During treatment for malignant lymphoma, cytopenia can develop for several reasons. In the treatment of cytopenia, various possibilities should be considered because inadequate treatment causes exacerbation of cytopenia and can lead to fatal conditions, such as infection and bleeding. Herein, we describe immune pancytopenia 3 months after the last exposure to chemotherapy in a patient with diffuse large B-cell lymphoma (DLBCL). She suffered from severe pancytopenia after two courses of rituximab and bendamustine therapy for a second relapse of DLBCL. Immune pancytopenia was diagnosed with bone marrow tests and the presence of autoantibodies; it promptly resolved after initiation of prednisolone therapy. Clinicians should be aware of immune cytopenia and monitor for it carefully, even if patients have already finished chemotherapy treatment.

Cessation of In-line Filters in Central Venous Catheters Does Not Significantly Influence the Incidence of Bloodstream Infections and Mortality in a Hospital Hematological Ward.

Objective The use of intravenous in-line filters is effective for the mechanical removal of large particles, precipitates, bacteria, fungi, large lipid globules, and air. However, the routine use of in-line filters remains controversial. Many patients with hematological diseases frequently suffer from bloodstream infections (BSIs) with fatal outcomes. Methods The year before cessation of an in-line filter was defined as the "filter period" and the year after its cessation was defined as the "non-filter period." The number of central line-associated bloodstream infections (CLABSIs), which are defined through surveillance, the catheter utilization rate, the number of patient deaths within 7 days after removal of the central venous catheters (CVCs), and the overall survival rate following CVC insertion were measured. Results During both periods, 84 patients had a total of 140 CVCs with a total number of catheter days of 3,407. There were 10 CVCs with CLABSIs, and the overall CLABSI rate was 2.9/1,000 catheter days, including 4 CVCs with CLABSIs (2.5/1,000 catheter days) during the filter period and 6 CVCs with CLABSIs (3.3/1,000 catheter days) during the non-filter period. The CLABSI rate, catheter utilization rate, and mortality did not differ significantly between the two periods. The only independent variable that was found to be significantly associated with the development of CLABSIs was a neutrophil count of <500×10(6)/L (p<0.05). Conclusion Our study revealed that the cessation of in-line filters from CVCs does not significantly influence the incidence of BSIs and mortality in patients with hematological disease. To confirm our results, however, a large-scale randomized controlled study is warranted.

Successful Allogeneic Stem Cell Transplantation for Severe Aplastic Anemia after Treatment of Lymphoproliferative Disorder Caused by Rabbit Antithymocyte Globulin.

Immunosuppressive therapy (IST) with a combination of antithymocyte globulin (ATG) and cyclosporine (CsA) is an effective therapeutic modality for patients with aplastic anemia (AA) who are not eligible for allogeneic stem cell transplantation (Allo-SCT) from a human leukocyte antigen-identical sibling donor. However, there have been reports of some patients developing lymphoproliferative disorder (LPD) after IST for AA. We herein report a case of a 26-year-old man with severe AA (SAA) complicated by LPD after a single course of IST, who was successfully treated with Allo-SCT from an unrelated donor. Two months after starting IST for SAA, he developed LPD in the stomach. CsA was reduced, however, his neutrophil counts decreased, and CsA could not be discontinued. The patient was treated with rituximab monotherapy, and LPD resulted in complete remission. However, he failed IST for SAA and underwent Allo-SCT with reduced-intensity conditioning to recover his hematopoiesis. The patient has achieved complete hematopoietic recovery without the recurrence of LPD for five years after transplantation. This is the first report of successful Allo-SCT for SAA after the treatment of LPD caused by the use of rabbit ATG. This case provides useful information for the management of SAA with the development of LPD after IST.

Brachial Plexus Involvement of Myeloid Sarcoma Detected by Reconstruction Magnetic Resonance Neurography.

Myeloid sarcoma is a rare hematological disorder that presents as an extramedullary mass of immature myeloid precursors. We herein present the case of a 57-year-old man with a seven-month history of progressive weakness in the right upper extremity. Reconstruction magnetic resonance neurography showed a marked enlargement of the right brachial plexus. Fluorodeoxyglucose positron emission tomography revealed a radioactive lesion in the sacrum, in addition to the right brachial plexus, and a biopsy of the sacrum revealed myeloid sarcoma. The brachial plexus lesion was also regarded as myeloid sarcoma because of the treatment response. Isolated myeloid sarcoma involving the brachial plexus is very rare and its diagnosis is difficult as there was neither a history of leukemia nor bone marrow involvement in this patient. In this case, reconstructed magnetic resonance neurography was useful for detecting the brachial plexus mass lesion which led to an early diagnosis and good recovery.

Efficacy of myeloablative allogeneic hematopoietic stem cell transplantation in adult patients with MLL-ELL-positive acute myeloid leukemia.

Acute myeloid leukemia (AML) with mixed lineage leukemia-eleven-nineteen lysine-rich leukemia (MLL-ELL) is a rare subtype of MLL-rearranged AML. The outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with this disease remains unknown. In the present study, we retrospectively investigated the efficacy of allo-HSCT in eight adult MLL-ELL-positive AML patients. Although all eight patients achieved first complete remission (CR1), three (37.5 %) patients experienced relapse after induction therapy. Five (62.5 %) patients underwent allo-HSCT during CR1, whereas two (25.0 %) underwent allo-HSCT during disease relapse, and one (12.5 %) during CR2. All three patients who received allo-HSCT beyond CR1 died due to AML progression after allo-HSCT. Of the five patients who received allo-HSCT during CR1, three (60.0 %) remained alive at study conclusion. The overall survival rate at five years was 50.0 %. Intriguingly, clonally expanded non-leukemic cells expressing MLL-ELL during consolidation therapy were found to be eradicated after allo-HSCT during the monitoring of minimal residual disease in one patient; this indicates that allo-HSCT is efficacious for eliminating pre-leukemic cells resistant to chemotherapy. In conclusion, allo-HSCT soon after CR1 represents a promising therapeutic option for adult AML patients with MLL-ELL, although the outcome of allo-HSCT for patients beyond CR1 was dismal.

Early-Onset Severe Diffuse Alveolar Hemorrhage after Bortezomib Administration Suggestive of Pulmonary Involvement of Myeloma Cells.

Severe acute lung injury is a rare but life-threatening complication associated with bortezomib. We report a patient with multiple myeloma who developed a severe diffuse alveolar hemorrhage (DAH) immediately after the first bortezomib administration. The patient was suspected to have pulmonary involvement of myeloma, which caused DAH after rapidly eradicating myeloma cells in the lungs with bortezomib. Rechallenge with bortezomib was performed without recurrent DAH. In patients with multiple myeloma who manifest abnormal pulmonary shadow, we should be aware of early-onset severe DAH after bortezomib administration, which might be due to pulmonary involvement of myeloma cells.

Acute myeloid leukemia concurrent with spinal epidural extramedullary myeloid sarcoma accompanied by a high CD25 expression and the FLT3-ITD mutation.

Myeloid sarcoma (MS) is an extramedullary myeloid tumor that sometimes presents with antedating systemic leukemia, leading physicians to the misdiagnosis of lymphoma. CD25 is expressed in 13% of patients with acute myeloid leukemia (AML), and its expression is associated with FLT3-ITD mutations, an elevated serum soluble interleukin 2 receptor (sIL-2R) level and a lower survival rate. However, there are no reports concerning the relationship between MS and the CD25 expression. We herein report a case of AML accompanied by thoracic epidural MS with a high CD25 expression, the FLT3-ITD mutation and an extremely elevated serum sIL-2R level in a 59-year-old man who presented with paraplegia.

Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes.

LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding on cleavage with a disintegrin and metalloproteinase 17 (ADAM17). A shedding mechanism is presumed to have a key role in the functions of LR11, but the evidence for this has not yet been demonstrated. Tetraspanin CD9 has been recently shown to regulate the ADAM17-mediated shedding of tumor necrosis factor-α and intercellular adhesion molecule-1 on the cell surface. Here, we investigated the role of CD9 on the shedding of LR11 in leukocytes. LR11 was not expressed in THP-1 monocytes, but it was expressed and released in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 macrophages (PMA/THP-1). Confocal microscopy showed colocalization of LR11 and CD9 proteins on the cell surface of PMA/THP-1. Ectopic neo-expression of CD9 in CCRF-SB cells, which are LR11-positive and CD9-negative, reduced the amount of sLR11 released from the cells. In contrast, incubation of LR11-transfected THP-1 cells with neutralizing anti-CD9 monoclonal antibodies increased the amount of sLR11 released from the cells. Likewise, the PMA-stimulated release of sLR11 increased in THP-1 cells transfected with CD9-targeted shRNAs, which was negated by treatment with the metalloproteinase inhibitor GM6001. These results suggest that the tetraspanin CD9 modulates the ADAM17-mediated shedding of LR11 in various leukemia cell lines and that the association between LR11 and CD9 on the cell surface has an important role in the ADAM17-mediated shedding mechanism.