Yoshitoyo Kagami

Prognostic factors for mature natural killer (NK) cell neoplasms: aggressive NK cell leukemia and extranodal NK cell lymphoma, nasal type

BACKGROUNDnPatients with natural killer (NK) cell neoplasms, aggressive NK cell leukemia (ANKL) and extranodal NK cell lymphoma, nasal type (ENKL), have poor outcome. Both diseases show a spectrum and the boundary of them remains unclear. The purpose of this study is to draw a prognostic model of total NK cell neoplasms.nnnPATIENTS AND METHODSnWe retrospectively analyzed 172 patients (22 with ANKL and 150 with ENKL). The ENKLs consisted of 123 nasal and 27 extranasal (16 cutaneous, 9 hepatosplenic, 1 intestinal and 1 nodal) lymphomas.nnnRESULTSnComplete remission rate for ENKL was 73% in stage I, but 15% in stage IV, which was consistent with that for ANKL (18%). The prognosis of ENKL was better than that of ANKL (median survival 10 versus 1.9 months, P < 0.0001) but was comparable when restricted to stage IV cases (4.0 months, P = 0.16). Multivariate analysis showed that four factors (non-nasal type, stage, performance status and numbers of extranodal involvement) were significant prognostic factors. Using these four variables, an NK prognostic index was successfully constructed. Four-year overall survival of patients with zero, one, two and three or four adverse factors were 55%, 33%, 15% and 6%, respectively.nnnCONCLUSIONnThe current prognostic model successfully stratified patients with NK cell neoplasms with different outcomes.

Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling†

We performed comprehensive genome‐wide gene expression profiling (GEP) of extranodal nasal‐type natural killer/T‐cell lymphoma (NKTL) using formalin‐fixed, paraffin‐embedded tissue (n = 9) and NK cell lines (n = 5) in comparison with normal NK cells, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTL and to identify potential therapeutic targets. Pathway and network analysis of genes differentially expressed between NKTL and normal NK cells revealed significant enrichment for cell cycle‐related genes and pathways, such as PLK1, CDK1, and Aurora‐A. Furthermore, our results demonstrated a pro‐proliferative and anti‐apoptotic phenotype in NKTL characterized by activation of Myc and nuclear factor kappa B (NF‐κB), and deregulation of p53. In corroboration with GEP findings, a significant percentage of NKTLs (n = 33) overexpressed c‐Myc (45.4%), p53 (87.9%), and NF‐κB p50 (67.7%) on immunohistochemistry using a tissue microarray containing 33 NKTL samples. Notably, overexpression of survivin was observed in 97% of cases. Based on our findings, we propose a model of NKTL pathogenesis where deregulation of p53 together with activation of Myc and NF‐κB, possibly driven by EBV LMP‐1, results in the cumulative up‐regulation of survivin. Down‐regulation of survivin with Terameprocol (EM‐1421, a survivin inhibitor) results in reduced cell viability and increased apoptosis in tumour cells, suggesting that targeting survivin may be a potential novel therapeutic strategy in NKTL. Copyright

Clinical impact and predisposing factors of delayed-onset neutropenia after autologous hematopoietic stem-cell transplantation for B-cell non-Hodgkin lymphoma: association with an incremental risk of infectious events

BACKGROUNDnClinical significance of delayed-onset neutropenia (DON) after autologous hematopoietic stem-cell transplantation (ASCT) has not been well described. We conducted a retrospective cohort study to examine risk factors and clinical impact of DON.nnnDESIGN AND METHODSnSubjects were consecutive 108 patients with B-cell lymphoma receiving ASCT. We defined DON as absolute neutrophil counts <1.0 x 10(9)/l at any point from 30 days onward after ASCT without apparent causes of neutropenia. Documented infectious events were reviewed from 1 to 18 months after ASCT.nnnRESULTSnFifty-two percent of patients received rituximab. Cumulative incidence of DON was 50% at 1 year. Rituximab usage was identified as an independent risk factor of DON. A total of 117 infectious events were documented, of which 24 events occurred during DON period. Cumulative incidence of total infectious events was 75% and 42% in the groups with and without DON, respectively (P = 0.001). Varicella-zoster virus (P = 0.033) and upper respiratory infection (P = 0.016) were frequent in the patients experiencing DON. In a multivariable analysis, DON remained a significant factor for total infectious events and upper respiratory infection.nnnCONCLUSIONSnRituximab usage is an independent risk factor of DON. DON correlates with increased occurrence of infectious events. Careful follow-up would be needed after the onset of DON.

Phase II study of ABVd therapy for newly diagnosed clinical stage II–IV Hodgkin lymphoma: Japan Clinical Oncology Group study (JCOG 9305)

Although ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy has been regarded as a standard of care for advanced-stage Hodgkin lymphoma (HL) since 1992, there has been no prospective data of ABVD therapy in Japan. To investigate the efficacy and safety of ABVd therapy with the lower dose of dacarbazine (250xa0mg/m2) in patients with newly diagnosed stage II–IV HL, Lymphoma Study Group of Japan Clinical Oncology Group conducted a phase II study. The primary endpoints were complete response rate (%CR) and progression-free survival (PFS). A total of 128 patients with age less than 70xa0years were enrolled and received 6–8 cycles of ABVd followed by radiation to initial bulky mass. The %CR in 118 eligible patients was 81.4% [95% confidence interval (CI) 73.1–87.9%]. Major toxicity was grade 4 neutropenia (45.3%). Grade 3 nausea/vomiting was the most frequent non-hematological toxicity (10.9%). Transient grade 4 constipation, infection (abscess), hypoxemia and hyperbilirubinemia were observed in 4 patients. No treatment-related death was observed. PFS and overall survival at 5xa0years were 78.4% (95% CI 70.9–85.9%) and 91.3% (95% CI 86.1–96.5%), respectively. In conclusion, ABVd is effective in Japanese patients with stage II–IV HL with acceptable toxicities (UMIN-CTR Number: C000000092).

Cytotoxic molecule expression is predictive of prognosis in Hodgkin's-like anaplastic large cell lymphoma.

Aims:u2002 The Revised European American Lymphoma classification uses the term Hodgkins‐like anaplastic large cell lymphoma (HD‐like ALCL) for borderline cases with features of both anaplastic large cell lymphoma (ALCL) and classical Hodgkins lymphoma (HL). The aim of this study was to clarify the association between cytotoxic molecule (CM) expression and clinical outcome in HD‐like ALCL.

Phase II study of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) therapy for newly diagnosed patients with low- and low-intermediate risk, aggressive non-Hodgkin's lymphoma: final results of the Japan Clinical Oncology Group Study, JCOG9508.

The regimen of cyclophosphamide, doxorubicin, vincristine, and prednisolone, known as CHOP therapy, has been established as the standard treatment for aggressive non-Hodgkin’s lymphoma (NHL). Although patients categorized as low (L) and low–intermediate (L–I) risk using the International Prognostic Index have favorable prognoses in Western countries, the efficacy and safety of CHOP therapy has not been prospectively evaluated in Japan. We conducted a phase II study of CHOP in L and L–I risk Japanese patients, evaluating overall survival (OS) as the primary endpoint. A total of 213 patients were enrolled and treated with eight courses of CHOP. Efficacy was evaluated in 168 eligible patients (L risk, 87; L–I risk, 81). Five-year OS rates in all eligible, L, and L–I risk patients were 68xa0% [95xa0% confidence interval (CI): 61–76xa0%], 73xa0% (95xa0% CI: 63–82xa0%), and 64xa0% (95xa0% CI: 53–74xa0%), respectively. The major toxicity observed was grade 4 neutropenia (64xa0%). Grade 4 non-hematological toxicities were observed as follows: one case each of paralytic ileus, convulsions, hypoxemia due to interstitial pneumonia, and reactivated fulminant hepatitis B. These results show reasonable efficacy and safety of the CHOP regimen in Japanese patients with lower risk aggressive NHL (UMIN-CTR Number C000000053).

A case of MYH9 disorders caused by a novel mutation (p.K74E)

Dear Editor, MYH9 disorders are rare hereditary autosomal dominant disorders characterized by macrothrombocytopenia and Dohle body-like cytoplasmic inclusion bodies in granulocytes [1–3]. Though most MYH9 disorders are caused by missense mutations, differences in the location or the type of amino acid substitution can result in differences in phenotypes of blood cells or Alport manifestations (nephritis, sensory deafness, and cataract) [4]. Mutations in the head domain of nonmuscle myosin heavy chain-IIA (NMMHC-IIA) cause MYH9 disorders with a high frequency of Alport manifestations [4, 5]. It is sometimes difficult to identify cytoplasmic inclusion bodies in granulocytes by May-Giemsa staining, which often leads to a misdiagnosis of the condition as immune thrombocytopenic purpura (ITP). Here, we report a 40-year-old woman with MYH9 disorders who had been diagnosed with ITP in her childhood. When she was 35 years old, she developed renal failure, and hemodialysis was initiated 3 years later. Symptoms are inherited in an autosomal dominant manner (Fig. 1a). Results of laboratory testing were as follows: WBC 9.3×10/L, RBC 4.65×10/L, Hb 136 g/L, Plt 55× 10/L. On her peripheral blood smear, there were giant platelets and Dohle body-like cytoplasmic inclusion bodies in granulocytes (Fig. 1b). Immunofluorescence staining for NMMHC-IIA revealed abnormal NMMHC-IIA localization (Fig. 1c). Pure-tone audiogram showed bilateral sensorineural hearing loss. Genetic analysis showed p.K74E mutation in exon 1. The NMMHC-IIA sequence alignments near K74 are highly conserved residues among species. Based on the crystal structure of highly homologous smooth muscle myosin, K74 is located near the SH1-helix in the head domain (Fig. 1d). The detection of abnormal NMMHC-IIA localization by immunofluorescence staining is gold standard for diagnosis of MYH9 disorders [6]. Indeed, in the present case, cytoplasmic inclusion bodies in granulocytes were seen more clearly with immunofluorescence analysis than with May-Giemsa staining. The pattern of cytoplasmic inclusion bodies is strongly associated with the type of mutation, and the localization pattern of NMMHC-IIA can be classified into several groups based on the number, size, and shape of the aggregated NMMHC-IIA granules [6]. In patients with rod domain mutation, NMMHC-IIA forms one or two large intensely stained cytoplasmic foci. In patients with head domain mutation, the inclusion bodies are sometimes invisible with May-Giemsa staining, whereas immunofluorescence shows small cytoplasmic spots with circular to oval shapes. Because SH1-helix in the head domain of NMMHC-IIA is a critical segment for ATP hydrolysis and interaction with actin [4, 7, 8], patients with mutation in SH1-helix (e.g., p.R702C, p.R702H, * Nobuaki Suzuki suzukin@med.nagoya-u.ac.jp

IL2/IL-4, OX40L and FDC-like cell line support the in vitro tumor cell growth of adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with an extremely poor prognosis. Maintaining ATLL cells in vitro is difficult and little is known about how they maintain themselves or grow in patients. Elucidating the interaction between ATLL cells and surrounding host factors might therefore provide important insights into pathophysiology. We cultured primary ATLL cells in various culture conditions using IL-2, IL-4 and feeder cells, and established two cell lines dependent on IL-2, IL-4 and a follicular dendritic cell-derived cell line, HK, in which OX40-ligand was induced. Our study indicates the importance of microenvironment in the homeostasis of ATLL.

A low birth weight infant with no malformations delivered by a primary immune thrombocytopenia patient treated with eltrombopag

Primary immune thrombocytopenia (ITP) is defined by a low platelet count secondary to antibody-mediated platelet destruction or reductions in platelet production. Although eltrombopag is a thrombopoietin receptor agonist that increases platelet production in refractory or relapsed ITP, the influence on pregnancy is limited. We present the case of a pregnant 25-year-old ITP patient referred to our hospital with a history of two induced abortions. After eradication of Helicobacter pylori and with oral prednisolone at 8xa0mg/day, platelet count remained below 10,000/µl. Because she declined splenectomy, eltrombopag was initiated at 12.5xa0mg/day. Afterward, platelet count was maintained at over 50,000/µl. Twenty-one months later, pregnancy became apparent. She continued treatment, and cesarean section was performed at 37xa0weeks of gestation after administration of intravenous immunoglobulin, platelet transfusions, and steroids. The baby weighed only 1670xa0g but showed no malformations, and platelet count at birth was 416,000/µl. Studies of eltrombopag in pregnancy have not been reported. A case with administration of eltrombopag from the last trimester of pregnancy that resulted in low birth weight has been reported. Embryo lethality and reduced fetal weights have been reported from animal experiments. Further investigation about the relationship between low birth weight deliveries and eltrombopag is necessary.

Immune thrombocytopenia induced by vonoprazan fumarate: a single center retrospective study

Dear Editor, Vonoprazan fumarate is a first-in-class potassiumcompetitive acid blocker developed in Japan. Compared with conventional proton-pump inhibitors (PPI), vonoprazan is absorbed rapidly and reaches maximum plasma concentration shortly after oral administration because activation by gastric acid is no longer required [1]. It is approved for treatment in gastroduodenal ulcers, reflux esophagitis, and Helicobacter pylori eradication [2–4]. Drugs can cause thrombocytopenia by several mechanisms, including drug-induced immune thrombocytopenia (DITP): an antibody-mediated platelet destruction caused by exposure to a drug [5]. DITP due to PPI has been described previously [6–8]; however, no studies have examined induction of thrombocytopenia by vonoprazan exposure. We report a retrospective study on immune thrombocytopenia caused by vonoprazan. From August 2015 to December 2016, 1577 patients were administered vonoprazan for 7 days or longer in our hospital. The median age was 67 years (range, 16– 99 years), and 909 were male. Four hundred seventy-one received vonoprazan for Helicobacter pylori eradication, and 29 kept on using afterwards. Seven hundred sixty-one received vonoprazan for 2 months or longer. Out of the whole cohort, only 3 cases were suspected to have developed immune-associated thrombocytopenia (Table 1). All patients had taken vonoprazan for more than 2 weeks, and cases 1 and 3 underwent bone marrow aspiration showing primary immune thrombocytopenia (ITP)-like features. Vonoprazan was discontinued in all 3 cases, and steroids were given in 2 cases. In cases 1 and 2, platelet counts improved immediately and these were diagnosed as DITP. In the remaining case, platelet counts did not improve enough and this was therefore diagnosed as ITP. In cases 1 and 3, high-immature platelet fraction (IPF) and bone marrow examination showed ITP observations implying immunological mechanisms as the cause of thrombocytopenia. Case 2 was an outpatient, and examination of IPF and bone marrow was not performed. In this study, the probability of vonoprazan-induced thrombocytopenia was only 0.127% (2 cases out of 1577 cases). There were other causes for all other thrombocytopenia patients. Sixty-seven in the Helicobacter pylori eradication group had blood tests within 3 days after eradication, and 3 had platelets below 10/μl. Of the 3 patients, 2 had previously diagnosed ITP and 1 had liver cirrhosis. None were assumed to be induced by vonoprazan. Other than the Helicobacter pylori eradication group, 911 patients received blood tests before and after vonoprazan administration, and 69 patients had platelets below 10/μl. The causes for thrombocytopenia other than DITP and ITP were as follows: 21 were surgery, 17 were chemotherapy, 8 were liver cirrhosis or liver failure, 7 were terminal state, 4 were hematologic disease, 4 were infection, 3 were autoimmune disease, and 2 were bleeding. DITPinduced vonoprazan was very rare, but in 1 case, platelet decreased as low as 4000/μl and had possibility of fatal hemorrhage. Since none had vonoprazan-induced thrombocytopenia in the eradication group, thrombocytopenia may be induced when vonoprazan was administered for 2 weeks or longer. One case had 4 days of steroids, so common ITP cannot be excluded, but complete remission of ITP is rare in short terms of steroid hormone, suggesting that discontinuation of vonoprazan affected the results. Drug-induced thrombocytopenia is known to improve within 10 days by discontinuing the drug * Naruko Suzuki narukohattori@gmail.com