Predictive significance of high neutrophil ratio for thrombosis in myeloproliferative neoplasms: JSH-MPN-R18 subanalysis.

Thrombosis in myeloproliferative neoplasms (MPNs) is an important clinical problem, and risk-stratified management is essential. To identify the clinical characteristics of thrombosis in patients with MPNs, a nationwide multi-institutional retrospective analysis (JSH-MPN-R18) was conducted. The aim of the present study was to perform a sub-analysis of JSH-MPN-R18 findings to clarify the predictive parameters for thrombosis among complete blood count (CBC) results. Among the patients enrolled in JSH-MPN-R18, those with essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456) were investigated. We analyzed and compared CBC parameters between patients with and those without any thrombotic events using Welch's T-test. Statistical analyses were performed using the R statistical software. Thrombotic events were observed in 74 patients with ET. In multivariate analysis, only the neutrophil ratio was slightly but significantly higher for ET patients with thrombosis than for those without (p < 0.05). Of note, the absolute neutrophil count (aNeu) was considered a useful predictive tool for thrombosis among patients classified as low-risk according to the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia. Among PV patients, those with thrombosis showed significantly higher hematocrit and aNeu than did those without thrombosis. As a thrombosis-associated factor, the neutrophil ratio was slightly but significantly elevated in patients with ET. This myeloid skew might reflect a higher value of JAK2 V617F allelic frequency in patients with ET with thrombosis; this was not clarified in JSH-MPN-R18. Further accumulation of evidence, including genetic information for JAK2 and other passenger mutations, is warranted.

Real-world status of treatment for lymphoid neoplasms developed during the course of myeloproliferative neoplasms in Japan.

OBJECTIVES: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. METHODS: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. RESULTS: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. CONCLUSION: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

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.

High incidence of disseminated intravascular coagulation and acute cerebral infarction in acute myeloid leukemia with cup-like nuclei.

In this study, we examined a cohort of Japanese patients with acute myeloid leukemia (AML) with cup-like nuclei. In particular, we attempted to provide a detailed definition of the clinical features of AML with cup-like nuclei. The clinical records of patients diagnosed with de novo AML were collected retrospectively. We showed that approximately 23% of all patients with AML diagnosed during the study period had AML with cup-like nuclei. All three cup-like AML cases had FLT3-ITD mutations. In addition, we reported a high incidence of disseminated intravascular coagulation and acute cerebral infarction in patients with AML with cup-like nuclei. Our results show that AML with cup-like nuclei may be more common than expected. Due to these unique characteristics, recognition of this morphology is recommended.

Development of Acute Adult T-cell Leukemia Following PD-1 Blockade Therapy for Lung Cancer.

Immune checkpoint inhibitors (ICIs) are widely used for the treatment of various cancers. However, paradoxical exacerbation of neoplasms, referred to as "hyperprogressive disease," has been reported in a proportion of patients treated with anti-programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) blockade. We herein report a case of acute adult T-cell leukemia (ATL) that developed shortly after the administration of nivolumab, a PD-1 inhibitor, to treat non-small-cell lung cancer. There were no signs of ATL before the administration of nivolumab, and seropositivity for human T-cell leukemia virus type-1 (HTLV-1) was confirmed after the development of acute ATL. We speculate that nivolumab likely contributed to the development of acute ATL.

Adult paroxysmal cold hemoglobinuria following mRNA COVID-19 vaccination.

Paroxysmal cold hemoglobinuria (PCH) is an extremely rare subtype of autoimmune hemolytic anemia (AIHA) in adults. PCH is caused by the biphasic Donath-Landsteiner (DL) antibody which fixes complement to red blood cells at low temperatures and dissociates at warmer temperatures, leading to complement-mediated intravascular hemolysis. Autoimmune hematological disorders including AIHA and immune thrombocytopenia have been reported to develop following the mRNA COVID-19 vaccination. However, PCH developing subsequent to mRNA vaccination has never been reported. We report a 59-year-old male who developed PCH approximately a month after his second mRNA COVID-19 vaccination.

Clinical characteristics of Japanese patients with polycythemia vera: results of the JSH-MPN-R18 study.

The presence of a JAK2 V617F or JAK2 exon 12 mutation is one of the three major criteria listed for the diagnosis of polycythemia vera (PV) in the 2017 World Health Organization Classification. However, a nationwide study has not yet been conducted in Japan since the discovery of JAK2 mutations. Therefore, the Japanese Society of Hematology (JSH) retrospectively analyzed the clinical characteristics of 596 Japanese patients with PV diagnosed between April 2005 and March 2018. Among the 473 patients with complete data on JAK2 mutations available, 446 (94.3%) and 10 (2.1%) were positive for the JAK2 V617F and JAK2 exon 12 mutations, respectively. During a median follow-up of 46 months (range: 0-179 months), 47 (7.9%) deaths occurred. The major causes of death were secondary malignancies (23.4%), acute leukemia (12.8%), non-leukemic progressive disease (10.6%) and thrombotic (6.4%) and hemorrhagic complications (6.4%). Thrombotic and hemorrhagic events occurred during the clinical course in 4.0% (n = 24) and 3.5% (n = 21) of patients, respectively. These results show that the international PV prognostic score (age, venous thrombosis and leukocytosis) is applicable to Japanese patients with PV.

A pilot study examining the efficacy of hochuekkito for improving quality of life in patients with myeloproliferative neoplasms.

BACKGROUND: The prognosis of Philadelphia chromosome-negative myeloproliferative neoplasms is relatively favorable, but the quality of life can be severely affected by myeloproliferative neoplasm-related symptoms such as fatigue, pruritus, night sweats, bone pain, fever and weight loss. In this study, we administered hochuekkito, a traditional herbal medicine, to patients with myeloproliferative neoplasms and investigated whether there was a reduction in myeloproliferative neoplasm-related symptoms. METHODS: We conducted a randomized parallel-group pilot study. Patients were assigned to a hochuekkito administration or non-hochuekkito administration group. Myeloproliferative neoplasm-related symptoms based on Myeloproliferative Neoplasm Symptom Assessment Form total symptom score and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 were examined before hochuekkito administration and 4 and 8 weeks after administration. RESULTS: Among the 42 patients included in the analysis, 21 were assigned to the hochuekkito group and 21 were assigned to the control group. After administering hochuekkito, the median values of Myeloproliferative Neoplasms Symptom Assessment Form total symptom score at 4 and 8 weeks in the hochuekkito group demonstrated a decreasing trend; however, the difference between the two groups was not significant. CONCLUSIONS: In this study, we were unable to demonstrate significant differences between the hochuekkito and control groups in terms of the efficacy of hochuekkito in treating myeloproliferative neoplasm-related symptoms. However, there were cases that presented prominent improvement in symptoms in the hochuekkito group. The only reported adverse event was grade 1 impaired hepatic function. Therefore, hochuekkito might be a therapeutic option for patients with severely affected quality of life due to myeloproliferative neoplasm-related symptoms.

[Systemic chemotherapy combined with thrombopoietin receptor agonist for the treatment of diffuse large B-cell lymphoma complicated with aplastic anemia].

Immunosuppressive therapies, including antithymocyte globulin and cyclosporine (CsA), are used for the treatment of aplastic anemia, but they reportedly cause lymphoproliferative diseases. Here, we report two cases of aplastic anemia in which diffuse large B-cell lymphoma developed during treatment with CsA. In both the cases, CsA was discontinued and combination therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisolone) plus the thrombopoietin receptor agonist eltrombopag was initiated. Furthermore, supportive care, including blood transfusion and granulocyte colony-stimulating factor, was provided. After six or eight courses of R-CHOP therapy, a complete metabolic response was achieved without serious adverse events. These cases illustrate the safety of combining R-CHOP with eltrombopag therapy in patients at a high risk of severe pancytopenia.

Clinical characteristics, prognostic factors, and outcomes of patients with essential thrombocythemia in Japan: the JSH-MPN-R18 study.

We conducted a large-scale, nationwide retrospective study of Japanese patients who were diagnosed with essential thrombocythemia based on the diagnostic criteria in the World Health Organization classification. We investigated clinical characteristics, survival rates, and the incidence of thrombohemorrhagic events as well as risk factors for these events. A total of 1152 patients were analyzed in the present study. Median age at diagnosis was 65 years, the median platelet count was 832 × 109/L, and the positive mutation rates of JAK2V617F, CALR, and MPL were 62.8, 25.1, and 4.1%, respectively. Compared with European and American patients, Japanese patients were more likely to have cardiovascular risk factors and less likely to have systemic symptoms including palpable splenomegaly. Thrombocytosis was identified as a risk factor for hemorrhagic events and prognosis, but not for thrombotic events. The prognostic factors and risk classifications reported in Europe and the United States were generally applicable to Japanese patients. Regarding transformations, secondary myelofibrosis progressed in a time-dependent manner, but progression to acute leukemia was low in "true" ET patients. Skin cancers were less common and gastrointestinal cancers more common as secondary malignancies in Japanese patients, suggesting ethnic differences.

Two autopsy cases of pulmonary leukemic infiltration mimicking severe pneumonia in patients with acute myeloid leukemia.

Although a previous autopsy series demonstrated that pulmonary leukemic infiltration (PLI) is a major pulmonary complication in patients with acute myeloid leukemia (AML), an antemortem diagnosis of PLI is rare. Diverse pulmonary complications cause acute respiratory failure (ARF) in patients with AML undergoing chemotherapy. This article reports two elderly patients with AML who presented with ARF due to PLI mimicking severe pneumonia during induction chemotherapy. Accurate antemortem diagnosis of PLI was almost impossible without pathological examination since the clinical course was not typical of PLI. We recommend considering PLI in patients with AML who have an unknown etiology of ARF.

Primary Skeletal Muscle Peripheral T-cell Lymphoma: An Autopsy Case Report and Review of the Literature.

Primary skeletal muscle lymphoma is extremely uncommon, and there have only been eight previous case reports on primary skeletal muscle peripheral T-cell lymphoma, not otherwise specified (PSM-PTCL, NOS). We herein report an autopsy case of a 71-year-old woman with PSM-PTCL, NOS, who had a 24-year history of systemic sclerosis treated with immunosuppressive drugs. A post-mortem examination revealed infiltration of lymphoma cells positive for T-cell markers, cytotoxic markers, and p53. This case was considered to be one of other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD). This is the first case categorized under both PSM-PTCL, NOS, and OIIA-LPD.

Hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus-positive diffuse large B-cell lymphoma, NOS of bone marrow-liver-spleen type: an autopsy case report.

Lymphoma-associated hemophagocytic lymphohistiocytosis (HLH) has a significantly poor prognosis among secondary HLH. We describe the rare case of a 74-year-old female with secondary HLH presenting with a rapidly fatal course. Post-mortem examination revealed Epstein-Barr virus (EBV) -positive diffuse large B-cell lymphoma (DLBCL). We were unable to make a definite antemortem diagnosis because the patient did not exhibit lymphadenopathy and bone marrow biopsy demonstrated hemophagocytosis without evidence of lymphoma. She died of multiple organ failure on the twelfth day of hospitalization despite a temporary response to steroids. Autopsy revealed diffuse lymphoma cell infiltration of the bone marrow, liver and spleen, suggesting "bone marrow-liver-spleen" (BLS)-type large B-cell lymphoma (LBCL). BLS-type LBCL is a rare and clinically aggressive lymphoma, usually associated with fever, cytopenia and HLH. The disease has a high mortality rate due to the delay in diagnosis and a highly aggressive clinical course. Further studies are required to improve our understanding of this rare extranodal DLBCL.

[Microgranular-type acute promyelocytic leukemia with weak myeloperoxidase staining: difficulty of morphological diagnosis].

The 2017 World Health Organization (WHO) classification states that acute promyelocytic leukemia (APL) always presents with strong myeloperoxidase staining. However, we herein report of a 40-year-old woman with the microgranular variant of acute promyelocytic leukemia presenting with weak myeloperoxidase (MPO) staining. The leukemic cells were morphologically similar to monocytic cells, showing distorted-shaped nuclei and weak MPO staining. However, flow cytometry revealed positivity of CD2, CD34, and human leucocyte antigen-DR (HLA-DR) and pointed toward a diagnosis of APL. PML-RARA mRNA detection finally led the patient to a definitive diagnosis. The patient achieved complete remission by induction chemotherapy including tretinoin, cytarabine and idarubicin, and no differentiation syndrome was observed.

[Rapidly fatal streptococcal toxic shock syndrome due to Streptococcus agalactiae in a patient with chronic myeloid leukemia and cirrhosis].

A 72-year-old woman with chronic myeloid leukemia (CML) and cirrhosis complicated with blood blisters on her right upper arm and ascites was admitted. She presented with shock vital on admission. Initial gram staining of blood cultures showed gram-positive cocci in chains, suggesting streptococcal toxic shock syndrome (STSS). Amputation of the right upper arm was performed owing to necrotizing fasciitis. Despite continued antibiotic therapy and systemic management, the blood blisters rapidly spread to the skin of the whole body, and she died 41 h after admission. Blood and fluid cultures from the blisters showed group B streptococci. Reports of patients with leukemia complicated with STSS are rare, and all cases have followed fatal courses. Particularly in this case, various risk factors, such as neutropenia due to tyrosine kinase inhibitor, neutrophil dysfunction due to cirrhosis, and elderly CML, overlapped. In the future, we believe that the lives of patients with leukemia complicated with STSS may be saved by establishing treatment methods and determining the detailed pathogenesis of STSS.

Dasatinib-induced anti-leukemia cellular immunity through a novel subset of CD57 positive helper/cytotoxic CD4 T cells in chronic myelogenous leukemia patients.

Dasatinib induces lymphocytosis of large granular lymphocytes (LGLs) in a proportion of patients with chronic myelogenous leukemia (CML), and is associated with better clinical outcomes. LGLs consist of cytotoxic T lymphocytes and natural killer cells; however, the context and phenotypic/functional features of each type of LGL are unknown. To better define features of these LGLs, we investigated lymphocytosis in CML patients treated with dasatinib. D57-positive and CD4-positive type I T-helper (Th) cells (CD57+ Th cells) rarely occur in CML patients without lymphocytosis and in healthy individuals; however, a substantial increase in the proportion of CD57+ Th cells was observed in CML patients treated with dasatinib. In addition, these cells showed appreciable levels of cytocidal activity via cytotoxic degranulation. Analysis of T-cell receptor α and ß sequences showed a skewed T-cell repertoire in the CD57+ Th cells. Furthermore, patients with LGLs and CD57+ Th lymphocytosis achieved stronger molecular responses than did those without lymphocytosis. While further studies are warranted, our observations suggest that dasatinib induces the expansion of CD57+ Th-LGLs, which may play a crucial role in the dasatinib-induced response against Philadelphia chromosome-positive leukemia.

A phase 3b, multicenter, open-label extension study of the long-term safety of anagrelide in Japanese adults with essential thrombocythemia.

Cytoreductive therapy is used in high-risk essential thrombocythemia (ET) to reduce risk of thrombohemorrhagic complications. Anagrelide is an orally active, quinazolone-derived platelet-lowering agent approved for first-line treatment of high-risk ET in Japan. Long-term safety and efficacy data were collected from 53 Japanese high-risk ET patients (Study 308); 41 patients who completed Study 308 entered this phase 3b, open-label extension (Study 309; NCT01467661). Reductions in mean platelet counts occurred throughout the study, from 1021.6 × 109/L (at Study 308 baseline) to 675.4 × 109/L at final assessment. At month 48 (since Study 308 enrollment), mean platelet count was 444.5 × 109/L in the 10 patients who completed 4 years of therapy. Overall, platelet counts decreased from 1088.3 × 109/L at Study 308 baseline (n = 33) to 473.5 × 109/L at final assessment (n = 31). Long-term platelet count reductions were maintained without marked changes in mean anagrelide dose. Anagrelide was generally well tolerated, with anemia (54.7%) and headache (49.1%) as the most frequent adverse events. These findings indicate that anagrelide effectively reduces platelet counts in high-risk Japanese ET patients, with titration resulting in a well-tolerated, effective and sustainable dose. In conclusion, these results support anagrelide administration to high-risk Japanese ET patients using individualized dosing strategies defined in instructions previously approved in Europe and the USA.

[A novel quantitative JAK2V617F detection kit: prospective clinical performance study comparing MPN patients and healthy subjects].

The JAK2V617F mutation is the commonest major genetic mutation of myeloproliferative neoplasms (MPNs) and has been defined in the WHO diagnostic criteria for MPNs. However, there is still no approved in vitro diagnostic test kit available in Japan. We evaluated a JAK2V617F allele quantification kit (test method) in a prospective, multicenter clinical performance study involving patients with MPNs who were diagnosed with polycythemia vera, essential thrombocythemia, and primary myelofibrosis; healthy volunteers were also included in the analysis. Good correlation was observed between the allele burden determined using the test method vs. that determined using next-generation sequencing (NGS) in the patient group (r=0.998, y=1.071x-0.069; n=156). Furthermore, all allele burdens in the healthy group (n=54) were below the lower limit of the measurement range of the test method (0.042%). Our results confirmed that the test method could quantitatively measure the JAK2V617F allele burden in patients with MPN. Thus, the novel JAK2V617F allele quantification kit can be considered useful for the diagnosis of MPNs.