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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This correction notice from the Annals of Hematology addresses errors in the original article titled "Predictive significance of high neutrophil ratio for thrombosis in myeloproliferative neoplasms: JSH-MPN-R18 subanalysis." The correction notes that a portion of Supplementary Figure 1 was highlighted in red and Supplementary Figure 2 lacked figures. The original article has been corrected, and Springer Nature remains neutral regarding jurisdictional claims and affiliations. The correction was authored by a group of researchers listed at the end of the notice. [Extracted from the article]

Risk-adapted therapy is recommended to prevent thrombosis in essential thrombocythemia (ET) patients. An advanced age, a history of thrombosis, and the presence of the JAK2V617F mutation are well-defined risk factors for thrombosis in ET; however, the impact of cardiovascular risk (CVR) factors on thrombosis in ET remains elusive. Therefore, we herein investigated the impact of CVR factors on thrombosis in 580 ET patients who met the 2017 World Health Organization Classification diagnostic criteria. A univariate analysis identified hypertriglyceridemia and multiple CVR factors as strong risk factors for thrombosis (hazard ratio [HR] 3.530, 95% confidence interval [CI] 1.630–7.643, P = 0.001 and HR 3.368, 95% CI 1.284–8.833, P = 0.014, respectively) and hyper-LDL cholesterolemia as a potential risk factor (HR 2.191, 95% CI 0.966–4.971, P = 0.061). A multivariate analysis revealed that hypertriglyceridemia was an independent risk factor for thrombosis (HR 3.364, 95% CI 1.541–7.346, P = 0.002). Furthermore, poor thrombosis-free survival was observed in patients with a serum triglyceride level ≥ 1.2 mmol/L (HR = 2.592, P = 0.026 vs. < 1.2 mmol/L) or two or more CVR factors (P = 0.011 vs. no CVR factors and P = 0.005 vs. one CVR factor). These results revealed the impact of CVR factors on thrombosis in ET. Since CVR factors are manageable, lifestyle interventions, such as the control of serum triglyceride levels, may effectively prevent thrombosis in ET patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ropeginterferon alfa-2b is a novel, site-selective, monopegylated recombinant human interferon alfa-2b. Safety and efficacy of ropeginterferon alfa-2b for the treatment of polycythemia vera were demonstrated in clinical studies conducted in European countries, but clinical studies in Japanese patients are lacking. This phase 2, open-label, multicenter, single-arm study investigated the safety and efficacy of ropeginterferon alfa-2b in 29 Japanese patients with polycythemia vera including young patients and patients with low thrombosis risk who are difficult to receive guideline-based standard treatments. The primary outcome of durable complete hematologic response without phlebotomy at months 9 and 12 was achieved by 8/29 (27.6%) patients. The fastest complete hematologic response was observed at week 12. A corresponding reduction in the JAK2 V617F allele burden from baseline to 52 weeks was also observed (mean ± standard deviation = − 19.2% ± 22.6%). No new safety concerns were identified in Japanese patients when compared with previous studies of ropeginterferon alfa-2b in European populations; the most common treatment-related adverse events were alopecia (55.2%), fatigue (27.6%) and influenza-like illness (27.6%). Most treatment-related adverse events were mild or moderate, with none of grade ≥ 3. Ropeginterferon alfa-2b is a safe and efficacious treatment option in Japanese patients with polycythemia vera. [ABSTRACT FROM AUTHOR]

Polycythemia vera (PV) and essential thrombocythemia (ET) are the two most common subtypes of Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). PV results in erythrocytosis and ET in thrombocytosis. The discovery of JAK2 mutations in the majority of patients with MPN over the last 2 decades has led to the development of JAK inhibitors. Because PV and ET progress relatively slowly, the main treatment strategy for these two diseases is to prevent thrombotic complications. The first-line agent for both PV and ET is hydroxyurea, although some patients are intolerant or refractory to this compound and need other treatment options. Notably, hydroxyurea is contraindicated during pregnancy. In addition to JAK inhibitors, several new agents, such as HDAC inhibitors, LSD1 inhibitors, MDM2 inhibitors and hepcidin mimetics, have been developed as treatment options. Classical agents, such as busulfan and interferon, are still used to treat patients with PV or ET as well. Based on this context, treatment options and pregnancy management for patients with PV or ET are discussed in this review. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The WBC count (C), Hb value (D), platelet count (E), and LDH level (F) for the patients classified based on driver mutation status are shown. Finally, in the Results, under the subheading 'Noncanonical JAK2 and MPL mutant exhibits wild-type-equivalent levels of STAT5 activation', "One such patient was found to harbor MPL S204F in the abovementioned screening of noncanonical JAK2 and MPL mutations." now reads "One such patient was found to harbor MPL S204F." NC-JAK2/MPL: noncanonical JAK2 and MPL mutation. [Extracted from the article]

Ruxolitinib (RUX), a JAK1/2-inhibitor, is effective for myeloproliferative neoplasm (MPN) with both JAK2V617 F and calreticulin (CALR) mutations. However, many MPN patients develop resistance to RUX. Although mechanisms of RUX-resistance in cells with JAK2V617 F have already been characterized, those in cells with CALR mutations remain to be elucidated. In this study, we established RUX-resistant human cell lines with CALR mutations and characterized mechanisms of RUX-resistance. Here, we found that RUX-resistant cells had high levels of MPL transcripts, overexpression of both MPL and JAK2, and increased phosphorylation of JAK2 and STAT5. We also found that mature MPL proteins were more stable in RUX-resistant cells. Knockdown of MPL in RUX-resistant cells by shRNAs decreased JAK/STAT signaling. Immunoprecipitation assays showed that binding of mutant CALR to MPL was increased in RUX-resistant cells. Reduction of mutated CALR decreased proliferation of the resistant cells. When resistant cells were cultured in the absence of RUX, the RUX-resistance was reversed, with reduction of the mutant-CALR/MPL complex. In conclusion, MPL overexpression induces higher levels of a mutant-CALR/MPL complex, which may cause RUX-resistance in cells with CALR mutations. This mechanism may be a new therapeutic target to overcome RUX-resistance. [ABSTRACT FROM AUTHOR]

A subset of essential thrombocythemia (ET) cases are negative for disease-defining mutations on JAK2, MPL, and CALR and defined as triple negative (TN). The lack of recurrent mutations in TN-ET patients makes its pathogenesis ambiguous. Here, we screened 483 patients with suspected ET in a single institution, centrally reviewed bone marrow specimens, and identified 23 TN-ET patients. Analysis of clinical records revealed that TN-ET patients were mostly young female, without a history of thrombosis or progression to secondary myelofibrosis and leukemia. Sequencing analysis and human androgen receptor assays revealed that the majority of TN-ET patients exhibited polyclonal hematopoiesis, suggesting a possibility of reactive thrombocytosis in TN-ET. However, the serum levels of thrombopoietin (TPO) and interleukin-6 in TN-ET patients were not significantly different from those in ET patients with canonical mutations and healthy individuals. Rather, CD34-positive cells from TN-ET patients showed a capacity to form megakaryocytic colonies, even in the absence of TPO. No signs of thrombocytosis were observed before TN-ET development, denying the possibility of hereditary thrombocytosis in TN-ET. Overall, these findings indicate that TN-ET is a distinctive disease entity associated with polyclonal hematopoiesis and is paradoxically caused by hematopoietic stem cells harboring a capacity for cell-autonomous megakaryopoiesis. [ABSTRACT FROM AUTHOR]

Patients with primary myelofibrosis (PMF) have a poorer prognosis than those with other subtypes of myeloproliferative neoplasms (MPNs). To investigate the relationship between gene mutations and the prognosis of Japanese PMF patients, we analyzed mutations in 72 regions located in 14 MPN-relevant genes (CSF3R, MPL, JAK2, CALR, DNMT3A, TET2, EZH2, ASXL1, IDH1/2, SRSF2, SF3B1, U2AF1, and TP53) utilizing a target resequencing platform. In our cohort, ASXL1 mutations were more frequently detected in both overt and prefibrotic PMF patients than other mutations. The frequency of ASXL1 mutations was slightly higher among overt PMF patients than among prefibrotic PMF patients (44.6% vs 25.0%, FDR = 0.472). Decision tree classification algorithms revealed that ASXL1, EZH2, and SRSF2 mutations were associated with a poor prognosis for overt PMF. Overall survival was significantly shorter in patients harboring ASXL1, EZH2, or SRSF2 mutations than in those without these mutations (p = 0.03). These results suggest that, as reported in Western countries, MIPSS70 is applicable to Japanese PMF patients and ASXL1, EZH2, and SRSF2 mutations may be utilized as surrogate markers of a poor prognosis. [ABSTRACT FROM AUTHOR]

Essential thrombocythemia (ET) mainly affects the elderly, but can also develop in women of childbearing age. The risk of miscarriage and other complications during pregnancy in ET patients are reported to be higher than that compared to the general population. Therefore, management of pregnancy in ET patients requires special considerations. Several groups recommend interferon (IFN) therapy for ET patients with high-risk pregnancies, but currently no guidelines are available in Japan. We report the outcomes of nine ET patients with ten consecutive high-risk pregnancies. All patients were successfully managed with IFN-α during their pregnancies. All patients also received aspirin and switched to unfractionated heparin around 36 weeks of gestation. As for the seven pregnancies in which IFN-α was started after detection of pregnancy, median platelet counts decreased from 910 to 573 × 109/L after 2 months of IFN-α therapy, and median platelet counts at the time of delivery for all ten pregnancies was 361 × 109/L. All patients gave birth to healthy children. IFN-α was well tolerated, safe, and effective as a cytoreductive therapy for all patients. Although evidence is limited and the use of IFN is not approved in Japan, we suggest considering IFN therapy for high-risk ET pregnancies. [ABSTRACT FROM AUTHOR]

Pregnancy-associated primary red cell aplasia (pPRCA) is a rare disorder that may occur at various time points during pregnancy. Unlike pregnancy-associated aplastic anemia, pPRCA is usually reversible, and no maternal deaths attributable to pPRCA have been reported. Herein, we report a woman diagnosed with pPRCA in two consecutive pregnancies. Corticosteroids were found to be ineffective, and she required a large number of red blood cell transfusions during both pregnancies. Despite severe anemia developing in both pregnancies, two healthy babies were vaginally born and spontaneous remission of pPRCA was seen after delivery. Interestingly, in both events of pPRCA described here, a transient rise of reticulocytes was observed precedent to the authentic recovery phase of reticulocytes and remission of pPRCA, which is a novel finding that has not been reported. The significance of this phenomenon has yet to be elucidated. Along with this case report, we review all 15 cases with 21 events of pPRCA in the literature, including the present case. [ABSTRACT FROM AUTHOR]

Background: JAK2 V617F mutation increases the risk of thrombosis, and both ischemic and hemorrhagic strokes can occur in essential thrombocythemia (ET). The mechanisms underlying ischemic stroke in ET are diverse, and hemorrhagic stroke has rarely been reported in ET. Methods: Among 627 stroke patients, those identified as having ET were investigated retrospectively. A comprehensive systemic literature search of the PubMed database was also conducted. Results: Two cases were extracted with the diagnosis of ET who developed SAH and then ischemic stroke. In Case 1, a 47-year-old woman developed SAH in the left high convexity. Eleven hours later, acute cerebellar infarction suddenly developed due to right vertebral artery dissection. In Case 2, a 70-year-old woman developed SAH in the right high convexity. Magnetic resonance angiography showed multifocal stenotic changes in intracranial arteries. Three days later, she developed acute brain infarcts in the right middle cerebral artery territory. Eight weeks later, multifocal stenotic lesions improved. The literature review revealed 5 patients with hemorrhagic stroke and 40 patients with ischemic stroke associated with ET. Age at onset varied, female gender predominated, and the frequency of JAK2 V617F mutation was high. Atherosclerotic vascular risk factors were more common in ischemic stroke, but not in hemorrhagic stroke. Conclusions: The current study describes rare cases of SAH accompanied by ischemic stroke secondary to ET along with a review of the current literature, implying specific mechanisms for cerebral artery disorders associated with JAK2 V617F mutation. [ABSTRACT FROM AUTHOR]

The majority of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) harbor JAK2, CALR, or MPL mutations. We compared clinical manifestations of different subtypes of JAK2 and CALR mutations in Japanese patients with MPNs. Within our cohort, we diagnosed 166 patients as polycythemia vera (PV), 212 patients as essential thrombocythemia (ET), 23 patients as pre-primary myelofibrosis (PMF), 65 patients as overt PMF, and 27 patients as secondary myelofibrosis following the 2016 WHO criteria. Compared to patients with JAK2V617F-mutated PV, JAK2 exon 12-mutated PV patients were younger, showed lower white blood cell (WBC) counts, lower platelet counts, higher red blood cell counts, and higher frequency of thrombotic events. Compared to JAK2-mutated ET patients, CALR-mutated ET patients were younger, showed lower WBC counts, lower hemoglobin levels, higher platelet counts, and fewer thrombotic events. CALR type 1-like mutation was the dominant subtype in CALR-mutated overt PMF patients. Compared with JAK2V617F-mutated ET patients, JAK2V617F-mutated pre-PMF patients showed higher LDH levels, lower hemoglobin levels, higher JAK2V617F allele burden, and higher frequency of splenomegaly. In conclusion, Japanese patients with MPNs grouped by different mutation subtypes exhibit characteristics similar to those of their Western counterparts. In addition, ET and pre-PMF patients show different characteristics, even when restricted to JAK2V617F-mutated patients. [ABSTRACT FROM AUTHOR]

Early intracranial hemorrhage (eICH) is a potentially fatal complication of acute leukemia. We analyzed risk factors for eICH in patients with de novo acute leukemia. Ninety-one de novo acute leukemia patients at our institution between September 2003 and June 2014 were included. Of the 91 patients, eight (8.8 %) and 83 were included in the eICH and non-eICH groups, respectively. Univariate analysis demonstrated that white blood cell (WBC) count (P = 0.018), fibrin-fibrinogen degradation product (FDP) level (P = 0.0075), co-occurrence of WBC ≥50,000/µl and FDP level >40 µg/ml (P < 0.001), and fever (P = 0.248) were all significant predictors of eICH at the 0.25 level. In a subsequent multivariate analysis involving these parameters, only the combination of hyperleukocytosis and elevated FDP levels was found to be significant at the 0.05 level. A significant difference in the duration of the overall survival (OS) period was detected between patients that did and did not exhibit the combination of hyperleukocytosis and elevated FDP levels (P < 0.001). Co-occurrence of hyperleukocytosis and elevated FDP levels is a significant risk factor for eICH in patients with de novo acute leukemia and has a significant adverse affect on OS. [ABSTRACT FROM AUTHOR]

Patients diagnosed with polycythemia vera (PV) or essential thrombocythemia (ET) sometimes suffer transformation of the disease into myelofibrosis (MF), which is associated with a poorer prognosis. This study investigated the prognostic value of the allele burden of JAK2V617F, a somatic driver mutation in these diseases, by comparing the allele burden between formalin-fixed paraffin-embedded bone marrow collected at initial diagnosis and peripheral blood from follow-up visits. Although the annual changes in the JAK2V617F allele burden were comparable between MF-transformed ( n = 11) and untransformed ( n = 23) patients, the burden was significantly increased in MF-transformed patients exhibiting a longer disease duration than untransformed patients. Furthermore, MF transformation was only observed in patients whose JAK2V617F allele burden exceeded the mean values for each disease (PV, 71.7 %; ET, 35.5 %) at initial diagnosis or during follow-up. Finally, we showed that hydroxycarbamide treatment exerted neither a preventive effect on MF transformation nor a suppressive effect on the increased JAK2V617F allele burden. In conclusion, a high JAK2V617F allele burden at initial diagnosis or during follow-up is predictive of MF transformation in PV and ET. Therefore, routine measurement of the JAK2V617F allele burden using an accurate assay system is recommended to predict MF transformation. [ABSTRACT FROM AUTHOR]

JAK2V617F, a gain-of-function mutation in the tyrosine kinase JAK2, is frequently detected in classical myeloproliferative neoplasms (MPNs). In the present study, we determined the JAK2V617F allele burden in Japanese MPN patients using alternately binding probe competitive-polymerase chain reaction, a highly quantitative method recently developed by our group. Although we observed strong similarities in terms of epidemiological parameters associated with the JAK2V617F allele burden between our cohort and others, we found a higher JAK2V617F allele burden in Japanese polycythemia vera (PV) patients and lower frequencies of thrombosis in Japanese MPN patients compared with previous reports. In addition, despite the presence of high red blood cell counts, some patients bearing the JAK2V617F mutation were not diagnosed as PV, as their hemoglobin values were lower than the WHO PV criterion. In these patients, the JAK2V617F allele burden was strikingly similar to that in PV patients fulfilling the 2008 WHO criteria, suggesting that these patients can be classified as PV. Although isotopic measurement of red cell mass (RCM) is required for definitive diagnosis of PV, our data suggest that precise measurement of the JAK2V617F allele burden may improve the diagnosis of PV when RCM has not been determined. [ABSTRACT FROM AUTHOR]

Background: Acquired von Willebrand syndrome (aVWS) is a rare bleeding disorder with laboratory findings similar to those of congenital von Willebrand disease (VWD). Patients with aVWS may require prophylactic treatment to prevent excessive bleeding following surgery. To our knowledge, to date, there have been no reports on perioperative management for breast cancer patients with aVWS.Case presentation: A 60-year-old woman with breast cancer was diagnosed with aVWS due to polycythemia vera. Pre-operative laboratory testing showed a high platelet count and low von Willebrand factor (VWF) activity. The VWF activity did not improve despite an attempt to suppress platelet count with hydroxyurea. Therefore, we decided to perioperatively supplement with plasma-derived factor VIII (FVIII) containing von Willebrand factor (FVIII/VWF concentrates) to perform curative surgery for breast cancer safely. Consequently, the patient did not develop hemorrhage during/after surgery and was discharged on postoperative day 7, as planned, without problems.Conclusions: For a patient with aVWS, which carries a high risk of hemorrhage during the perioperative period, initiation of appropriate management like supplementation of FVIII/VWF concentrates might enable safe curative surgery for breast cancer, and collaboration with the hematology department is critical. [ABSTRACT FROM AUTHOR]