Whole-genome landscape of adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform-specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3'-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell-like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.

Calreticulin haploinsufficiency augments stem cell activity and is required for onset of myeloproliferative neoplasms in mice.

Mutations in JAK2, myeloproliferative leukemia virus (MPL), or calreticulin (CALR) occur in hematopoietic stem cells (HSCs) and are detected in more than 80% of patients with myeloproliferative neoplasms (MPNs). They are thought to play a driver role in MPN pathogenesis via autosomal activation of the JAK-STAT signaling cascade. Mutant CALR binds to MPL, activates downstream MPL signaling cascades, and induces essential thrombocythemia in mice. However, embryonic lethality of Calr-deficient mice precludes determination of a role for CALR in hematopoiesis. To clarify the role of CALR in normal hematopoiesis and MPN pathogenesis, we generated hematopoietic cell-specific Calr-deficient mice. CALR deficiency had little effect on the leukocyte count, hemoglobin levels, or platelet count in peripheral blood. However, Calr-deficient mice showed some hematopoietic properties of MPN, including decreased erythropoiesis and increased myeloid progenitor cells in the bone marrow and extramedullary hematopoiesis in the spleen. Transplantation experiments revealed that Calr haploinsufficiency promoted the self-renewal capacity of HSCs. We generated CALRdel52 mutant transgenic mice with Calr haploinsufficiency as a model that mimics human MPN patients and found that Calr haploinsufficiency restored the self-renewal capacity of HSCs damaged by CALR mutations. Only recipient mice transplanted with Lineage-Sca1+c-kit+ cells harboring both CALR mutation and Calr haploinsufficiency developed MPN in competitive conditions, showing that CALR haploinsufficiency was necessary for the onset of CALR-mutated MPNs.

Higher average chemotherapy dose intensity improves prognosis in patients with aggressive adult T-cell leukemia/lymphoma.

OBJECTIVE AND METHOD: Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma with poor prognosis. We retrospectively reviewed the medical records of 312 patients with aggressive ATL and analyzed the effect of chemotherapy dose intensity on prognosis in clinical practice. RESULT: As first-line therapy, 62 patients underwent best supportive care (BSC) or single-agent chemotherapy, and 235 underwent intensive chemotherapy. The median survival time (MST) was 0.58 years in the 312 total patients, and 0.13 years and 0.75 years in the BSC/single-agent chemotherapy group and intensive chemotherapy group, respectively. The median average relative dose intensity (ARDI) of patients who received intensive chemotherapy was 60%. We divided patients into 3 groups according to ARDI. Those in the top tertile of ARDI (ARDI ≥ 75%, n = 82) had better overall survival compared with those in the intermediate tertile (45% ≤ ARDI < 75%, n = 79) (P < .0001), with MSTs of 4.69 and 0.75 years, respectively. The occurrence of organ dysfunction and infectious complications was comparable between the two ARDI groups. CONCLUSION: Higher ARDI improves prognosis in patients with aggressive ATL in clinical practice.

TP53 and PTEN mutations were shared in concurrent germ cell tumor and acute megakaryoblastic leukemia.

BACKGROUND: The occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Due to its rarity, there have been only two reports of the concurrent cases undergoing detailed genetic analysis with whole-exome sequencing (WES), and the possible clonal relationship between the both tumors remained not fully elucidated. METHODS: We performed whole-exome sequencing analysis of mediastinal GCT and acute myeloid leukemia (AML) samples obtained from one young Japanese male adult patient with concurrent both tumors, and investigated the possible clonal relationship between them. RESULTS: Sixteen somatic mutations were detected in the mediastinal GCT sample and 18 somatic mutations in the AML sample. Mutations in nine genes, including TP53 and PTEN both known as tumor suppressor genes, were shared in both tumors. CONCLUSIONS: All in our case and in the previous two cases with concurrent mediastinal GCT and AML undergoing with whole-exome sequencing analysis, TP53 and PTEN mutations were commonly shared in both tumors. These data not only suggest that these tumors share a common founding clone, but also indicate that associated mediastinal GCT and AML harboring TP53 and PTEN mutations represent a unique biological entity.

Outcome of allogeneic hematopoietic cell transplantation in patients with adult T-cell leukemia.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell neoplasm, and the outcome of patients with ATL after chemotherapy is poor. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment modality for ATL, and four factors, namely, age > 50 years, male recipient, lack of complete remission at transplantation, and transplantation of cord blood, were previously shown to be associated with poor survival. We retrospectively analyzed the outcome of 21 patients with ATL who had undergone allo-HSCT at our hospital during a 3-year period. Of 21 patients, all had at least one of the above risk factors, and 18 had two or more. With a median follow-up of 19.7 months for living patients, the 1- and 2-year overall survival (OS) rates after transplantation were 34% and 27%, respectively. All relapse/progression events occurred within 1 year after allo-HSCT, and the cumulative incidence of relapse/progression at 1 year after allo-HSCT was 46.9%. The 100-day and 1-year nonrelapse mortality (NRM) rates were 19% and 42%, respectively. No significant difference in OS was observed between myeloablative and reduced-intensity conditioning regimens. The 3-year OS (27%) of ATL patients who received allo-HSCT and who had at least one adverse factor was somewhat poorer than the 3-year OS of 33% identified in a nationwide study of allo-HSCT in ATL patients in Japan. The high relapse/progression and NRM rates are major problems to be solved to achieve better outcome.

Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator.

Acquired mutations of JAK2 and TET2 are frequent in myeloproliferative neoplasms (MPNs). We examined the individual and cooperative effects of these mutations on MPN development. Recipients of JAK2V617F cells developed primary myelofibrosis-like features; the addition of loss of TET2 worsened this JAK2V617F-induced disease, causing prolonged leukocytosis, splenomegaly, extramedullary hematopoiesis, and modestly shorter survival. Double-mutant (JAK2V617F plus loss of TET2) myeloid cells were more likely to be in a proliferative state than JAK2V617F single-mutant myeloid cells. In a serial competitive transplantation assay, JAK2V617F cells resulted in decreased chimerism in the second recipients, which did not develop MPNs. In marked contrast, cooperation between JAK2V617F and loss of TET2 developed and maintained MPNs in the second recipients by compensating for impaired hematopoietic stem cell (HSC) functioning. In-vitro sequential colony formation assays also supported the observation that JAK2V617F did not maintain HSC functioning over the long-term, but concurrent loss of TET2 mutation restored it. Transcriptional profiling revealed that loss of TET2 affected the expression of many HSC signature genes. We conclude that loss of TET2 has two different roles in MPNs: disease accelerator and disease initiator and sustainer in combination with JAK2V617F.

Effects of mogamulizumab in adult T-cell leukemia/lymphoma in clinical practice.

OBJECTIVE: The efficacy of mogamulizumab in adult T-cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study. Compared with patients in clinical trials, however, most patients in real-life settings have demonstrated worse outcomes. METHOD: We retrospectively analyzed 96 patients with relapsed/refractory ATLL who received mogamulizumab treatment. RESULTS: Relapsed/refractory ATLL patients with a median age of 70 years received a median of five courses of mogamulizumab. Hematologic toxicity and skin rash were the most common adverse events, and both were manageable. Of 96 patients, 87 were evaluable for efficacy. The overall response rate was 36%, and the median progression-free survival (PFS) and overall survival (OS) from the start of mogamulizumab therapy were 1.8 and 4.0 months, respectively. Of the original 96 patients, only 25 fulfilled the inclusion criteria of the phase 2 study. Those who met the criteria demonstrated longer median PFS and OS durations of 2.7 and 8.5 months, respectively. The median OS from diagnosis in relapsed/refractory ATLL patients receiving mogamulizumab was 12 months, longer than the 5.8 months in a historical cohort without mogamulizumab. CONCLUSION: In clinical practice, mogamulizumab exhibited antitumor activity in patients with relapsed/refractory ATLL, with an acceptable toxicity profile. Mogamulizumab therapy improved the OS of ATLL patients.

Prevalence of chromosome 8p11.2 translocations and correlation with myeloid and lymphoid neoplasms associated with FGFR1 abnormalities in a consecutive cohort from nine institutions in Japan.

Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities (MLN-FGFR1 abnormalities) are rare hematologic malignancies associated with chromosome 8p11.2 abnormalities. Translocations of 8p11.2 were detected in 10 of 17,039 (0.06%) unique patient cytogenetic studies performed at nine institutions in Japan. No inversions or insertions of 8p11.2 were detected. Among the 10 patients with 8p11.2 translocations, three patients were diagnosed with MLN-FGFR1 abnormalities, which were confirmed by FISH analysis. Peripheral blood eosinophilia was observed in all three patients, and all progressed to AML or T-lymphoblastic lymphoma/leukemia. The prevalence of 8p11.2 translocations in clinical practice and the proportion of MLN-FGFR1 abnormalities in patients with 8p11.2 translocations in Japan were consistent with those in previous reports from Western countries.

Potentiated activation of VLA-4 and VLA-5 accelerates proplatelet-like formation.

Fibronectin (FN) plays important roles in the proliferation, differentiation, and maintenance of megakaryocytic-lineage cells through FN receptors. However, substantial role of FN receptors and their functional assignment in proplatelet-like formation (PPF) of megakaryocytes are not yet fully understood. Herein, we investigated the effects of FN receptors on PPF using the CHRF-288 human megakaryoblastic cell line, which expresses VLA-4 and VLA-5 as FN receptors. FN and phorbol 12-myristate 13-acetate (PMA) were essential for inducing PPF in CHRF-288 cells. Blocking experiments using anti-ß1-integrin monoclonal antibodies indicated that the adhesive interaction with FN via VLA-4 and VLA-5 were required for PPF. PPF induced by FN plus PMA was accelerated when CHRF-288 cells were enforced adhering to FN by TNIIIA2, a peptide derived from tenascin-C, which we recently found to induce ß1-integrin activation. Adhesion to FN enhanced PMA-stimulated activation of extracellular signal-regulated protein kinase 1 (ERK1)/2 and enforced adhesion to FN via VLA-4 and VLA-5 by TNIIIA2-accelerated activation of ERK1/2 with FN plus PMA. However, c-Jun amino-terminal kinase 1 (JNK1), p38, and phosphoinositide-3 kinase (PI3K)/Akt were not stimulated by FN plus PMA, even with TNIIIA2. Thus, the enhanced activation of ERK1/2 by FN, PMA plus TNIIIA2 was responsible for acceleration of PPF with FN plus PMA.

[Measures by local government--actions to take in dealing with heat stroke for firefighters].

This paper expresses educational viewpoints on preventing "heat stroke (hyperthermia)" for firefighters who are in charge of pre-hospital care such as "life saving and relieving the sick/wounded" considering how firefighters are liable to heat stroke and knowledge that is needed, based on example cases. It is essential to have knowledge and measures to prevent heat stroke considering its particularity not only to firefighters engaged in disaster relief activities but also to people with other occupation and sports.

Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma.

A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL.

CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). In addition to HTLV-1 bZIP factor (HBZ), a leukemogenic antisense transcript of HTLV-1, abnormalities of genes involved in TCR-NF-κB signaling, such as CARD11, are detected in about 90% of patients. Utilizing mice expressing CD4+ T cell-specific CARD11(E626K) and/or CD4+ T cell-specific HBZ, namely CARD11(E626K)CD4-Cre mice, HBZ transgenic (Tg) mice, and CARD11(E626K)CD4-Cre;HBZ Tg double transgenic mice, we clarify these genes' pathogenetic effects. CARD11(E626K)CD4-Cre and HBZ Tg mice exhibit lymphocytic invasion to many organs, including the lungs, and double transgenic mice develop lymphoproliferative disease and increase CD4+ T cells in vivo. CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.

[BLS in adults].

This manuscript expresses viewpoints on future pre-hospital care, mainly focusing on basic life support (BLS) by ambulance crew at emergency scenes, following recommendations of G2010. Ambulance workers need to have an ability to decide instantly "what you can do now to others" in every emergency scenes. Also it is necessary to always treat patients with the spirit of "generosity".

Relationship between CYP3A5 Polymorphism and Tacrolimus Blood Concentration Changes in Allogeneic Hematopoietic Stem Cell Transplant Recipients during Continuous Infusion.

A polymorphism in the gene encoding the metabolic enzyme cytochrome P450 family 3 subfamily A member 5 (CYP3A5) is a particularly influential factor in the use of tacrolimus in Japanese patients. Those who are homozygotic for the *3 mutation lack CYP3A5 activity, which results in substantial individual differences in tacrolimus metabolism. The aim of this study was to analyze the relationship between individual differences in tacrolimus blood concentration changes and CYP3A5 polymorphisms in allogeneic hematopoietic stem cell transplantation recipients during the period of increasing blood concentration of the drug following treatment onset. This was a prospective observational cohort study, involving 20 patients administered tacrolimus by continuous infusion. The subjects were divided into the *1/*3 and *3/*3 groups based on CYP3A5 polymorphism analysis. The tacrolimus blood concentration/dose (C/D) ratio increased from day 1 and was largely stable on day 5, and a significant difference was observed between the *1/*3 and *3/*3 groups in the time course of the C/D ratio during this period (p < 0.05). This study reveals the effects of CYP3A5 polymorphism on continuous changes in tacrolimus blood concentration.

Neoplastic fibrocytes play an essential role in bone marrow fibrosis in Jak2V617F-induced primary myelofibrosis mice.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by clonal myeloproliferation, progressive bone marrow (BM) fibrosis, splenomegaly, and anemia. BM fibrosis was previously thought to be a reactive phenomenon induced by mesenchymal stromal cells that are stimulated by the overproduction of cytokines such as transforming growth factor (TGF)-ß1. However, the involvement of neoplastic fibrocytes in BM fibrosis was recently reported. In this study, we showed that the vast majority of collagen- and fibronectin-producing cells in the BM and spleens of Jak2V617F-induced myelofibrosis (MF) mice were fibrocytes derived from neoplastic hematopoietic cells. Neoplastic monocyte depletion eliminated collagen- and fibronectin-producing fibrocytes in BM and spleen, and ameliorated most characteristic MF features in Jak2V617F transgenic mice, including BM fibrosis, anemia, and splenomegaly, while had little effect on the elevated numbers of megakaryocytes and stem cells in BM, and leukothrombocytosis in peripheral blood. TGF-ß1, which was produced by hematopoietic cells including fibrocytes, promoted the differentiation of neoplastic monocytes to fibrocytes, and elevated plasma TGF-ß1 levels were normalized by monocyte depletion. Collectively, our data suggest that neoplastic fibrocytes are the major contributor to BM fibrosis in PMF, and TGF-ß1 is required for their differentiation.

Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1.

Premalignant clonal expansion of human T-cell leukemia virus type-1 (HTLV-1)-infected cells occurs before viral carcinogenesis. Here we characterize premalignant cells and the multicellular ecosystem in HTLV-1 infection with and without adult T-cell leukemia/lymphoma (ATL) by genome sequencing and single-cell simultaneous transcriptome and T/B-cell receptor sequencing with surface protein analysis. We distinguish malignant phenotypes caused by HTLV-1 infection and leukemogenesis and dissect clonal evolution of malignant cells with different clinical behavior. Within HTLV-1-infected cells, a regulatory T-cell phenotype associates with premalignant clonal expansion. We also delineate differences between virus- and tumor-related changes in the nonmalignant hematopoietic pool, including tumor-specific myeloid propagation. In a newly generated conditional knockout mouse model recapitulating T-cell-restricted CD274 (encoding PD-L1) gene lesions found in ATL, we demonstrate that PD-L1 overexpressed by T cells is transferred to surrounding cells, leading to their PD-L1 upregulation. Our findings provide insights into clonal evolution and immune landscape of multistep virus carcinogenesis. SIGNIFICANCE: Our multimodal single-cell analyses comprehensively dissect the cellular and molecular alterations of the peripheral blood in HTLV-1 infection, with and without progression to leukemia. This study not only sheds light on premalignant clonal expansion in viral carcinogenesis, but also helps to devise novel diagnostic and therapeutic strategies for HTLV-1-related disorders.

Real-World Data on Clinical Features, Outcomes, and Prognostic Factors in Multiple Myeloma from Miyazaki Prefecture, Japan.

The prognosis of multiple myeloma (MM) has improved with the introduction of novel agents. These data are largely derived from clinical trials and might not reflect real-world patient outcomes accurately. We surveyed real-world data from 284 patients newly diagnosed with MM between 2010 and 2018 in Miyazaki Prefecture. The median follow-up period was 32.8 months. The median age at diagnosis was 71 years, with 68% of patients aged >65 years. The International Staging System (ISS) stage at diagnosis was I in 18.4% of patients, II in 34.1%, and III in 47.5%. Bortezomib-containing regimens were preferred as initial treatment; they were used in 147 patients (51.8%). In total, 80% of patients were treated with one or more novel agents (thalidomide, lenalidomide, or bortezomib). Among 228 patients who were treated with novel agents as an initial treatment, the overall response rate (partial response (PR) or better) to initial treatment was 78.4%, and the median time to next treatment (TTNT) was 11.6 months. In the multivariate analysis, PR or better responses to initial treatment were independently favorable prognostic factors for TTNT. The median survival time after initial therapy for patients with novel agents was 56.4 months and 3-year overall survival (OS) was 70.4%. In multivariate analysis, ISS stage I/II disease and PR or better response to initial treatment, and autologous stem cell transplantation (ASCT) were identified as independent prognostic factors for overall survival (OS).

Mice with Calr mutations homologous to human CALR mutations only exhibit mild thrombocytosis.

Calreticulin (CALR) exon 9 frameshift mutations, commonly detected in essential thrombocythemia (ET) and primary myelofibrosis patients, activate signal transducer and activator of transcription (STAT) proteins in the presence of Myeloproliferative Leukemia Virus (MPL) and induce ET in vivo. Loss of the KDEL motif, an endoplasmic reticulum retention signal, and generation of many positively charged amino acids (AAs) in the mutated C-terminus are thought to be important for disease induction. To test this hypothesis, we generated mice harboring a Calr frameshift mutation using the CRISPR/Cas9 system. Deletion of 19-base pairs in exon 9 (c.1099-1117del), designated the del19 mutation, induced loss of the KDEL motif and generated many positively charged AAs, similar to human mutants. Calr del19 mice exhibited mild thrombocytosis, slightly increased megakaryocytes, and mild splenomegaly. In vitro experiments revealed that the murine CALR del19 mutant had a weaker ability to combine with murine MPL than the human CALR del52 mutant. Consequently, STAT5 activation was also very weak downstream of the murine mutant and murine MPL, and may be the reason for the mild disease severity. In summary, loss of the KDEL motif and positively charged AAs in the C-terminus of CALR is insufficient for MPL binding and ET development.

Early/prefibrotic primary myelofibrosis in patients who were initially diagnosed with essential thrombocythemia.

A new entity, namely early/prefibrotic primary myelofibrosis (PMF), was introduced as a subtype of PMF in the 2016 revised World Health Organization (WHO) criteria for myeloproliferative neoplasms (MPN). It was diagnosed based on histopathological features of bone marrow (BM) biopsy specimens together with clinical parameters [leukocytosis, anemia, elevated lactate dehydrogenase (LDH) values, and splenomegaly]. The aim of this study was to evaluate the prevalence of early/prefibrotic PMF in patients who were previously diagnosed with ET, and to compare clinical features at diagnosis and outcomes between early/prefibrotic PMF and essential thrombocythemia (ET) patients. BM biopsy samples obtained at the time of ET diagnosis were available in 42 patients. Sample reevaluation according to the 2016 revised WHO criteria revealed that early/prefibrotic PMF accounted for 14% of patients who were previously diagnosed with ET, which was comparable to the rates in previous reports. Compared to patients with ET, patients with early/prefibrotic PMF had higher LDH values and higher frequencies of splenomegaly. Overall, myelofibrosis-free and acute myeloid leukemia-free survivals were comparable between the 2 groups. Accurate diagnosis is required to clarify the clinical features of Japanese ET patients.

Thrombohemorrhagic events, disease progression, and survival in polycythemia vera and essential thrombocythemia: a retrospective survey in Miyazaki prefecture, Japan.

Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with life-threatening thrombohemorrhagic events, and disease progression and development of non-hematological malignancies also reduce long-term survival. We retrospectively surveyed thrombohemorrhagic events and overall survival (OS) in 62 PV and 117 ET patients. The cumulative incidences of thrombohemorrhagic events in PV and ET patients were 11.3 and 10.3%, and the incidence rates were 2.42 and 1.85 per 100 person-years. The combined incidence rates of disease progression and development of non-hematological malignancies in PV and ET patients were 1.73 and 1.69 per 100 person-years. The incidence rates of thrombohemorrhagic events in our Japanese PV/ET patients were lower than those reported by most Western studies, but were comparable to those in the largest prospective observational study in ET patients. The combined incidence rates of disease progression and development of non-hematological malignancies were similar between Japanese and Western PV/ET patients. In ET patients, the conventional risk stratification model based on the presence of advanced age or history of thrombosis was useful to predict thrombosis risk, and both the conventional model and the International Prognostic Score of thrombosis in ET based on the above 2 risk factors plus increased leukocyte count could predict poor survival.