Search

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. [ABSTRACT FROM AUTHOR]

Objectives: Hemorrhagic events are a rare but potentially fatal complication in patients with polycythemia vera (PV). Methods: We analyzed the characteristics of hemorrhagic events in 267 patients with PV. Results: A median follow-up of 4.8 years revealed that 23 (8.6%) hemorrhagic events occurred. Significantly more hemorrhagic events occurred in younger patients aged below 60 years (n = 72) than in older patients aged 60 years or above (n = 191) (n = 12 [16.7%] vs. n = 11 [5.8%], respectively, P = 0.012). In univariate analysis among the younger patients, white blood cell (WBC) count ≥ 15 × 109/L (hazard ratio [HR] = 7.746, 95% confidence interval [CI] 2.082-28.830, P = 0.002), palpable splenomegaly (HR = 5.629, 95% CI 1.193–26.550, P = 0.029), and JAK2V617F allele burden ≥ 80% (HR = 22.850, 95% CI 2.885–181.00, P = 0.003) were associated with an increased risk of hemorrhagic events. In multivariate analysis, JAK2V617F allele burden ≥ 80% (HR = 9.394, 95% CI 1.046–84.380, P = 0.046) was a significant risk factor. Conclusions: There is an increased risk of hemorrhagic events after diagnosis in younger PV patients with a high JAK2V617F allele burden, high WBC count or palpable splenomegaly. It is important to consider treatment options that aim to avoid hemorrhagic events by reducing the JAK2V617F allele burden in younger PV patients. Plain language summary: Polycythemia vera (PV) is a subtype of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) that results in the overproduction of red blood cells (RBCs) due to persistent activation of the JAK2-STAT5 pathway caused by mutations in the Janus kinase 2 (JAK2) gene. Complications associated with elevated RBC counts include thrombosis, hemorrhage, and microvascular symptoms (such as headache and erythromelalgia) due to microcirculatory insufficiency, resulting in reduced quality of life. Hemorrhagic events are a rare but potentially fatal complication in patients with PV. However, specific risk factors for hemorrhagic events in PV remain to be elucidated. In this study, we sought to analyze the association between clinical characteristics and hemorrhagic events in 267 patients with PV in order to clarify the characteristics of these events. We found that patients with PV younger than 60 years, those with a high JAK2V617F allele burden (≥ 80%) (hazard ratio [HR] = 22.850, 95% confidence interval [CI] 2.885–181.000, P = 0.003), a higher white blood cell (WBC) count (WBC ≥ 15 × 109/L) (HR = 7.746, 95% CI 2.082–28.830, P = 0.002)or palpable splenomegaly (HR = 5.629, 95% CI 1.193–26.550, P = 0.029) at diagnosis may be at an increased risk of hemorrhagic events after diagnosis. Based on these observations, it would be important to consider the potential benefits of drug therapies aimed at reducing the JAK2V617F allele burden in younger patients with PV. Here, we suggest that these therapies may help to reduce the incidence of hemorrhagic events. [ABSTRACT FROM AUTHOR]

Summary: Risk‐adapted therapy is recommended to prevent major clinical complications, such as thrombo‐haemorrhagic events, in patients with essential thrombocythaemia (ET). In this study, we analysed the association between non‐driver gene mutations and thrombo‐haemorrhagic events in 579 patients with ET. ASXL1 and TP53 mutations were frequently identified in patients with ET complicated by thrombosis (22.7% and 23.1%, respectively), and the DNMT3A mutation was frequently identified in patients who experienced haemorrhage (15.2%). Multivariate analyses of thrombosis‐free survival (TFS) revealed that ASXL1 and TP53 mutations are associated with thrombosis (hazard ratio [HR] = 3.140 and 3.752 respectively). Patients harbouring the ASXL1 or TP53 mutation had significantly worse TFS rates than those without mutation (p = 0.002 and p < 0.001 respectively). Furthermore, JAK2V617F‐mutated patients with accompanying ASXL1 mutations showed significantly shorter TFS compared with those without ASXL1 mutations (p = 0.003). Multivariate analyses of haemorrhage‐free survival (HFS) revealed that the DNMT3A mutation (HR = 2.784) is associated with haemorrhage. DNMT3A‐mutated patients showed significantly shorter HFS than those without the mutation (p = 0.026). Non‐driver gene mutations should be considered in treatment strategies and may provide important information for personalised treatment approaches. [ABSTRACT FROM AUTHOR]

Since MPL mutation is a rare driver gene mutation found in a small number of essential thrombocythemia (ET) patients, the clinical characteristics of patients with MPL mutations and their association with thrombotic events have not yet been elucidated in Japan. We enrolled 579 Japanese ET patients based on the diagnostic criteria of the WHO classification 2017 and compared clinical characteristics of MPL-mutated patients (n = 22; 3.8%) to JAK2V617F-mutated (n = 299; 51.6%), CALR-mutated (n = 144; 24.9%), and triple-negative (TN) (n = 114; 19.7%) patients. Thrombosis during follow up was observed in 4 out of 22 (18.2%) in the MPL-mutated group, which was the highest among all driver gene mutation groups (JAK2V617F-mutated, 8.7%; CALR-mutated, 3.5%; TN,1.8%). The MPL- and JAK2V617F-mutated groups had worse thrombosis-free survival (TFS) than the CALR-mutated (p = 0.043) and TN groups (p = 0.006). Univariable analysis revealed that a history of thrombosis was a possible risk factor for thrombosis among MPL-mutated patients (hazard ratio: 9.572, p = 0.032). MPL-mutated ET patients should require more intensive management to prevent recurrence of thrombosis. [ABSTRACT FROM AUTHOR]

Objectives: A proportion of patients with polycythemia vera (PV) and essential thrombocythemia (ET) harbor non‐driver mutations associated with poor prognosis. In this study, we analyzed the frequency of non‐driver mutations in a large Japanese PV and ET cohort. Furthermore, we studied the relationship of these mutations and prognosis in Japanese patients. Methods: We enrolled 843 Japanese patients with PV or ET. Non‐driver mutations were analyzed by target resequencing using next‐generation sequencing. The association of the mutations with the prognosis was estimated using multivariable logistic regression analysis and log‐rank test. Results: Non‐driver mutations were detected in 31.1% and 24.5% patients with PV and ET, respectively. Among them, ASXL1 mutations were identified as a risk factor for leukemic/myelofibrotic transformation in PV and ET patients (hazard ratio: 4.68, p =.006). The higher‐risk groups of the mutation‐enhanced international prognostic system (MIPSS)‐PV and MIPSS‐ET incorporating non‐driver mutations exhibited significantly shorter overall survival compared with the low‐risk group (p <.001). Conclusions: These results implicate the importance of studying non‐driver mutations for predicting the prognosis and survival of Japanese PV and ET patients. [ABSTRACT FROM AUTHOR]

Background: Acquired erythrocytosis can be classified into polycythemia vera (PV) and non‐neoplastic erythrocytosis (NNE). The vast majority of PV patients harbor JAK2 mutations, but differentiating JAK2 mutation‐negative PV from NNE is challenging due to a lack of definitive molecular markers. Methods: We studied the clinical features of 121 patients with erythrocytosis of which 47 (38.8%) were JAK2 mutation‐positive and also fulfilled the diagnostic criteria for PV, and 67 (55.4%) JAK2 mutation‐negative erythrocytosis patients who were diagnosed as NNE. Diagnosis was strictly based on driver mutation analysis and central pathology review. Results: No JAK2 mutation‐negative PV patients were found in our cohort. The NNE group showed significantly younger (p < 0.01) age with higher frequency of smoking (p < 0.001), alcohol consumption (p < 0.001), and diabetes mellitus (p < 0.05), whereas the PV group (n = 47) showed significantly higher white blood cell count, platelet count, and lactate dehydrogenase (p < 0.001). Although serum erythropoietin (EPO) levels were significantly higher in NNE compared to PV (p < 0.001), approximately 40% of the NNE patients had EPO levels below the lower range of normal, fulfilling a minor diagnostic criterion of PV and raising the possibility of PV misdiagnosis. Conclusion: Low EPO levels in JAK2 mutation‐negative erythrocytosis may not be a reliable diagnostic criterion for distinguishing PV from NNE. [ABSTRACT FROM AUTHOR]

Current guidelines for essential thrombocythemia (ET) patients recommend different treatment approaches based on thrombosis risk stratification models. However, these recommendations may not be applicable to some patients under real clinical settings. Therefore, we carried out a retrospective real-world validation study. Thrombosis-free survival (TFS) was compared between treatment naïve ET patients receiving different treatment approaches. ET patients were stratified by three representative risk models, the conventional, the International Prognostic Score for thrombosis in ET (IPSET-thrombosis), and revised IPSET-thrombosis. Treatment decisions were largely made by individual physicians, taking into account patient preferences and backgrounds. A total of 179 ET patients were included, and thrombotic events were observed in 26 patients. TFS was significantly longer in high-risk patients of all risk models receiving a combination of cytoreductive therapy (CRT) and antiplatelet therapy (APT) compared to CRT alone. Similar results were seen in intermediate-risk patients stratified by IPSET-thrombosis. In contrast, in very low- and low-risk patients of all risk models, TFS was not affected by addition of CRT, indicating that observation or APT alone is an appropriate treatment approach for these patients. We demonstrate that current guidelines provide optimal treatment approaches for Japanese ET patients under real-world clinical settings. [ABSTRACT FROM AUTHOR]