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Background:  Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes ( DNMT3A, TET2, and ASXL1 ). The objective of this study was to confirm this observation in a larger series of PV patients., Methods:  PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias., Results:  Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort ( p  = 0.007), as well as in low-risk patients ( p  = 0.039) and older patients ( p  = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case-control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation., Conclusion:  Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

The SARS-CoV-2 pandemic has favored the expansion of telemedicine. Philadelphia-negative chronic myeloproliferative neoplasms (Ph-MPN) might be good candidates for virtual follow-up. In this study, we aimed to analyze the follow-up of patients with Ph-MPN in Spain during COVID-19, its effectiveness, and acceptance among patients. We present a multicenter retrospective study from 30 centers. Five hundred forty-one patients were included with a median age of 67 years (yr). With a median follow-up of 19 months, 4410 appointments were recorded. The median of visits per patient was 7 and median periodicity was 2.7 months; significantly more visits and a higher frequency of them were registered in myelofibrosis (MF) patients. 60.1% of visits were in-person, 39.5% were by telephone, and 0.3% were videocall visits, with a predominance of telephone visits for essential thrombocythemia (ET) and polycythemia vera (PV) patients over MF, as well as for younger patients (< 50 yr). The proportion of phone visits significantly decreased after the first semester of the pandemic. Pharmacological modifications were performed only in 25.7% of the visits, and, considering overall management, ET patients needed fewer global treatment changes. Telephone contact effectiveness reached 90% and only 5.4% required a complementary in-person appointment. Although 56.2% of the cohort preferred in-person visits, 90.5% of our patients claimed to be satisfied with follow-up during the pandemic, with an 83% of positive comments. In view of our results, telemedicine has proven effective and efficient, and might continue to play a complementary role in Ph-MPN patients' follow-up., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hematological control, incidence of complications, and need for cytoreduction were studied in 453 patients with low-risk polycythemia vera (PV) treated with phlebotomies alone. Median hematocrit value decreased from 54% at diagnosis to 45% at 12 months, and adequate hematocrit control over time (< 45%) was observed in 36%, 44%, and 32% of the patients at 6, 12, and 24 months, respectively. More than 5 phlebotomies per year in the maintenance phase were required in 19% of patients. Worsening thrombocytosis, age > 60 years, and microvascular symptoms constituted the main indications for starting cytoreduction. Median duration without initiating cytoreduction was significantly longer in patients younger than 50 years (< 0.0001). The incidence rate of thrombosis under phlebotomies alone was 0.8% per year and the estimated probability of thrombosis at 10 years was 8.5%. The probability of arterial thrombosis was significantly higher in patients with arterial hypertension whereas there was a trend to higher risk of venous thrombosis in cases with high JAK2V617F allele burden. Rates of major bleeding and second primary neoplasm were low. With a median follow-up of 9 years, survival probability at 10 years was 97%, whereas the probability of myelofibrosis at 10 and 20 years was 7% and 20%, respectively. Progression to acute myeloid leukemia was documented in 3 cases (1%). Current management of low-risk PV patients is associated with low rate of thrombosis and long survival. New treatment strategies are needed for improving hematological control and, in the long term, reducing progression to myelofibrosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Polycythaemia vera is associated with a reduced quality of life, a high rate of vascular events, and an intrinsic risk of disease evolution. The results of several randomised trials for the treatment of this disorder are now available, and both a new ropegylated formulation of interferon alfa-2b (ropeginterferon alfa-2b; 2018) and ruxolitinib (2015) have been approved in Europe. European LeukemiaNet (ELN) investigators have therefore deemed it appropriate to provide recommendations for the use of these drugs in clinical practice. An expert panel of 14 senior haematologists from ELN centres that had actively participated in previous ELN projects or relevant randomised trials, chaired by a member of the ELN Steering Committee, developed a list of clinical questions, and a methodologist established three patient, intervention, comparator, outcome (PICO) questions and systematically reviewed the evidence. Recommendations were approved by six Delphi consensus rounds and two virtual meetings (on Jan 26, 2021, and June 24, 2021). The expert panel recommended that patients with polycythaemia vera who are younger than 60 years and have not had previous thrombotic events should start cytoreductive drug therapy if at least one of the following criteria are fulfilled: strictly defined intolerance to phlebotomy, symptomatic progressive splenomegaly, persistent leukocytosis (>15 × 10 9 white blood cells per L), progressive leukocytosis (at least 100% increase if baseline count is <10 × 10 9 cells per L or at least 50% increase if baseline count is >10 × 10 9 cells per L), extreme thrombocytosis (>1500 × 10 9 platelets per L), inadequate haematocrit control requiring phlebotomies, persistently high cardiovascular risk, and persistently high symptom burden. Recombinant interferon alfa, either in the form of ropeginterferon alfa-2b or pegylated interferon alfa-2a, is the recommended cytoreductive treatment for these patients. The expert panel suggested that either interferon alfa or ruxolitinib should be considered for patients who are being treated with hydroxyurea but require a therapy change., Competing Interests: Declaration of interests MM has received consulting fees from Gilead Sciences, speaker fees from Amgen, support for attending meetings from Takeda, and is a member of the guideline committee of the Italian Society of Hematology. AMV has received speaker fees from Novartis, AOP Health, Incyte, AbbVie, GlaxoSmithKline (GSK), and Bristol Myers Squibb (BMS); and has participated on the advisory boards of Novartis, Incyte, AOP Orphan Pharmaceuticals, AbbVie, GSK, BMS, and Roche. MG has received consulting and speaker fees, support for attending meetings, and participated on advisory boards for AOP Health, Novartis, Celgene, Amgen, AstraZeneca, CTI BioPharma, Shire, Pfizer, Roche, Janssen Pharmaceuticals, and Gilead Sciences. CH has received grants or contracts with payment to her institution from Novartis, Celgene, and Constellation Pharmaceuticals; consulting fees from Keros Therapeutics, Galecto Biotech, and Roche; speaker fees from Novartis, Celgene, CTI BioPharma, AbbVie, Gilead Sciences, Janssen Pharmaceuticals, Promedior, and Geron Corporation; support for attending meetings from Novartis and Celgene, and has participated on advisory boards for Roche, CTI Biopharma, Geron Corporation, Promedior, AbbVie, AOP Orphan Pharmaceuticals, and Galecto. SK has received research grants from AOP Health, Novartis, Janssen Pharmaceuticals, and Imago BioScience; consulting fees from Pfizer, CTI BioPharma, Sanofi, Novartis, BMS/Celgene, Incyte/ARIAD, Roche, AOP Orphan Pharmaceuticals, and Janssen Pharmaceuticals; speaker fees from Pfizer, CTI BioPharma, Sanofi, Novartis, BMS/Celgene, Incyte/ARIAD, Roche, AOP Orphan Pharmaceuticals, Janssen Pharmaceuticals, Kartos Therapeutics, and Imago BioScience; support for attending meetings from Alexion Pharmaceuticals, Novartis, BMS/Celgene, Incyte/ARIAD, AOP Orphan Pharmaceuticals, CTI BioPharma, Pfizer, Sanofi, Janssen Pharmaceuticals, Geron Corporation, Kartos Therapeutics, Sierra Oncology, Imago BioScience; has participated on advisory boards for Pfizer, CTI BioPharma, Sanofi, Novartis, BMS/Celgene, Incyte/ARIAD, Roche, AOP Orphan Pharmaceuticals, Kartos Therapeutics, and Imago BioScience; has patents planned, issued, or pending from Rheinisch-Westfalische Technische Hochschule Aachen; and has a leadership role in Deutsche Gesellschaft fur Hamatologie und Medizinische Onkologie. HG has received research grants and support for attending meetings from AOP Orphan Pharmaceuticals and Novartis; consulting fees from AOP Orphan Pharmaceuticals, Novartis, and BMS/Celgene; and speaker fees from AOP Orphan Pharmaceuticals, Novartis, BMS/Celgene, and Janssen. AÁ-L has participated on advisory boards and has received speaker fees from Novartis, AOP Orphan Pharmaceuticals, and Celgene; and has received support for attending meetings from Novartis and Pfizer. VDS has received speaker fees from AbbVie and Novartis, and participated on advisory boards of AOP Health and Novartis. PG has received speaker fees from AbbVie and Novartis, and support for attending meetings from Sanofi. FPal has received speaker fees from Novartis and Incyte; consulting fees from AOP Health, CTI BioPharma, Novartis, and Celgene/BMS; and support for attending meetings from Celgene/BMS. FPas has received consulting fees from AbbVie, Novartis, BMS, and Amomed Pharma; and speaker fees from AbbVie, Janssen Pharmaceuticals, Novartis, and BMS. RTS has received research grants from the Cancer Research & Treatment Fund and Johns Family Fund, received speaker fees and payment for expert testimony from PharmaEssentia, participated on an advisory board for PharmaEssentia, and has a leadership role (Vice-President and Medical Director) at the Cancer Research & Treatment Fund. J-JK received consulting fees from AbbVie and Novartis; speaker fees from AOP Orphan Pharmaceuticals, Novartis, and BMS; and has participated on advisory boards for Incyte. TB has received research grants and speaker fees from AOP Orphan Pharmaceuticals and Novartis, and consultancy fees from AOP Orphan Pharmaceuticals. GB and RH declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In 2016, the WHO included haemoglobin values within normal ranges as a diagnostic criterion for Polycythaemia Vera (PV). Since then, concerns have arisen that a large number of patients are undergoing unnecessary screening for PV. To address this issue, we estimated the prevalence of JAK2 p.V617F in individuals with elevated haemoglobin or haematocrit and developed and validated a screening algorithm for PV. A total of 15,366 blood counts performed in seven non-consecutive days were reviewed, of which 1001 were selected for subsequent JAK2 p.V617F mutation screening. Eight (0.8%) new JAK2 p.V617F-mutated cases were detected. From ROC curves, a two-step algorithm was developed based on the optimal cut-off for the detection of the JAK2 p.V617F mutation. The algorithm was prospectively validated in an independent cohort of 15,298 blood counts. A total of 1595 (10.4%) cases met the criterion for haemoglobin or haematocrit, of whom 581 passed to step 2 (3.8% of the total). The JAK2 p.V617F mutation was detected in 7 of the 501 patients tested, which accounts for 0.04% of the total cohort and 0.4% of patients with erythrocytosis. In conclusion, this data show that our two-step algorithm improves the selection of candidates for JAK2 p.V617F testing.

JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n = 50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations × 100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n = 12) with these patients having a rate of 25.6 mutations × 100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1-6.8, p = 0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6-57.1, p = 0.001) with mutations in ASXL1 (p < 0.0001), TP53 (p = 0.01), SRSF2 (p < 0.0001), IDH1/2 (p < 0.0001), and RUNX1 (p < 0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p = 0.02) and IDH1/2 (p < 0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4-49.1, p = 0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.

Objectives: Population-based studies have reported an increased incidence of skin cancer in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We have examined the risk factors for non-melanoma skin cancer (NMSC) in patients diagnosed with ET or PV during 1973-2012., Methods: A case-control study was performed to compare the clinical and treatment-related data of 51 ET/PV patients who had NMSC with that of 401 patients who did not. We also evaluated whether polymorphisms in 12 genes involved in DNA integrity predisposed to NMSC., Results: By multivariate logistic regression analysis, risk factors for NMSC were older age (OR: 1.7, 95% CI: 1.3-2.1, P < 0.001), male sex (OR: 2.1, 95% CI: 1.1-3.8, P = 0.023), higher cumulated hydroxycarbamide dose (OR: 1.3, 95% CI: 1.1-1.7, P = 0.017), and busulphan exposure (OR: 3.2, 95% CI: 1.05-10.0, P = 0.041). On the time-to-event prognostic model, factors independently associated with increased cumulative incidence of NMSC were age (5% increased risk per year; P < 0.001), male sex (91% increased risk; P = 0.022), and hydroxycarbamide exposure (22% increased risk; P = 0.065). No susceptibility gene variant was identified., Conclusions: These findings suggest that the risk to develop NMSC in ET/PV patients results from the combined effect of common risk factors (age, male sex) together with cytoreductive treatment., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Simple Summary: Myelofibrosis is a heterogeneous disease regarding its mutation landscape as well as its clinical presentation and outcome. A genomic classification with prognostic implications of myeloproliferative neoplasms has been previously proposed, however, this classification has hardly been implemented in myelofibrosis. The aim of our work is to evaluate this genomic classification in a large series of myelofibrosis patients from a single institution, taking into account whether cases are primary or secondary. We found that both primary and secondary myelofibrosis have distinctive molecular landscapes and that genomic profiling provides accurate information regarding prognosis and disease progression. Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic classification of MF considering whether it is primary or secondary. One-hundred seventy-five patients, 81 with primary MF (PMF) and 94 with secondary MF (SMF) were hierarchically allocated into eight molecular groups. We found that TP53 disruption/aneuploidy (n = 16, 9%) was more frequent (12% versus 6%) and showed higher allele burden (57% versus 15%, p = 0.01) in SMF than in PMF, and was associated with shorter survival (median 3.5 years). Mutations in chromatin/spliceosome genes (n = 72, 41%) represented the most frequent genomic group in PMF. Homozygous JAK2 mutation (n = 40, 23%) was enriched with old patients with SMF after long-standing polycythemia vera, whereas MF with heterozygous JAK2 mutation (n = 22, 13%) was similarly distributed among PMF and SMF. MF with CALR mutation (n = 19, 11%) predominated in post-essential thrombocythemia MF. The remaining genomic groups were infrequent. TP53 disruption, chromatin/spliceosome mutation, and homozygous JAK2 mutation were associated with significantly shorter survival and higher risk of progression. In conclusion, genomic classification reveals different pathogenic pathways between PMF and SMF and provides relevant information regarding disease phenotype and outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: The coexistence of cancer with other chronic conditions has substantial implications for treatment decisions and outcomes for both neoplasms and chronic disease. Reports have demonstrated the impact of comorbidities on survival in different hematologic disorders. Myelofibrosis (MF) guidelines do not consider the complex interrelations between MF and comorbidity. Several works have shown how MF patients have a wide variety and high burden of comorbidities and demonstrated that the comorbidity burden was significantly associated with an unfavorable impact on survival. These previous studies about comorbidity on MF are retrospective and consider the cumulative rather than individual comorbidity burden. The influence of individual comorbidities on outcome in MF patients has not been studied. We sought to identify the comorbidities in MF patients at diagnosis and to assess the influence of those different comorbidities on survival. Considering them individually may contribute to the personalization of MF management and optimizing outcomes. The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF. [ABSTRACT FROM AUTHOR]

Low serum erythropoietin ( EPO) is a minor criterion of Polycythaemia Vera ( PV) but its diagnostic usefulness relies on studies performed before the discovery of JAK2 V617F mutation. The objective of the present study was to evaluate the diagnostic accuracy of serum EPO and JAK2 V617F allele burden as markers of PV as well as the combination of different diagnostic criteria in 287 patients (99 with PV, 137 with Essential Thrombocythaemia and 51 with non-clonal erythrocytosis). Low EPO showed good diagnostic accuracy as a marker for PV, with the area under the curve ( AUC) of the chemiluminescent-enhanced enzyme immunoassay ( CEIA) being better than that of radioimmunoassay ( RIA) (0·87 and 0·76 for CEIA and RIA, respectively). JAK2 V617F quantification displayed an excellent diagnostic accuracy, with an AUC of 0·95. A haematocrit >52% (males) or >48% (females) plus the presence of the JAK2 V617F mutation had a sensitivity and specificity of 79% and 97%, respectively. Adding low EPO or the JAK2 V617F allele burden did not improve the diagnostic accuracy for PV whereas the inclusion of both improved the sensitivity up to 83% and maintaining 96% specificity. Haematocrit and qualitative JAK2 V617F mutation allow a reliable diagnosis of PV. Incorporation of EPO and/or JAK2 V617F mutant load does not improve the diagnostic accuracy. [ABSTRACT FROM AUTHOR]