Myeloproliferative neoplasms in the adolescent and young adult population: A comprehensive review of the literature.

Myeloproliferative neoplasms (MPN) are characterized by a clonal proliferation of myeloid lineage cells within the bone marrow. The classical BCR-ABL negative MPNs are comprised of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Historically, the majority of MPNs are diagnosed in adults older than 60 years of age; however, in recent years, there has been recognition of MPNs in the adolescent and young adult (AYA) population. AYAs with MPN, typically defined as between the ages of 15 and 39 years old, may comprise up to 20% of patients diagnosed with MPN. They demonstrate unique patterns of driver mutations and thrombotic events and remain at risk for progression to more aggressive disease states. Given the likely long length of time they will live with their disease, there is a significant unmet need in identifying well-tolerated and effective treatment options for these patients, particularly with the advent of disease modification. In this review, we provide a comprehensive overview of the clinical features, disease course and management of AYA patients with MPN and, in doing so, highlight key characteristics that distinguish them from their older counterparts.

Thromboembolic events, major bleeding and mortality in essential thrombocythaemia and polycythaemia vera-A matched nationwide population-based study.

Thromboembolic events and bleeding are known complications in essential thrombocythaemia (ET) and polycythaemia vera (PV). Using multiple Swedish health care registers, we assessed the rate of arterial and venous events, major bleeding, all-cause stroke and all-cause mortality in ET and PV compared to matched controls. For each patient with ET (n = 3141) and PV (n = 2604), five matched controls were randomly selected. In total, 327 and 405 arterial or venous events were seen in the group of ET and PV patients respectively. Compared to corresponding controls, the rate of venous thromboembolism, major bleeding and all-cause mortality per 100 treatment years was significantly increased among both ET (0.63, 0.79 and 3.70) and PV patients (0.94, 1.20 and 4.80). The PV patients also displayed a significantly higher rate of arterial events and all-cause stroke compared to controls. When dividing the cohort into age groups, we found a significantly higher rate of arterial and venous events in all age groups of PV patients, and the rate of all-cause mortality was significantly higher in both ET and PV patients in all ages above the age of 50. This study confirms that PV and ET are diseases truly marked by thromboembolic complications and bleeding.

The personal impact of living with a myeloproliferative neoplasm.

OBJECTIVE: The aim of this study is to gain insight into the physical, psychological and social impact of having a myeloproliferative neoplasm (MPN), a rare type of cancer with an often chronic course. METHODS: An online survey was conducted among 455 Dutch MPN patients (62.7% female, age M 63) to explore the impact of the disease by measuring the MPN symptom burden (MPN-SAF TSS) and quality of life (QoL) (EORTC QLQ-C30) and its subscales within a hierarchical QoL model. We examined differences in MPN symptom burden and QoL in relation to sociodemographic and disease-related factors. Hierarchical regression analysis was used to explain variances in QoL. RESULTS: Most patients (97%) experienced MPN-related health complaints, with a significantly higher MPN symptom burden in women (M 31.50) compared to men (M 24.10). Regarding to fatigue and cognitive functioning MPN patients suffered more compared to a reference group of other cancers. MPN subtype or type of treatment did not show significant differences in MPN symptom burden or QoL. However, experiencing side effects, complications or comorbidities significantly negatively affected MPN symptom burden and QoL. 48.8% of patients reported that MPN affected their ability to work. The explained variance in overall QoL was 58%, most importantly by disease progression, comorbidities, MPN symptom burden and role, emotional and social functioning. CONCLUSION: This study revealed that having an MPN has a negative impact on several domains of QoL. Symptom assessment and support should be included in the healthcare management of MPN patients.

Exposure-efficacy and exposure-safety analyses of ropeginterferon alfa-2b treatment in patients with polycythaemia vera.

AIMS: To investigate the exposure-response (E-R) relationship, including exposure-efficacy and exposure-safety, of ropeginterferon alfa-2b treatment in patients with polycythaemia vera (PV). METHODS: Based on the results of the phase II trial A20-202 regarding ropeginterferon alfa-2b in patients with PV, E-R analyses were performed to evaluate the efficacy and safety of the given dosing regimen. The E-R analyses were based on logistic and linear regression and the relationship between exposure to ropeginterferon alfa-2b and key efficacy and safety variables. The key efficacy variables included complete haematologic response (CHR) and reduction of the driver mutation JAK2V617F. The safety variable was treatment-related adverse events (TRAEs). RESULTS: A clear relationship between the exposure to ropeginterferon alfa-2b and CHR was observed, with an increase in drug exposure resulting in an increased probability of achieving CHR. Similar CHR probabilities were observed in the third and fourth quantiles of the average concentration at Week 24. The results from the exposure-JAK2V617F model indicated that the JAK2V617F allele burden decreased with increasing exposure to ropeginterferon alfa-2b and baseline body surface area. Exposure-safety analysis revealed a risk of AEs associated with transaminase abnormalities, which were not associated with clinical significance. CONCLUSIONS: Our analyses have shown that patients with PV treated with ropeginterferon alfa-2b had an increased probability of achieving CHR and a molecular response with acceptable safety risks at the 250-350-500 µg titration dosing regimen. This study has provided the relevant data for the application of a biologics licence of ropeginterferon alfa-2b for PV treatment in China.

Characterization of myeloproliferative neoplasms in the paediatric and young adult population.

The aim of this study was to compare the genomic features and clinical outcomes between paediatric and young adult patients (PAYA, <40 years) and older adults (OA, ≥40 years) with myeloproliferative neoplasms (MPN) to gain insight into pathogenesis, disease prognosis and management. Of 630 MPN patients, 171 (27%) were PAYA with an average age at diagnosis of 31 years. Females were more prevalent in PAYA than OA (71% vs 58%; p = 0.002), and PAYA more frequently presented with essential thrombocytosis (ET) at diagnosis (67% vs 39%; p < 0.001). The presence of a JAK2 somatic mutation was higher in OA (80.4% vs 64.3%; p < 0.001), while a CALR mutation or lack of any traditional driver mutation was more common in PAYA (20.5% vs 10.5%; p = 0.001, 8.8% vs 3.7%; p = 0.01 respectively). Venous thrombosis was more common in PAYA compared to OA (19.8% vs 10.7%; p = 0.002). PAYA had a higher prevalence of familial MPN and familial cancer predisposition, and two PAYA patients harboured pathogenic germline JAK2 lesions. PAYA demonstrated longer survival from diagnosis than OA (median not reached vs 13 years), while disease transformation was less frequent (19.3% vs 37.9%).

Updates on accelerated and blast phase myeloproliferative neoplasms: Are we making progress?

Management approaches for accelerated and blast phase myeloproliferative neoplasms remain challenging for clinicians and patients alike. Despite many therapeutic advances, outcomes for those patients who are not allogeneic haematopoietic cell transplant eligible remain, in general, very poor. Estimated survival rates for such blast phase patients is frequently reported as less than 6 months. No specific immunological, genomic or clinicopathological signature currently exists that accurately predicts the risk and timing of transformation, which frequently induces a high degree of anxiety among patients and clinicians alike. Within this review article, we provide an up-to-date summary of current understanding of the underlying pathogenesis of accelerated and blast phase disease and discuss current therapeutic approaches and realistic outcomes. Finally, we discuss how the horizon may look with the introduction of more novel agents into the clinical arena.

Mortality outcomes and survival patterns of patients with myeloproliferative neoplasms in Malaysia.

BACKGROUND: Prognostication of myeloproliferative neoplasm (MPN) has always been challenging, even with the advent of Janus kinase 2 (JAK2 V617F) molecular studies. The survival pattern of patients diagnosed with MPN in developing countries is still undetermined. MATERIALS AND METHODS: The national MPN registry conducted from 2009 to 2015 in Malaysia provided a comprehensive insight into the demographics, clinical characteristics and laboratory parameters of patients diagnosed with MPN nationwide. The study analysed the survival patterns and mortality outcomes and risk among 671 patients diagnosed with essential thrombocythaemia (ET), polycythaemia vera (PV), primary myelofibrosis (PMF) and unclassified MPN (MPN-U). Mortality status was traced and confirmed until the end of December 2018, with right censoring applied to patients alive beyond that. RESULTS: The analysed cohort consisted of 283 (42.2%) ET, 269 (40.1%) PV, 62 (9.2%) PMF and 57 (8.5%) MPN-U incident cases with diagnosis made between 2007 and 2015. The majority of patients were male (52.3%) and Malay (48.9%), except for ET, in which the majority of patients were female (60.1%) and of Chinese origin (47.0%). Female patients were found to have significantly better overall survival (OS) rates in ET (p = 0.0285) and MPN-U (p = 0.0070). Patients with JAK2 V617F mutation were found to have marginally inferior OS over time. Multivariable Cox regression identified patients with increased age [hazard ratio (HR) 1.055, 95% CI 1.031; 1.064], reduced haemoglobin (HB) level (HR 0.886, 95% CI 0.831; 0.945, p = 0.0002), being male (HR 1.545, 95% CI 1.077; 2.217, p = 0.0182), and having MPN-U (HR 2.383, 95% CI 1.261; 4.503, p = 0.0075) and PMF (HR 1.975, 95% CI 1.054; 3.701, p = 0.0335) at increased risk for worse mortality outcomes. CONCLUSION: Myeloproliferative neoplasm reduces patient survival. The degree of impact on survival varies according to sub-type, sex, bone marrow fibrosis and HB levels. The JAK2 V617F mutation was not found to affect the survival pattern or mortality outcome significantly.

Polycythaemia Vera and Coronary Artery Bypass Graft Surgery: A Systematic Review of the Literature.

OBJECTIVES: Polycythaemia vera (PV) is a condition that may potentially put patients undergoing cardiac surgery at an increased risk of bleeding and thrombosis; however, there is currently a paucity of literature regarding the management of these patients. We aim to examine the literature in this systematic review to indicate the interventions that may be considered to minimise complications. METHODS: We conducted a literature search using keywords and MeSH terms to identify articles discussing PV and cardiac surgery. The studies were identified and qualitatively analysed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol. RESULTS: In total, 10 case reports representing 11 patients were identified for this systematic review and were included in qualitative analysis. 63.6% of patients had preoperative intermittent phlebotomy, and the majority of patients received postoperative therapy that involved one antiplatelet agent and one anticoagulant. Generous perioperative fluid management, phlebotomy, preservation of core body temperature, early extubation, monitoring of myocardial ischaemia, infarction and vascular events, intense chest physiotherapy and patient mobilisation are important to consider to reduce the risk of complications arising from surgery. CONCLUSION: These considerations should be systematically discussed in a multidisciplinary team, where the acute surgical need can be balanced appropriately against the risk of haemorrhage and thrombosis.

How we manage Philadelphia-negative myeloproliferative neoplasms in pregnancy.

The combined incidence of classical Philadelphia-negative myeloproliferative neoplasm (MPN) is 6-9/100 000 with a peak frequency between 50 and 70 years. MPN is less frequent in women of reproductive age. However, for essential thrombocythaemia (ET) in particular there is a second peak in women of reproductive age and 15% of polycythaemia vera (PV) patients are less than 40 years of age at the time of diagnosis. Thus these diseases are encountered in women of reproductive potential and may be diagnosed in pregnancy or in women being investigated for recurrent pregnancy loss. The incidence of MPN pregnancies is 3·2/100 000 maternities per year in the UK. The majority of data regarding Philadelphia-negative MPNs relates to patients with ET, for which the literature suggests significant maternal morbidity and poor fetal outcome; specifically maternal thrombosis and haemorrhage, miscarriage, pre-eclampsia, intrauterine growth restriction (IUGR), stillbirth and premature delivery as summarised in the recent systematic review and meta-analysis in Blood, 2018, 132, 3046. The literature for PV is more sparse but increasing and is concordant with ET pregnancy outcomes. The literature regarding primary myelofibrosis (PMF) is even more scarce. Treatment options include aspirin, venesection, low molecular weight heparin (LMWH) and cytoreductive therapy. Data and management recommendations are often extrapolated from other pro-thrombotic conditions or from ET to PV and PMF. Women of reproductive age with a diagnosis of MPN should receive information and assurance regarding management and outcome of future pregnancies. From pre-conceptual planning to the post-partum period, women should have access to joint care from an obstetrician with experience of high-risk pregnancies and a haematologist in a multidisciplinary setting. This paper provides an update with regards to Philadelphia-negative MPN in pregnancy, details local practise in an internationally recognised centre for patients with MPN and outlines a future research strategy.

ASXL1 mutations, previous vascular complications and age at diagnosis predict survival in 85 WHO-defined polycythaemia vera patients.

Polycythaemia vera (PV) patients have an overall comparatively favourable prognosis, but disease progression is very heterogeneous and life-threatening thrombosis and bleedings are frequent complications in untreated disease. Moreover, transformation to more severe secondary myelofibrosis and acute myeloid leukaemia can occur. The aim of this study was to identify gene mutations that could be used together with clinical data as prognostic markers to guide treatment decisions in PV patients. A well-characterized WHO-defined cohort of PV patients was used. Clinical data and blood values were evaluated and a myeloid sequencing panel was used to screen for additional mutations other than the diagnostic JAK2 V617F and JAK2 exon 12 mutations. In 78% of the PV patients, at least one mutation additional to JAK2 V617F was detected. Additional mutations in genes coding for epigenetic modifiers, like TET2, DNMT3A and ASXL1, were most frequent. When correlated to overall survival, mutations in ASXL1 were significantly associated with inferior survival. In an attempt to obtain prognostic guidance in a larger number of patients, the presence of ASXL1 mutations was combined with age and vascular complications prior to diagnosis. Based on these data we were able to define three risk groups that predicted survival.

Smoking, blood cells and myeloproliferative neoplasms: meta-analysis and Mendelian randomization of 2·3 million people.

Meta-analyses and Mendelian randomization (MR) may clarify the associations of smoking, blood cells and myeloproliferative neoplasms (MPN). We investigated the association of smoking with blood cells in the Danish General Suburban Population Study (GESUS, n = 11 083), by meta-analyses (including GESUS) of 92 studies (n = 531 741) and MR of smoking variant CHRNA3 (rs1051730[A]) in UK Biobank, and with MPN in a meta-analysis of six studies (n (total/cases):1 425 529/2187), totalling 2 307 745 participants. In the meta-analysis the random-effects standardized mean difference (SMD) in current smokers versus non-smokers was 0·82 (0·75-0·89, P = 2·0 * 10-108 ) for leukocytes, 0·09 (-0·02 to 0·21, P = 0·12) for erythrocytes, 0·53 (0·42-0·64, P = 8·0 * 10-22 ) for haematocrit, 0·42 (0·34-0·51, P = 7·1 * 10-21 ) for haemoglobin, 0·19 (0·08-0·31, P = 1·2 * 10-3 ) for mean corpuscular haemoglobin (MCH), 0·29 (0·19-0·39, P = 1·6 * 10-8 ) for mean corpuscular volume (MCV), and 0·04 (-0·04 to 0·13, P = 0·34) for platelets with trends for ever/ex-/current smokers, light/heavy smokers and female/male smokers. Analyses presented high heterogeneity but low publication bias. Per allele in CHRNA3, cigarettes per day in current smokers was associated with increased blood cell counts (leukocytes, neutrophils), MCH, red cell distribution width (RDW) and MCV. The pooled fixed-effects odds ratio for MPN was 1·44 [95% confidence interval (CI): 1·33-1·56; P = 1·8 * 10-19 ; I2  = 0%] in current smokers, 1·29 (1·15-1·44; P = 8·0 * 10-6 ; I2  = 0%) in ex-smokers, 1·49 (1·26-1·77; P = 4·4 * 10-6 ; I2  = 0%) in light smokers and 2·04 (1·74-2·39, P = 2·3 * 10-18 ; I2  = 51%) in heavy smokers compared with non-smokers. Smoking is observationally and genetically associated with increased leukocyte counts and red blood cell indices (MCH, MCV, RDW) and observationally with risk of MPN in current and ex-smokers versus non/never-smokers.

The red blood cell count and the erythrocyte sedimentation rate in the diagnosis of polycythaemia vera.

BACKGROUND: Iron deficiency in polycythaemia vera (PV) may impact the validity of the haematocrit (HCT), since HCT is red blood cell count (RBC) × mean corpuscular volume (MCV). OBJECTIVES: To investigate (a) the effect of microcytosis on HCT, (b) the erythrocyte sedimentation rate (ESR) as a possible additional diagnostic marker for PV. MATERIAL AND METHODS: This study included 182 subjects: 39 with PV, 27 with essential thrombocythemia (ET) and 116 suspected of myeloproliferative neoplasm (MPN) with a secondary cause for either thrombocytosis or erythrocytosis. RESULTS: Patients with PV had significantly lower ratio of MCV and serum ferritin compared to MPN suspects. A good correlation of RBC versus HCT was found for PV and MPN subjects when individuals with microcytosis were excluded (R2  = .87 in PV and R2  = .82 in MPN suspects). We found a specificity of 98% and a sensitivity of 37% for ESR <2 mm in the diagnosis of PV. CONCLUSION: The RBC may more precisely reflect the total red cell mass and accordingly the hypercoagulable state of the PV patient, which is integrated in the ESR. A combination of RBC and ESR is proposed as a novel tool to substitute the Hb concentration and the HCT in the diagnosis of PV.

A journey through infectious risk associated with ruxolitinib.

Ruxolitinib has proved to be effective for the treatment of patients with myelofibrosis (either primary or secondary) and polycythaemia vera, and its approval led to a significant change in the current treatment algorithm. Despite its efficacy and beyond its well described haematological toxicity, a peculiar immunosuppressive effect emerged as our clinical experience grew, both within and outside of a clinical trial setting. Definite and negative interactions with multiple pathways of the immune system of patients have been reported so far, involving both adaptive and innate immune responses. These pathophysiological mechanisms may contribute to the increased risk of reactivation of silent infections (e.g., tuberculosis, hepatitis B virus and varicella zoster virus) that have been associated with the drug. Even though such infectious events may be fatal or may lead to significant impairment of organ function, compromising the eligibility of patients for an allotransplant procedure, there are no dedicated guidelines that may help us in assessing and managing the risk of developing serious infections. On this basis, our aim for the present work was to review the current knowledge on the pathophysiological mechanisms through which ruxolitinib may exert its immunosuppressive effect, and to illustrate our personal approach to the management of three peculiar clinical scenarios, for which a risk-based algorithm is suggested.

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms.

The myeloproliferative neoplasms (MPN), polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are linked by a propensity to thrombosis formation and a risk of leukaemic transformation. Activation of cytokine independent signalling through the JAK/STAT cascade is a feature of these disorders. A point mutation in exon 14 of the JAK2 gene resulting in the formation of the JAK2 V617F transcript occurs in 95% of PV patients and around 50% of ET and PMF patients driving constitutive activation of the JAK/STAT pathway. Mutations in CALR or MPL are present as driving mutations in the majority of remaining ET and PMF patients. Ruxolitinib is a tyrosine kinase inhibitor which inhibits JAK1 and JAK2. It is approved for use in intermediate and high risk PMF, and in PV patients who are resistant or intolerant to hydroxycarbamide. In randomised controlled trials it has demonstrated efficacy in spleen volume reduction and symptom burden reduction with a moderate improvement in overall survival in PMF. In PV, there is demonstrated benefit in haematocrit control and spleen volume. Despite these benefits, there is limited impact to induce complete haematological remission with normalisation of blood counts, reduce the mutant allele burden or reverse bone marrow fibrosis. Clonal evolution has been observed on ruxolitinib therapy and transformation to acute leukaemia can still occur. This review will concentrate on understanding the clinical and molecular effects of ruxolitinib in MPN. We will focus on understanding the limitations of JAK inhibition and the challenges to improving therapeutic efficacy in these disorders. We will explore the demonstrated benefits and disadvantages of ruxolitinib in the clinic, the role of genomic and clonal variability in pathogenesis and response to JAK inhibition, epigenetic changes which impact on response to therapy, the role of DNA damage and the role of inflammation in these disorders. Finally, we will summarise the future prospects for improving therapy in MPN in the JAK inhibition era.

Recommendations for the diagnosis and treatment of patients with polycythaemia vera.

OBJECTIVES: To present the Central European Myeloproliferative Neoplasm Organisation (CEMPO) treatment recommendations for polycythaemia vera (PV). METHODS: During meetings held from 2015 through 2017, CEMPO discussed PV and its treatment and recent data. RESULTS: PV is associated with increased risks of thrombosis/thrombo-haemorrhagic complications, fibrotic progression and leukaemic transformation. Presence of Janus kinase (JAK)-2 gene mutations is a diagnostic marker and standard diagnostic criterion. World Health Organization 2016 diagnostic criteria for PV, focusing on haemoglobin levels and bone marrow morphology, are mandatory. PV therapy aims at managing long-term risks of vascular complications and progression towards transformation to acute myeloid leukaemia and myelodysplastic syndrome. Risk stratification for thrombotic complications guides therapeutic decisions. Low-risk patients are treated first line with low-dose aspirin and phlebotomy. Cytoreduction is considered for low-risk (phlebotomy intolerance, severe/progressive symptoms, cardiovascular risk factors) and high-risk patients. Hydroxyurea is suspected of leukaemogenic potential. IFN-α has demonstrated efficacy in many clinical trials; its pegylated form is best tolerated, enabling less frequent administration than standard interferon. Ropeginterferon alfa-2b has been shown to be more efficacious than hydroxyurea. JAK1/JAK2 inhibitor ruxolitinib is approved for hydroxyurea resistant/intolerant patients. CONCLUSIONS: Greater understanding of PV is serving as a platform for new therapy development and treatment response predictors.

A retrospective analysis of the impact of treatments and blood counts on survival and the risk of vascular events during the course of polycythaemia vera.

Vascular and non-vascular complications are common in patients with polycythaemia vera. This retrospective study of 217 patients with polycythaemia vera aimed to determine whether blood counts with respect to different treatments influenced the complication rate and survival. We found that 78 (36%) patients suffered from at least one complication during follow-up. Older age and elevated lactate dehydrogenase at diagnosis were found to be risk factors for vascular complications. When the vascular complication occurred, 41% of the patients with a complication had elevated white blood cells (WBC) compared with 20% of patients without a complication (P = 0·042). Patients treated with hydroxycarbamide (HC; also termed hydroxyurea) experienced significantly fewer vascular complications (11%) than patients treated with phlebotomy only (27%) (P = 0·013). We also found a survival advantage for patients treated with HC, when adjusted for age, gender and time period of diagnosis (Hazard ratio for phlebotomy-treated patients compared to HC-treated patients at 5 years was 2·42, 95% confidence interval 1·03-5·72, P = 0·043). Concerning survival and vascular complications, HC-treated patients who needed at least one phlebotomy per year were not significantly different from HC-treated patients with a low phlebotomy requirement. We conclude that complementary phlebotomy in HC-treated patients in order to maintain the haematocrit, is safe.

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF).

The randomized, double-blind, double-dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)-related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV-related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm -symptom assessment form total symptom score cytokine symptom cluster (TSS-C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib- and hydroxycarbamide-treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82-4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13-16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening-to-baseline TSS-C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV-related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

Impact of genotype on leukaemic transformation in polycythaemia vera and essential thrombocythaemia.

The influence of driver mutations on leukaemic transformation was analysed in 1747 patients with polycythaemia vera or essential thrombocythaemia. With a median follow-up of 7·2 years, 349 patients died and 62 progressed to acute leukaemia or myelodysplastic syndrome. Taking death as a competing risk, CALR genotype was associated with a lower risk of transformation [subdistribution hazard ratio (SHR): 0·13, 95% confidence interval (CI): 0·2-0·9, P = 0·039], whereas JAK2 V617F showed borderline significance for higher risk (SHR: 2·05, 95% CI: 0·9-4·6, P = 0·09). Myelofibrotic transformation increased leukaemic risk, except in CALR-mutated patients. Next generation sequencing of 51 genes at the time of transformation showed additional mutations (median number: 3; range: 1-5) in 25 out of 29 (86%) assessable cases. Mutations (median: 1; range: 1-3) were detected in 67% of paired samples from the chronic phase. Leukaemia appeared in a JAK2 V617F negative clone in 17 (58%) cases, eleven of them being previously JAK2 V617F-positive. JAK2 V617F-mutated leukaemia was significantly associated with complex karyotype and acquisition of TP53 mutations, whereas EZH2 and RUNX1 mutations were more frequent in JAK2 V617F-negative leukaemia. Survival was longer in JAK2 V617F-unmutated leukaemia (343 days vs. 95 days, P = 0·003). In conclusion, CALR genotype is associated with a lower risk of leukaemic transformation. Leukaemia arising in a JAK2 V617F-negative clone is TP53 independent and shows better survival.

[Hungarian Philadelphia negative chronic myeloproliferative neoplasia registry. Evaluation of the Polycythemia vera patients]. / Philadelphia-negatív krónikus Myeloproliferativ Neoplasia Magyarországi Regiszter. Polycythaemia verás betegeink adatainak elemzése.

Intruduction and aim: The Hungarian National Registry for Philadelphia chromosome negative myeloproliferative neoplasms has been developed. The aim of the recent study is to assess the clinical characteristics of Hungarian patients with polycythemia vera. METHOD: Data of 351 JAK2V617F and exon 12 mutation positive polycythemia vera patients were collected online from 15 haematology centres reporting epidemiologic, clinical characteristics, diagnostic tools, therapeutic interventions, thromboembolic complications, disease transformations. Vascular events prior to and after diagnosis were evaluated upon the Landolfi risk assessment scale. RESULTS: 116 thromboembolic events were reported in 106 PV patients prior to diagnosis and 152 occasions in 102 patients during follow-up. The frequency of major arterial events were significantly reduced (p<0.0001) and the minor venous events were significantly elevated (p<0.0001) after the diagnosis. Major hemorrhagic complications were found in 25 and transformation in 26 cases. CONCLUSIONS: Our registry allows to collect and evaluate the features of patients with polycythemia vera. The Landolfi risk stratification was proven to be useful. Based on evaluated data, accuracy of diagnostic criteria and compliance to risk-adapted therapeutic guidelines are needed. Orv Hetil. 2017; 158(23): 901-909.

[Epidemiologic features of Philadelphia-negative chronic myeloproliferative disorders in Szabolcs-Szatmár-Bereg county, Hungary. Analysis of data of a 33-year period]. / A Philadelphia-negatív krónikus myeloproliferativ kórképek epidemiológiai jellemzoi Szabolcs-Szatmár-Bereg megyében. 33 év adatainak elemzése.

INTRODUCTION: In their previous work, the authors reported findings from 30 years on the incidence of hematological malignancies in Szabolcs-Szatmár-Bereg county, Hungary. Until now there are no other studies on this topic available in Hungary. AIM: Detailed analysis of epidemiologic features of patients with Philadelphia-negative chronic myeloproliferative disorders was carried out. METHOD: During a 33-year period (between January 1, 1983 and December 31, 2015) 4523 adult patients with hematologic malignancies were recorded in the leukaemia/lymphoma registry of Szabolcs-Szatmár-Bereg county. Among them, 255 patients with polycytaemia vera, 102 with primary myelofibrosis, and 331 with essential thrombocytaemia were registered. RESULTS: The incidence of polycythaemia vera and essential thrombocythaemia in Szabolcs-Szatmár-Bereg county showed an increasing tendency, with an overall incidence rate of 1.35 and 1.75/100 000 inhabitants/year, respectively; while the incidence of primary myelofibrosis decreased in the course of years (0.54/100 000 inhabitants/year). In cases of polycythaemia vera and primary myelofibrosis the male:female ratio was found to be equal, however essential thrombocythaemia showed a female dominance. The mean age of patients with polycythaemia vera was 65 (21-95) years, similar to essential thrombocythaemia with 65 (19-85) years, and to primary myelofibrosis with 65.5 (33-84) years. There were only two villages found in this county where the occurrence of patients with Philadelphia-negative chronic myeloproliferative disorders per one thousand inhabitants was significantly higher, than the average (1.22). In every familial cases of these, the manifestation of the disease in the second and the third generations became earlier than in the first genetration. The perceived average degree of the anteposition (anticipation) was found to be 22 years. CONCLUSION: The epidemiologic features of Philadelphia-negative chronic myeloproliferative disorders in Szabolcs-Szatmár-Bereg county are essentially similar to data published in the literature. Orv. Hetil., 2017, 158(15), 572-578.