Cardiovascular risk in a contemporary cohort of patients with myeloproliferative neoplasms'.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of disorders of clonal haemopoiesis associated with an inherent risk of arterial and venous thrombotic complications. The prevalence of thrombotic complications and the impact of cardiovascular risk factors (CVRFs) in contemporary patient cohorts within the current era of MPN treatments have not been completely defined. OBJECTIVES: We aim to characterise the cardiovascular risk of patients with MPN by identifying the prevalence of CVRFs and describing the pattern of thrombotic events. We also aim to utilise the QRISK3 algorithm, which is a validated model used to estimate an individual's risk of developing cardiovascular disease, to further phenotype this cohort of patients. METHODS: We perform a retrospective analysis on a single-centre cohort of 438 patients with MPN. RESULTS: MPN patients continue to carry a high burden of vascular morbidity with a prevalence of arterial thrombotic events in 15.8 % (69/438) and venous thrombotic events in 13.2 % (58/438) of the cohort. The novel use of the QRISK3 algorithm, which showed a mean score of 13.7 % across the MPN population, provides further evidence to suggest an increased cardiovascular risk in MPN patients. CONCLUSION: With an increased risk of cardiovascular disease in patients with MPN, we propose an integrated approach between primary and specialised healthcare services using risk stratification tools such as QRISK3, which will allow aggressive optimisation of CVRFs to prevent thrombosis and reduce the overall morbidity and mortality in patients with MPN.

Myeloproliferative neoplasms in adolescents and young adults.

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders commonly diagnosed in the seventh decade of life. With increasing access to blood surveillance, the number of adolescent and young adults (AYAs) diagnosed with MPNs is increasing. AYAs represent a unique cohort of MPN patients with differing challenges and psychosocial needs. The majority of AYA patients are females diagnosed with essential thrombocythaemia and most are asymptomatic at diagnosis. There is a striking predisposition to venous thrombotic events with a significant number experiencing splanchnic venous thrombosis (up to 70% of venous events). When compared to older patients, AYAs appear to have an indolent disease course. Interferon is the preferred cytoreductive agent in this population; indications for commencing treatment mirror those of older adults and are determined by the presence of high-risk features for thromboembolic events.

Patients with triple-negative, JAK2V617F- and CALR-mutated essential thrombocythemia share a unique gene expression signature.

Approximately 10% to 15% of patients with essential thrombocythemia (ET) lack the common driver mutations, so-called "triple-negative" (TN) disease. We undertook a systematic approach to investigate for somatic mutations and delineate gene expression signatures in 46 TN patients and compared the results to those with known driver mutations and healthy volunteers. Deep, error-corrected, next-generation sequencing of peripheral blood mononuclear cells using the HaloPlexHS platform and whole-exome sequencing was performed. Using this platform, 10 (22%) of 46 patients had detectable mutations (MPL, n = 6; JAK2V617F, n = 4) with 3 of 10 cases harboring germline MPL mutations. RNA-sequencing and DNA methylation analysis were also performed by using peripheral blood mononuclear cells. Pathway analysis comparing healthy volunteers and ET patients (regardless of mutational status) identified significant enrichment for genes in the tumor necrosis factor, NFκB, and MAPK pathways and upregulation of platelet proliferative drivers such as ITGA2B and ITGB3. Correlation with DNA methylation showed a consistent pattern of hypomethylation at upregulated gene promoters. Interrogation of these promoter regions highlighted enrichment of transcriptional regulators, which were significantly upregulated in patients with ET regardless of mutation status, including CEBPß and NFκB. For "true" TN ET, patterns of gene expression and DNA methylation were similar to those in ET patients with known driver mutations. These observations suggest that the resultant ET phenotype may, at least in part and regardless of mutation type, be driven by transcriptional misregulation and may propagate downstream via the MAPK, tumor necrosis factor, and NFκB pathways with resultant JAK-STAT activation. These findings identify potential novel mechanisms of disease initiation that require further evaluation.

Altered immune response to the annual influenza A vaccine in patients with myeloproliferative neoplasms.

The seasonal influenza A vaccine is recommended for patients with myeloproliferative neoplasms (MPNs). We hypothesised that immune deregulation associated with MPNs may affect the immune response gained following vaccinations when compared to healthy controls. Using deep immunophenotyping with high-dimensional single-cell analysis and mass cytometry we could demonstrate an altered immune response in MPN patients following vaccination. We found that prior to vaccination, MPN patients had reduced numbers of naive CD4 T cells. Furthermore, at 3-weeks and 3-months post-vaccination there was evidence of both delayed and impaired B- and T-memory cells responses. Thus, although, the immune systems of MPN patients can 'recognise' the Influenza A vaccine, the response appears inferior compared to healthy controls.

Molecular MRD status and outcome after transplantation in NPM1-mutated AML.

Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).

Essential thrombocythaemia treated with recombinant interferon: 'real world' United Kingdom referral centre experience.

Standard first-line therapy choice for essential thrombocythaemia (ET) requiring cytoreduction, supported by randomized trials, is low-dose aspirin with hydroxycarbamide, but the role of recombinant interferon-alfa (IFNα)-2a/2b and pegylated (PEG)-IFN-α-2a/2b is increasingly highlighted. Longer-term outcome data, however, remains somewhat scarce, particularly in the 'real world'. We hereby report on a large, well-annotated cohort of ET patients from a single referral centre undergoing therapy with either IFNα or (PEG)-IFN-α-2a/2b and demonstrate high rates of complete haematological responses, good tolerability and safety, low rates of thromboembolic events in compliant patients and confirm feasibility of long-term therapy in a significant proportion of patients.

Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide.

Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT (P = .40). At 2 years, rates of thrombosis, hemorrhage, and transformation were not significantly different; however, some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were 2 complete molecular responses (CMR) and 1 partial molecular response in CALR-positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in 1 CMR patient, presumably because of the emergence of a different clone, raising questions about the relevance of CMR in ET patients. Grade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grade 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients. Rates of discontinuation or treatment switching did not differ between the 2 trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET. This trial was registered at www.isrctn.com as #ISRCTN61925716.

Experience with ruxolitinib in the treatment of polycythaemia vera.

Polycythaemia vera (PV) is a myeloproliferative neoplasm classically characterized by an erythrocytosis and is associated with a high risk of thromboembolic events, constitutional symptoms burden and risk of transformation to myelofibrosis and acute myeloid leukaemia. Therapy is directed at the haematocrit (HCT) to reduce the risk of thrombotic events and usually comprises low-dose aspirin and phlebotomy to maintain HCT at >45%. Frequently in addition, cytoreductive therapy is indicated in high-risk patients for normalizing haematological parameters to mitigate the occurrence of thromboembolic events. Unfortunately, there is no clear evidence that current therapies reduce the risk of transformation to myelofibrosis and for some a risk of a therapy related complication is unknown for example leukaemia due to hydroxycarbamide (HC). First-line therapy for treating PV remains HC or interferon, the latter most often in younger patients, especially those of childbearing age. However, therapy related intolerance or resistance is a common feature and results in limited treatment options for such patients. The discovery of the JAK2 V617F mutation and consequently targeted therapy with Janus kinase inhibitors, in particular ruxolitinib, has extended the spectrum of agents that can be used as second or third line in PV. The findings of the phase II trial RESPONSE and the preliminary data from RESPONSE 2 trial have identified a role for ruxolitinib in PV patients who are resistant or intolerant to HC. In this article, using clinical cases we demonstrate our experience with ruxolitinib highlighting the clinical benefits and limitations we encountered in clinical practice.

Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis.

We performed a meta-analysis to evaluate the risk of venous thromboembolism (VTE) in pregnant women with essential thrombocythemia. Twenty-one trials and 756 pregnancies met inclusion criteria. The absolute VTE risk in the antepartum period is not above a threshold where low-molecular-weight heparin (LMWH) prophylaxis is clearly indicated or below a threshold where LMWH should be withheld (2.5%; 95% CI, 1.3-4.3). Postpartum, the absolute VTE risk is above a threshold where postpartum LMWH prophylaxis should be considered (4.4%; 95% CI, 1.2-9.5).

Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study.

The reported higher risk of maternal and fetal complications in women with myeloproliferative neoplasms (MPN) poses challenge during pregnancy. A national prospective study of maternal and fetal outcomes of pregnant women with a diagnosis of MPN was undertaken via the United Kingdom Obstetric Surveillance System between January 2010 and December 2012. Fifty-eight women with a diagnosis of MPN were identified; 47 (81%) essential thrombocythaemia, five (9%) polycythaemia vera, five (9%) myelofibrosis and one (2%) MPN-unclassified. There were 58 live births. The incidence of miscarriage was 1·7/100 (95% confidence interval [CI]: 0·04-9·24) and the perinatal mortality rate was 17/1000 (95% CI: 0·44-92·36) live and stillbirths. Incidence of maternal complications was 9% (5/57) pre-eclampsia, 9% (5/57) post-partum haemorrhage and 3·5% (2/57) post-partum haematoma. There were no maternal deaths or thrombotic events. Delivery was induced in 45% (24/53) of women and the Caesarean section rate was 45% (24/53). The majority (85%, 45/53) delivered at term (>37 weeks gestation). Twenty-two percent (12/54) of neonates were below the 10% centile for growth and 13% (7/54) required admission to a neonatal care-unit; there were no neonatal deaths. The findings of this large, UK prospective study suggests women with MPN appear to have successful pregnancies with better outcomes than would be anticipated from the literature.

Disease characteristics and outcomes in younger adults with primary and secondary myelofibrosis.

Myelofibrosis (MF) is a rare haematopoietic disorder, commonly diagnosed in the 6th decade: less than 20% are diagnosed before the age of 50 years. In this retrospective study we included all patients given a diagnosis of World Health Organization-defined primary or secondary MF when aged ≤50 years. Forty-three patients with a median age of 43 years were included. Median follow up was 44 months. Twenty-two (51%) harboured the JAK2 V617F mutation, 18/43 (42%) CALR, 0/43 (0%) MPL mutations and 3/43 (7%) were 'Triple Negative' (TN). At the time of diagnosis, no significant differences existed in haematological and clinical phenotypes between JAK2, CALR and TN patients. The frequency of splenomegaly was greater (P = 0·047) in the JAK2-mutated group compared to CALR-mutated patients. In the whole cohort, the 5-year probability of developing anaemia, thrombocytopenia and marked leucocytosis was 24%, 10% and 13% respectively. Finally, the cumulative incidence of thrombotic events and progression to acute myeloid leukaemia was 1% and 0·5% patient-year respectively. No death was reported during the follow-up. These findings suggest that MF in younger patients may have a more indolent course when compared to older patients.

How we diagnose and treat essential thrombocythaemia.

The approach to the diagnosis and management of essential thrombocythaemia (ET) is steadily changing, influenced by advances in molecular biology, data from clinical trials and retrospective analyses of patient cohorts. In the past decade options for clinical management largely remain unchanged, but who we treat, and with what target in mind, is evolving. A further area of change is recognition of symptoms that may be associated with ET, as well as other myeloproliferative neoplasms, and that potential options for their management are becoming available. Judicious and careful diagnosis is increasingly a fundamental key to successful management followed by cytoreductive therapy in a subset of patients. In this review we demonstrate our management strategies for ET using a case-based format.

The use of JAK inhibitors for low-risk myelofibrosis.

Myelofibrosis is a heterogeneous disorder, which, although sometimes asymptomatic in the early stages, is frequently associated with debilitating constitutional symptoms, poor quality of life and high degree of morbidity as the disease progresses. Ruxolitinib, a JAK1/2-inhibitor, has transformed the management of many patients by reducing disease-related symptoms and splenomegaly in intermediate-2 and high-risk patients. As demonstrated by the COMFORT studies, unprecedented clinical benefit can be gained by some patients on ruxolitinib; however, this is not without potential adverse effects, notably cytopenias, weight-gain and an increased risk of opportunistic infections. No other JAK inhibitors are currently approved for myelofibrosis. Moreover, long-term effects of JAK-inhibitor agents, such as ruxolitinib, remain unknown. Consequently, the use of ruxolitinib in the low-risk patient, in the absence of high symptom burden remains controversial and requires further randomized clinical trials. In such patients, an individualized approach should be adopted, balancing likely clinical benefit with the potential side-effect profile.