Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study
Alimam S, et al. BJH. 2016;175:31-36

Background:

Myeloproliferative neoplasms (MPNs) including primary myelofibrosis (PMF), essential thrombocythaemia (ET) and polycythaemia vera (PV), are associated with increased incidence of haemorrhage and thrombosis, progression to myelofibrosis (MF) and acute myeloid leukaemia (AML). MPNs most frequently occur in the later decades of life but they can occur in patients of childbearing age, particularly ET. MPN prevalence in pregnancy is increasing as a result of the increased availability of diagnostic tools and a higher maternal childbearing age. There are several potential issues when managing MPNs in pregnancy, including an increased risk of maternal haemorrhage, thrombosis and loss of pregnancy. As there is no international agreement for the management of MPN in pregnancy, the management of pregnant women with acquired thrombophilia is used as a basis for treatment plans. Women are currently risk stratified into either standard or high risk groups and treated based on this assignment.

Aim:

The aim of this large prospective study was to estimate the UK incidence of pregnancies in MPN patients and to report on maternal and perinatal outcomes of current management.

Method:

  • The UK Obstetric Surveillance System (UKOSS) was used in this UK wide multicenter cohort study to collect data and identify patients between January 2010 and December 2012
  • Maternal demographics and characteristics, antenatal and postnatal maternal complications and perinatal outcomes were all recorded
  • Fetal losses before 24 weeks, rate of still birth, early neonatal death and perinatal mortality were all calculated per 1000 total births

Results:

58 pregnant women with a confirmed MPN were included in the study. ET accounted for 81% of these women and only 9% had PV, the same incidence rate as for MF. For the 48 women where information on JAK2V617F mutational status was available, 58% were positive. Prior to pregnancy half of the women were being treated with prophylactic aspirin and 31% were prescribed cytoreductive therapy either alone or in combination. During pregnancy 88% of women were treated with aspirin and over a third were also prescribed low molecular weight heparin. Antenatal complications included pre-eclampsia in five women, four of whom were receiving aspirin treatment. 74% of women went into labour, 45% were induced and 45% had caesarean sections. Of the 58 (2 incidences of twins) women, there was one miscarriage, 58 live births and one still birth.

Conclusion:

In this study of pregnant MPN patients there was increased maternal and fetal risk compared to the general population, independent of MPN type or JAK2V617F positivity, in line with the lack of consensus in the current literature. Physicians need to recognise that a maternal MPN may negatively affect fetal outcomes and can increase the likelihood of still birth, pre-eclampsia, caesarean section and post-partum haemorrhage. It is therefore important to manage MPN pregnancies as high risk. Most women in the study had a successful birth at term, however many of the infants were small for gestational age, suggesting a placental dysfunction. The increased rate of unplanned caesarean section resulted from fetal distress emergencies. Many of the women in this study were on aspirin therapy during pregnancy however some were not, and the reason why is unclear. This shows the differences in management and local risk assessment of pregnant MPN patients. This finding, in conjunction with the large number of invasive maternal interventions, may highlight the lack of information on the optimum approach to managing pregnant women with MPNs and the need for collaboration between haematology and obstetrics. Overall this study shows that positive maternal and fetal outcomes can be achieved in MPN pregnant women and that cooperative networking could enable the development of optimal management in the future that should be tested in randomised controlled trials.

Laboratory Investigation of Myeloproliferative Neoplasms (MPNs)
Recommendations of the Canadian MPN Group
Busque L,, et al. Am J Clin Pathol. 2016; 146:408-422

Background:

Recent discoveries in the molecular pathogenesis of MPN diseases such as essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) have led to the development of new diagnostic techniques and a need to streamline diagnostic approaches. Latest mutational data carries prognostic value and could assist in selecting appropriate therapeutic approaches and thus better treatment outcomes. Diagnostic criteria for MPNs is currently based on the 2008 World Health Organisation (WHO) classification which does not include the recently identified driver mutations in the calreticulin (CALR) or MPL genes which should be considered in recently published 2016 revision of WHO criteria.

Although focused on the Canadian reality, the recommendations of the author’s group can apply to many other countries that value cost-effectiveness data.

Aim:

This investigation aim was to homogenise MPN patient care in the most efficient and cost effective manner to standardise diagnostic procedure.

Method:

  • The expert consensus recommendations for the review of MPN diagnosis included clinical evidence, daily practice, existing treatment guidelines and availability of existing tools
  • Group members were each assigned a topic to discuss with the entire group at consensus meetings

Results:

The Canadian MPN group recommends that laboratory investigations for MPN diagnosis include a complete blood count, erythropoietin levels, peripheral blood smear and biochemistry tests. WHO criteria suggest raised hemoglobin/hematocrit levels, confirmed on two separate occasions, alongside suboptimal erythropoietin levels would indicate PV, however the Canadian MPN group suggests a higher hemoglobin level of 18.5 g/dL in men and 16.5 g/dL in women could serve as a sufficient cut off for diagnosis. A persistently elevated platelet count (>450 x103/µl) would indicate ET whereas anemia, splenomegaly and elevated LDH may suggest PMF. A pretreatment bone marrow examination is a core part of MPN patient diagnosis and should include age-matched bone cellularity, iron distribution, myeloblast description, granulopoiesis and erythropoiesis. The discovery of molecular markers of MPN disease has led to significant MPN investigation advances over the last few decades. If a patient is suspected of an MPN, they should then be tested for JAK2V617F mutations. If patients are JAK2V617F negative but meet criteria for ET or PMF they should also be screened for CALR mutations, whereas suspicion of PV should lead to screening for JAK2 exon 12 mutations. If patients suspected of ET or PMF are negative for JAK2V617F and CALR mutations they should then be tested for MPL, and triple negative patients should additionally be screened for BCR-ABL1. Ideally cytogenetic testing should be performed in all cases of MF and considered for PV/ET patients. Hemostasis evaluation of all patients should include basic coagulation screening, and screening for von Willebrand disease (vWD) should be carried out in patients with a platelet count above 1000 x103/µl as these patients may have an increased risk of bleeding.

Conclusion:

The latest molecular insights into MPNs has led to the development of new tests that should be included in routine diagnostics but only based on scientific evidence and according to the proposed cost-effective strategy. The new WHO 2016 PV diagnostic criteria should be used cautiously, as taking them at face value will lead to unnecessary testing for a large number of the healthy population. Precise MPN diagnosis will become more important due to the arrival of innovative therapeutics that could potentially change clinical outcomes for these disorders.

 

Erythromelalgia in patients with essential thrombocythemia and polycythemia vera
Hou J, et al. Leuk Lymphoma. 2016; [Epub ahead of print]

Letter to the editor:

Erythromelalgia is a neurovascular pain syndrome characterised by attacks of increased temperature, a burningsensation primarily in the feet and hands, erythema and reduced quality of life. This condition can arise in primary form or as a secondary symptom of an alternative disease, such as essential thrombocythemia (ET) or polycythemia vera (PV). Erythromelalgia may be the initial manifestation of a myeloproliferative neoplasm (MPN) therefore diagnosis should prompt MPN evaluation. It is proposed that in these cases erythromelalgia arises as a result of intravascular platelet activation causing arterial microcirculation occlusion, which aspirin can be effective in reducing. It therefore seems likely that the treatment of an underlying MPN may reduce the symptoms of erythromelalgia.

The study aimed to describe clinical and laboratory characteristics of erythromelalgia and the result of MPN treatment on secondary erythromelalgia in ET and PV patients. Bone marrow confirmation was carried out for ten ET patients and eight PV patients diagnosed with erythromelalgia. All patients, with the exception of one who was suffering from ET, were diagnosed with ET or PV simultaneously or prior to erythromelalgia. For five of the ten ET patients treatment details were available and confirmed that treating the MPN resolved or greatly reduced erythromelalgia symptoms. Control or reduction of symptoms was also seen in five of the eight PV patients, all five of whom were treated with phlebotomy.

The study described the clinical and laboratory characteristics and treatment responses of ET and PV patients with secondary erythromelalgia; of note, limitations of this report include its retrospective nature, small number of patients, tertiary care referral bias, and short follow-up. Aspirin and treatment of the MPN were both found to improve erythromelalgia in almost all patients, highlighting the need for further research into this rare disease and the importance of considering underlying causes such as ET and PV after diagnosis.

Differences in Treatment Goals and Perception of Symptom Burden Between Patients with Myeloproliferative Neoplasms (MPNs) and Hematologists/Oncologists in the United States: Findings from the MPN Landmark Survey
Mesa R, et al. Cancer. 2016; [Epub ahead of print]

Background:

There is limited data regarding patient and physician perception of the symptoms and treatment goals of myeloproliferative neoplasms (MPNs) even though these are diseases that have notable symptoms and negative impacts on quality of life (QoL). The MPN landmark survey was the first large observational study to assess MPN patient and physician perceptions. The initial report summarised the effects of MPNs on overall patient health and productivity, but it did not make a comparison between physician and patient perceptions, or evaluate data regarding treatment goals or satisfaction.

Aim:

The aim of this study was to carry out an additional analysis of the MPN landmark survey to establish if there were gaps between patient perception of their disease management and physician self-reported practices.

Method:

  • Patients previously diagnosed with myelofibrosis (MF), essential thrombocythaemia (ET) or polycythaemia vera (PV) in the United States were eligible to be included in the study
  • Hematology or oncology physicians who were in direct patient care and passed all eligibility requirements for the study were contacted to participate
  • Questionnaires specific to MF, PV or ET based on symptoms and QoL were used to gather data using questions from validated survey instruments such as the MPN Symptom assessment form (MPN-SAF)
  • The survey was completed online and interviews were only included if the survey was complete

 

Results:

207 MF, 380 PV and 226 ET patients and 457 physicians, who were treating on average 11 to 20 MPN patients, were included in the survey. Compared to physicians a smaller proportion of patients reported that they had been stratified by prognostic risk, asked about their most important symptom or discussed a full list of disease symptoms and its progression with their physician. Patients often did not recognise that their symptoms, such as difficulty sleeping, were related to their MPN whereas physicians attributed the majority of symptoms to the condition. Patients reported having symptoms at the point of diagnosis (MF: 81%, PV: 89%), whereas physicians recalled significantly fewer (50% of ET and PV). It was also recorded that patients attributed reductions in QoL to their MPN whereas physicians generally only did so if splenomegaly was severe. Interestingly, both physicians and patients strongly felt that MPNs were associated with functional impairments, such as difficulty concentrating. However, perceptions of treatment goals were misaligned as patients thought slowing the progression of the condition was the most important, whereas physicians chose symptom improvement and preventing thrombotic events. Both patients and physicians thought fatigue was the most important symptom to relieve in with all three types of MPN patient, although stroke was also highlighted for ET.

Conclusion:

This is the first study in the MPN setting to highlight the differences between patient and physician views on MPN prognosis, disease burden and treatment goal perception. It also shows how physicians can overestimate the ability of their patients to attribute their symptoms to their MPN. These findings suggest that patients may benefit from further education on their condition to communicate the key aspects of their disease and manage their expectations regarding their treatment. Managing expectations will be particularly important as many patients reported slowing disease progression as their primary treatment goal, however no current treatment options have been shown to delay or cure MPNs. Finally, access to effective therapy options that improve QoL may help to resolve communication problems between patients and physicians and improve overall patient satisfaction.

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