Spleen enlargement is a risk factor for thrombosis in essential thrombocythaemia: evaluation on 1,297 patients.
Adriani A, et al. Am J Hematol. 91:318-321.

Background:

Essential thrombocythaemia (ET) is usually characterized by persistently high platelet counts. There have been numerous studies investigating the risk factors for thrombosis within this disorder, however few have investigated the impact of splenomegaly on thrombosis. Currently it is known that 5-20% of patients diagnosed with ET have a mild to moderate spleen enlargement.

Aim:

The investigation looked at spleen enlargement in relation to baseline disease characteristics and outcome with particular focus on thrombotic risk.

Method:

  • A retrospective analysis was carried out on data acquired from patients diagnosed with essential thrombocythaemia between January 1979 and December 2013
  • The analysis focused on spleen size, JAK2 mutation and cardiovascular risk factors (CVRF)
  • Diagnosis of ET was carried out using both the Polycythemia Vera Study Group (PVSG) criteria prior to 2001 and the World Health Organisation (WHO) criteria post 2001
  • Spleen enlargement was defined as a palpable spleen under costal margin. The presence of the JAK2 allele was checked with polymerase chain reaction (PCR) and CV risk factors were recorded

Results:

Out of the 1,297 patients that were evaluated, 172 were found to have enlarged spleen of which 94.7% of the cases were palpable ≤ 5 cm below the costal margin. The majority of the patients that presented with an enlarged spleen were younger and predominantly male, with elevated platelet counts. The overall rate of thrombosis was significantly higher in patients with palpable splenomegaly (15.7% versus 8.6%, p=0.003). Other base line features such as the International Prognostic Score for Essential Thrombocythaemia (IPSET) (p=0.053), presence of CV risk factor (p=0.066) and age ≥ 60 years showed a trend for association with thrombotic risk. On contrary, the JAK2 mutation did not show this association in the investigation.

Conclusion:

The significant and independent association of splenomegaly and thrombotic risk has led to a plausible hypothesis that spleen enlargement could identify a particular subset of patients at greater risk of thrombosis. For the purpose of the study the distinction between ET and early-PMF was not of pivotal importance when looking at thrombotic risk factors, since incidence of thrombosis has been reported comparable between the two clinical entities.

Current opinion and consensus statement regarding the diagnosis, prognosis and treatment of patients with essential thrombocythemia: survey of the Spanish Group of Ph-negative Myeloproliferative Neoplasms (GEMFIN) using the Delphi method.
Besses C, et al. Ann Hematol. 2016;95:719-32.

Background:

The criteria for the World Health Organisation (WHO) for diagnosing essential thrombocythaemia (ET) is the presence of persistent thrombocytosis (> 450 x 109/L) along with hyperplasia of mature megakaryocytes. Controversies have arisen with different mutational status in ET and the potential impact it has on diagnosis, prognosis and management of patients.

Aim:

The investigation looked at two steps:
1.  The opinion and degree of consensus on current approaches on diagnosis, prognosis and treatment of ET patients using the Delphi technique
2. How the ELN guidelines concerning ET are perceived amongst MPN experts in Spain

Method:

  • The investigation utilized the Delphi method, collating a number of questionnaires from a select panel of individuals
  • Answers to the questionnaires (consisting of 80 questions) were anonymous and participants were allowed to reassess their own answers
  • A panel of leading experts on MPNs from the Spanish Group of Ph-negative Myeloproliferative Neoplasms (GEMFIN) created the questions which were subdivided into 4 categories
    • Diagnosis
    • Risk stratification
    • Treatment goals
    • Treatment strategy

Results:

A positive consensus was observed in diagnosis amongst the Spanish haematologists for a molecular analysis for the mutations JAK2V617F, CALR and MPL. The significance of identification of prefibrotic primary myelofibrosis in MPN histology was also found to be a common opinion shared by the participants.  Certain diagnostic techniques such as isotopic red blood cell mass measurement and in vitro culture of haematopoeitic progenitors were not considered to be as useful. When looking at risk stratification, the history of thrombosis and assessment of cardiovascular risk factors were both considered as important clinical variables to be measured. An interesting result to note was the positive trend for the creation of an intermediate risk category, which currently is not supported by the ELN guidelines. The general treatment goals established by the ELN guidelines seemed to be widely accepted along with the need to start cytoreductive therapy where thrombocytosis resulted with platelets (> 1500 x 109/L). There was a disagreement however when looking at the need to normalize leukocyte counts.

Conclusion:

The survey provided a country perspective from specialists in MPNs regarding academic literature and also showed a general acceptance of the ELN guidelines. The majority of the participants adopted a practical approach that is adapted to guidelines and recommendations.

Closing the gap: genetic landscape of MPN.
Harrison CN and Vannucchi AM, Blood. 2016;127:276-278.

Review:

The concept of ‘triple negative’ mutational status was first used for breast cancer patients where their tumours were negative for oestrogen or progesterone (receptors) and HER2 mutations. This didn’t turn out to be completely correct as other pathogenic mutations were slowly being discovered. Professors Harrison and Vannucchi reviewed two publications:

  • Milosevic Feenestra JD, et al. Blood. 2016;127:325-332
  • Cabagnols X, et al. Blood. 2016;127:33-342

Both publications were reviewed from this viewpoint when looking at these polyclonal disorders in MPNs. Milosevic Feenestra et al.  assessed granulocytes and T-lymphocytes of 8 ‘triple negative’  essential thrombocythaemia (ET) and primary myelofobrosis (PMF ) patients with whole exon sequencing (WES). A novel MPL mutation was found in 1 on the patients which prompted in an additional 61 ‘triple negative’ ET and PMF patients being assessed, this time with the Sanger sequencing method. This revealed additional mutations including novel JAK2 mutations. These newly discovered mutations seemed to have a milder effect on the gain of function in the JAK2 signaling pathway.  The second study from Cabanols et al. initially looked at 17 patients who were ‘triple negative’ using WES. Specific focus was given to both JAK2 and MPL mutations and as per Milosevic Feenestra et al. similar mutations were discovered which also contributed to a weak effect on gain of function mutations. The findings from both studies revealed that possibly a review for a reclassification of diagnosis could up for discussion. The discovery of these mutations was a result of targeted deep sequencing, which is not always applicable in clinical practice.

Myeloproliferative neoplasms (MPNs) have a significant impact on patients’ overall health and productivity: the MPN landmark survey.
Mesa R, et al. BMC Cancer. 2016;16:167.

Background:

There have been several queries into the disease burden of Phildaelphia-negative myeloproliferative neoplasms (MPNs). There is currently limited data on the impact of MPNs on daily living of affected individuals.

Aim:

The MPN Landmark survey looked to evaluate the disease burden in patients with Philadelphia chromosome negative MPNs.

Method:

  • Patients in the US who were already diagnosed with Myelofibrosis (MF), Polycythemia vera  (PV) or Essential thrombocythaemia (ET), were recruited through physicians’ offices, advocacy groups and or media campaigns
  • A 65 multiple choice questionnaire web base survey was provided to each of the participants. A total of 813 participants (MF–n=207, PV-n=380, ET-n=226) completed the survey
  • Questions were based on 5 categories: 1) Respondent demographic 2) Disease features 3) Symptom burden 4) Disease burden based on QoL 5) Current treatment management.
    MPN related symptoms were measured via the MPN assessment form (MPN-SAF) using a scale from 0 (symptoms absent) to 5 (symptoms overtly present)

Results:

The median age of the respondents between each of the MPNs was similar (MF – 66 years, PV – 64 years, ET – 62 years). From collecting information on medical history via the survey, it was seen that the majority of the respondents had a prognostic risk score that was intermediate/high. Most of the symptoms experienced by the participants were recorded at diagnosis of their MPN (MF-78%, PV-88%, ET-81%) with fatigue being the most frequent. Participants with PV and ET stated that their most common symptoms such as fatigue and headaches manifested at least 1 year before their diagnosis. Over 45% of the participants from each of the groups reported that their daily activities were limited by pain/discomfort. Other characteristics were identified as having an impact on QoL such as depression, stress and altered sleeping habits to name a few.  Fatigue was the main symptom that most respondents from all the MPN groups wanted to resolve. Many respondents, even those who had a low calculated prognostic risk, were reported to reduce their working hours and/or call in sick at least once in 30 days. One of the biggest limitations of the study was the design of self-reporting of the survey making it not possible to confirm the clinical aspects of the patients’ medical history.

Conclusion:

Patients with MPNs do seem to experience a broad symptom burden that has a marked impact on daily activities and quality of life. The symptoms that patients experience, related to MPNs can be informative in an early diagnosis and assessing the clinical needs of the patient. Results from the study itself also indicate that disease burden experienced by patients with MPNs and low prognostic risk scores is under-reported. The findings reported in the survey, further substantiate previous research on symptom burden experienced by patients.  In addition the results highlight the challenges that patients with MPNs face, resulting in a reduction of their daily activities and word productivity.

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