Life expectancy of patients with Chronic Myeloid Leukemia approaches the life expectancy of the general population
Bower H, et al. J Clin Oncol. 2016;34:2851-2858

Background:

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm (MPN) resulting from a chromosomal translocation that subsequently leads to the constitutive activation of the tyrosine kinase BCR-ABL1. If untreated CML is fatal and median survival is expected to be 2-3 years. Therefore, for the 90% of Swedish patients who are diagnosed in the chronic phase of disease, a major goal is to avoid disease progression to the advanced phases. Treatment of CML improved dramatically with the development of tyrosine kinase inhibitors (TKIs) that specifically target the BCR-ABL1 oncoprotein, increasing patient quality of life and survival. Although a positive step in the treatment of CML, it will be important to consider the effect of life-long treatment with TKIs and understand the effect of cancer diagnosis on patient life expectancy and the loss of expectation of life (LEL), a survival measure that represents the reduction in life expectancy as a result of cancer diagnosis.

Aim:

The aim of this investigation was to assess the changes in CML patient life expectancy and LEL over a 40-year period in Sweden, particularly following the introduction of TKIs.

Method:

  • Patients diagnosed between 1973 and 2013 from the nationwide Swedish Cancer Registry were included in the study
  • Patients were followed until death, emigration or the end of the study period
  • Patients were included if aged 50+ at diagnosis to avoid long extrapolation when calculating LEL
  • LEL is the difference between patient life expectancy and that of a similar individual in the general population. The proportion of remaining life years lost as a result of cancer diagnosis (PELL) was also considered. The LEL and PELL were predicted using a relative survival model

Results:

The median age of CML diagnosis of the 2662 study patients was 69 years. Life expectancy for both the general population and the CML study group increased over the follow-up period. Younger patients saw a large increase in life expectancy after 1990, especially between 1990-2000. Life expectancy of those aged 55 at diagnosis continued to increase until the end of the study period. By 2013 the life expectancy of the study group approached that of the general population. LEL decreased for all age groups over the length of the investigation, with the most significant decrease being in younger patients diagnosed after 1990. PELL estimates also suggested a dramatic improvement in CML patient outcomes at all ages.

Conclusion:

A significant reduction was made to life-years lost in CML patients diagnosed in Sweden between 1973 and 2013. There were significant benefits for patients aged 55 when diagnosed since 1990 and results indicate that CML patients now have a life expectancy similar to the general population. However, there are reports of an increased incidence of other cancers in TKI users and 10% of CML patients in Sweden are not diagnosed until the advanced phase of the disease, therefore it is unlikely CML patients will ever reach the life expectancy of the general population. Although some patients have been able to stop taking TKI medication, the majority will have to continue to medicate for life. Generally, this course of treatment is considered an acceptable cost by most health authorities. Through use of the Swedish Cancer Registry, it has been possible to determine that excellent progress has been made in CML treatment, through TKIs and allogenic stem cell treatment, to bring the life expectancy of this group of patients close to that of the general population.

 

Associations between gender, disease features and symptom burden in the MPN population: An analysis by the MPN QOL International Working Group
Geyer HK, et al. Hematologica. 2016; Epub ahead of print

Background:

Polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are all debilitating myeloproliferative neoplasms (MPNs). The impact of gender on MPN development and progression is interesting as sex differences are becoming apparent e.g. the increased prevalence of females with ET and males with PV. It is recognized that genotypic expression, clonal expansion and allele burden may differ between genders, yet little is known about how gender relates to symptomatic profiles. Tools such as the Myelofibrosis Symptom Assessment Form (MF-SAF), Myleoproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and MPN-10 enable quantification of symptom burden and quality of life.

Aim:

The investigation aim was to identify associations between gender, patient symptoms, disease features, laboratory abnormalities and overall quality of life.

Method:

  • 2006 patients were recruited from an international cohort and asked to fill in the MPN-SAF and the Brief Fatigue Inventory (BFI)
  • Symptom evaluation was carried out to assess patient perception of common MPN-symptoms and overall quality of life
  • The International Prognostic Scoring for Essential Thrombocythemia (IPSET), Leukemia 2013 prognostic scoring model and Dynamic International Prognostic Scoring System (DIPSS) were used for prognostic scoring of ET, PV and MF patients respectively

Results:

2006 MPN patients (711 PV, 830 ET and 460 MF patients) were enrolled, including 917 males and 1089 females. As expected the prevalence of MPN subtype differed between genders with most females (48.6%) diagnosed with ET, then PV (30.3%) and least with MF (21.2%) whereas the largest male MPN cohort was diagnosed with PV (41.8%) then ET (33.0%) then MF (25.2%). Females displayed higher platelet counts compared to males who had higher hemoglobin and white blood cell counts. Symptom assessment identified that females assigned their symptoms higher scores than males, both overall and for individual variables, although fatigue was the most severe symptom for both genders. Symptoms were also considered in relation to religion/culture by comparing Western and Chinese cohorts. Female Chinese patients were found to report the most severe symptoms particularly for sexuality related complaints. Chinese males also reported more severe symptoms compared to Western males although both scored sexuality concerns and fatigue as the worst symptoms.

Conclusion:

This investigation highlighted the importance of gender in haematological malignancies, through symptomatic reporting and gender specific variation in MPN subtype prevalence. It is suggested prevalence differences may result from the gender specific variation in circulating sex hormones. The higher symptom burden reported by females may be explained by females experiencing more undetected microvascular events, indicated by the high scoring of certain symptoms. It is unclear if the reported cultural differences in symptom burden are due to alternative cultural expression or true phenotypic differences between races. It is possible that the overall gender variation in symptom burden could arise from reporting discrepancies e.g. if females have a greater bodily vigilance and/or males are socially encouraged to limit the expression of discomfort. Regardless, females expressed the same quality of life as males, which may signify that females can counteract their larger burden or they are more adept at highlighting their complaints. Further investigation is needed to explore gender differences in disease progression and prevalence of driver mutations. These findings will be important when considering disease heterogeneity and future treatment.

 

Prognostic value of CALR vs. JAK2V617F mutations on splenomegaly, leukemic transformation, thrombosis, and overall survival in patients with primary fibrosis: a meta-analysis
Pei YQ, et al. Ann Hematol. 2016;95(9):1391-1398

Background:

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by clonal myeloproliferation derived from stem cells, bone marrow fibrosis and abnormal cytokine expression. The JAK2V617F and CALR mutations have been found in 60% and 15-35% of PMF cases respectively. These two mutations are almost completely exclusive of each other in PMF patients and appear to have distinct genotypes, however the exact features of these two genotypes are ambiguous, particularly in JAK2V617F mutated individuals.

Aim:

The investigation aim was to compare clinical complications of PMF to understand the JAK2V617F and CALR genotypes.

Method:

  • A search of Pubmed, Embase and Web of Science was carried out to find studies that evaluated the association of CALR-mutated and JAK2-mutated PMF
  • 2 reviewers selected the studies
  • Data for meta-analysis was based on patient characteristics including incidence of splenomegaly, leukemic transformation and thrombosis

Results:

After study evaluation and selection, 12 studies were included in the meta-analysis, encompassing a total of 1551 PMF patients, of which 1116 had a JAK2 mutation and 435 had a CALR mutation. CALR mutated PMF patients were generally younger and had lower white blood cell counts. Studies that included data on splenomegaly showed 80/114 CALR mutated patients and 259/317 JAK2 mutated patients had palpable spleens and random effect modelling confirmed that CALR mutated patients were less likely to suffer splenomegaly compared to those with a JAK2 mutation. Modelling also found no significant difference in the rate of transformation to leukemia between the two mutation groups. However, modelling also revealed CALR mutated patients were at a lower risk of thrombosis and had a better overall survival rate compared to the JAK2 mutated group.

Conclusion:

This study demonstrates the genetic classification of PMF and how this is relevant to both diagnosis and prognosis of the disease. A CALR mutation indicates a lower risk of splenomegaly and thrombosis compared to JAK2 mutated patients. No significant difference was found in the incidence of thrombotic transformation between the two mutation groups, which contradicts the findings of other studies. However, these differences only confirm the known variability in clinical PMF features and the need for large, multi-regional studies. The increased value of mutational status suggests it should be included in the existing prognostic scoring systems, as patients with a JAK2 mutation may require additional considerations. If included, further genetic classification may be required as it has been indicated that the positive prognosis associated with a CALR mutation may result from a type1 (L367fs*46) CALR mutation but not a type2 (K385fs*47). Therefore, it will be important to clarify the type of CALR mutation for accurate prognosis. Additional investigations will be needed to further clarify how mutational status should be considered when designing clinical trials and in the clinical decision making process.

Clinical characteristics of cerebrovascular pathology with patients suffering from Ph-Negative Myeloproliferative Disease
Tanashyan MM, et al. Cerebrovasc Dis. 2016;6:66-70

Background:

Cerebrovascular disease (CVD), both acute and chronic, is the second largest cause of death in the world. As CVD presents high rates of disability, financial burden and mortality it is important to understand broad aspects of etiology, clinical characteristics and progression of vascular brain pathology. CVD is often accompanied by rheological abnormalities, e.g. an increase in the proliferation of a myelopoietic cell line, as seen in patients with Ph-negative myeloproliferative neoplasms (MPNs). High hematocrit rate dramatically increases the risk of thrombotic complications and if this occurs in the carotid or vertebrobasilar region with hemispheric infarction it can be life-threatening. Mortality rates in MPN patients are 1.5 times higher than the general population, making it important to understand the mechanisms of both large and small thrombotic events.

Aim:

The aim of this study was to determine the clinical and laboratory features of CVD in MPN patients.

Method:

  • 167 patients (102 with MPNs and 65 controls with CVD) (those with advanced cardiac disease were excluded) were assessed clinically and neurologically by MRI brain scan, MR angiography, MR imaging of the cerebral venous sinuses, duplex sonography, blood tests and a biochemical tourniquet test
  • MPN patients were diagnosed as having essential thrombocythemia (ET), polycythemia vera (PV) or primary myelofibrosis (PMF) and compared to the control group

Results:

79% of MPN patients developed chronic CVD, displaying symptoms such as asthenia and headache (the latter being particularly prevalent in PMF patients). 53% of chronic CVD cases displayed neurological symptoms that corresponded to focal changes in the brain, identified by MRI scan to be located in the subcortical area of the frontal and parietal lobes. 21 patients had an acute cerebrovascular accident and 8 had thrombotic occlusion of an internal carotid artery (ICA) followed by a hemispheric infarct. 13 patients had small cortical infarctions possibly related to hemorheological micro-occlusion. MPN patients who suffered from CVD differed significantly in erythrocyte deformability characteristics and displayed higher hematocrit values compared to the control CVD group. Patients with MPNs showed significantly lower endothelial dysfunction rates in comparison to the CVD control group. The athrombogenic potential was reduced due to anti-aggregational and fibronolytical components, yet the anticoagulation function of the endothelium was unaltered.

Conclusion:

CVD may be the initial indication of MPN. Chronic brain ischemia often first displays itself as a headache or asthenia, as seen in both this investigation and studies of PV and ET patients where these were the initial indications of MPN. In MPN patients a headache is often of a secondary origin and is connected to platelet count. MPN patients present with focal changes in the frontal and parietal lobes and this is suggested to occur due to the vascular architecture of the terminal branches at the middle of the cerebral artery which are thrombosis prone. It is of concern that MPN patients suffer from asymptomatic focal changes in the brain in the absence of previous vascular disease as this suggests MPNs if undiagnosed, can be a serious cerebrovascular issue.

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