Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases including polycythemia vera (PV), essential thrombocythemia (ET), and primary(idiopathic) myelofibrosis (PMF). In this systematic review, we provide a comprehensive report on the incidence and prevalence of MPNs across the globe. Electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) were searched from their inception to August 2012 for articles reporting MPN incidence or prevalence rates. A random effects meta‐analysis was undertaken to produce combined incidence rates for PV, ET, and PMF. Both heterogeneity and small study bias were assessed. Thirty‐four studies were included. Reported annual incidence rates ranged from 0.01 to 2.61, 0.21 to 2.27, and 0.22 to 0.99 per 100,000 for PV, ET, and PMF, respectively. The combined annual incidence rates for PV, ET, and PMF were 0.84, 1.03, and 0.47 per 100,000. There was high heterogeneity across disease entities (I2 97.1–99.8%) and evidence of publication bias for ET and PMF (Egger test, P = 0.007 and P ≤ 0.001, respectively).The pooled incidence reflects the rarity of MPNs. The calculated pooled incidence rates do not reflect MPN incidence across the globe due to the high unexplained heterogeneity. Improved, widespread registration of MPNs would provide better information for global comparison of the incidence and prevalence of MPNs. Am. J. Hematol. 89:581–587, 2014. © 2014 Wiley Periodicals, Inc.

How common are the myeloproliferative neoplasms: a systematic review and meta-analysis.

Chemotherapy remains a widely used cancer treatment. Acquired drug resistance may greatly reduce the efficacy of treatment and means to overcome it are a topic of active discussion among researchers. One of the proposed solutions is to shift the therapeutic paradigm from complete eradication of cancer to maintenance, i.e., to treat it as a chronic disease. A concept of metronomic therapy (low chemotherapy doses applied continuously) emerged in early 2000s and was henceforth shown to offer a number of benefits, including targeting endothelial cells and reducing acquired drug resistance. Using mathematical modeling and optimal control techniques, we investigate the hypothesis that lower doses of chemotherapy are beneficial for patients. Our analysis of a mathematical model of tumor growth under angiogenic signaling proposed by Hahnfeldt et al. adapted to heterogeneous tumors treated by combined anti-angiogenic agent and chemotherapy offers insights into the effects of metronomic therapy. Firstly, assuming constant long-term drug delivery, the model suggests that the longest survival time is achieved for intermediate drug doses. Secondly, by formalizing the notion of the therapeutic target being maintenance rather than eradication, we show that in the short term, optimal chemotherapy scheduling consists mainly of a drug applied at a low dose. In conclusion, we suggest that metronomic therapy is an attractive alternative to maximum tolerated dose therapies to be investigated in experimental settings and clinical trials.

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Angiogenesis and chemotherapy resistance: optimizing chemotherapy scheduling using mathematical modeling

New Perspectives of Interferon-alpha2 and Inflammation in Treating Philadelphia-negative Chronic Myeloproliferative Neoplasms.

Heterogeneity of stem cell clones provide a key ingredient in altered hematopoiesis and is of main interest in the study of predisease states as well as in the development of blood cancers such as chronic myeloid leukemia (CML) and the Philadelphia-negative myeloprofilerative neoplasms (MPNs). A mathematical model based on biological mechanisms and basic cell descriptors such as proliferation rates and apoptosis rates is suggested, connecting stem cell dynamics with mature blood cells and immune mediated feedback. The flexible approach allows for arbitrary numbers of mutated stem cell clones with perturbed properties. In particular, the stem cell niche provides a competition between wild type and mutated stem cells. Hence, the stem cell niche can mediate suppression of the wild type clones and up-regulation of one or more malignant clones. The model is parameterized using clinical data to show typical disease progression in several blood cancers and the hematological and molecular response to treatment. Intriguingly, occasional oscillatory cell counts observed during treatment of CML and MPNs can be explained by heterogeneous stem cell clone dynamics. Thus, the vital heterogeneous stem cell dynamics may be inferred from mathematical modeling in synergy with clinical data to elucidate hematopoiesis, blood cancers and the outcome of interventions.

Dynamics of competing heterogeneous clones in blood cancers explains multiple observations - a mathematical modeling approach

Conventional cytoreductive therapy for patients with chronic Philadelphia‐negative myeloproliferative neoplasms (MPNs) includes hydroxyurea (HU), interferon‐alpha2 (IFN), and anagrelide. HU is worldwide the most used cytoreductive agent, which lowers elevated blood cell counts within days in the large majority of patients. However, some patients may experience rebound cytosis when HU is reduced due to cytopenia, thereby potentially giving rise to fluctuating cell counts during therapy. Such rapid oscillations may be harmful and potentially elicit thrombosis. Treatment with IFN gradually lowers elevated cell counts within weeks and when the dosage is reduced, the cell counts do not rapidly increase but are sustained within the normal range in the large majority of patients. Conventional hematological response criteria are among others based upon single absolute cell count values and do not take into account the relative decreases toward normal for each cell count.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cam4.5285

A novel integrated biomarker index for the assessment of hematological responses in MPNs during treatment with hydroxyurea and interferon‐alpha2

(1) Background: myeloproliferative neoplasms (MPNs) are slowly developing hematological cancers characterized by few driver mutations, with JAK2V617F being the most prevalent. (2) Methods: using mechanism-based mathematical modeling (MM) of hematopoietic stem cells, mutated hematopoietic stem cells, differentiated blood cells, and immune response along with longitudinal data from the randomized Danish DALIAH trial, we investigate the effect of the treatment of MPNs with interferon-α2 on disease progression. (3) Results: At the population level, the JAK2V617F allele burden is halved every 25 months. At the individual level, MM describes and predicts the JAK2V617F kinetics and leukocyte- and thrombocyte counts over time. The model estimates the patient-specific treatment duration, relapse time, and threshold dose for achieving a good response to treatment. (4) Conclusions: MM in concert with clinical data is an important supplement to understand and predict the disease progression and impact of interventions at the individual level.

/pdf/mathematical-modeling-of-mpns-offers-understanding-and-2mm7swlmeo.pdf

Mathematical Modeling of MPNs Offers Understanding and Decision Support for Personalized Treatment

BACKGROUND Hydroxyurea (HU) treatment of patients with essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) (MPNs) normalizes elevated blood cell counts within weeks in the large majority of patients. Studies on the impact of HU upon the kinetics of the JAK2V617F allele burden, leukocyte, and platelet counts over time are scarce. PURPOSE Using data-driven analysis as a novel tool to model the kinetics of the JAK2V617F allele burden and blood cell counts over time during treatment with HU. MATERIAL AND METHODS Using serial measurements of JAK2V617F and correlation analysis of routine hematological values (the Hb-concentration, leukocyte count, platelet count, and lactic dehydrogenase), we present a detailed description and analysis of the kinetics of the JAK2V617F, leukocyte, and platelet counts and lactic dehydrogenase in 27 patients (PV = 18; ET = 7; PMF = 2), who were followed in the Danish randomized trial (DALIAH). To further analyze the JAK2V617F kinetics, we use a machine learning clustering algorithm to group the response patterns. RESULTS Response patterns were highly heterogeneous, with clustering resulting in 3 groups and 3 outliers. In the large majority of patients, HU treatment was initially associated with a modest decline in the JAK2V617F allele burden in concert with a decline in leukocyte and platelet counts. However, HU did not induce a sustained and continuous decrease in the JAK2V617F allele burden. CONCLUSION Using data-driven analysis of the JAK2V617F allele burden, leukocyte, and platelet kinetics during treatment with HU, we have shown that HU does not induce a sustained decrease in the JAK2V617F allele burden and neither induces sustained normalization of elevated cell counts in MPN patients. Our results may explain why MPN patients during treatment with HU still have a substantially increased risk of thrombosis.

Data-driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

Marc John Bordier Dam

Papers

Mathematical Modeling of MPNs Offers Understanding and Decision Support for Personalized Treatment

Data-driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis.