Vascular diseases in patients with chronic myeloproliferative neoplasms:Impact of comorbidity

Background: Patients with chronic myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are at high risk of vascular complications. However, the magnitude of this is risk not well known and the possible effect of comorbidity is poorly understood. Aim: Our aim was to compare the risk of vascular diseases in patients with MPNs and matched comparisons from the general population and to study the effect modification of comorbidity. Methods: We followed 3087 patients with ET, 6076 with PV, 3719 with PMF or unspecified MPN, and age- and sex-matched general population comparisons to estimate the risks of cardiovascular diseases such as myocardial infarction and stroke. We computed 5-year cumulative incidences (risks) for vascular disease in patients with MPNs and comparisons as well as 1-year and 5-year risks, risk differences, and hazard ratios (HRs) for vascular diseases comparing rates in each group of patients with their comparison cohort by level of comorbidity based on the Charlson Comorbidity Index (CCI) [score of 0 (low comorbidity), of 1–2 (moderate comorbidity), and of >2 (severe comorbidity)], as well as other comorbid conditions. Results: The overall 5-year risk of vascular disease ranged from 0.5% to 7.7% in patients with MPNs, which was higher than the risk in the general population. In the same period, the adjusted HRs for vascular disease were 1.3 to 3.7 folds higher in patients with MPNs compared to the general population. An increase in CCI score was associated with an equally increased rate of most types of vascular diseases during the first 5 years of follow-up in both MPN and comparisons. Conclusion: Patients with MPNs have a higher risk of vascular diseases during the first 5 years than that of the general population; however, comorbidity modifies the rates similarly in MPN and in the general population

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

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