Avi Leader

Are platelet volume indices of clinical use? A multidisciplinary review

Abstract Platelet size correlates with platelet activity and can be assessed by platelet volume indices (PVI). The PVI, mean platelet volume (MPV), is universally available with routine blood counts by automated hemograms and therefore is an attractive index to study in clinical scenarios. PVI are useful in assessing the etiology of thrombocytopenia. In addition, a normal platelet distribution width in the setting of thrombocytosis is highly suggestive of a reactive etiology. Higher MPV is also associated with the presence of cardiovascular risk factors, chest pain due to acute coronary syndrome, and adverse outcome after acute coronary syndrome. Results from studies evaluating MPV in patients with peripheral artery disease, unprovoked deep vein thrombosis, and pulmonary embolism further advocate a potential role for MPV in identifying patients at high risk of thrombosis. Nevertheless, most of these data come from retrospective studies some of which have small study populations and confounding factors influencing platelet volume. Moreover, the cut-off values derived from these retrospective studies have not been validated prospectively. Despite the potential for clinical utility evident from these studies, the above-mentioned flaws together with technical problems in measuring MPV currently limit its clinical usefulness. Our review provides a perspective on PVIs potential clinical use.

Fertility considerations and preservation in haemato-oncology patients undergoing treatment

The improved survival rates among patients with haematological malignancies, such as lymphoma and leukaemia, are shifting areas of focus towards understanding and preventing treatment‐induced sequelae. Of these, infertility is one of the most devastating consequences for patients with reproductive potential. The degree of treatment‐induced gonadal dysfunction depends on age and gender‐related differences, the type and dosage of chemotherapy used and the field and cumulative dose of abdomino‐pelvic irradiation. There is also the interesting phenomenon of reduced pre‐treatment fertility among male lymphoma patients. At present, the only established methods of fertility preservation are cryopreservation of sperm, oocytes and embryos, as well as gonadal shielding and transposition of ovaries during irradiation. Several other methods, such as cryopreservation and subsequent transplantation of gonadal tissue and the gonadoprotective role of hormonal suppression, are under investigation. Pre‐pubertal patients present a unique constellation of fertility considerations, especially as embryo and sperm cryopreservation are not applicable to this age group.

Thyrotropin Levels Within the Lower Normal Range Are Associated With an Increased Risk of Hip Fractures in Euthyroid Women, But Not Men, Over the Age of 65 Years

CONTEXT The contemporary literature on the relationship between serum TSH levels and osteoporotic fractures in euthyroid individuals is limited by conflicting results and analyses conducted on a small number of fractures. OBJECTIVE Our objective was to examine the association between the normal range of variation of TSH and the incidence of hip fractures in male and female euthyroid patients aged 65 years or older. DESIGN AND SETTING We performed a population-based historical prospective cohort study within the Clalit Health Services population. PARTICIPANTS Clalit Health Services members aged ≥65 years with at least 1 TSH measurement during the year 2004. We excluded patients with preexisting hip fracture, thyroid disease, malignancy, or chronic kidney disease. OUTCOME MEASURES The primary outcome was hip fracture, and the secondary outcome was any other osteoporotic fracture. STATISTICAL ANALYSIS Adjusted odds ratios comparing episodes of each outcome across 3 TSH groups (low, 0.35-1.6 mIU/L; intermediate, 1.7-2.9 mIU/L; high, 3-4.2 mIU/L) were generated using logistic regression models. RESULTS The 14 325 included participants suffered from 514 hip fractures (mean follow-up, 102 ± 3 months). Women, but not men, in the lowest TSH group had a higher incidence of hip fractures (odds ratio = 1.28, 95% confidence interval = 1.03-1.59, P = .029) when compared with the intermediate group, after multivariate adjustment for age, comorbidities, and use of drugs affecting bone metabolism. There was no difference in hip fracture incidence between intermediate- and high-TSH groups. No association was found between TSH levels and other osteoporotic fractures. CONCLUSIONS TSH levels within the lower normal range are associated with an increased risk of hip fractures in euthyroid women, but not men, aged 65 years and more.

Has the time for first-line treatment with second generation tyrosine kinase inhibitors in patients with chronic myelogenous leukemia already come? Systematic review and meta-analysis

Second generation tyrosine kinase inhibitors have recently been introduced as first-line treatment for chronic phase chronic myelogenous leukemia. We aimed to evaluate the efficacy and safety of 2nd generation tyrosine kinase inhibitors versus imatinib as first-line treatment for these patients. We carried out a systematic review and meta-analysis of randomized controlled trials comparing 2nd generation tyrosine kinase inhibitors to imatinib as first-line treatment in chronic phase chronic myelogenous leukemia patients. Outcomes assessed were: complete cytogenetic response and major molecular response at 12, 18 and 24 months, all-cause mortality and progression to accelerated phase/blastic crisis at 12, 18 and 24 months, and chronic myelogenous leukemia related mortality and toxicity at last follow up. Relative risks were estimated and pooled using a fixed effect model. Our search yielded four trials including 2,120 patients. At 12 months, treatment with 2nd generation tyrosine kinase inhibitors significantly improved both complete cytogenetic response and major molecular response (relative risk 1.16, 95% CI: 1.09-1.23, and 1.68, 95% CI: 1.48-1.91, respectively). While major molecular response was improved at all time points, complete cytogenetic response improved at 18 months but not at 24 months. Importantly, rate of progression to accelerated phase/blastic crisis was significantly lower with the newer tyrosine kinase inhibitors throughout all time points. Second generation tyrosine kinase inhibitors improved chronic myelogenous leukemia related mortality without a statistically significant difference in all-cause mortality at 12, 18 and 24 months. We conclude that 2nd generation tyrosine kinase inhibitors can be added safely to the first-line treatment armamentarium of chronic phase chronic myelogenous leukemia patients. Although an advantage is suggested by surrogate parameters, longer follow up is necessary to see if this translates into superior overall survival.

High‐dose imatinib for newly diagnosed chronic phase chronic myeloid leukemia patients—Systematic review and meta‐analysis

Imatinib at a dose of 400 mg daily is considered frontline treatment in chronic phase chronic myeloid leukemia (CP‐CML).

Tyrosine kinase inhibitor associated vascular toxicity in chronic myeloid leukemia

Tyrosine kinase inhibitors (TKIs) have revolutionized the management and outcomes of chronic myeloid leukemia (CML) patients. Improved disease control and prolonged life expectancy now mandate focus on improving TKIs’ safety profile. Recently, vascular adverse events (VAEs) have emerged as a serious consequence of some of the newer TKIs. In this review, we describe the clinical spectrum of TKI-associated VAE, and examine the unique vascular safety profile of the main TKIs currently used in the treatment of CML: imatinib, nilotinib, dasatinib, bosutinib and ponatinib. The issue of TKI-related platelet dysfunction is discussed as well. We describe the contemporary research findings regarding the possible pathogenesis of the VAE. Finally, the different aspects of TKI-associated VAE management are addressed, including prevention methods, monitoring strategies and treatment options.

Ponatinib reduces viability, migration, and functionality of human endothelial cells

Abstract Tyrosine kinase inhibitors (TKIs) have revolutionized the prognosis of chronic myeloid leukemia. With the advent of highly efficacious therapy, the focus has shifted toward managing TKI adverse effects, such as vascular adverse events (VAEs). We used an in vitro angiogenesis model to investigate the TKI-associated VAEs. Our data show that imatinib, nilotinib, and ponatinib reduce human umbilical vein endothelial cells (HUVECs) viability. Pharmacological concentrations of ponatinib induced apoptosis, reduced migration, inhibited tube formation of HUVECs, and had a negative effect on endothelial progenitor cell (EPC) function. Furthermore, in HUVECs transfected with VEGF receptor 2 (VEGFR2), the effect of ponatinib on tube formation and on all parameters representing normal endothelial cell function was less prominent than in control cells. This is the first report regarding the pathogenesis of ponatinib-associated VAEs. The antiangiogenic effect of ponatinib, possibly mediated by VEGFR2 inhibition, as shown in our study, is another piece in the intricate puzzle of TKI-associated VAEs.

Hypertension in cancer patients treated with anti-angiogenic based regimens

New anti-cancer drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway are highly effective in the treatment of solid tumors, however concerns remain regarding their cardiovascular safety. The most common side effect of VEGF signaling pathway (VSP) inhibition is the development of systemic hypertension. We review the incidence, possible mechanisms, significance and management of hypertension in patients treated with VSP inhibitors.

The Effect of Combined Aspirin and Clopidogrel Treatment on Cancer Incidence

BACKGROUND Multiple studies have shown an association between aspirin treatment and a reduction in newly diagnosed cancer. Conversely, there are conflicting clinical and laboratory data on the effect of combined clopidogrel and aspirin therapy on cancer incidence, including analyses suggesting an increased cancer risk. No large-scale cohort study has been performed to address this issue in a heterogeneous real-world scenario. We investigated the effect of clopidogrel and aspirin on cancer incidence compared with aspirin alone and no antiplatelet therapy. METHODS A population-based historical cohort study of subjects aged ≥50 years covered by Clalit Health Services, an Israeli health maintenance organization, was performed. Patients treated with the newer antiplatelet drugs, prasugrel or ticagrelor, which, like clopidogrel, inhibit adenosine diphosphate receptors, and those with prior cancer were excluded. Prescription records of antiplatelet medication were retrieved. RESULTS The cohort included 183,912 subjects diagnosed with 21,974 cancer cases based upon the International Classification of Diseases, Ninth Revision. Dual aspirin and clopidogrel was prescribed in 9.6%, while 49% received aspirin alone and 41% used neither. Compared with nonusers, there was a lower risk of cancer in subjects exposed to aspirin with (hazard ratio [HR] 0.46; 95% confidence interval [CI], 0.44-0.49) or without clopidogrel (HR 0.54; 95% CI, 0.52-0.56), on long-term follow-up. Combined treatment was associated with a lower cancer risk than the aspirin-only group (HR 0.92; 95% CI, 0.86-0.97). CONCLUSIONS Dual clopidogrel and aspirin treatment is safe regarding the cancer risk. This study generates the hypothesis that clopidogrel may reduce cancer incidence.

Adherence-Related Issues in Adolescents and Young Adults with Hematological Disorders

Nonadherence to medical recommendations is a widespread problem well documented in a multitude of clinical settings. Nonadherence may adversely affect clinical outcomes such as survival and quality of life and increase health-care-related costs. An understanding of the factors driving nonadherence is key to developing effective adherence-enhancing interventions (AEIs). There are ongoing attempts in contemporary adherence research to better define the various components of adherence, to find optimal measures of adherence and correlations with clinical outcomes, and to create a classification system for AEIs. Nonadherence is also widely prevalent among adolescents and young adults (AYAs) with chronic hematological diseases, affecting up to 50% of patients and increasing with age. Combined use of objective (i.e. electronic monitoring, EM) and subjective (i.e. self-report) measures of adherence may be the preferred approach to assess adherence. The unique physical, social and emotional aspects of the AYA life stage are closely related to intricate causes of nonadherence in AYAs such as problems in transition to adult care. Until proven otherwise, the empirical target in AYAs with hematological disorders should be perfect adherence. Multilevel AEIs, EM feedback and behavioral interventions are among the most effective types of AEIs. Despite the magnitude of the problem, only a handful of AEIs have been evaluated among AYAs with hematological disorders. Thus, this is a field with unmet needs warranting high-quality trials using standardized and well-specified assessment methods and interventions. This review discusses the prevalence, definition, causes and clinical implications of nonadherence among AYAs with hematological disorders, along with strategies to measure and improve adherence.