Purpose: The biological and clinical heterogeneity of chronic myelomonocytic leukemia features renders its classification difficult. Moreover, because of the limited knowledge of the mechanisms involved in malignant evolution, chronic myelomonocytic leukemia remains a diagnostic and therapeutic challenge and a poor prognosis disease. We aimed to verify the biological and clinical significance of the discrimination, based on the leukocyte count, between myelodysplastic chronic myelomonocytic leukemia (MD-CMML) and myeloproliferative chronic myelomonocytic leukemia (MP-CMML).Experimental Design: Peripheral blood samples from 22 patients classified as MD-CMML and 18 as MP-CMML were collected at different time points during disease course, and patients' clinical characteristics were examined. RAS mutational screening was done by sequencing and, for each substitution identified, a highly selective allele-specific PCR was set up to screen all specimens.Results: MP-CMML patients showed a significantly poorer survival (P = 0.003) and a higher frequency of RAS mutations (P = 0.033) by sequencing compared with MD-CMML. Overall, five MD-CMML patients progressed to myeloproliferative disease: in two, allele-specific PCR unveiled low levels of the RAS mutations predominating in the myeloproliferative phase at the time of myelodysplastic disease, documenting for the first time the expansion of a RAS mutated clone in concomitance with chronic myelomonocytic leukemia evolution. Moreover, one of the progressed patients harbored the FLT3-ITD and two MP-CMML patients presented with the JAK2 V617F substitution. All these lesions were mutually exclusive.Conclusions: Our results strongly suggest RAS mutations to function as a secondary event that contributes to development of the chronic myelomonocytic leukemia variant with the poorer prognosis (MP-CMML) and therefore advise their detection to be implemented in chronic myelomonocytic leukemia diagnostics and monitoring. Clin Cancer Res; 16(8); 2246-56. ©2010 AACR.

Vitamin K Antagonists (VKAs) are widely used in clinical practice and nearly 1% of the entire population receives oral anticoagulation at least once in life. However, the rate of prescription of anticoagulation is low, compared to what it should be. No more than 50-60% of patients affected by atrial fibrillation (AF) receive anticoagulation. In the setting of AF, VKAs are safe and effective when properly managed, reducing stroke and systemic embolism by more than 60%. VKAs safety and effectiveness are closely related to the quality of anticoagulation (e.g. time in therapeutic range), and anticoagulation clinics offer the best management of anticoagulant therapy. However, a sizeable proportion of patients are managed elsewhere. In clinical practice, in the setting of AF, a low prescription rate of VKAs is frequently observed and this is due also to difficulties in managing laboratory monitoring and drug dose adjustment. The suboptimal management of therapy with VKAs leads to a lesser efficacy than that reported in clinical trials, and to an increase in adverse reactions. VKAs still remain the first and only available therapy for a number of diseases (e.g. valvular atrial fibrillation and mechanical prosthetic heart valves). Now, since approval of the new oral anticoagulants (NOAs), the choice of anticoagulant therapy in definite settings, such as stroke prevention in non-valvular atrial fibrillation (SPAF) or treatment of venous thromboembolism, has surely become more intriguing but also more problematic. In light of these new therapeutic options, we reviewed VKAs therapy, in the setting of atrial fibrillation, focusing on VKAs impact in real life. We analyzed the data about efficacy and safety of warfarin at three levels: clinical trial and real life, outside and inside anticoagulation clinics.

We found important heterogeneity and uncertainties in the answers given by physicians who usually treat patients with AF, as evidence of the lack of precise and unique definitions of the origin of AF (valvular/non-valvular). It is urgent to issue clear widely accepted definitions of the origin of AF, which should improve clinical practice and research.