Effect of thrombopoietin receptor agonists on the apoptotic profile of platelets in patients with chronic immune thrombocytopenia.

Platelet survival depends upon mediators of apoptosis e.g., Bcl-xL, Bax, and Bak, which are regulated by thrombopoietin (TPO)-mediated AKT signaling. Thrombopoietin receptor (TPO-R) signaling might decrease platelet and/or megakaryocyte apoptosis and increase the platelet count. This study therefore explored anti-apoptotic effects of TPO-R-agonists in vivo on platelets of patients with immune thrombocytopenia. Patients received eltrombopag or romiplostim for two weeks. Total, immature, and large platelet counts were assessed as were Bcl-xL inhibitor assay; Bcl-xL Western blot; and flow cytometric (FACS) analysis of the AKT-signaling pathway. Eight/ten patients had platelet responses to eltrombopag and all three to romiplostim. Platelet sensitivity to apoptosis by Bcl-xL inhibition was greater in pretreatment patients than controls. This sensitivity normalized after one week of therapy, but surprisingly returned to pretreatment levels at week two. FACS analysis revealed increased AKT-pathway signaling after one week, followed by a decrease at week two. Platelet counts correlated with the Bcl-xL /Bak ratio. Platelet survival may be enhanced by TPO-R-agonists as a transient decrease in platelet sensitivity to apoptosis was accompanied by transient activation of AKT. However, this mechanism has only a short-lived effect. Megakaryocytes and platelets already present at the start of TPO-R-agonist treatment appear to respond differently than those generated de novo.

Eltrombopag.

The current concepts and the management of ITP have significantly changed in the past decade. Decreased use of cytotoxic therapy and the introduction of new selective modalities of drug such as TPO-r mimetics are the landmarks of this change. Discovered in the middle of last decade, followed by experiments in mice and then approved in humans, Eltrombopag is the first TPO-r mimetic available. It has been used and validated in several clinical studies in different etiologies of thrombocytopenia, including primary ITP (chronic Immune ThrombocytoPenia) and secondary ITP, due to hepatitis C and more recently in bone marrow failure as myelodysplastic syndromes. Good tolerability and low side effects are the strengths of this drug, contrasted with issues regarding administration (it must be taken every day apart from specific meals containing high levels of calcium, which leads to problems with compliance). We review the first clinical studies with this agent, emphasizing the significant findings.

Factors influencing survival in myelodysplastic syndromes in a Brazilian population: comparison of FAB and WHO classifications.

The WHO classification for myelodysplastic syndromes (MDS) has introduced new categories with prognostic relevance. Our aim was to examine the predictive value of the WHO and the FAB classification compared to parameters of peripheral blood, bone marrow and IPSS. Clinical data, peripheral blood counts, bone marrow (BM) cytology and histology and survival were analyzed in consecutive newly diagnosed adult patients with MDS. All cases were diagnosed according to FAB criteria and reclassified by the WHO proposal. Among 150 patients entering the study median age was 58 years (12-90). According to FAB, 90 patients had refractory anemia (RA), 18 sideroblastic anemia, 34 refractory anemia with excess of blasts (RAEB), three RAEB-t and five chronic myelomonocytic leukemia. Using the WHO proposal, one half of the patients with RA changed category. One patient had the 5q-syndrome. There were 25 cases with refractory cytopenias with multilineage dysplasia (RCMD) and 23 WHO "unclassified". These last patients presented few cell atypias, favorable IPSS and a good survival as has been described for refractory cytopenias in pediatric MDS. Hypocellular BM was found in 24% of the patients. Karyotype was available in only 85 cases. In the univariate analysis, both classifications, hemoglobin values, hypercellular bone marrow and IPSS had an influence on survival. Using the bootstrap resampling as stability test for the model created by the multivariate analysis, the WHO classification entered the model in 73%, FAB in 38% and IPSS in only 7%. Therefore, in a setting with a high number of low-risk MDS, the WHO classification is the best predictor of survival of the patients.

Bone marrow lymphoid aggregates in myelodysplastic syndromes: incidence, immunomorphological characteristics and correlation with clinical features and survival.

Lymphoid aggregates (LA) are a common finding in bone marrow biopsies but little is known about their clinical implications and biological significance. We found LA in 51/206 patients with myelodysplastic syndromes (MDS). There was no correlation with age, disease progression or overall survival. The group with LA had lower hemoglobin values (P=0.03), and was associated with an increase in reticulin fibres (P=0.01). Although they were more frequent in RAEB, this did not reach statistical significance. Most LA had a benign morphology and showed CD20 expression in three distinct patterns: central, perinodular or diffuse. No evidence of an association with lymphoproliferative disease was observed. LA probably represent an ongoing immune stimulation and are probably related to an altered bone marrow microenvironment, with no impact on prognosis.