Hairy cell leukemia. Clinical recommendations

Hairy cell leukemia. Clinical recommendation

ELEVATE-TN Study. New data of acalabrutinib in first-line treatment of chronic lymphocytic leukemia. Resolution

Over the past decade, we have seen a significant change in modern approaches in the first-line treatment of chronic lymphocytic leukemia (CLL). The CLL-10 study data established the FCR regimen as the treatment of choice for younger patients with limited comorbidities, while for patients older than 65 years, the BR regimen is more often considered as less toxic one. According to published data, 46% of patients with newly diagnosed CLL have comorbidities. Moreover, high-risk patients with del(17p) and/or TP53 mutation do not have response on immunochemotherapy (ICT) most often. Thus, about 1/2 of the patients cannot be treated or will not respond to standard ICT regimens. Targeted therapy with Brutons tyrosine kinase (BTK) inhibitors is an important option of the first-line treatment of patients with CLL. Acalabrutinib is a highly selective second-generation BTK inhibitor that does not inhibit EGFR, ITK or TEC targets. Acalabrutinib in combination with obinutuzumab or as monotherapy can be considered as a highly effective and safe option of the first line of CLL therapy. Based on the hight selectivity of the agent, acalabrutinib can be considered as the preferable option for patients who are not eligible for ICT, including patients with commodities, such as cardiovascular diseases or risk factors for their development

Study of Structure–Activity Relationships of the Marine Alkaloid Fascaplysin and Its Derivatives as Potent Anticancer Agents

Marine alkaloid fascaplysin and its derivatives are known to exhibit promising anticancer properties in vitro and in vivo. However, toxicity of these molecules to non-cancer cells was identified as a main limitation for their clinical use. Here, for the very first time, we synthesized a library of fascaplysin derivatives covering all possible substituent introduction sites, i.e., cycles A, C and E of the 12H-pyrido[1-2-a:3,4-b’]diindole system. Their selectivity towards human prostate cancer versus non-cancer cells, as well as the effects on cellular metabolism, membrane integrity, cell cycle progression, apoptosis induction and their ability to intercalate into DNA were investigated. A pronounced selectivity for cancer cells was observed for the family of di- and trisubstituted halogen derivatives (modification of cycles A and E), while a modification of cycle C resulted in a stronger activity in therapy-resistant PC-3 cells. Among others, 3,10-dibromofascaplysin exhibited the highest selectivity, presumably due to the cytostatic effects executed via the targeting of cellular metabolism. Moreover, an introduction of radical substituents at C-9, C-10 or C-10 plus C-3 resulted in a notable reduction in DNA intercalating activity and improved selectivity. Taken together, our research contributes to understanding the structure–activity relationships of fascaplysin alkaloids and defines further directions of the structural optimization