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Chronic lymphocytic leukemia (CLL) therapies differ in efficacy, side effects, route, frequency, and duration of administration. We assessed patient preferences for treatment attributes and evaluated associations with disease stage, treatment line, and socio‐demographic characteristics in a cross sectional, observational study conducted at 16 Italian hematology centers. Study visits occurred between February and July 2020; 401 adult patients with CLL (201 Watch and Wait (W&W), 200 treated) participated in a discrete choice experiment (DCE), composed of 8 choices between pairs of treatment profiles with different levels of 5 attributes of currently available CLL treatments (length of response, route and duration of administration, risk of side effects including diarrhea, infections, or organ damage). Health‐related quality of life was assessed with the EQ‐5D‐5L, EORTC QLQ‐C30 and QLQ CLL‐16. Previously treated patients had longer disease duration (7 vs. 5 years), higher prevalence of serious comorbidities (45.5% vs. 36.2%) and high‐risk molecular markers (unmutated IGHV 55.6% vs. 17.1%; TP53 mutation 15.2% vs. 4.0%). Health‐related quality of life scores were similar between groups. In the DCE, W&W patients rated "possible occurrence of infections" highest (relative importance [RI] = 36.2%), followed by "treatment and relevant duration" (RI = 28.0%) and "progression‐free survival (PFS)" (RI = 16.9%). Previously treated patients rated "treatment and relevant duration" highest (RI = 33.3%), followed by "possible occurrence of infections" (RI = 28.8%), "possible occurrence of organ damage" (RI = 19.4%), and "PFS" (RI = 9.8%). Concern over infection was rated highest overall; unexpectedly PFS was not among the most important criteria in either group, suggesting that the first COVID‐19 pandemic wave may have influenced patient preferences and concerns about CLL therapy options. [ABSTRACT FROM AUTHOR]

The treatment landscape of chronic lymphocytic leukemia (CLL) has been challenged by the advent of novel classes of drugs, such as B-cell receptor (BCR)-inhibitors and BCL-2 antagonists. In selected high-risk patients, the choice to start allogeneic hematopoietic stem cell transplantation (alloHCT) or continue these agents is a matter of debate. Furthermore, published data about the impact on the feasibility of alloHCT and the optimal timing of administration are limited. Here we present a case of relapsed TP53 mutated CLL treated with ibrutinib as a bridge to alloHCT, discussing risks and benefits of different treatment options in a “real life” situation.

Keywords: chronic lymphocytic leukemia; IRF4 L116R mutation; proliferation; MYC EN chronic lymphocytic leukemia IRF4 L116R mutation proliferation MYC 707 711 5 12/07/21 20211201 NES 211201 DATA AVAIBILITY STATEMENT The data that support the findings of the study are available on requests from the corresponding author. MYC protein level was inspected in IRF4 transfected CLL cells by immunoblotting after 72 h of co-culture, observing increased MYC protein in IRF4-mutant CLL cells as compared to IRF4-WT cells and control samples (Figure 2E). We first screened a multicenter cohort of 460 CLL patients that comprised 365 untreated CLL cases, 51 treated CLL, including 32 pluri-treated CLL, and 44 Richter transformed cases. [Extracted from the article]

Lenalidomide is a therapeutically effective drug in chronic lymphocytic leukemia (CLL). Twenty-seven CLL patients were treated with lenalidomide in a phase II clinical trial. Ten patients were grouped as responders (R) and 6 as nonresponders (NR). We evaluated T lymphocytes, NK, monocytes and dendritic cells at baseline and after treatment. A gene expression analysis was performed on 16 CLL samples collected before treatment. The levels of immune cells or immune-related cytokines are not different between R and NR patients. However, CLL patients sensitive to lenalidomide clearly show a peculiar gene expression profile in leukemic cells. The most up-regulated gene (fold change =  +23 in R vs. NR) is Wnt inhibitor SHISA homolog 3 (SHISA3). SHISA3highCLL are characterized by a restrained activation of Wnt signaling and sensibility to lenalidomide-induced apoptosis. In conclusion, SHISA3 is a candidate gene for the identification of CLL patients who will benefit of lenalidomide treatment as single agent. [ABSTRACT FROM AUTHOR]

The endothelin axis, comprising endothelins (ET-1, ET-2 and ET-3) and their receptors (ETAR and ETBR), has emerged as relevant player in tumor growth and metastasis. Here, we investigated the involvement of ET-1/ETAR axis in chronic lymphocytic leukemia (CLL). CLL cells expressed higher levels of ET-1 and ETA receptor as compared to normal B cells. ET-1 peptide stimulated phosphoinositide-3-kinase and mitogen-activated protein kinase signaling pathways, improved survival and promoted proliferation of leukemic cells throughout ETAR triggering. Moreover, the blockade of ETAR by the selective antagonist BQ-123 inhibited the survival advantage acquired by CLL cells in contact with endothelial layers. We also found that blocking ETAR via BQ-123 interferes with ERK phosphorylation and CLL pro-survival effect mediated by B-cell receptor (BCR) activation. The pro-apoptotic effect of phosphoinositide-3-kinase δ inhibitor idelalisib and mitogen-activated protein kinase inhibitor PD98059 was decreased by the addition of ET-1 peptide. Then, ET-1 also reduced the cytotoxic effect of fludarabine on CLL cells cultured alone or co-cultured on endothelial layers. ETAR blockade by BQ-123 inhibited the ET-1-mediated protection against drug-induced apoptosis. Lastly, higher plasma levels of big ET-1 were detected in patients (n = 151) with unfavourable prognostic factors and shorter time to first treatment. In conclusion, our data describe for the first time a role of ET-1/ETAR signaling in CLL pathobiology. ET-1 mediates survival, drug-resistance, and growth signals in CLL cells that can be blocked by ETAR inhibition. [ABSTRACT FROM AUTHOR]