Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Cloning and structural characterization of ECTACC, a new member of the transforming acidic coiled coil (TACC) gene family: cDNA sequence and expression analysis in human microvascular endothelial cells.

Erythropoietin (Epo) transduces mitogenic and chemoattractant signals to human endothelial cells. Identifications of Epo-responsive genes are important for understanding the molecular nature of Epo signaling in endothelial cells. The effects of Epo on differential expression of various genes were examined in human microvascular endothelial cells (HMVEC) by differential display reverse transcriptase polymerase chain reaction (RT-PCR). In the current study we obtained from Epo-treated HMVEC a cDNA fragment with characteristics of the 3' end of mRNA. Using the cDNA fragment, we then selectively isolated a full-length clone by screening an unamplified endothelial cell cDNA library followed by 5' rapid amplification of cDNA ends by polymerase chain reaction (RACE-PCR). The nucleotide sequence of the longest cDNA revealed an open reading frame of 3311 nucleotides that encodes a protein consisting of approximately 906 amino acids with a predicted MW of approximately 100 kDa. The nucleotide sequence of the cDNA is nearly identical to that of transforming acidic coiled coil-containing (TACC2) and anti-zuai-1 (AZU-1) cDNA clones except at the 5'- and 3'-ends. Northern blot analysis showed an increase in endothelial-TACC-related mRNA levels in Epo-treated cells in comparison to that of the control cells. Endothelial-TACC-related mRNA was highly expressed in heart and skeletal muscle tissue. Placenta and brain tissue exhibited low levels of expression of endothelial-TACC-related gene. Southern blot analysis of genomic DNA from somatic cell hybrids showed that endothelial-TACC-related cDNA maps to chromosome 10. Immunofluorescence microscopy and the occurrence of several putative phosphorylation and SH3 binding sites on the deduced protein suggest that endothelial-TACC-related protein may be involved in Epo signaling cascades in endothelial cells.