Molly Fanning

Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in Chronic Lymphocytic Leukemia: Results from a Multi-Center Study of 683 Patients.

BackgroundnIbrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.nnnPatients and methodsnWe 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).nnnResultsnA 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).nnnConclusionsnIn 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.BACKGROUNDnIbrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the US. However, there is no guidance as to their optimal sequence.nnnPATIENTS AND METHODSnWe 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).nnnRESULTSnA 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 (vs. idelalisib) as first KI had a significantly better PFS in all settings; front-line (HR 2.8, CI1.3-6.3 p=.01), relapsed-refractory (HR 2.8, CI 1.9-4.1 p<.001), del17p (HR 2.0, CI 1.2-3.4 p=.008), and complex karyotype (HR 2.5, CI 1.2-5.2 p=.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS as compared to chemoimmunotherapy (CIT). 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=.06).nnnCONCLUSIONSnIn the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Further, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to CIT 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.

What Makes New Ischemic Lesions Symptomatic after Aortic Valve Replacement

BACKGROUNDnAcute cerebral infarctions on diffusion-weighted magnetic resonance imaging (MRI) are common after cardiothoracic surgery. However, most are asymptomatic and we aimed to identify features associated with clinical stroke symptoms.nnnMETHODSnPatients over 65 years of age undergoing surgical aortic valve replacement (AVR) for calcific stenosis were prospectively recruited (Nu2009=u2009196). All patients underwent neurological evaluation preoperatively and on postoperative days 1, 3, and 7, and MRI on planned postoperative day 5. Among those with new postoperative DWI lesions, we performed univariate and multivariable analyses to identify clinical, demographic, surgical, and imaging factors associated with clinical stroke symptoms.nnnRESULTSnOf the 129 patients who completed a postsurgical MRI, 79 (61%) had DWI lesions and 17 (21.5%) of these had new stroke symptoms concordant with the infarct distribution. In an exploratory multivariable analysis, focal neurological symptoms were associated with increased age, a longer bypass duration, and a larger pre-existing lesion burden on fluid-attenuated inversion recovery. Limiting the analysis to the 61 patients with analyzable volume and location data, logistic regression failed to identify any location-related determinant of symptomatic lesions.nnnCONCLUSIONSnNew DWI lesions are common after AVR, but most are asymptomatic. Patients are more likely to have symptoms with longer bypass durations, increasing age, and larger pre-existing lesion burdens.