Search

Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m 2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m 2 onalespib when given with paclitaxel at 80 mg/m 2 . PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m 2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173 .

Abstract A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.

Abstract Background Post-market analyses revealed unanticipated links between first-generation Bruton’s tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown. Methods Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed. Results Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P

Abstract: Atrial fibrillation (AF) has been reported in up to 16% of patients taking ibrutinib. Data regarding the management of AF in this patient population are limited, and stroke prevention poses a challenge because of increased risk of bleeding with ibrutinib treatment. Our study sought to describe the incidence of AF in adult patients treated with ibrutinib for a hematologic malignancy, assess management strategies, evaluate stroke and bleeding outcomes, and identify risk factors for occurrence. Of 582 patients treated with ibrutinib, 76 developed AF. With a median follow-up of 32 months, the estimated cumulative incidence at 6 months, 1 year, and 2 years was 5.9% (95% confidence interval [CI]: 4.2-8.0), 7.5% (95% CI: 5.5-9.9), and 10.3% (95% CI: 8.0-13.0), respectively. Median time to onset of AF was 7.6 months. History of AF and Framingham Heart Study (FHS) AF risk score were found to be significant risk factors for development of AF. Most patients were treated with rate control–only strategies (61.8%), and concomitant aspirin or anticoagulant therapy with ibrutinib was used in 52.6% and 28.9% of patients, respectively. One patient on aspirin developed symptoms consistent with stroke. Nine major bleeds were noted in 7 patients, and 34 clinically relevant nonmajor bleeds were noted in 24 patients. Twenty-one bleeds (4 major bleeds) occurred in 18 patients on aspirin, and 10 bleeds (all clinically relevant nonmajor bleeds) occurred in 6 patients with anticoagulant therapy. These results provide risk factor assessment, impact of management strategies, and outcomes of patients with AF on ibrutinib and serve as basis for formal guidelines.