No abstract

No abstract

Fixed-duration venetoclax plus rituximab (VenR) has a manageable safety profile and improves survival in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We present data from the phase III MURANO study on the impact of venetoclax modification or premature discontinuation on outcomes in patients with R/R CLL. Time-dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of venetoclax discontinuation/modification on investigator-assessed progression-free survival (PFS) and overall survival (OS). Analyses were performed retrospectively (without type-1 error control) in intention-to-treat patients from the VenR arm of MURANO. Overall, 140/194 (72%) patients in the VenR arm completed 2 years of therapy; 54/194 (28%) patients prematurely discontinued treatment. Inferior PFS was observed in patients prematurely discontinuing venetoclax for any reason (disease progression excluded; p

Patients with chronic lymphocyticleukemia (CLL) typically have innate/adaptive immune system dysregulation, thus the protective effect of coronavirus disease 2019 (COVID-19) vaccination remains uncertain. This prospective review evaluates vaccination response in these patients, including seropositivity rates by CLL treatment status, type of treatment received, and timing of vaccination. Antibody persistence, predictors of poor vaccine response, and severity of COVID-19 infection in vaccinated patients were also analyzed. Practical advice on the clinical management of patients with CLL is provided. Articles reporting COVID-19 vaccination in patients with CLL, published January 1, 2021-May 1, 2022, were included. Patients with CLL displayed the lowest vaccination responses among hematologic malignancies; however, seropositivity increased with each vaccination. One of the most commonly reported independent risk factors for poor vaccine response was active CLL treatment; others included hypogammaglobulinemia and age >65-70 years. Patients who were treatment-naive, off therapy, in remission, or who had a prior COVID-19 infection displayed the greatest responses. Further data are needed on breakthrough infection rates and a heterologous booster approach in patients with hematologic malignancies. Although vaccine response was poor for patients on active therapy regardless of treatment type, CLL management in the context of COVID-19 should aim to avoid delays in antileukemic treatment, especially with the advent of numerous strategies to mitigate risk of severe COVID-19 such as pre-exposure prophylaxis, and highly effective antivirals and monoclonal antibody therapy upon confirmed infection. Patients with CLL should remain vigilant in retaining standard prevention measures such as masks, social distancing, and hand hygiene.

Introduction: The approval of several new, targeted agents has been transformative in the treatment of CLL. Prospective clinical trial data support the use of Ven after Ibr in CLL (Jones JA et al. Lancet Oncol 2018); however, limited data are available on the inverse sequencing of these agents (Mato AR et al. Br J Haematol 2018; Anderson M et al. Blood 2017). Given the recent FDA approval of Ven + obinutuzumab in first-line (1L) CLL, an upsurge in Ibr-naïve pts needing therapy post-Ven is likely; characterizing this sequencing is of the upmost importance. Here we present a US multicentre, retrospective, chart-review analysis to explore outcomes of Ibr post-Ven, in Ibr-naïve pts with CLL. Methods: Efficacy and safety outcomes were investigated for pts with Ibr-naïve CLL, treated with Ven +/- CD20 monoclonal antibody (mAb), who developed progressive disease ([PD] or discontinued Ven) and received Ibr salvage therapy (+/- CD20 mAb). Analyses included pts in 1L or relapsed/refractory setting. Pts were treated between Feb 14, 2012 and Jun 6, 2019, across four institutions (US); data cutoff was Jul 18, 2019. Results: Data were available for 27 pts with CLL who received Ibr post-Ven - the largest cohort to date. Median age was 64 (41-79) years, median time from diagnosis to first therapy was 9.0 (0-117.7) months (mo), and the median number of therapies prior to Ven was 2 (0-9). Prior therapies were varied and included: 1 Bruton's tyrosine kinase inhibitor (BTKi; not Ibr), 3 lenalidomide, 1 pt received 9 lines of therapy (including: idelalisib, lenalidomide, anti-CD22 and temsirolimus), others received chemo- or chemoimmunotherapy, or CD20 mAb only. Median time from diagnosis to initiation of Ven was 56.3 (0-157.7) mo. At baseline, the median lymphocyte count was 2.2 (0.2-220.0) K/µL; 8/24 (33.3%) pts had a lymph node ≥ 5cm. All evaluable pts (26/26) had ≥1 unfavourable prognostic risk factor; 12/20 (60.0%) pts had del17p, 10/16 (62.5%) had del11q, 12/24 (50.0%) had complex karyotype (CK) and 13/15 (86.7%) pts had unmutated IGHV. A complete or partial response (CR or PR) to Ven was achieved in 4/26 (15.4%) and 18/26 (69.2%) evaluable pts, respectively. The median time to PD on Ven was 29.0 (1.0-118.0) mo, with a median treatment duration of 18.0 (0.1-64.3) mo. Pts discontinued Ven due to PD (n=18), consent withdrawal (n=2), non-compliance (n=1), and other (n=6; allogeneic stem cell transplantation n=2, physician decision n=3, not evaluable n=1). Prior to initiation of Ibr, the median lymphocyte count was 1.9 (0.01-179.0) K/µL; 15/26 (57.7%) pts had adenopathy, and 5/13 (38.5%) had a lymph node ≥ 5cm. Risk factors included: del17p (4/10; 40.0%), del11q (4/9; 44.4%), CK (8/17; 47.1%) and unmutated IGHV (11/14; 78.6%). Median time from Ven initiation to Ibr initiation was 31.9 (1.8-60.3) mo; median time to Ibr initiation post-Ven was 0.7 (0-39.7) mo. The overall response rate to Ibr was 56.0% (CR: 1/25, PR: 13/25). The time to progression on Ibr, post-Ven, varied from 3.0 to 53.0 mo (n=10). The median duration of Ibr therapy was 18.3 (3.7-53.2) mo and 20.0 (4.9-44.3) mo for those remaining on Ibr (8/27); the median follow-up time matched the median therapy duration. Nineteen pts discontinued Ibr due to: PD (n=9), physician decision (n=4), adverse events (AEs; n=2), transplant (n=2), symptomatic deterioration and unknown reason (n=1 each). The median number of therapies prior to Ven for the 9 pts who discontinued Ibr due to PD was 2 (1-9); 4/9 pts received novel targeted therapies. Richter's transformation occurred in 1 pt (1/9). The 2 pts who discontinued Ibr due to AEs experienced either atrial fibrillation (AF)/brain abscess or pneumonia after 11.6 and 18.2 mo of Ibr, respectively. Other notable AEs were: major bleeding (n=1), AF (n=2), infection (n=1), neutropenia (n=1), myalgia/arthralgia (n=2), and other cardiac event (n=1). Ibr dose reductions due to fatigue and general malaise occurred in 1 pt. Conclusions: With the limitations of a retrospective series using real-world data, these data suggest that Ibr had substantial clinical activity post-Ven in heavily pre-treated, high-risk CLL pts; no new safety signals arose. Larger, prospective studies are required to fully characterize the efficacy of Ibr after Ven. Meanwhile, salvage therapy with Ibr remains a good option for pts with CLL who relapse after Ven. Disclosures Brown: Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Morphosys: Other: Data safety monitoring board; Janssen: Honoraria; Dynamo Therapeutics: Consultancy; Teva: Honoraria; Sun Pharmaceuticals: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie: Consultancy; Juno/Celgene: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding. Davids:Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Chang:Genentech: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies: Research Funding. Ma:Kite: Consultancy; Xeme: Research Funding; Abbvie: Research Funding; Beigene: Research Funding; Bioverativ: Consultancy; Incyte: Research Funding; Genentech: Consultancy; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Janssen: Consultancy, Speakers Bureau; Novartis: Research Funding; Juno: Research Funding; Acerta: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau. Biondo:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Breuleux:F. Hoffmann - La Roche Ltd: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea Ltd: Equity Ownership. Wierda:Janssen: Research Funding; Xencor: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC: Research Funding; Cyclcel: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; KITE pharma: Research Funding; Miragen: Research Funding; Juno Therapeutics: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Loxo Oncology Inc.: Research Funding; Genentech: Research Funding; Acerta Pharma Inc: Research Funding.