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Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

ABSTRACT: Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (? 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.

SUBMITTER: Mato AR

PROVIDER: S-EPMC6119152 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

Mato Anthony R AR Thompson Meghan M Allan John N JN Brander Danielle M DM Pagel John M JM Ujjani Chaitra S CS Hill Brian T BT Lamanna Nicole N Lansigan Frederick F Jacobs Ryan R Shadman Mazyar M Skarbnik Alan P AP Pu Jeffrey J JJ Barr Paul M PM Sehgal Alison R AR Cheson Bruce D BD Zent Clive S CS Tuncer Hande H HH Schuster Stephen J SJ Pickens Peter V PV Shah Nirav N NN Goy Andre A Winter Allison M AM Garcia Christine C Kennard Kaitlin K Isaac Krista K Dorsey Colleen C Gashonia Lisa M LM Singavi Arun K AK Roeker Lindsey E LE Zelenetz Andrew A Williams Annalynn A Howlett Christina C Weissbrot Hanna H Ali Naveed N Khajavian Sirin S Sitlinger Andrea A Tranchito Eve E Rhodes Joanna J Felsenfeld Joshua J Bailey Neil N Patel Bhavisha B Burns Timothy F TF Yacur Melissa M Malhotra Mansi M Svoboda Jakub J Furman Richard R RR Nabhan Chadi C

Haematologica 20180607 9

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation ...[more]

PMID: 29880613

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Project description:Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Project description:This study demonstrates real-world effectiveness of teriparatide in reducing the risk of hip and other fragility fractures. Fracture incidence significantly decreased as adherence and persistence increased for any clinical, vertebral, nonvertebral, and hip fractures among patients who were observed for 2 years after teriparatide initiation.IntroductionExamine the relationship of treatment adherence and persistence to teriparatide with hip and other fractures.MethodsTruven MarketScan Research Databases, 2004 through 2014, provided teriparatide users ?18 years old with continuous coverage 12 months pre- and 24 months post-teriparatide prescription. Adherence (medication possession ratio, MPR) groups were defined as high (?0.80), medium (0.50 ? MPR < 0.80), and low (<0.50). Persistence, allowing for ?90-day gaps between prescriptions, was defined as 1-6, 7-12, 13-18, and 19-24 months. Fracture incidence was summarized and compared by using ANOVA and logistic regression models; the effects of adherence were examined with Cox proportional hazard models with time-dependent covariates for teriparatide exposure.ResultsAmong 14,284 teriparatide subjects, mean age was 68.4 years, 89.8% were female, and 29.6% had a fracture in the previous year; these characteristics were similar across MPR and persistence groups. The effects of adherence and persistence to teriparatide were statistically significant (P < .001) for all fracture types except wrist (P ? .125). By logistic regression, high vs low adherence was associated with reduced risk for any (OR = 0.67; P < .001); vertebral (OR = 0.64; P < .001); nonvertebral (OR = 0.71; P < .001); and hip fractures (OR = 0.52; P < .001) and longer (19-24 months) vs shorter persistence (1-6 months) was associated with reduced risk for any (OR = 0.63, P < .001); vertebral (OR = 0.56, P < .001); nonvertebral (OR = 0.69, P < .001); and hip fractures (OR = 0.48, P < .001). Cox models revealed a significantly reduced risk between high and low adherence for any (OR = 0.69, P < .001); vertebral (OR = 0.60, P < .001); nonvertebral (OR = 0.77, P < .001); and hip fractures (OR = 0.55, P < .001).ConclusionFracture incidence significantly decreased as persistence and adherence to teriparatide increased.

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Project description:BackgroundNew treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.MethodsWe conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.ResultsThe majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.ConclusionsSelective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).

Dataset Information

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

Publications

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

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