Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial.

BACKGROUND: Most patients with chronic lymphocytic leukaemia progress after treatment or retreatment with targeted therapy or chemoimmunotherapy and have limited subsequent treatment options. Response levels to the single-agent venetoclax in the relapsed setting is unknown. We aimed to assess venetoclax activity in patients with or without previous B-cell receptor-associated kinase inhibitor (BCRi) treatment. METHODS: This multicentre, open-label, single-arm, phase 3b trial (VENICE-1) assessed activity and safety of venetoclax monotherapy in adults with relapsed or refractory chronic lymphocytic leukaemia, stratified by previous exposure to a BCRi. Eligible participants were aged 18 years or older with previously treated relapsed or refractory chronic lymphocytic leukaemia. Presence of del(17p) or TP53 aberrations and previous BCRi treatment were permitted. Patients received 5-week ramp-up to 400 mg of oral venetoclax once daily and were treated for up to 108 weeks, with 2 years follow-up after discontinuation, or optional extended access. The primary activity endpoint was complete remission rate (complete remission or complete remission with incomplete marrow recovery) in BCRi-naive patients. Analyses used the intent-to-treat (ie, all enrolled patients, which coincided with those who received at least one dose of venetoclax). This study was registered with ClinicalTrials.gov, NCT02756611, and is complete. FINDINGS: Between June 22, 2016, and March 11, 2022, we enrolled 258 patients with relapsed or refractory chronic lymphocytic leukaemia (180 [70%] were male; 252 [98%] were White; 191 were BCRi-naive and 67 were BCRi-pretreated). Median follow-up in the overall cohort was 49·5 months (IQR 47·2-54·1), 49·2 months (47·2-53·2) in the BCRi-naive group, and 49·7 months (47·4-54·3) in the BCRi-pretreated group. Of 191 BCRi-naive patients, 66 (35%; 95% CI 27·8-41·8) had complete remission or complete remission with incomplete marrow recovery. 18 (27%; 95% CI 16·8-39·1) of 67 patients in the BCRi-pretreated group had complete remission or complete remission with incomplete marrow recovery. Grade 3 or worse treatment-emergent adverse events were reported in 203 (79%) and serious adverse events were reported in 136 (53%) of 258 patients in the overall cohort. The most common treatment-emergent adverse event was neutropenia (96 [37%]) and the most common and serious adverse event was pneumonia (21 [8%]). There were 13 (5%) deaths reported due to adverse events; one of these deaths (autoimmune haemolytic anaemia) was possibly related to venetoclax. No new safety signals were identified. INTERPRETATION: These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukaemia, including BCRi-pretreated patients, suggesting that venetoclax monotherapy is an effective strategy for treating BCRi-naive and BCRi-pretreated patients. FUNDING: AbbVie.

Treatment Discontinuation Patterns for Patients With Chronic Lymphocytic Leukemia in Real-World Settings: Results From a Multi-Center International Study.

INTRODUCTION: This study assessed treatment discontinuation patterns and reasons among chronic lymphocytic leukemia (CLL) patients initiating first-line (1L) and second-line (2L) treatments in real-world settings. MATERIALS AND METHODS: Using deidentified electronic medical records from the CLL Collaborative Study of Real-World Evidence, premature treatment discontinuation was assessed among FCR, BR, BTKi-based, and BCL-2-based regimen cohorts. RESULTS: Of 1364 1L patients (initiated in 1997-2021), 190/13.9% received FCR (23.7% discontinued prematurely); 255/18.7% received BR (34.5% discontinued prematurely); 473/34.7% received BTKi-based regimens, of whom 28.1% discontinued prematurely; and 43/3.2% received venetoclax-based regimens, of whom 16.3% discontinued prematurely (venetoclax monotherapy: 7/0.5%, of whom 42.9% discontinued; VG/VR: 36/2.6%, of whom 11.1% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 25/13.2%; BR: 36/14.1%; BTKi-based regimens: 75/15.9%) and disease progression (venetoclax-based: 3/7.0%). Of 626 2L patients, 20/3.2% received FCR (50.0% discontinued); 62/9.9% received BR (35.5% discontinued); 303/48.4% received BTKi-based regimens, of whom 38.0% discontinued; and 73/11.7% received venetoclax-based regimens, of whom 30.1% discontinued (venetoclax monotherapy: 27/4.3%, of whom 29.6% discontinued; VG/VR: 43/6.9%, of whom 27.9% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 6/30.0%; BR: 11/17.7%; BTKi-based regimens: 60/19.8%; venetoclax-based: 6/8.2%). CONCLUSION: The findings of this study highlight the continued need for tolerable therapies in CLL, with finite therapy offering a better tolerated option for patients who are newly diagnosed or relapsed/refractory to prior treatments.

Systematic review of outcomes and patient heterogeneity in relapsed or refractory diffuse large B-cell lymphoma.

Aim: To evaluate trials of systemic therapies in transplant-ineligible or -experienced, relapsed/refractory diffuse large-B cell lymphoma and the impact of patient characteristics on overall response rate (ORR). Patients & methods: Systematically reviewed multiple databases through 22 July 2021. Analyzed variations in patient characteristics and their relationship with ORR across trials. Results: Among 17 included trials, key patient characteristics varied substantially: primary refractory (0-69%), refractory to last line of therapy (LOT) (12-100%), ≥2 prior LOTs (14-100%), ≥3 prior LOTs (0-64%), IPI ≥3 (23-73%), tumor stage III/IV (50-90%) and median age (56-74 years). ORRs varied substantially (25-83%), correlating with these characteristics. Conclusion: Differences in patient characteristics significantly contribute to the variability in ORR across these trials and should be considered when contextualizing efficacy data.

A Probabilistic Cost-Effectiveness Analysis of Venetoclax and Obinutuzumab as a First-Line Therapy in Chronic Lymphocytic Leukemia in Canada.

BACKGROUND: Venetoclax is a first-in-class targeted therapy option that is an inducer of apoptosis in chronic lymphocytic leukemia (CLL) cells. The open-label phase III CLL14 clinical trial showed that venetoclax combined with obinutuzumab (VEN+O) is superior to obinutuzumab combined with chlorambucil in newly diagnosed patients with CLL. The aim of this study was to assess the health economic value of VEN+O for the frontline treatment of CLL in Canada from a publicly funded healthcare system perspective. METHODS: A partitioned survival analyses model was developed including three health states: progression free, progressed, and death. A cycle length of 28 days and a time horizon of 10 years was assumed. VEN+O treatment for a fixed duration of 12 months was compared to obinutuzumab combined with chlorambucil, fludarabine plus cyclophosphamide plus rituximab, bendamustine plus rituximab, chlorambucil plus rituximab, ibrutinib, and acalabrutinib. The population in the model included both unfit and overall frontline CLL patients, two subgroups were also assessed (patients with del17p/TP53 mutations and patients without del17p/TP53 mutations). Survival data extrapolated from the CLL14 trial were used to populate the model. Uncertainty was assessed via one-way sensitivity analyses, probabilistic analyses, and scenario analyses. RESULTS: Based on the probabilistic analyses, unfit frontline CLL patients receiving VEN+O were estimated to incur costs of Canadian dollars ($) 217,727 [confidence interval (CI) $170,725, $300,761] (del17p/TP53: $209,102 [CI $159,698, $386,190], non-del17p/TP53: $217,732 [CI $171,232, $299,063]) and accrue 4.96 [CI 4.04, 5.82] quality-adjusted life-years (del17p/TP53: 3.11 [CI 2.00, 4.20], non-del17p/TP53: 5.04 [CI 4.05, 5.92]). Obinutuzumab combined with chlorambucil, bendamustine plus rituximab, chlorambucil plus rituximab, and ibrutinib accrued lower quality-adjusted life-years and higher costs and as such, VEN+O was the dominant treatment option. The full incremental analysis showed that acalabrutinib was more expensive and more efficacious compared with VEN+O with an incremental-cost-effectiveness-ratio of $2,139,180/quality-adjusted life-year versus VEN+O and not a cost-effective option in Canada. Probabilistic analyses show that at a willingness to pay of $50,000/quality-adjusted life-year gained, VEN+O has the greatest probability of being cost effective. CONCLUSIONS: VEN+O is a cost-effective treatment option for unfit frontline CLL patients and provides value for money to healthcare payers.

Impact of venetoclax monotherapy on the quality of life of patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 3b VENICE II trial.

Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for ≤2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received ≥1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of +9.3 points (n = 156, 95% confidence interval 6.1-12.5; p=.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported.

Cost-effectiveness of a 12-month fixed-duration venetoclax treatment in combination with obinutuzumab in first-line, unfit chronic lymphocytic leukemia in the United States.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a significant health and economic burden in the United States. Treatments include chemoimmunotherapy, such as obinutuzumab (G) plus chlorambucil (Clb) or bendamustine plus rituximab (BR), and chemotherapy-free regimens incorporating oral targeted therapies such as ibrutinib (Ibr), acalabrutinib (Acala), or venetoclax (Ven). Most chemotherapy-free regimens require continuous treatment to progression, while Ven plus G (VenG) is given for a fixed duration of 12 months, based on the CLL14 trial that led to its approval. Fixed-duration VenG has the potential for cost savings compared with treat-to-progression chemotherapy-free regimens. OBJECTIVE: To evaluate the cost-effectiveness of 12 months fixed-duration VenG in first-line treatment of unfit patients with CLL from a US health care payer perspective compared with GClb, BR, Ibr, Ibr + G, Ibr + R, Acala, and Acala + G. METHODS: A partitioned survival model was developed with 3 health states: progression-free survival (PFS), postprogression survival, and dead. The patient population, as based on the CLL14 trial, comprised previously untreated unfit patients with CLL (mean age 71.1 years, 33.1% female). The distribution of patients in each health state over time was estimated using extrapolated PFS and overall survival (OS) curves for VenG and GClb, based on CLL14 data 2 or more years after treatment cessation. PFS and OS for the other comparators were estimated using hazard ratios vs VenG, based on a network metaanalysis. Adverse events, utility values, and costs were obtained from published literature. The model estimated life-years gained, quality-adjusted life-years (QALYs) gained, and costs. The time horizon was 20 years, with a cycle time of 28 days. Outcomes and costs were discounted at 3.0% per year, and costs were estimated from a US health care payer perspective. One-way and probabilistic sensitivity analyses were conducted. RESULTS: In this cross-trial analysis of unfit CLL patients, in the base case, VenG had lower projected total costs than all comparators investigated. VenG also had larger projected health benefits (more QALYs gained) than GClb, BR, Ibr, and Ibr + R. VenG was therefore more effective and less costly than these comparators (dominant). Ibr + G, Acala, and Acala + G showed higher QALYs gained vs VenG (0.022, 0.672, and 0.961, respectively), and substantially higher projected costs vs VenG ($1,488,400, $1,579,737, and $1,656,154, respectively). Thus, Ibr + G, Acala, and Acala + G would cost more than $1,000,000 per QALY gained vs VenG. At the commonly used willingness-to-pay threshold of $150,000 per QALY gained, Ibr + G, Acala, and Acala + G were not cost-effective compared with VenG. CONCLUSIONS: Fixed-duration VenG for 12 months is a cost-effective first-line treatment option for unfit CLL patients compared with other available options and provides value for money to US health care payers at a threshold of $150,000 per QALY gained. Future studies with longer trial follow-up and more mature survival data may help to confirm longer-term cost benefits of VenG. DISCLOSURES: Genentech Inc. and AbbVie provided financial support for this study. Genentech Inc., AbbVie, and Pharmerit - An OPEN Health Company participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. Venetoclax is being developed in a collaboration between Genentech Inc. and AbbVie. Ravelo and Shapouri are employed by Genentech Inc. and have ownership interests. Manzoor and Sail are employed by AbbVie and have ownership interests. Chatterjee, van de Wetering, and Qendri, employees of Pharmerit - An OPEN Health Company, received consultancy fees from AbbVie. Davids has received consultancy fees from AbbVie, AstraZeneca, Eli Lilly, Genentech Inc., Janssen, MEI Pharma, Novartis, Pharmacyclics, and Verastem; research funding from Ascentage Pharma, Genentech Inc., MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, and Verastem; and has served on board of directors or advisory committees for AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, Eli Lilly, Genentech Inc., Janssen, Pharmacyclics, TG Therapeutics, and Verastem. This study was presented as a poster at ASH 61st Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

Health-related quality of life with fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Results from the randomized, phase 3 CLL14 trial.

Chronic lymphocytic leukemia (CLL)-related symptoms impair the well-being of patients, making improvement of health-related quality of life (QoL) a goal of treatment. The CLL14 trial demonstrated higher efficacy of fixed-duration venetoclax-obinutuzumab (Ven-Obi) compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated CLL. To assess patients' QoL, the following patient-reported outcomes (PRO) measures were assessed: the M.D. Anderson Symptom Inventory (MDASI) core instrument and CLL module and the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). At treatment start, physical functioning (mean 75.9 [standard deviation (SD) ± 20.1] in the Clb-Obi arm and 76.9 [±19.4] in the Ven-Obi arm), role functioning (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms per EORTC QLQ-C30 scale scores. Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with Ven-Obi showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least eight points at cycle three, whereas improvement was delayed until cycle eight with Clb-Obi. According to MDASI scores, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]) and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline and were maintained throughout treatment and follow-up. This analysis demonstrates that the higher efficacy of Ven-Obi is not associated with QoL impairment and that Ven-Obi achieves early relief of CLL-related symptoms in elderly unfit patients.

Epidemiology, longitudinal treatment patterns and outcomes of chronic lymphocytic leukemia in Israel.

This study aims to describe chronic lymphocytic leukemia (CLL) epidemiology, treatment patterns and outcomes in a 2.3-million-member healthcare provider database (Maccabi Healthcare Services, Israel). Newly-diagnosed CLL patients (1999-2017) were followed through 31/3/2018. A total of 1857 newly-diagnosed CLL patients were included. Annual incidence was 5.82 per 100,000 population. Median overall survival (OS) was 12.7 (95%CI: 11.8-13.5) years since diagnosis. Approximately 1/3 initiated treatment within 5 y. A statistical trend (p = 0.066) for improved OS over time was observed among younger patients (age <70 y) treated in 2009-2017 vs. 1999-2008). Among patients treated since 2009 (n = 411; median age = 68y), fludarabine-cyclophosphamide-rituximab (FCR), bendamustine-rituximab and obinutuzumab ± chlorambucil accounted for 19.5%, 12.2% and 11.4% of first line, respectively. Median (95%CI) time to next treatment and OS were 3.1(2.6-3.6) and 7.0(6.3-7.7) years, respectively. CLL incidence in Israel is comparable to developed countries. Real-world data suggest a trend of improved survival over the last decade among patients treated before age 70.

Budget Impact of 12-Month Fixed Treatment Duration Venetoclax in Combination with Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia Patients in the United States.

OBJECTIVES: This study aimed to assess the total cost of care (TCC) and budget impact of introducing 12-month fixed duration venetoclax + obinutuzumab (VEN+G) as first-line treatment for chronic lymphocytic leukemia (CLL) from the perspective of a US health plan with 1,000,000 (1M) members. METHODS: The 3-year model included the following comparators: fludarabine + cyclophosphamide + rituximab (FCR), bendamustine + rituximab (BR), obinutuzumab + chlorambucil (GClb), ibrutinib (Ibr), and Ibr+Rituximab/obinutuzumab [Ibr+R/Ibr+G]). TCC included US-specific costs associated with treatment (i.e., drug, administration, and wastage), adverse events, routine care, and monitoring. Dosing and safety data were drawn from clinical trials and US package inserts. Budget impact outcomes were presented on an absolute and per-member per-month (PMPM) basis. Sensitivity analyses explored uncertainty in influential parameters, including scenarios testing the duration of treat-to-progression agents. RESULTS: Over the 3-year time horizon, introducing VEN+G in a 1M-member health plan resulted in total cost savings of $1,550,663 (PMPM - $0.04), compared to a scenario without VEN+G. The fixed 12-month duration of VEN+G contributed to this cost saving by reducing cumulative treatment costs compared with Ibr-based regimens. By year 3, the cumulative difference in TCC of VEN+G compared with Ibr, Ibr+G, and Ibr+R amounted to - $300,942, - $367,001, and - $369,784, respectively. Extensive sensitivity analyses supported the base case findings. CONCLUSIONS: Introducing VEN+G among first-line CLL treatments to a US health plan resulted in cost savings compared to a plan with chemoimmunotherapies and Ibr-based therapies only. Economic benefits of VEN+G, a novel agent with fixed treatment duration, coupled with proven clinical benefits should help inform formulary adoption decisions and treatment recommendations.

The Social Value of Improvement in Activities of Daily Living among the Advanced Parkinson's Disease Population.

OBJECTIVES: Quantify the value of functional status (FS) improvements consistent in magnitude with improvements due to levodopa-carbidopa intestinal gel (LCIG) treatment, among the advanced Parkinson's disease (APD) population. METHODS: The Health Economic Medical Innovation Simulation (THEMIS), a microsimulation that estimates future health conditions and medical spending, was used to quantify the health and cost burden of disability among the APD population, and the value of quality-adjusted life-years gained from FS improvement due to LCIG treatment compared to standard of care (SoC). A US-representative Parkinson's disease (PD)-comparable cohort was constructed in THEMIS based on observed PD patient characteristics in a nationally representative dataset. APD was defined from the literature and clinical expert input. The PD and APD cohorts were followed from 2010 over their remaining lifetimes. All individuals were ages 65 and over at the start of the simulation. To estimate the value of FS improvement due to LCIG treatment, decreases in activities of daily living (ADL) limitations caused by LCIG treatment were calculated using data from a randomized, controlled, double-blind, double-dummy clinical trial and applied to the APD population in THEMIS. RESULTS: Total burden of disability associated with APD was $17.7 billion (B). From clinical trial data, LCIG treatment versus SoC lowers the odds of difficulties in walking, dressing, and bathing by 76%, 42% and 39%, respectively. Among the APD population, these reductions generated $2.6B in value to patients and cost savings to payers. The added value was 15% of the burden of disability associated with APD and offsets 15% of the cost of LCIG treatment. CONCLUSIONS: FS improvements, consistent with improvements due to LCIG treatment, in the APD population created health benefits and reduced healthcare costs in the US.

The effect of functional status impairment on nursing home admission risk among patients with advanced Parkinson's disease.

Aims: To estimate the relationship between functional status (FS) impairment and nursing home admission (NHA) risk in Parkinson's disease (PD) patients, and quantify the effect of advanced PD (APD) treatment on NHA risk relative to standard of care (SoC).Materials and methods: PD patients were identified in the Medicare Current Beneficiary Survey (MCBS) (1992-2010). A working definition based on the literature and clinical expert input determined APD status. A logit model estimated the relationship between FS impairment and NHA risk. The effect of levodopa-carbidopa intestinal gel (LCIG) on NHA risk relative to SoC was simulated using clinical trial data (control: optimized oral levodopa-carbidopa IR, ClinicalTrials.gov NCT00660387 and NCT0357994).Results: Non-advanced PD and APD significantly increased NHA risk when controlling for demographics (p < 0.01). APD status was no longer significant after controlling for FS limitations, implying that FS limitations explain the increased NHA risk in APD patients. Reduced impairment in FS in patients with APD treated with LCIG reduced risk of NHA by 13.5% relative to SoC.Limitations: This study applies clinical trial results to real-world data. LCIG treatment might have a different effect on NHA risk for the nationally representative population than the effect measured in the trial. Both data sources employ different instruments to measure FS, instrument wording and study follow-up differed, which might bias our estimates. Finally, there lacks consensus on a definition of APD. The prevalence of APD in this study is high, perhaps due to the specific definition used.Conclusions: Patients with APD experience a higher risk in NHA than those with non-advanced disease. This increased risk in NHA in patients with APD is explained by greater limitations in FS. The relative reduction in risk of NHA for the APD population treated with LCIG is quantitatively similar to doubling Medicaid home care services.

Characterizing advanced Parkinson's disease: OBSERVE-PD observational study results of 2615 patients.

BACKGROUND: There are currently no standard diagnostic criteria for characterizing advanced Parkinson's disease (APD) in clinical practice, a critical component in determining ongoing clinical care and therapeutic strategies, including transitioning to device-aided treatment. The goal of this analysis was to determine the proportion of APD vs. non-advanced PD (non-APD) patients attending specialist PD clinics and to demonstrate the clinical burden of APD. METHODS: OBSERVE-PD, a cross-sectional, international, observational study, was conducted with 2615 PD patients at 128 movement disorder centers in 18 countries. Motor and non-motor symptoms, activities of daily living, and quality-of-life end points were assessed. The correlation between physician's global assessment of advanced PD and the advanced PD criteria from a consensus of an international group of experts (Delphi criteria for APD) were evaluated. RESULTS: According to physician's judgment, 51% of patients were considered to have APD. There was a moderate correlation between physician's judgment and Delphi criteria for APD (K = 0.430; 95% CI 0.406-0.473). Activities of daily living, motor symptom severity, dyskinesia duration/disability, "Off" time duration, non-motor symptoms, and quality-of-life scores were worse among APD vs. non-APD patients (p < 0.0001 for all). APD patients (assessed by physicians) had higher disease burden by motor and non-motor symptoms compared with non-APD patients and a negative impact on activities of daily living and quality of life. CONCLUSIONS: These findings aid in identifying standard APD classification parameters for use in practicing physicians. Improvements in identification of APD patients may be particularly relevant for optimizing treatment strategies including transitioning to device-aided treatment.

The long-term direct and indirect economic burden among Parkinson's disease caregivers in the United States.

BACKGROUND: Parkinson's disease is a progressive, disabling neurodegenerative disorder associated with significant economic burden for patients and caregivers. The objective of this study was to compare the direct and indirect economic burden of Parkinson's patients' caregivers with demographically matched controls in the United States, in the 5 years after first diagnosis of Parkinson's disease. METHODS: Policyholders (18-64 years old) linked to a Parkinson's disease patient (≥2 diagnoses of Parkinson's disease; first diagnosis is the index date) from January 1, 1998 to March 31, 2014, were selected from a private-insurer claims database and categorized as Parkinson's caregivers. Eligible Parkinson's caregivers were matched 1:5 to policyholders with a non-Parkinson's dependent (controls). Multivariable regression adjusted for baseline characteristics estimated direct costs (all-cause insurer cost [medical and prescription] and comorbidity-related medical costs; patient out-of-pocket costs) and indirect costs (disability and medically related absenteeism costs). Income progression was also compared between cohorts. RESULTS: A total of 1211 eligible Parkinson's caregivers (mean age, 56 years; 54% female) were matched to 6055 controls. In adjusted analyses, Parkinson's caregivers incurred significantly higher year 1 total all-cause insurer costs ($8999 vs $7117) and medical costs ($7081 vs $5568) (both P < 0.01) and higher prescription costs (range for years 1-5, $2506-2573 vs $1405-$1687) and total out-of-pocket costs ($1259-1585 vs $902-$1192) in years 1-5 (all P < 0.01). Parkinson's caregivers had significantly higher adjusted indirect costs in years 1-3 (range for years 1-3, $2054-$2464 vs $1681-$1857; all P < 0.05) and higher cumulative income loss over 5 years ($5967 vs $2634 by year 5; P for interaction = 0.03). CONCLUSIONS: Parkinson's caregivers exhibited higher direct and indirect costs and greater income loss compared with matched controls. © 2018 International Parkinson and Movement Disorder Society © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Developing consensus among movement disorder specialists on clinical indicators for identification and management of advanced Parkinson's disease: a multi-country Delphi-panel approach.

BACKGROUND: Lack of a global consensus on the definition of advanced Parkinson's disease (APD) and considerations for timing of device-aided therapies may result in heterogeneity in care. OBJECTIVES: To reach consensus among movement disorder specialists regarding key patient characteristics indicating transition to APD and guiding appropriate use of device-aided therapies in the management of PD symptoms. METHODS: A Delphi-panel approach was utilized to synthesize opinions of movement disorder specialists and build consensus. RESULTS: A panel was comprised of movement disorder specialists from 10 European countries with extensive experience of treating PD patients (mean =24.8 ± 7.2 years). Consensus on indicators of suspected APD and eligibility for device-aided therapies were based on motor symptoms, non-motor symptoms, and functional impairments. Key indicators of APD included: (i) motor-moderate troublesome motor fluctuations, ≥1 h of troublesome dyskinesia/day, ≥2 h "off" symptoms/day, and ≥5-times oral levodopa doses/day; (ii) non-motor-mild dementia, and non-transitory troublesome hallucinations; (iii) functional impairment-repeated falls despite optimal treatment, and difficulty with activities of daily living. Patients with good levodopa response, good cognition, and <70 years of age were deemed as good candidates for all three device-aided therapies. Patients with troublesome dyskinesia were considered good candidates for both levodopa-carbidopa intestinal gel and Deep Brain Stimulation (DBS). PD patients with levodopa-resistant tremor were considered good candidates for DBS. CONCLUSION: Identifying patients progressing to APD and suitable for device-aided therapies will enable general neurologists to assess the need for referral to movement disorder specialists and improve the quality of care and patient outcomes.

Effect of Levodopa-carbidopa Intestinal Gel on Non-motor Symptoms in Patients with Advanced Parkinson's Disease.

Background: Levodopa-carbidopa intestinal gel (LCIG; carbidopa-levodopa enteral suspension in the United States), delivered via percutaneous gastrojejunostomy (PEG-J) and titrated in the inpatient setting, is an established treatment option for advanced Parkinson's disease (PD) patients with motor fluctuations. However, long-term prospective data on the efficacy of LCIG on non-motor symptoms and the safety of outpatient titration are limited. Methods: In this 60-week, open-label phase 3b study, LCIG titration was initiated in an outpatient setting following PEG-J placement in PD patients. The efficacy of LCIG on motor and non-motor symptoms, quality of life, and safety was assessed. Results: Thirty-nine patients were enrolled in the study and 28 patients completed the treatment. A majority of patients (54%) completed outpatient titration within the first week of LCIG infusion. LCIG led to significant reductions from baseline in Non-Motor Symptom Scale (NMSS) total score (least squares mean ± SE = -17.6 ± 3.6, P < 0.001) and 6 of the NMSS domain scores (sleep/fatigue, attention/memory, gastrointestinal tract, urinary, sexual function, miscellaneous) at week 12. These reductions were maintained at week 60 with the exception of the urinary domain. "Off" time (-4.9 ± 0.5 hours/day, P < 0.001) and "On" time without troublesome dyskinesia (-4.3 ± 0.6 hours/day, P < 0.001) were improved at week 60. Adverse events (AEs) were reported in 37 (95%) patients. Conclusions: LCIG treatment led to reductions in non-motor symptom burden and motor fluctuations in advanced PD patients. The safety profile was consistent with previous studies that used inpatient titration and outpatient titration did not appear to pose additional risk.

The cost-effectiveness of levodopa/carbidopa intestinal gel compared to standard care in advanced Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is an incurable, progressive neurological condition, with symptoms impacting movement, walking, and posture that eventually become severely disabling. Advanced PD (aPD) has a significant impact on quality-of-life (QoL) for patients and their caregivers/families. Levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of advanced levodopa-responsive PD with severe motor fluctuations and hyper-/dyskinesia when available combinations of therapy have not given satisfactory results. AIMS: To determine the cost-effectiveness of LCIG vs standard of care (SoC) for the treatment of aPD patients. METHODS: A Markov model was used to evaluate LCIG vs SoC in a hypothetical cohort of 100 aPD patients with severe motor fluctuations from an Irish healthcare perspective. Model health states were defined by Hoehn & Yahr (H&Y) scale-combined with amount of time in OFF-time-and death. SoC comprised of standard oral therapy ± subcutaneous apomorphine infusion and standard follow-up visits. Clinical efficacy, utilities, and transition probabilities were derived from published studies. Resource use was estimated from individual patient-level data from Adelphi 2012 UK dataset, using Irish costs, where possible. Time horizon was 20 years. Costs and outcomes were discounted at 4%. Both one-way and probabilistic sensitivity analyses were conducted. RESULTS: The incremental cost-effectiveness ratio for LCIG vs SOC was €26,944/quality adjusted life year (QALY) (total costs and QALYs for LCIG vs SoC: €537,687 vs €514,037 and 4.37 vs 3.49, respectively). LCIG is cost-effective at a payer threshold of €45,000. The model was most sensitive to health state costs. CONCLUSION: LCIG is a cost-effective treatment option compared with SoC in patients with aPD.

Assessment of treatment and monitoring patterns and subsequent outcomes among patients with chronic myeloid leukemia treated with imatinib in a community setting.

INTRODUCTION: Real-world treatment and monitoring patterns have not been well documented among imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients. Thus, we evaluated these patterns and responses to imatinib in CP-CML patients. METHODS: This retrospective study, based on the Georgia Cancer Specialists' electronic medical record (EMR) system, identified CP-CML patients initiating treatment with imatinib from 01/01/2002 to 11/01/2011 who were subsequently followed for ≥6 months. RESULTS: A total of 177 patients met the study criteria. Imatinib dose modification occurred in 59 patients (33%). Rates of treatment interruption, discontinuation, and switching to another therapy were 16%, 24%, and 23%, respectively. Of 27 patients discontinuing imatinib for lack of efficacy, 9 (33%) had initial dose escalation; 26 patients (96%) eventually switched to a second-generation tyrosine kinase inhibitor. By 3 months, 168 patients remained on imatinib, of whom 96 (57%) had undergone cytogenetic and/or molecular testing. The frequency of response monitoring fluctuated over time, with rates as high as 28% for cytogenetic and 69% for molecular testing. Cumulative response rates steadily increased; 18 month rates were 47% for complete cytogenetic response and 26% for major or complete molecular response. There were no cases of progression and/or death among 38 patients who were regularly monitored for molecular response within the first 12 months of imatinib. Ten of 98 patients (10%) not regularly monitored had progressed or died. CONCLUSIONS: Almost one-third of patients initiating imatinib for CP-CML required dose modification, treatment interruption, or discontinuation. Opportunities for improved monitoring in this setting were identified. Limitations include those inherent to retrospective analyses based on EMR and the uncertain extrapolability of the results.

Modeling causes of aggressive behavior in patients with dementia.

PURPOSE OF THE STUDY: To examine factors predicting development of aggression in patients with dementia as a step toward developing preventive strategies and nonpharmacologic therapies. DESIGN AND METHODS: Study participants were 171 nonaggressive, community-residing VA patients aged more than 60, newly diagnosed with dementia. Patients and caregivers were assessed at baseline and at months 5, 9, 13, 17, 21, and 25. Aggression was evaluated using the Cohen-Mansfield Agitation Inventory. Survival models incorporating direct and indirect effects were conducted to estimate associations between psychosocial factors (baseline and change measures of dementia severity, pain, depression, caregiver burden, patient-caregiver relationship, and nonaggressive physical agitation) and time to aggression onset. RESULTS: Higher levels of baseline caregiver burden, worst pain, declining patient-caregiver relationship, and increasing nonaggressive physical agitation predicted increased risk of aggression. Baseline dementia severity and depression were indirectly related to onset of aggression. The association between increasing nonaggressive physical agitation and time to aggression onset was independent of the associations between our psychosocial measures and time to aggression onset. IMPLICATIONS: Potentially mutable factors were associated with development of aggression. The longitudinal design of this study and its sample of newly diagnosed, previously nonaggressive dementia patients strengthen prior findings in the literature.

Clinical and economic outcomes associated with adjuvant chemotherapy in elderly patients with early stage operable breast cancer.

OBJECTIVES: Breast cancer poses a huge medical burden to the U.S. health-care system, and chemotherapy is an important contributor to cancer costs. This article examines the differences between breast cancer patients who received chemotherapy and those who did not in costs and survival by age, treatment, and axillary node status. METHODS: We studied a cohort of 23,110 node-positive and 31,572 node-negative women aged 65 years and older diagnosed with incident American Joint Committee on Cancer stage I, II, or IIIA breast cancer between January 1, 1991, and December 31, 2002, using Surveillance Epidemiology and End Results-Medicare data. Total treatment costs and costs associated with the use of chemotherapy were estimated by using the phase-of-care approach. The phase-specific costs were combined to estimate total Medicare payments for cancer care from diagnosis to death. Cox proportional hazard ratio of mortality was used to determine the effectiveness of adjuvant chemotherapy after adjusting for selected patient and tumor characteristics. We used propensity scores to minimize the bias associated with the receipt of adjuvant chemotherapy. RESULTS: Regression-adjusted difference in the average lifetime cost estimates for all node-positive patients receiving chemotherapy was approximately $2438 and was significantly higher (P < 0.05) than for patients not receiving chemotherapy. Mortality was significantly lower in node-positive and node-negative women aged 65 to 74 years receiving chemotherapy. CONCLUSIONS: Decision makers can use cost and effectiveness estimates from this study to assess the relative value of chemotherapy in different age groups.