Geriatric assessment measures are predictive of outcomes in chronic lymphocytic leukemia.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) commonly affects older adults. However, few studies have examined the relationship between baseline geriatric domains and clinical outcomes in this population. Here, we aim to evaluate the use of a comprehensive geriatric assessment in older (>65 years) untreated patients with CLL to predict outcomes. MATERIALS AND METHODS: We conducted a planned analysis of 369 patients with CLL age 65 or older treated in a phase 3 randomized trial of bendamustine plus rituximab versus ibrutinib plus rituximab versus ibrutinib alone (A041202). Patients underwent evaluations of geriatric domains including functional status, psychological status, social activity, cognition, social support, and nutritional status. We examined associations among baseline geriatric domains with grade 3+ adverse events using multivariable logistic regression and overall survival (OS) and progression-free survival (PFS) using multivariable Cox regression models. RESULTS: In this study, the median age was 71 years (range: 65-87). In the combined multivariable model, the following geriatric domains were significantly associated with PFS: Medical Outcomes Study (MOS) - social activities survey score (hazard ratio [HR] [95% confidence interval (CI)] 0.974(0.961, 0.988), p = 0.0002) and nutritional status (≥5% weight loss in the preceding six months: (HR [95% CI] 2.717[1.696, 4.354], p < 0.001). MOS - social activities score [HR (95% CI) 0.978(0.958, 0.999), p = 0.038] was associated with OS. No geriatric domains were significantly associated with toxicity. There were no statistically significant interactions between geriatric domains and treatment. DISCUSSION: Geriatric domains of social activity and nutritional status were associated with OS and/or PFS in older adults with CLL. These findings highlight the importance of assessing geriatric domains to identify high-risk patients with CLL who may benefit from additional support during treatment.

Impact of Fixed-Duration Oral Targeted Therapies on the Economic Burden of Chronic Lymphocytic Leukemia in Canada.

BACKGROUND: Continuous oral targeted therapies (OTT) represent a major economic burden on the Canadian healthcare system, due to their high cost and administration until disease progression/toxicity. The recent introduction of venetoclax-based fixed-duration combination therapies has the potential to reduce such costs. This study aims to estimate the prevalence and the cost of CLL in Canada with the introduction of fixed OTT. METHODS: A state transition Markov model was developed and included five health states: watchful waiting, first-line treatment, relapsed/refractory treatment, and death. The number of CLL patients and total cost associated with CLL management in Canada for both continuous- and fixed-treatment-duration OTT were projected from 2020 to 2025. Costs included drug acquisition, follow-up/monitoring, adverse event, and palliative care. RESULTS: The CLL prevalence in Canada is projected to increase from 15,512 to 19,517 between 2020 and 2025. Annual costs were projected at C$880.7 and C$703.1 million in 2025, for continuous and fixed OTT scenarios, respectively. Correspondingly, fixed OTT would provide a total cost reduction of C$213.8 million (5.94%) from 2020 to 2025, compared to continuous OTT. CONCLUSIONS: Fixed OTT is expected to result in major reductions in cost burden over the 5-year projection, compared to continuous OTT.

Return on investment of the lymphoma diagnostic pathway implementation in Alberta, Canada.

The Lymphoma Diagnostic Pathway (LDP) was developed based upon clinical best practice guidelines and implemented in large urban centers where lymphoma treatment is provided in Alberta, Canada. A return-on-investment analysis of the implementation of this care pathway was conducted to inform future sustainability and expansion. A cohort design with propensity score matching and difference-in-difference estimation methods were used comparing both cost and return (reduced health service utilization) between patients who were diagnosed within the LDP and those who were diagnosed outside the LDP. LDP resulted in $1800 avoided HSU costs per patient. The LDP has been found to be cost-saving with an ROI of 5.3 (ranging from 3.95-8.97) - for every $1 invested, LDP resulted in a $5.30 return for the health system due to capacity improvements in ED, inpatient, outpatient, and a reduction in GP service utilization. Further study of implementation including patient/provider satisfaction and uptake is recommended.

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.

A Prospective Economic Analysis of Early Outcome Data From the Alliance A041202/ CCTG CLC.2 Randomized Phase III Trial Of Bendamustine-Rituximab Compared With Ibrutinib-Based Regimens in Untreated Older Patients With Chronic Lymphocytic Leukemia.

INTRODUCTION: The Alliance A041202/CCTG CLC.2 trial demonstrated superior progression-free survival with ibrutinib-based therapy compared to chemoimmunotherapy with bendamustine-rituximab (BR) in previously untreated older patients with chronic lymphocytic leukemia. We completed a prospective trial-based economic analysis of Canadian patients to study the direct medical costs and quality-adjusted benefit associated with these therapies. METHODS: Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months. Health state utilities were collected using the EuroQOL EQ-5D instrument with Canadian tariffs applied to calculate quality-adjusted life years (QALYs). Costs were applied to resource utilization data (expressed in 2019 US dollars). We examined costs and QALYs associated ibrutinib, ibrutinib with rituximab (IR), and BR therapy. RESULTS: A total of 55 patients were enrolled; two patients were excluded from the analysis. On-protocol costs (associated with protocol-specified resource use) were higher for patients receiving ibrutinib (mean $189,335; P < 0.0001) and IR (mean $219,908; P < 0.0001) compared to BR (mean $51,345), driven by higher acquisition costs for ibrutinib. Total mean costs (over 2-years) were $192,615 with ibrutinib, $223,761 with IR, and $55,413 with BR (P < 0.0001 for ibrutinib vs. BR and P < 0.0001 for IR vs. BR). QALYs were similar between the three treatment arms: 1.66 (0.16) for ibrutinib alone, 1.65 (0.24) for IR, and 1.66 (0.17) for BR; therefore, a formal cost-utility analysis was not conducted. CONCLUSIONS: Direct medical costs are higher for patients receiving ibrutinib-based therapies compared to chemoimmunotherapy in frontline chronic lymphocytic leukemia, with the cost of ibrutinib representing a key driver.

Impact of Oral Targeted Therapy on the Economic Burden of Chronic Lymphocytic Leukemia in Canada.

Background: Continuous oral targeted therapy (OTT) for chronic lymphocytic leukemia (CLL) represents an effective therapy but also a major economic burden on the healthcare system. This study aimed to estimate future direct costs, along with the prevalence, of CLL in the era of continuous OTT in Canada. Methods: The economic burden of OTT was modelled and compared to chemoimmunotherapy (CIT), for CLL treatment. The burden was assessed/projected from 2011 to 2025. For the OTT scenario, CIT was considered the standard of care before 2015, while OTT was considered standard of care for patients with either unmutated immunoglobulin heavy-chain variable (IGHV) or del(17p)/TP53 mutations starting in 2015 and, from 2020 onwards, for all first-line treatments except for patients with mutated IGHV. A Markov model was developed including four health states: watchful-waiting, first-line treatment, relapse and death. Costs of therapy, follow-up/monitoring and adverse events were included. Key clinical parameters were extracted from pivotal clinical trials. Results: As incidence rates and rate of survival are increasing, the prevalence of CLL in Canada is projected to increase 1.8-fold, from 8301 patients in 2011 to 14,654 by 2025. Correspondingly, the total annual costs of CLL management are predicted to increase 15.7-fold, from $60.8 million to $957.5 million during that same period. Conclusions: Although OTT enhances survival for patients with CLL, it is nonetheless associated with an important economic burden due to the projected vast increase in costs from 2011 to 2025. Changes in clinical strategies, such as implementation of a fixed OTT treatment duration, could help alleviate financial burden.

Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia.

Progress in chronic lymphocytic leukemia (CLL) therapies has extended greatly the length and depth of remission, with the goal of treatment advancing towards a cure for some patients. Accordingly, clinical endpoints must evolve to capture these outcomes, and to provide faster access to novel therapies. Minimal residual disease (MRD) is an important endpoint representing more accurately the depth of remission than complete response (CR), and is highly prognostic of progression-free survival (PFS) and overall survival (OS). MRD could be considered a key outcome of clinical trials and, as a surrogate for PFS, could identify the most cost-effective and durable treatment sequencing. MRD testing could also determine which patients would benefit from additional therapy and, accordingly, ascertain when therapy should be stopped earlier, to reduce toxicity and increase treatment-free intervals. Our article discusses possible uses of MRD in the modern era of CLL, including its definition, measurement, and value as a surrogate endpoint in clinical trials, and its potential roles in clinical practice.

Does this patient have deep vein thrombosis?

CONTEXT: Outpatients with suspected deep vein thrombosis (DVT) have nonspecific signs and symptoms. Missed DVT diagnosis may result in fatal pulmonary embolism. Since many patients may have DVT, a selective and efficient diagnostic process is needed. OBJECTIVE: To systematically review trials that determined the prevalence of DVT using clinical prediction rules either with or without D-dimer, for the diagnosis of DVT. DATA SOURCES: English- and French-language studies were identified from MEDLINE from 1990 to July 2004 and supplemented by a review of all relevant bibliographies. STUDY SELECTION: We included studies that prospectively enrolled consecutive, unselected outpatients with suspected DVT and applied clinical prediction rules before D-dimer testing or diagnostic imaging. All studies included sufficient information to allow the calculation of the prevalence of DVT for at least 1 of the 3 clinical probability estimates (low, moderate, or high). We required that patients be followed up for a minimum 3-month period. Unless the clinical model incorporated prior DVT, studies were excluded if patients with a history of prior DVT were enrolled. DATA EXTRACTION: Two reviewers independently reviewed and abstracted data for estimating the prevalence of DVT, sensitivity, specificity, and likelihood ratios (LRs) of D-dimer in each of the 3 clinical probability estimates. Data for the D-dimer in all studies were pooled and analyzed as high-sensitivity/low-specificity test or a moderate-sensitivity/moderate-specificity test. DATA SYNTHESIS: Fourteen studies involving more than 8000 patients used 1 clinical prediction rule for diagnosing DVT, of which 11 incorporated D-dimer testing in the diagnostic algorithm. The prevalence of DVT in the low, moderate, and high clinical probability groups was 5.0% (95% CI, 4.0%-8.0%), 17% (95% CI, 13%-23%), and 53% (95% CI, 44%-61%), respectively. The overall prevalence of DVT was 19% (95% CI, 16%-23%). Pooling all studies, the sensitivity, specificity, and negative LRs of D-dimer testing in the low probability group were 88% (95% CI, 81%-92%), 72% (95% CI, 65%-78%), and 0.18% (95% CI, 0.12-0.18); in the moderate probability group: 90% (95% CI, 80%-95%), 58% (95% CI, 49%-67%), and 0.19% (95% CI, 0.11-0.32); and in the high probability group: 92% (95% CI, 85%-96%), 45% (95% CI, 37%-52%), and 0.16% (95% CI, 0.09-0.30). The LRs for a normal result on a high or moderately sensitive D-dimer assay among patients with: (1) low clinical suspicion were 0.10 (95% CI, 0.03-0.37) and 0.20 (95% CI, 0.12-0.31); (2) moderate clinical suspicion were 0.05 (95% CI, 0.01-0.21) and 0.23 (95% CI, 0.13-0.39); and (3) high clinical suspicion were 0.07 (95% CI, 0.03-0.18) and 0.15 (95% CI, 0.10-0.38). CONCLUSIONS: Diagnostic accuracy for DVT improves when clinical probability is estimated before diagnostic tests. Patients with low clinical probability on the predictive rule have prevalence of DVT of less than 5%. In low-probability patients with negative D-dimer results, diagnosis of DVT can be excluded without ultrasound; in patients with high clinical suspicion for DVT, results should not affect clinical decisions.