AbstractCostly targeted cancer treatments challenge publicly-funded healthcare systems seeking to align expected benefit with value for money. In 2021, The Canadian Agency for Drugs and Technologies in Health (CADTH) published a provisional funding algorithm for risk-based treatment of chronic lymphocytic leukemia (CLL).

摘要昂贵的靶向癌症治疗挑战了公共资助的医疗保健系统，这些系统寻求将预期收益与资金价值相一致。2021年，加拿大药物和技术卫生署（CADTH）发布了一项临时资助算法，用于基于风险的慢性淋巴细胞白血病（CLL）治疗。

We estimate the cost-effectiveness of this algorithm against current standard of care. We constructed a probabilistic Markov model comparing next generation sequencing (NGS) assay-guided front-line treatment of acalabrutinib versus venetoclax with obinutuzumab to a comparator wherein patients initiate acalabrutinib.

我们根据当前的护理标准估计了该算法的成本效益。我们构建了一个概率马尔可夫模型，比较了下一代测序（NGS）分析指导的阿卡鲁替尼与venetoclax与obinutuzumab的一线治疗与患者启动阿卡鲁替尼的比较。

The primary outcome was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained. Analyses were conducted from the British Columbia healthcare system perspective, with outcomes discounted at 1.5%. Assay informed treatment for patients with CLL resulted in an incremental cost effectiveness ratio of $18,040 (95% CI $16,491–$19,501) per quality adjusted life-year (QALY) gained.

主要结果是获得的每个质量调整生命年（QALY）的增量成本效益比（ICER）。从不列颠哥伦比亚省医疗保健系统的角度进行分析，结果折扣为1.5%。CLL患者的分析知情治疗导致每增加一个质量调整生命年（QALY），成本效益比增加18040美元（95%可信区间16491-19501美元）。

The probability of the NGS guided treatment algorithm being cost effective was 80% at a willingness to pay threshold of $50,000 and a corresponding ICER of $18,040. Assay-guided treatment sequencing adds additional costs to healthcare but may be a cost-effective intervention for adult patients with CLL.

NGS指导的治疗算法具有成本效益的概率为80%，支付意愿阈值为50000美元，相应的ICER为18040美元。分析指导的治疗测序增加了医疗保健的额外成本，但对于成年CLL患者可能是一种具有成本效益的干预措施。

Integration of real-world evidence would improve the validity and reliability of model estimated for decision-makers..

整合真实世界的证据将提高决策者估计模型的有效性和可靠性。。

IntroductionChronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries, making up 25–35% of diagnoses1. The incidence of CLL is estimated to be 6.3 cases per 100,000 men and 3.3 cases per 100,000 women2. Patients with CLL have favourable survival compared with other cancers, with five-year survival estimates approximating 90%, and a median survival of approximately 10 years; however, there is significant variability in survival based on a number of clinical and disease related characteristics3,4.

引言慢性淋巴细胞白血病（CLL）是西方国家成年人中最常见的白血病，占诊断的25-35%1。据估计，CLL的发病率为每10万名男性6.3例，每10万名女性3.3例2。与其他癌症相比，CLL患者的生存率良好，五年生存率估计约为90%，中位生存期约为10年；然而，基于许多临床和疾病相关特征，生存率存在显着差异3,4。

Treatment is reserved for patients with advanced stage or symptomatic disease5,6.With an increased understanding of heterogeneous disease trajectories, there has been considerable effort to develop prognostic and predictive biomarkers to guide therapeutic sequencing decisions. These biomarkers are now included in a number of genomic testing strategies, many of which are not routinely available in Canada.

治疗保留给晚期或有症状疾病的患者5,6。随着对异质性疾病轨迹的了解增加，已经做出了相当大的努力来开发预后和预测性生物标志物以指导治疗测序决策。这些生物标志物现在包括在许多基因组测试策略中，其中许多在加拿大并不常见。

For CLL patients requiring treatment, multiple options are available in Canada including: chemoimmunotherapy (such as fludarabine, cyclophosphamide, rituximab [FCR] and bendamustine and rituximab [BR]), and small molecule inhibitors such as BCL2 inhibitors (venetoclax), PI3-kinase inhibitors (idelalisib), as well as Bruton tyrosine kinase inhibitors (BTKIs) (ibrutinib and acalabrutinib).

对于需要治疗的CLL患者，加拿大有多种选择，包括：化学免疫疗法（如氟达拉滨，环磷酰胺，利妥昔单抗[FCR]和苯达莫司汀和利妥昔单抗[BR]），小分子抑制剂如BCL2抑制剂（venetoclax），PI3激酶抑制剂（idelalisib）以及布鲁顿酪氨酸激酶抑制剂（BTKIs）（依鲁替尼和阿卡鲁替尼）。

These small molecular inhibitors are often combined with anti-CD20 monoclonal antibodies, obinutuzumab or rituximab7,8.Emerging research efforts investigating novel targeted CLL treatments have led to a shift away from traditional chemotherapy towards small molecule inhibitors. Currently, two such competing treatment strategies demonstrate efficacy and are included in standard care treatment of patients with CLL.

这些小分子抑制剂通常与抗CD20单克隆抗体，obinutuzumab或利妥昔单抗联合使用[7,8]。研究新型靶向CLL治疗的新兴研究工作已导致从传统化疗转向小分子抑制剂。目前，两种这样的竞争性治疗策略证明了疗效，并被纳入CLL患者的标准护理治疗中。

Venetoclax, combined with an anti-CD20 monoclon.

Venetoclax与抗CD20单克隆抗体结合。

Table 1 Model parameters: clinical data used to generate model transition probabilities.Full size tablePublished Kaplan–Meier (KM) curves were digitized, extrapolated using parametric distributions, and converted into probabilistic time-dependent transition probabilities. In the reference case analysis, a Weibull distribution was used to extrapolate the data over the model time horizon.

表1模型参数：用于生成模型转换概率的临床数据。全尺寸表已发布的Kaplan–Meier（KM）曲线被数字化，使用参数分布进行外推，并转换为概率随时间变化的过渡概率。在参考案例分析中，使用威布尔分布来推断模型时间范围内的数据。

High-risk patients were defined as those that had del17p alteration, TP53 mutation, and/or an unmutated IGHV status.Survival estimates were sourced from relevant clinical trials depending on the line of therapy. Kaplan–Meier curves were digitized and extrapolated over the model time horizon. Utility values were derived from Beusterien et al.30 using the standard gamble technique to elicit utility values among patients with CLL.

高危患者被定义为具有del17p改变，TP53突变和/或未突变IGHV状态的患者。生存率估计值来自相关的临床试验，具体取决于治疗方案。Kaplan–Meier曲线被数字化并在模型时间范围内外推。效用值来自Beusterien等[30]，使用标准赌博技术得出CLL患者的效用值。

QALYs were calculated using these utility weights which were assigned to each mutually exclusive health state30. Costs of CLL treatment were sources from available Canadian list prices (see Table 2) and are presented in 2021 Canadian dollars..

QALYs是使用这些效用权重计算的，这些权重被分配给每个互斥的健康状态30。CLL治疗的费用来源于可用的加拿大标价（见表2），以2021加元表示。。

Table 2 Model parameters: costs used in the economic model.Full size tableAdditional costs for adverse events were obtained from the published literature. Specific parameter values for each health state are presented in Table 3.

表2模型参数：经济模型中使用的成本。全尺寸表不良事件的额外费用来自已发表的文献。表3列出了每个健康状态的具体参数值。

Table 3 Model parameters: utility values used to calculate quality-adjusted life-years (QALYs).Full size tableOur model assumes that the NGS assay would accurately detect 50% of patients as high-risk, at a cost of $1000 CAD. The basis for the proportion of high-risk patients is based on available evidence and expert clinical consultation21.

表3模型参数：用于计算质量调整生命年（QALY）的效用值。全尺寸表我们的模型假设NGS分析可以准确检测出50%的高风险患者，成本为1000加元。高风险患者比例的基础是基于现有证据和专家临床咨询21。

Assumed cost of the NGS assay is informed by a conservative estimate of the individual costs for detecting mutations that would categorize a patient as high-risk.AnalysisWe conducted a probabilistic analysis in alignment with guidance for economic evaluation published by CADTH/CDA25. Whenever possible, transition probabilities were time-dependent over the model time horizon.

NGS分析的假设成本是通过保守估计检测突变的个体成本来确定的，突变将患者归类为高风险。分析我们根据CADTH/CDA25发布的经济评估指南进行了概率分析。只要有可能，过渡概率在模型时间范围内都是随时间变化的。

For the probabilistic analysis, 1000 iterations were run and plotted on a cost-effectiveness plane. We conducted probabilistic scenario analyses by varying the predictive probabilities of the NGS assay and an additional analysis varied the cost of the NGS assay. The rationale underlying the analytic approach is that the value of this NGS assay is linked to the prevalence of, and ability to, detect high-risk patients.

对于概率分析，运行了1000次迭代并绘制在成本效益平面上。我们通过改变NGS分析的预测概率进行了概率情景分析，另外的分析改变了NGS分析的成本。分析方法的基本原理是，这种NGS分析的价值与高危患者的患病率和检测能力有关。

If all patients are high-risk or the genetic test identifies all patients as high-risk, this will almost exactly match the standard of care arm where all patients are treated with acalabrutinib in the first-line setting.Ethics and consent to participateThis study was approved by the University of British Columbia BC Cancer Behavioural Research Ethics Board (H18-00490).

如果所有患者都是高风险患者，或者基因检测将所有患者确定为高风险患者，那么这几乎完全符合护理部门的标准，所有患者都在一线接受阿卡鲁替尼治疗。伦理和参与同意这项研究得到了不列颠哥伦比亚大学BC癌症行为研究伦理委员会（H18-00490）的批准。

No human subjects were used as part of this research.ResultsResults of our analysis illustrate that the treatment algorithm incorporating the NGS assay was associated with both greater costs and effects. The intervention of a genetic assay into a treatment algorithm for patients with C.

这项研究没有使用人类受试者。结果我们的分析结果表明，结合NGS分析的治疗算法与更高的成本和效果相关。将遗传分析干预到C患者的治疗算法中。

Table 4 Results in terms of incremental costs, incremental effects (quality-adjusted life-years) from the reference case probabilistic analysis.Full size tableThe NGS assay intervention also resulted in an incremental gain in QALYs of 1.01 (95%CI 0.12, 1.91). The resulting ICER was $18,040 (95% CI $16,491-$19,501) per QALY gained (see Fig. 2).

表4根据参考案例概率分析得出的增量成本、增量效应（质量调整寿命年）的结果。全尺寸表NGS分析干预还导致QALY的增量增加1.01（95%CI 0.12、1.91）。由此产生的ICER为每QALY获得18040美元（95%可信区间为16491美元至19501美元）（见图2）。

Using a WTP of $50,000 per QALY gained, the corresponding net monetary benefit statistic was $32,354 (95% CI 30,804.99 – 33,815.99), indicating a cost-effective intervention.Figure 2Scatterplot of incremental costs and incremental effects (QALYs) based on 1000 probabilistic model iterations. Dots/simulations to the right of the vertical axis represent a scenario where the intervention arm is considered more effective to the standard of care.

使用每QALY获得50000美元的WTP，相应的净货币收益统计为32354美元（95%CI 30804.99-33815.99），表明干预具有成本效益。图2基于1000次概率模型迭代的增量成本和增量效应（QALY）分布图。垂直轴右侧的点/模拟代表了干预组被认为对护理标准更有效的情况。

Similarly, dots/simulations below the horizontal axis represent simulations where the intervention arm was estimated to be less costly than the standard of care.Full size imageAt a willingness-to-pay (WTP) threshold of $50,000 per QALY gained, the probability of the introduction of the NGS assay being cost-effective was 80%.

类似地，水平轴下方的点/模拟表示模拟，其中干预臂估计比标准护理成本更低。全尺寸图像在每QALY获得50000美元的支付意愿（WTP）阈值下，引入NGS测定具有成本效益的可能性为80%。

Approximately 19% of the 1000 probabilistic iterations resulted in a scenario where the addition of the genetic test into the algorithm resulted in lower costs and greater effects (QALYs) (i.e., dominated the standard of care; see Fig. 3).Figure 3Cost-effectiveness acceptability curve which represents the probability that the NGS assay intervention would be considered cost-effective at various thresholds of WTP per quality-adjusted life-year (QALY) gained.Full size imageIn scenario analyses, the assumed cost of the NGS assay varied from $0 to $2000.

在1000次概率迭代中，大约有19%产生了这样一种情况，即在算法中添加遗传测试会导致更低的成本和更大的效果（QALY）（即主导护理标准；见图3）。图3成本效益可接受性曲线，表示在获得的每个质量调整生命年（QALY）的WTP不同阈值下，NGS分析干预被认为具有成本效益的可能性。全尺寸图像在情景分析中，NGS分析的假设成本从0美元到2000美元不等。

The resulting ICER per QALY gained varied from $17,361 to $19,034 per QALY gained, respectively. This analysis demonstrates t.

每QALY获得的ICER分别从17361美元到19034美元不等。该分析表明t。

Table 5 Scenario analyses of varying the cost of the NGS assay and the probability of accurately predicting high-risk patients. All analyses are probabilistic.Full size tableDiscussionWithin publicly funded healthcare systems, genetic testing and treatment costs pose budgetary and affordability challenges, particularly for more prevalent cancers31.

表5改变NGS测定成本和准确预测高危患者的可能性的情景分析。所有分析都是概率的。全尺寸表格讨论在公共资助的医疗保健系统中，基因检测和治疗费用构成了预算和负担能力的挑战，特别是对于更普遍的癌症31。

Optimizing treatment sequencing remains a policy priority to ensure that treatments are provided to the right patients at the right time. This analysis evaluated the introduction of an NGS assay to determine risk status among adult patients with CLL initiating front-line treatment. The CADTH/CDA treatment algorithm provided a basis for treatment of patients with CLL, with cost-effectiveness of the algorithm yet to be established.

优化治疗顺序仍然是政策重点，以确保在正确的时间为正确的患者提供治疗。该分析评估了NGS分析的引入，以确定CLL开始一线治疗的成年患者的风险状态。CADTH/CDA治疗算法为CLL患者的治疗提供了基础，该算法的成本效益尚未确定。

The hypothetical NGS assay used in our analysis would allow clinicians to sequence treatments for patients with CLL according to their risk status, reserving more costly treatments for later therapy lines. Results of this evaluation suggest that an NGS assay to risk-stratify patients with CLL could be cost-effective at commonly cited thresholds of WTP per QALY gained.

在我们的分析中使用的假设NGS分析将允许临床医生根据CLL患者的风险状态对其进行治疗排序，为以后的治疗线保留更昂贵的治疗。这项评估的结果表明，NGS分析对CLL患者进行风险分层，在通常引用的每QALY WTP阈值下可能具有成本效益。

This analysis demonstrates that CADTH/CDA’s algorithm that delivers treatment according to risk based on the status of del17p, TP53 mutation, and IGHV unmutated status is likely cost-effective from the perspective of a Canadian provincial healthcare system. Notably, reserving costly, long-term treatment strategies such as acalabrutinib for patients requiring second line treatment may be a cost-effective treatment sequencing approach to further improve outcomes for patients identified as low-risk.The ability to accurately predict risk status in patients with CLL would provide value to both patients and reimbursement decision-makers.

该分析表明，从加拿大省级医疗保健系统的角度来看，根据del17p，TP53突变和IGHV未突变状态的风险提供治疗的CADTH/CDA算法可能具有成本效益。值得注意的是，为需要二线治疗的患者保留昂贵的长期治疗策略，如阿卡鲁替尼，可能是一种具有成本效益的治疗测序方法，可进一步改善被确定为低风险患者的预后。准确预测CLL患者风险状态的能力将为患者和报销决策者提供价值。

Rece.

冷。

Data availability

数据可用性

All data generated or analysed during this study are included in this published article.

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Download referencesFundingThis investigation was funded by Genome Canada and Genome British Columbia (#G05CHS, #271LYM).Author informationAuthor notesThese authors jointly supervised this work: Adam J. N. Raymakers and Dean A. Regier.Authors and AffiliationsCancer Control Research, BC Cancer, Vancouver, CanadaSamantha Pollard, Brandon Chan, Adam J.

下载参考文献资助这项调查由加拿大基因组和不列颠哥伦比亚基因组资助（#G05CHS，#271LYM）。作者信息作者注意到这些作者共同监督了这项工作：AdamJ.N.Raymakers和DeanA.Regier。作者和附属机构癌症控制研究，不列颠哥伦比亚省癌症，温哥华，加拿大萨曼莎·波拉德，布兰登·陈，亚当·J。

N. Raymakers & Dean A. RegierFaculty of Health Sciences, Simon Fraser University, Burnaby, CanadaSamantha PollardDivision of Medical Oncology, Faculty of Medicine, University of British Columbia, Vancouver, CanadaAlina S. GerrieSchool of Population and Public Health, Faculty of Medicine, University of British Columbia, Vancouver, CanadaDean A.

N、 Raymakers＆Dean A.RegierFaculty of Health Sciences，Simon Fraser University，Burnaby，CanadaSamantha Pollard医学肿瘤学系，不列颠哥伦比亚大学医学院，温哥华，CanadaAlina S.GerrieSchool of Population and Public Health，Faculty of Medicine，British Columbia，Vancouver，CanadaDean A。

RegierBC Cancer, Centre for Lymphoid Cancer, Vancouver, CanadaAlina S. GerrieAuthorsSamantha PollardView author publicationsYou can also search for this author in.

。

PubMed Google ScholarBrandon ChanView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsFunding acquisition: DAR. Study design: all authors. Acquisition and analysis of data: AJNR, BC. Interpretation of data: All authors. Manuscript drafting: SP, AJNR. Manuscript revision: All authors. Supervision: AJNR and DAR. All authors read and approved the final manuscript.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献基金收购：DAR。研究设计：所有作者。数据采集和分析：AJNR，BC。数据解释：所有作者。手稿起草：SP，AJNR。稿件修订：所有作者。监督：AJNR和DAR。所有作者都阅读并批准了最终稿件。对应作者对应。

Dean A. Regier.Ethics declarations

迪安·雷吉尔。道德宣言

Competing interests

相互竞争的利益

Samantha Pollard has received personal fees from Roche Canada, Bitota Economics Group, and AstraZeneca Canada, as co-director at IMPRINT Research Consulting Ltd outside the submitted work. Adam Raymakers reports currently serving as a member of the pan-Canadian Oncology Drug Review Expert Review Committee (pERC) within the Canadian Agency for Drugs and Technologies in Health (CADTH).

。

Alina S Gerrie has received institutional research funding from Janssen, AstraZeneca, Abbvie, and Roche Canada, honoraria from Janssen, Astrazeneca, Abbvie, and Beigene, and has served as a clinical expert for CADTH. Dean A Regier has received travel funding from Illumina; his institution has received research funding for a project from Roche Canada.

Alina S Gerrie获得了Janssen，AstraZeneca，Abbvie和Roche Canada的机构研究资金，Janssen，AstraZeneca，Abbvie和Beigene的酬金，并担任CADTH的临床专家。Dean A Regier已获得Illumina的旅行资金；他的研究所获得了罗氏加拿大公司的一个项目的研究资金。

Brandon Chan has no competing interests to declare..

布兰登·陈（Brandon Chan）没有相互竞争的利益需要申报。。

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Reprints and permissionsAbout this articleCite this articlePollard, S., Chan, B., Gerrie, A.S. et al. Assay-guided treatment sequencing in chronic lymphocytic leukemia (CLL): a cost-effectiveness analysis.

转载和许可本文引用本文Pollard，S.，Chan，B.，Gerrie，A.S。等人。慢性淋巴细胞白血病（CLL）的测定指导治疗测序：成本效益分析。

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科学报告1417294（2024）。https://doi.org/10.1038/s41598-024-68431-6Download引文接收日期：2023年6月2日接收日期：2024年7月23日发布日期：2024年7月27日OI：https://doi.org/10.1038/s41598-024-68431-6Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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