5.1 Clinical Practice

Patient Pathway: The evaluation of cognitive impairment has consisted of routine gathering of patient/care partners history, cognitive screening, laboratory studies for reversible causes of dementia (B12, thyroid stimulating hormone, and rapid plasma reagin in select populations), and neuroimaging according to American Academy of Neurology (AAN) guidelines [6]. Depending on the healthcare institution’s resources, neuropsychological testing has also been an important diagnostic component of the dementia workup. The integration of AMAs into this clinical practice additionally requires (1) documentation of the presence of AD biomarkers in either the cerebrospinal fluid or on amyloid-based molecular PET imaging, (2) risk assessment for ARIA, and (3) evaluation of financial feasibility. Whereas the traditional evaluation for dementia has required a total of two visits, one for diagnostic purposes and another for diagnostic impression/treatment plan, the introduction of an AMA requires an additional one to two visits to review results from biomarker and APOE genotype studies.

Costs associated with lecanemab treatments and associated diagnostic tests are discussed during initial conversations about the potential of this drug treatment with families. Patients with Medicare coverage are informed about the potential for being responsible for 20% of the associated $26,500 in drug costs. Furthermore, those individuals with private medical insurance are informed about the possibility of coverage denial given that half of major private insurers have decided not to cover drug costs. Any patient unable to meet the financial requirements for either the co-pay or full drug cost are referred to a clinic nurse responsible for corresponding with Eisai financial support (https://www.leqembi.com/eisai-patient-support) to find drug access solutions.

5.1.1 Discussions of AMA Benefits and Risks

Our group discussed the role of obtaining informed consent for AMA administration, and ultimately decided that documenting in the EMR a discussion with the patient and family about benefits and risks was sufficient. In neurology, there are a few precedents for using informed consent, such as the use of thrombolytics in acute stroke; it was felt that the administration of an AMA would not incur the same degree of risk, and so no consent form was used.

Clinicians begin with a discussion about the significance of CSF AD biomarkers and how they are indicative of a 60% risk of progression in 3 years or, in the case of mild AD, confirm the presence of the disease itself. Conversations then center around the 27% slowing of the decline in Clinical Dementia Rating (CDR) relative to placebo, based on the CLARITY AD trial, as well as the fact that the drug successfully results in amyloid clearance [1]. This information is presented in a more patient-friendly manner by explaining that this slowing translated into an additional 4−5 months over the 18-month period [7]. Individuals are informed that AMAs do not necessarily lead to symptomatic improvement. All patients are counseled about the 21.5% risk of ARIA with lecanemab and the fact that fewer than 3% of ARIA cases are symptomatic. Patients are informed that ARIA is most likely to occur during the first 3 months of AMA treatment. We explain how steps were taken to prevent and assess risk prior to the first infusion, including obtaining a baseline brain MRI to ensure the absence of clinical features predisposing one to ARIA, excluding patients on anticoagulation, checking an APOE genotype in advance (cost is covered at our center), and drawing labs for coagulation factors. We chose to provide patients homozygous for APOE e4 the opportunity to start lecanemab, but also inform them that the risk for ARIA is increased 4−6 times compared with non-carriers (e.g., E3/E3) and that there is a 9% risk for symptomatic ARIA. In addition, the favorable effects of lecanemab on the CDR in this population may be reduced compared with other groups according to the CLARITY-AD subgroup analysis [5]. Those individuals who were either heterozygous for APOE4 or were non-carriers are educated about their relatively lower risk. Results of APOE testing and impact on disease/drug risk are disclosed by the treating clinician to the patient and family during a virtual or in-person visit. UW, as with many other institutions, lacks the resources to offer genetic counseling services to all families. Drug- and risk-related information is outlined on the UW lecanemab resource page: https://depts.washington.edu/mbwc/resources/lecanemab-leqembi-update.

Patients are followed up with every 3 months by their neurology clinician, at which time they are assessed for adverse effects, and surveillance imaging findings were shared with them.

Any patients with baseline risk factors for ARIA (e.g., having baseline microhemorrhages or a history of lobar hemorrhage) are excluded based on the inclusion/exclusion criteria (online resource #2).

5.1.2 Creation of an AMA Approval Board

Despite there being a predefined Appropriate Use criteria for lecanemab, the committee concluded that referrals meeting these criteria but with associated high risk for complications or those failing to meet Appropriate Use criteria could benefit from a formal adjudication process. The approval board consisted of eight dementia experts, a neuropsychologist, two radiologists, and a nuclear medicine radiologist. The approval board was scheduled to meet monthly and required at least two clinical dementia experts and one radiologist for guidance about whether or not to treat prospective infusion patients with complex presentations. After an initial few cycles of review that served to level set the clinicians and establish a review culture, any cases squarely within Appropriate Use parameters did not require the AMA board to formally review.

5.1.3 Neuroradiology Reporting

The UW Memory and Brain Wellness Center and neuroradiology agreed to tailor any surveillance MRI reports to address the presence and absence of ARIA-E/H as well as the severity of the findings. Any cases of ARIA are communicated urgently to the ordering provider by paging them.

5.1.4 Clinic Call Coverage

The transition of AD patient management from relatively well-tolerated oral medications such as donepezil and memantine to an IV-administered biologic where approximately a quarter of patients experience infusion reactions and a fifth experience a combination of ARIA-E/H symptoms represents a profound change in clinical practice for the dementia expert. A day call schedule was created where a provider of the day is appointed to address lecanemab-related queries within and outside of the organization. Any severe catastrophic adverse event related to lecanemab resulting in malignant cerebral edema or macrohemorrhage is referred to the UW stroke physician on call. Outside of working hours between 8 a.m. and 5 p.m., urgent patient issues related to lecanemab are addressed by the on-call neurology resident. All patients are given a nurse-staffed emergency line should they develop symptoms in the setting of lecanemab infusions.

5.1.5 ARIA Monitoring and Management

The monitoring strategy for ARIA was influenced by the CLARITY-AD protocol [8], the FDA drug label (https://www.leqembi.com/-/media/Files/Leqembi/Prescribing-Information.pdf?hash=77aa4a86-b786-457a-b894-01de37199024), and the Appropriate Use recommendations by Cummings et al [1]. As specified in these publications, brain MRIs are conducted at baseline and prior to the 5th, 7th, and 14th infusions and at 52 weeks (i.e., prior to the 26th infusion). Any additional infusions following the MRIs performed related to the 5th, 7th, 14th, and 26th infusions are placed on hold until the ordering clinician has reviewed MRI results and cleared the patient for further treatments with the HMC infusion center.

The approach to management of ARIA is discussed in Cummings et al [1] and is based on the radiological grading of ARIA severity as well as the presence of symptoms associated with the radiological findings. Any patients who developed radiological ARIA and associated symptoms required assessment in clinic within 24–48 h depending on the presentation.

5.2 Documents

For the purpose of standardizing lecanemab administration throughout the practice, the implementation group created a variety of documents to provide guidance to clinic support staff and clinicians with respect to operational workflow, treatment, and management of adverse drug effects.

5.2.1 AMA Protocol

A formalized protocol or standard operating procedure (SOP) was created to ensure consistent care quality and safety when administering the infusion. The protocol addressed the following topics: (1) development of inclusion/exclusion criteria for patients receiving lecanemab (online resource #2), (2) creation of an AMA approval board, (3) daytime and after-hours coverage for AMA-related queries, (4) treatment procedures for diagnostic workup and risk assessment, (5) monitoring and management of ARIA, (6) monitoring drug efficacy, and (7) stopping criteria. This document provides standardized criteria that could always be referenced throughout the monoclonal antibody infusion process.

5.2.2 Clinic Flowchart

Information related to clinic operations was consolidated to a Visio chart describing each the patient pathway that includes clinic visits, laboratory studies, neuroimaging, and infusion treatments for an 18-month treatment period (Fig. 1). The Visio chart ultimately served to standardize the patient experience for all clinic referrals and provide a visual summary of the lecanemab protocol. Due to lack of available clinical trial data or guidelines, we did not create any specific protocols for treatment beyond the infusion at 18 months.

Fig. 1

Vizio flowchart for amyloid monoclonal antibody treatment and monitoring

5.2.3 Lecanemab Checklist for Providers

A checklist was created to ensure that all treating clinicians were reminded of the new and more critical steps in the lecanemab pathway (Figs. 2, 3).

Fig. 2

Lecanemab checklist for memory and brain wellness provider(s)

Fig. 35.2.4 ARIA Flowchart

Recommendations from Cummings et al [1] and the UW lecanemab protocol provided radiographic criteria for determining whether cerebral ARIA-H/E changes were mild, moderate, or severe (Fig. 4). The severity of radiological ARIA has practical implications for medical decision-making, as mild changes may not necessarily impact treatment, whereas moderate/severe changes may prompt suspension of infusions. Furthermore, any symptoms accompanying MRI changes may also have implications in terms of halting therapies.

Fig. 45.3 EMR-Based Tools5.3.1 Clinic Flowsheet

The last task for the lecanemab committee was to create Epic-based tools to guide prescribing clinicians (Fig. 3). The working group created an Epic-based flowsheet checklist to guide clinicians through the patient pathway. This work required collaboration between a MBWC physician, a project manager, and members of the EMR (Epic) build/design team. The flowsheet was divided into three phases: There was the clinician-driven diagnostic workup section (phase # 1) that included the cognitive assessment, laboratory testing, imaging, and biomarkers to confirm the presence of AD pathology. There was the clinic support-staff driven lecanemab treatment planning (phase #2) that included information relating to the scheduling of brain MRI and clinic visits. The final portion, infusion therapy (phase #3), related to the completion and review of MRI findings and required participation from both the clinician and the infusion nurse (infusion nurse portion is highlighted red). All infusions would be placed on hold until the MRIs are read and cleared by the treating clinician. The clinician is responsible for denoting whether an MRI was completed, whether the hold could be lifted from the order, and whether the patient could proceed with treatment. This portion of the flowsheet was created to prevent patients with ARIA from receiving infusions, and serves as the primary indicator of treatment status between the MBWC and the infusion center. Clinicians complete the flowsheet and then send an inbox message to the clinic staff, which in turn would communicate with the infusion center. This flowsheet was created for the duration of 18 months, as described in the CLARITY AD trial [5].

5.3.2 Epic Smartset

The EMR-based Smartset was created (by A.F. and D.M.) to facilitate the workup for both dementia and lecanemab candidacy (Fig. 5). This EMR tool is inclusive of baseline labs and MRI to establish a diagnosis of dementia as well as AD-confirmatory biomarkers (CSF and amyloid PET imaging). Furthermore, the Smartset includes orders to ensure safety: APOE genetic screening, coagulation labs, and surveillance brain MRIs before the 5th, 7th, 14th, and 26th infusions.

Fig. 5

Sample Smartset for amyloid monoclonal antibody evaluation

5.3.3 Epic Therapy Plan

To create a treatment order that generated lecanemab infusions every 2 weeks for a period of 18 months, an EMR specialist (M.M.) developed an Epic-based therapy plan specifically for lecanemab (online resource #3). The template that was used for the lecanemab infusions was based on what had been previously used for multiple sclerosis treatments. By having this arrangement, the clinician places a single order as opposed to orders every 2 weeks. This work required collaboration between a MBWC physician, a project manager, and members of the EMR build/design team. The process of creating a therapy plan resembled that used for IV infusions used to treat multiple sclerosis. Clinicians go through the process of ordering the infusion as documented (online resource #3). There is, further, a process that required the clinician to place the therapy plan on hold in the case of ARIA or other adverse drug effects.

5.4 Oral Dementia Treatments in the Setting of AMAs

Similar to the patient demographic of the CLARITY AD trial, a large portion of the UW-MBWC early-stage AD cohort was receiving treatment with cholinesterase inhibitors and/or memantine. Whether or not a patient was taking or had recently started on an oral dementia medication had no influence on the timing or dosing of the AMA. All patients diagnosed with early onset AD were offered cholinesterase inhibitors prior to starting AMAs. In an effort to avoid confusing drug-related side effects, patients were required to be stable on a cholinesterase inhibitor for 1 month. However, we do not see any clear contraindication to starting both agents simultaneously. As was customary in our practice, memantine is not presented as an option for patients in the early stages of AD.

5.5 Internal and External Education5.5.1 Internal Education

In-service sessions were provided to the frontline and nursing staff to educate them regarding potential concerning symptoms in patients receiving monoclonal antibodies and how to appropriately triage these patients. Furthermore, the infusion nursing team were provided guidance regarding questions to gauge patient tolerance of lecanemab (online resource #1).

An educational session was also provided to the full AMA project team at its first meeting; it was focused on the nature of the therapeutic advance and the specific changes in approach to evaluation, diagnosis, and management that would need to be supported by the project.

All dementia clinicians received training from the Epic team related to utilization of EMR-based tools and Smartsets.

An in-service session was held with the neurology resident and stroke services about approaching symptoms related to ARIA. In addition, we discussed how thrombolytics were contraindicated in those patients receiving lecanemab due to the increased risk of intracranial hemorrhage. In healthcare organizations with emergency rooms lacking 24/7 in-person acute neurology coverage, it is recommended that similar educational sessions be held with the emergency and hospitalist attendings to avoid treatment of lecanemab patients with thrombolytics or anticoagulation.

5.5.2 Community Education

The MBWC clinicians partnered with a UW communications specialist to produce a webinar providing a broad overview of lecanemab, its mechanism of action, drug efficacy, and adverse side effects such as ARIA. The webinar (https://www.youtube.com/watch?v=FMDxn80fPXI&t=1s) was advertised on social media platforms, including Facebook and Twitter. It was also shared with the clinic support staff, including nursing, for training purposes.

The working group further created a list of questions commonly asked by patients related to anti-amyloid monoclonal antibody treatments and posted the document on the clinic website. This resource was used for the purpose of patient education (https://depts.washington.edu/mbwc/resources/lecanemab-leqembi-update).