Two New Deaths on Leqembi Highlight Need to Better Manage ARIA
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With two anti-amyloid antibodies now in clinical use, improving the safety of these treatments is front and center on clinicians’ minds. In the year since lecanemab was approved by the Food and Drug Administration, and gained insurance coverage, its use in clinical care has grown slowly, with perhaps 3,000 Americans now on the drug. Clinics had reported few safety problems—until now. At the Alzheimer’s Association International Conference in Philadelphia, Lawrence Honig of Columbia University in New York reported the recent death of an APOE4 homozygote on lecanemab. According to scuttlebutt at the conference, another similar death previously occurred elsewhere. These are the first two fatalities reported for amyloid immunotherapy in routine care. “Serious outcomes can occur even with the best monitoring,” Honig cautioned.
- Two ApoE4 carriers taking lecanemab in specialty care have died from ARIA-E.
- Clinicians suggest more careful screening at baseline.
- Patients with other conditions, such as a history of stroke or cancer, have done well on immunotherapy so far.
Stephen Salloway at Butler Hospital in Providence, Rhode Island, told Alzforum that in about three-quarters of deaths on amyloid immunotherapy to date, there were warning signs that might have lessons to teach about how to prevent this worst outcome. Other talks at AAIC sought to identify these clues, as clinicians explored gray areas around when to treat with anti-amyloid antibodies and when to discontinue treatment due to ARIA. There were no easy answers. One theme that emerged was the importance of using multiple different MRI sequences to check for vascular risk factors in cases that fall into that gray area.
In some cases, doctors deem higher risks acceptable. In younger people who carry an AD mutation, clinicians have been able to relax exclusion criteria and treat patients with more vascular issues at baseline, without serious consequences so far. For more on this, and possible mechanisms behind ARIA, see next story.
First Deaths in Specialty Care
In clinical trials, lecanemab triggered the edema known as ARIA-E in about 12 percent of participants. Most cases were asymptomatic, but occasional severe reactions occurred, including three deaths in the open-label extension (Jan 2023 news; Jan 2024 news). On donanemab, as well, five deaths were reported in the trial or open-label extension (Jun 2024 news). According to Salloway, most deaths on amyloid immunotherapy fall into one of three categories: an intracerebral hemorrhage due to underlying cerebral amyloid angiopathy; ARIA-E that mimics a stroke and prompts thrombolytic treatment; or severe ARIA-E resembling CAA-related inflammation.
The two new deaths seem to be of the third category. At baseline, the APOE4 homozygote at Columbia had one microhemorrhage on MRI, and no signs of CAA, and appeared to be a good candidate for the therapy, Honig said. After the third infusion, however, the patient developed severe ARIA-E. After five days of steroid treatment, it began to clear up. Nonetheless, the patient experienced uncontrolled seizures and died. According to hallway talk, the previous death was similar, also in an APOE4 carrier who developed inflammatory ARIA-E and succumbed to seizures. Details could not be confirmed.
The Food and Drug Administration’s adverse event reporting system (FAERS) bears this out, attributing two deaths on lecanemab to ARIA-E. One occurred in May in an 80-year-old man, the other in December 2023, in an 84-year-old man. A third death in FAERS, in a 79-year-old man taking lecanemab, was caused by a hemorrhagic stroke; it is unclear if this was related to the drug. Four other deaths listed in FAERS were considered due to falls or cardiovascular disease and unrelated to lecanemab.
Lawren VandeVrede of the University of California, San Francisco, told Alzforum that some APOE4 homozygotes can have an “explosive” response to amyloid immunotherapy. This response is unpredictable at present, as other homozygotes do well on the drugs. Homozygotes may need additional MRI scans at baseline to look for risk factors before prescribing immunotherapy, he suggested.
Mild ARIA-E. A patient with two APOE3 alleles and mild edema (arrow); doctors continued dosing with lecanemab, the edema went away, and the patient did well. [Courtesy of Stephen Salloway.]
Fewer ARIA Cases Than Expected
Honig noted that aside from this death, safety issues at his clinic have been less frequent than in the trials. At Columbia, 122 patients have now been treated with lecanemab, receiving an average of 10 infusions per person. Patients are 73 years old on average and mostly white. Of the 86 percent who agreed to APOE genotyping, half were E4 heterozygote, 16 percent homozygote.
Honig said this real-world memory clinic population was more medically diverse than the lecanemab trial cohort, as is typical when new drugs enter routine care. Trials excluded participants who had white-matter changes on MRI, a history of strokes or seizures, or other brain disorders. At Columbia, physicians only excluded patients who had more than four microhemorrhages on their baseline MRI. Two patients had recovered from previous strokes, and three had vascular malformations. So far, none have been on anticoagulants. This broad usage is in keeping with the FDA label, which lists only one contraindication for lecanemab treatment—known hypersensitivity to the drug.
In the first year, 7 percent of patients at Columbia developed ARIA-E, 6 percent ARIA-H. These rates are about half those in the clinical trial. One patient developed superficial siderosis, i.e., iron deposits on the surface of the brain that can indicate bleeds. None had macrohemorrhages. All the ARIA-E cases occurred within the first three months of dosing and, other than the death, were asymptomatic. Eight people stopped taking the drug, four of them due to ARIA.
Lecanemab use in a memory clinic is manageable and well-tolerated overall, Honig concluded. Other clinicians at AAIC agreed that patients with a wide variety of brain health conditions can be safely treated. Tammie Benzinger at Washington University in St. Louis noted that her clinic has given anti-amyloid antibodies to people with a history of subdural hematomas or encephalopathy. “Those patients have done really well. I’ve been surprised,” Benzinger said.
Salloway said people with small, benign meningiomas, tumors that form in the membranes around the brain, are eligible for lecanemab. Some level of white-matter disease at baseline is also allowable, Benzinger said, noting that in older people, white-matter hyperintensities on MRI are the norm. “If we excluded those, it would be a lot of patients,” she said.
Varied Views. Using multiple MRI modalities can help find microhemorrhages, as some are better distinguished from background on gradient echo sequences (upper right, circle) than with susceptibility-weighted imaging (upper left). Others (bottom, circles) show up better on SWI than GRE. [Courtesy of Tammie Benzinger, WashU.]
Making Difficult Calls on Eligibility
How, then, can physicians decide which patients run too high a risk? In Philadelphia, researchers debated how best to make those calls. In a teaching symposium for clinicians, VandeVrede presented hypothetical cases, and the audience voted on whether they would treat or not. This group process resembles decision-making at many clinics, where a multidisciplinary board discusses cases and comes to a joint decision.
VandeVrede said that at UCSF, physicians have developed guidelines based on the FDA label, clinical trial data, and the published Appropriate Use Recommendations for lecanemab (Apr 2023 conference news). Beyond excluding anyone with more than four microhemorrhages at baseline, the guidelines recommend not treating anyone with more than one small area of superficial siderosis, more than two lacunar infarcts, any territorial infarcts or intracerebral hemorrhages, or severe white-matter changes, VandeVrede said. The UCSF guidelines require APOE genotyping, and suggest excluding anyone on anticoagulants, or switching them to another medication such as an antiplatelet agent.
While these rules seem clear, in practice, decisions become tricky. Consider an APOE4 homozygote with three microhemorrhages at baseline. Even though this patient technically meets criteria for treatment, the higher risk for homozygotes gave many clinicians pause. Half the audience said they would treat, half not. Salloway noted that the three microhemorrhages could be evidence of CAA, warranting caution. VandeVrede agreed there is no right answer. “Entire centers have decided not to treat homozygotes. At UCSF, we want homozygotes to be at the earliest [disease] stage possible,” he said. Higher baseline amyloid loads are associated with a higher risk of ARIA.
One attendee asked whether lecanemab would be preferred over donanemab for E4 homozygotes, because the latter had twice the rate of ARIA in trials. Salloway noted that the rate of serious ARIA is comparable for both antibodies, at about 1.5 percent.
What about someone without an E4 allele, but with six microhemorrhages at baseline? Most said they wouldn’t treat. However, Benzinger noted that the number of visible microhemorrhages varies depending on the MRI protocol used. “At WashU, we wouldn’t exclude just for that,” she said. She suggested using different MRI modalities to fully assess risk. WashU recommends a minimum sequence consisting of fluid-attenuated inversion recovery and diffusion-weighted imaging, which reveal different types of lesions, as well as susceptibility-weighted imaging and gradient echo sequences to find hemorrhages. The scan takes 10 minutes.
Stroke specialist Jeffrey Saver at the University of California, Los Angeles, said clinicians should fully inform patients and their families of the risks and make the decision together. If a higher-risk patient wants to move forward, clinicians should monitor them closely.
Mild versus Severe ARIA-H. A single new microhemorrhage (left, arrow) does not require stopping, but multiple new indications of bleeding (right, arrows) do. [Courtesy of Tammie Benzinger, WashU.]
Avoiding Bad Outcomes
If ARIA develops, knowing when to suspend dosing and when to stop treatment altogether is a thorny issue. At UCSF, warning signs to stop permanently include more than 10 new microhemorrhages, any intracerebral hemorrhage, severe or symptomatic ARIA, or more than two episodes of ARIA, VandeVrede said. ARIA-E often triggers the microhemorrhages and siderosis known as ARIA-H. Benzinger noted that ARIA can fluctuate, and stressed the importance of allowing ARIA-E and H to fully stabilize before making decisions about continuing treatment.
Saver offered guidelines for handling stroke-like symptoms in an immunotherapy patient, where ARIA-E can masquerade as ischemia. If a CT scan does not reveal blockage in cerebral arteries, and stroke symptoms are mild, then no treatment is needed, he said. When CT shows a blockage in a large artery, then mechanical thrombectomy, rather than meds, is the treatment of choice. The most difficult cases are when stroke symptoms are moderate to severe, and CT detects no blocked artery. A follow-up MRI scan may reveal a clot in a smaller artery that could be removed by thrombectomy. Only when a clot is inaccessible, or MRI cannot find one, should doctors consider administering thrombolytic drugs, Saver said.
He described a case at his center where a patient developed trouble walking and speaking, and a CT scan showed a region of the brain with low blood flow. Alas, the scan revealed no blockage, and the patient was past the three-hour window for thrombolytic treatment. A follow-up MRI revealed ARIA-E as the cause of low blood flow. Doctors administered high-dose steroids, and the person recovered. “We need to be ready to off-road patients from stroke protocols,” Saver said.
Many clinics have put safety guidelines into place to prevent accidental prescription of thrombolytics to immunotherapy patients in emergency rooms. These include alerts in a patient’s medical record, or a bracelet patients can wear.
Benzinger recommended entering ARIA data into the ALZ-NET database to help other clinicians learn from these early experiences. ALZ-NET is hosted by the American College of Radiology, and collects real-world data on anti-amyloid antibody use (Aug 2022 conference news).—Madolyn Bowman Rogers
References
Therapeutics Citations
News Citations
- Implicated in ARIA: Perivascular Macrophages and Microglia
- Should People on Blood Thinners Forego Leqembi?
- Brain of Woman Who Died on Leqembi Shows Worst-Case Scenario
- Donanemab Approval Likely to Pose New Quandaries for Clinicians
- Next Goals for Immunotherapy: Make It Safer, Less of a Hassle
- Bringing Aduhelm—and Antibodies to Come—Into Practice
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