April 08, 2021
Note: This article originally appeared in the April 2021 issue of AABB News, a member benefit of AABB.
By Leah Lawrence
Clinicians that choose to study and practice apheresis are exposed to a multitude of medical conditions, diverse medical specialties and patients of all ages. This diversity is often what makes the field both exciting and challenging to practice, but it also makes progress in the field more difficult.
“I treat newborns and geriatric patients with a variety of disorders from metabolic disorders to malignant disorders to autoimmune disorders and more,” said Jeffrey L. Winters, MD, director of the Therapeutic Apheresis Unit at Mayo Clinic College of Medicine. “The problem, though, is that because so many of the disorders we treat are rare, it is often quite difficult to accrue patients to clinical trials.”
Modern apheresis has existed since the 1970s. Despite this long history, there are still conditions for which it is used as a treatment without a good, evidence-based understanding of why or how it works, or even if it provides benefits.
The American Society for Apheresis (ASFA) publishes regular updates to its guidelines on the use of therapeutic apheresis in clinical practice. Its most recent issue included 84 fact sheets for relevant diseases with 157 indications for therapeutic apheresis modalities.1 Many of these indications were categorized as “optimum role of apheresis therapy is not established.”
“These are resource and labor intensive treatments done in specialized institutions,” Winters said. “Not only is it important to do trials to show that apheresis provides a benefit, but also to show cases where it may not.”
Barriers to Trials
One of the barriers to performing clinical trials in therapeutic apheresis is a lack of funding, according to Yanyun Wu, MD, director of transfusion medicine at University of Miami Health System and Jackson Health System.
“The apheresis approach is often considered not as scientifically driven,” Wu said. “It can be considered more like a black box expedition versus specific targeted treatment.”
Additionally, there is a lack of industry-funded trials because the conduct of clinical trials may not be much of a value-add for these stakeholders and can be very costly, she said.
Apheresis researchers also struggle to obtain sufficient funding from the National Institutes of Health (NIH), Winters said.
“Apheresis ends up falling into a category where it is competing with trials in the hematology space,” Winters said. “The competition is fierce to get that funding, and we struggle because of the rarity of the diseases we deal with.”
Many grant applications for other clinical trials are supported by previously conducted basic science. Apheresis does not have a lot of relevant animal models upon which to research various treatments, Winters said. “That works against us as well,” he said.
Another barrier is patient accrual, Winters added. Even if one institution decides to lead a trial on apheresis, it is hard to find enough patients with these rare disorders. Often the trial has to be expanded to other centers, making it difficult to find other co-principal investigators to support the trial, Winters said. Apheresis is also frequently used in acute settings, which are very difficult to study in trials.
Trials are Vital
Based on the available evidence, the ASFA has categorized conditions treated with apheresis into four groups:
The most commonly known example of a Category I application of apheresis is the treatment of thrombotic microangiopathy (TTP), which also has grade IA evidence, Wu said.
TTP is a potentially fatal thrombotic disease. If untreated, mortality is estimated to be about 90%.1 The condition is associated with a severe deficiency of plasma ADAMTS13 enzyme activity, which maintains normal distribution of von Willebrand factor multimers.
One of the first trials to establish apheresis for TTP was published in 1991 by the Canadian Apheresis Study Group.2 The trial tested plasma exchange and plasma infusion in 102 patients with TTP and showed exchange to be significantly more effective.
“They essentially flipped the mortality on its head,” Winters said. “Instead of 90% dying, now only 10% were dying.”
Another well-established treatment area is in Guillain-Barre syndrome (GBS), a paralyzing disorder caused by inflammation of the peripheral nerves. Here studies have compared intravenous immunoglobulin, plasma exchange, supportive care and combination treatments.
In contrast, a recent trial showed that plasma exchange was not beneficial for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. In 2020, results of the PEXIVAS study showed that among patients with severe ANCA-associated vasculitis, plasma exchange did not reduce the incidence of death or end-stage kidney disease.3
“At my institution, we are not doing plasma exchange for that indication anymore,” Winters said.
“My colleagues in critical care and pulmonology don’t even ask anymore.”
New Therapeutic Areas
Another large area of exploration is the role of plasma exchange in the context of diseases related to aging, according to Zbigniew “Ziggy” M. Szczepiorkowski, MD, PhD, FCAP, professor of pathology and laboratory medicine at Dartmouth-Hitchcock Medical Center, Lebanon, N.H. The treatment is especially of interest in treating Alzheimer’s disease.
“The cause of Alzheimer’s disease still is not well understood, which limits therapeutic options, though many have been tried and failed,” Szczepiorkowski said. “However, a group in Barcelona decided to explore the two out of several things we did know about the disease: the accumulation of a protein in the brain that causes the brain to malfunction and abnormally behaving albumin.”
An early study looking at plasma exchange in Alzheimer’s showed that plasma exchange with albumin modified cerebrospinal fluid and plasma amyloid-βpeptide levels in patients with mild-to-moderate Alzheimer’s disease.4
More recently, results of the phase 2b/3 AMBAR randomized controlled study tested three plasma exchange treatment arms of albumin and intravenous immunoglobulin replacement compared with a sham procedure in patients with mild-to-moderate Alzheimer’s disease.5 Patients treated with plasma exchange performed significantly better on an Alzheimer’s Disease Cooperative Study – Activities of Daily Living score and had a trend toward better Alzheimer’s Disease Assessment Scale-Cognitive Scale.
“This was a big study looking at more than 300 patients for 14 months,” Szczepiorkowski said. “It showed an effect of slowing Alzheimer’s disease in those patients that received active treatment.”
Unfortunately, Wu noted, the results of this study do not seem to be widely accepted by neurologists or other relevant treating groups.
“Despite showing good evidence, it does not seem to have changed the perspective of providers,” Wu said. “We have to explore why that is and whether people perhaps think the outcome is not worth the treatment.”
Remaining Knowledge Gaps
Continued efforts to conduct clinical trials will help to further narrow down conditions for which treatment with apheresis is clinically and scientifically sound. Foremost among those knowledge gaps is gaining a better understanding of the mechanism of action of these treatments.
A great example of this need is in the area of photopheresis, Wu said. Photopheresis is a cell-based immunomodulatory therapy where leukocytes are collected from the peripheral blood and exposed to a photosensitizing agent then treated with ultraviolet radiation before they are re-infused.
“This was a type of ‘black box’ treatment where people did not really know what is happening,” she said.
Winters agreed, calling it a bit of an “oddball” procedure.
“This procedure can enhance the immune system response,” Winters said. “For example, in patients with a certain type of lymphoma, it can teach the immune system to recognize lymphoma cells. On the flip side, it can induce immune suppressive response to prevent things like graft-versus-host disease.”
Now there are major advancements in the understanding of the mechanism of photopheresis, the treatment can be polarized into both directions and clinical applications of these advancements need to be explored further, Wu added.
“Continued research can help us to understand how the treatment induces its effect and to adjust parameters of the procedure to try to maximize that effect,” Winters said.
Even in areas with more evidence, like in Alzheimer’s disease, more data needs to be generated to explain the mechanisms that produced the results seen in the AMBAR study, Winters said.
Finally, Winters said that he hopes the field of apheresis will continue to optimize available treatments.
“If we move outside of the United States and look to Europe and Japan, we see a lot of apheresis treatment that involves selective removal of substances from the blood,” Winters said. “In other words, they separate plasma out and pump that plasma though a column that contains something to clean the plasma before it is returned to the patient.”
These plasma fractionators and immunoadsorption columns are only just gaining traction in the U.S., Winters said, and only in certain therapeutic areas. There remains a great lack of access.
A recent example of a use of these columns is the Depuro D2000 Adsorption column used for the treatment of COVID-19, which received emergency authorization from the FDA in 2020.6 Patients admitted to the intensive care unit with confirmed or imminent respiratory failure can receive treatment with this system, which reduces the number of cytokines and other inflammatory mediators in the blood.7
Instead of using these types of columns, clinicians in the U.S. are forced to do bulk extractions.
“One of the big focuses we have is trying to get people to generate antibodies,” Winters said. “When I do that plasma exchange, I am removing any antibody the patient has generated.”
To continue to make progress, Wu said, apheresis clinicians and researchers have to continue to embrace a pioneering spirit.
“Often apheresis treatments go through a cycle,” she said. Meaning apheresis is often initially tried when nothing else is working.
“If it works, we then have to figure out why it worked,” Wu said.
Resulting research demonstrating how apheresis was effective often leads to a better understanding of disease mechanisms, and that may lead to a change in treatment or the development of drugs.
“As a result, apheresis may be removed as a treatment,” Wu said.
Szczepiorkowski said this is known in the field as being “one drug away” from extinction.
“Once we know the pathology, we may realize that what we are doing with apheresis could be replaced by a medication,” Szczepiorkowski said. “And there is nothing wrong with that.”
Specializing in the field of apheresis will likely always be associated with exploring a bit of the unknown, Wu said.
“We must continue to be innovative, adaptive and inquisitive,” Wu concluded. “If our discoveries alter treatment for one disease, we must just move on to helping with the next.”
1. Padmanabhan A, Connelly-Smith L, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice — evidence-based approach from the writing committee of the American Society for Apheresis: the eighth special issue. J Clin Apher. 2019;34:171-354.
2. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325:393-397.
3. Walsh M, Merkel PA, Peh C-A, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med. 2020;382:622-631.
4. Boada M, Anaya F, Ortiz P, et al. Efficacy and safety of plasma exchange with 5% albumin to
modify cerebrospinal fluid and plasma amyloid-concentrations and cognition outcomes in Alzheimer’s disease patients: a multicenter, randomized, controlled clinical trial. J Alzheimers Dis. 2017;56:129-143.
5. Boada M, Lopez OL, Olazaran J, et al. A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer’s disease: primary results of the AMBAR study. Alzheimer’s & Dementia. 2020;doi:16:1412-1425.
6. U.S. Food & Drug Administration. Spectra Optia Apheresis System with Depuro D2000. https://www.fda.gov/media/136834/download. Accessed March 10, 2021.
7. Terumo. Terumo BCT and Marker Therapeutics received the first device FDA Emergency Use Authorization (EUA) to treat acute respiratory failure in COVID-19 patients. April 10, 2010. https://www.terumobct.com/Pages/News/Press%20Releases/Terumo-BCT-and-Marker-Therapeutics-received-the-first-device-FDA-Emergency-Use-Authorization-(EUA)-to-treat-acuterespirato.aspx. Accessed March 10, 2021.