Outpatient therapy: Bringing CAR T cells closer to home
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Early clinical trials for the first chimeric antigen receptor T-cell therapies mandated recipients receive rigorous post-treatment monitoring, often requiring inpatient admittance lasting anywhere from 2 to 4 weeks.
Thanks to major advances in treatment technology over the past several years, CAR-T providers are wondering if a portion of patients can receive this therapy safely and effectively on an outpatient basis.
Outpatient administration won’t be possible for all patients but, as cell therapy moves into more diseases and larger patient populations, providing all of them with a lengthy inpatient admittance would become logistically and financially prohibitive, according to Richard T. Maziarz, MD, director of the adult blood and marrow stem cell transplant and cellular therapy program at Oregon Health & Science University Knight Cancer Institute.
Requiring continuous inpatient monitoring absent of symptoms also would be unnecessary due to the knowledge clinicians have acquired about how to treat common adverse events associated with these therapies, he added.
Maziarz acknowledged he is an oncologist and immunologist, not a health care policy or finance expert, but he has spent much of the last 15 years researching health care policy and how money flows through the system. As a result, he has become a de facto expert on issues related to CAR-T access and finance.
“About 5 or 6 years ago, I met with some of the [insurance] companies and said that this needs to be an outpatient procedure, when possible,” Maziarz told Healio.
“Historically, CAR-T has been mostly done as an inpatient, and we still admit many of our patients,” he said. “Many believe that CAR-T should only be done in the academic medical centers, but the fact is a lot of community-based centers want to provide these services for their patients.”
Many providers across the cancer care spectrum are involved in the push toward outpatient CAR T-cell therapy, including large academic medical centers and community-based practices. Some of their motivating factors overlap, but others do not.
Healio surveyed clinicians across the country about the status of their outpatient CAR-T programs, what they hope to accomplish, and the lessons they have learned along the journey.
The Motivating Factors
The financial viability of offering CAR-T is in doubt based on the current reimbursement model. It pushes many centers toward a “default” inpatient care model that results in less favorable reimbursement for providers, according to a review on CAR-T outpatient administration in Transplantation and Cellular Therapy.
“The current clinical and financial toxicities of these therapies make this treatment modality challenging to sustain without reform,” Maurice Alexander, PharmD, BCOP, PCC, clinical manager of hematology/oncology clinical pharmacy services at University of North Carolina Medical Center, and colleagues wrote.
Outpatient administration, when possible, would have a “favorable” impact to limit the expense of CAR T-cell therapies, they added.
“As the level of comfort improves, populations of patients offered these therapies expand, and more cellular therapies with improved toxicity profiles are introduced, outpatient treatment has the potential to become the mainstay for CAR T-cell practices,” Alexander and colleagues wrote. “This requires that programs build robust infrastructures and workflows that support outpatient management of CAR T-cell patients, with admission occurring only when clinically necessary.”
Outpatient administration alone won’t bring down the cost of CAR-T, but increased competition in terms of additional products and providers will, Maziarz said. In the short term, increasing outpatient administration will make CAR T-cell therapy more of a break-even proposition for centers that provide it commercially, he added.
Maziarz practices at a large academic medical center and has provided CAR-T on an outpatient basis. The standard of care after infusion is evolving and moving toward that direction, he said.
Regardless of the practice type, an effective outpatient program will require the infrastructure provided through a hospital or hospital partner, he said. It also needs a firm commitment to the program that includes support from the hospital’s ICU and a broad range of specialties, from neurology to infectious disease.
Although many providers focus on the clinical care aspect of outpatient programs — and for good reason — Maziarz said having experienced nurse navigators is one of the vital requirements of an effective outpatient program that is often overlooked during what can be a “scary” process for patients.
“We have a nurse navigator just for cell therapy — someone who can actually take the time to speak with the patients, go through the steps and talk about what to expect,” Maziarz said. “You really need someone who can educate.”
Big-City Problems
Leo I. Gordon, MD, FACP, is about to roll out his center’s outpatient CAR-T program, which has been in the planning phase for more than 2 years.
Gordon, a member of the Cell Therapy Next Peer Perspective Board, is co-director of the hematologic malignancies program at Northwestern University Feinberg School of Medicine and medical director of the John and Lillian Matthews Center for Cellular Therapy at Robert H. Lurie Comprehensive Cancer Center.
His center has treated approximately 200 patients with CAR-T since 2016 — either commercially or via clinical trials.
“I think outpatient CAR-T is feasible for about a third of patients,” Gordon told Healio. “The outcomes are very similar, and I don't think there's any higher risk.”
He based this assessment on his experience as an investigator in the TRANSCEND-NHL-001 clinical trial, which led to FDA approval earlier this year of lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb) for patients with relapsed or refractory large B-cell lymphoma. Results of the study showed only 46% of patients experienced cytokine release syndrome that requires immediate care.
More than a third of patients in the study received outpatient treatment, Gordon said.
“I anticipate that most patients are going to be admitted at some point during the course of treatment, because we probably would not try to manage CRS or neurologic toxicity as an outpatient,” he said. “It is really that small number of patients who do not develop CRS or neurologic toxicity who would wind up staying as an outpatient.”
One motivation for his center’s outpatient program is reimbursement — even though more than half of patients who receive CAR-T will end up being admitted into a hospital for treatment-related adverse effects.
“It’s a major factor,” he said. “We've talked to our financial people about this, and it is better for the hospital if [CAR-T] is done as an outpatient.”
However, there are several other reasons why centers may consider a shift toward outpatient CAR-T, Gordon added. Patient experience and outcomes are typically better in the outpatient setting, he said. Another benefit is less strain on hospital resources, which is especially important while healthcare professionals deal with the COVID-19 pandemic.
Gordon said his institution’s outpatient program rollout has been delayed by COVID-19 restrictions but, once implemented, it will be a 7-day-a-week operation. The clinic will be open 6 days a week for patient monitoring, with 1 day of telehealth monitoring for patients who are free of symptoms.
“We have to have the ability to see the patients in the morning, and then our plan is to do a telephone check with our advanced practice nurses or physician assistants in the afternoon,” he said. “It would be like a twice-a-day visit with the patient.”
Outpatient CAR-T programs located in urban areas must consider “big-city” logistical issues that easily can be overlooked, Gordon said. They have proven to be “some of the main obstacles facing the program, and foremost among these are parking and proximity to the treatment center,” he said.
Gordon’s institution requires that patients who receive outpatient CAR-T stay within an hour of their center for up to a month after therapy. Travel times in Chicago, like many urban areas, can vary greatly depending on time of day.
“People who are an hour away at midnight may be 2 hours away at 4 in the afternoon,” Gordon said.
A paucity of parking and potentially high related expenses compound an already complicated process.
“We're in the middle of the busiest area of downtown Chicago, and that has kept us from doing a lot of outpatient therapy — not just in CAR-T,” Gordon said. “If people have to come in on a daily basis, which is what we're wanting to do with outpatient CAR-T, then they must remain in close proximity and have easily accessible parking near our facility.”
‘A Multidisciplinary Commitment’
There are no parking issues at Astera Cancer Care, a community-based practice in central New Jersey that has been providing CAR T cells as outpatient therapy for several years.
This comes from its legacy as one of the centers involved in the pivotal clinical trial for lisocabtagene maraleucel, a next-generation CAR-T the manufacturer has marketed as having “inpatient or outpatient administration options” due to its favorable safety profile.
Lisocabtagene maraleucel, also known as liso-cel, is well-suited for community-based outpatient administration, according to Edward J. Licitra, MD, PhD, chairman and CEO of Astera Cancer Care.
“There are very few, if any, infusion reactions, and the incidence of toxicities typically doesn't start for a number of days,” he told Healio. “And if the patient is in close proximity, being closely monitored, and you have proper mechanisms in place, then you don't need to have people sitting in a hospital waiting for something to happen — especially if that ‘something’ occurs less than 50% of the time.”
Astera Cancer Care began providing commercial CAR-T through a community-based outpatient program after 2 years of planning. Infusions are given at their clinic, with any emergent post-infusion care handled by a local partner hospital with expertise treating CAR-T-related toxicities.
Licitra does not dismiss the financial motivation behind outpatient CAR-T; however, he said his practice has other objectives.
If every patient must visit a large academic center to receive this type of therapy, not only will the price remain “astronomical,” but issues related to access will persist or potentially get worse as CAR T cells gain approval for more indications or are used in earlier-stage disease, he said.
In this way, an outpatient program not only looks to address the short-term reimbursement issue but is forward-looking. Licitra said this sets his clinic up for a future in which the demand for these therapies will increase.
“Any sophisticated community oncology group should be able to organize and then create solutions to solve not only clinical problems, but health care delivery problems,” Licitra said. “That is our focus.”
Planning for the outpatient program wasn’t prohibitively expensive, but it required buy-in and human capital in terms of time spent creating policies, establishing treatment teams and developing communication frameworks, Licitra said.
“It’s absolutely doable, but it requires a multidisciplinary commitment to making it happen,” he said. “This is especially true for community-based practices and their partner hospitals without previous experience in bone marrow transplant.
“If you want to do outpatient CAR-T in a community-based setting, it requires more effort to assemble your teams and to educate the people that you want to be on your team,” he added. “If you have a partner hospital that is committed to doing it and a staff that is committed, as well, it is not difficult to provide CAR-T on an outpatient basis.”
Astera Cancer Care leveraged the outpatient strategy it had in place from its clinical trial experience to plan a similar commercial program. The provider is working with two commercial payers to develop a community-based CAR T-cell program that will reimburse Astera at a per-case or per-episode rate, much like is done for bone marrow transplant procedures.
The outpatient program required close cooperation with their partner hospital and started with having a way for hospital staff to easily identify someone as “a CAR T-cell patient” in electronic health records, Licitra said.
“We trained all of the requisite staff within the hospital to be aware for these patients — everybody from the ICU to the cardiologist to the nephrologist to the neurologist. We assembled an entire nonacademic care delivery team organized around the administration of CAR T cells,” he added. “I think it really highlights the power of what community oncology groups can do to create disruptive health care delivery models that improve outcomes and access while maintaining affordability of care.”
‘A Unique Situation’
Oncology Hematology Care (OHC) is another community-based practice with experience delivering outpatient CAR T-cell therapy. The organization serves the Cincinnati metro area, which includes portions of northern Kentucky and southern Indiana.
“We have a bit of a unique situation in that we are a private practice group that has had a very active autologous and allogeneic bone marrow transplant program since the early 1990s,” E. Randolph “Randy” Broun, MD, medical oncologist/hematologist and blood and marrow transplant specialist with OHC, said. “CAR-T, for us, is a natural outgrowth of that program.”
The similarities between the treatments and their expertise in dealing with them meant that OHC already had much of the infrastructure in place to provide CAR-T, which is unusual in the private practice setting, Broun said.
Except for one clinical trial with an outpatient arm, all OHC’s CAR-T infusions and acute care are done at their local hospital partner facility, The Jewish Hospital — Mercy Health in Cincinnati.
OHC’s clinical researchers provide the therapy at its infusion center and are trained to oversee the entire CAR-T process. The program required some basic investments in training and new equipment purchases but was far from prohibitive, Broun said. Patients who receive CAR-T in this trial must visit the center — open 365 days a year — daily for a specified period after their infusion for monitoring and testing.
Perhaps the most imperative part of any community-based outpatient CAR-T program is getting a partner hospital onboard that has enough resources to take a chance on providing the therapy despite its history of unreliable reimbursements. These hospitals prefer the type of single-case agreements that are the trend among private payers, according to Broun.
“It provides them some reassurance that they will get paid for this treatment, which is extremely expensive,” he said.
“We are hoping that these CAR-T therapies will be outpatient and that recipients will remain outpatients, but that's really a rare occurrence,” Broun added. “Almost everybody gets admitted for something at some point.”
Outpatient-First Approach
Fred Hutchinson Cancer Research Center operates what is perhaps the most extensive and mature outpatient CAR-T program.
David G. Maloney, MD, PhD, is medical director of cellular immunotherapy at Fred Hutch and medical director of the Bezos Family Immunotherapy Clinic at Seattle Cancer Care Alliance. His center’s goal is to treat all patients as outpatients, but this is only feasible in their experience with CAR T-cell therapies that contain a 4-1BB costimulatory domain, including liso-cel and tisagenlecleucel (Kymriah, Novartis).
The other FDA-approved CAR-T for lymphoma is axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences), also known as axi-cel, which uses a CD28 costimulatory domain.
The two CAR-T constructs differ in how quickly cells activate and produce treatment-related toxicities, Maloney said.
“We have not used axi-cel in the outpatient setting at all,” he told Healio. “With axi-cel, almost everyone gets CRS within the first 48 hours, so you lose any advantage you might gain if you gave this as an outpatient.”
Conversely, CAR-Ts that use the 4-1BB costimulatory domain have an approximate CRS onset of 5 or 6 days, if it occurs at all, Maloney said.
“Most of my [patients who receive tisagenlecleucel] can be treated in the outpatient setting,” he added. “Data show about 40% of those who receive Breyanzi in the outpatient setting do not require hospitalization.”
Patients receiving 4-1BB CAR T cells at the Bezos Clinic start with 2 to 3 days of outpatient lymphodepletion therapy followed by CAR-T infusion. Patients are then monitored at the clinic for 2 hours after completion of infusion and sent home or to local accommodations. Patients return the next day for labs and evaluation and do so daily for a number of weeks.
If any complications arise, patients are directed to clinical care partner sites at Seattle Cancer Care Alliance or University of Washington Medical Center, where they are taken care of by a team that has experience with CAR T-cell patients.
The motivation behind the outpatient-first approach was practicality, Maloney said.
“Patients don't want to be sitting in the hospital if they don't need to,” he added. “If we can save a number of patients from being treated in the hospital, then we can treat more patients and free up hospital resources to be used elsewhere.”
One aspect of outpatient CAR-T that interested centers should know about is the requirement for a 24/7 patient caregiver who can identify the symptoms of toxicity and contact the patient’s care team or emergency services if needed, Maloney said.
There is minimal risk to a well-planned and executed outpatient CAR-T program because toxicities can be safely treated within a short period of onset, Malone said. There is “absolutely no evidence” that outpatient administration of CAR-T compromises overall safety when done properly,” he said.
"If you want to do this in the community-based center then you have to have a really good system in place,” Maloney said.
“People should not be treated for cytokine release syndrome or neurologic toxicity in the outpatient setting,” he added. “They need to be hospitalized because the situation can spiral out of control."
‘Cheaper for All’
Maloney said he believes that a greater percentage of CAR T-cell therapies will be administered on an outpatient basis moving forward.
“I suspect there will be better ways of dealing with the toxicities so that they are less frequent or can be prevented,” he said.
Gordon said he doesn’t see inpatient CAR-T as an obstacle to patient access because the process is complicated enough that being required to stay in the hospital for a period should not be a deterring factor.
Inpatient requirements may not place a drag on patients seeking the therapy, but the ability to receive CAR-T as an outpatient would likely make it easier for some patients, he said.
The choice of whether to start the process as an outpatient is up to the person receiving the therapy, Gordon said.
“I don’t think outpatient options are a major requirement of successful CAR-T research or clinical programs,” he said. “But I do think it's important to have good infrastructure in place if that’s what you are trying to accomplish.”
The clinical strategy around delivering CAR T cells continues to evolve as therapies become more tolerable and efficient, Licitra said.
“It lends itself to the transition from hospital- and academic center-based therapy to the community, which is going to be more convenient, increase access, and be economically much more favorable to the patient or payer,” he said. “These are super interesting and innovative treatments, and I think they're probably just one of the many kinds of innovative cellular therapies that are going to be developed in the future.”
Broun agreed with this assessment but cautioned that as cellular therapies expand into more indications, clinicians who specialize in solid tumors will need to re-educate themselves on treatment-related toxicities and patient care.
“We have partners who are primarily solid tumor oncologists and are intensely interested in learning how to do CAR-T,” he said. “They have no background in taking care of these patients, so for them it's a very steep learning curve. That is going to be problematic.”
Despite the warning, Broun said the trend toward safe and effective outpatient CAR-T is certain provided that the appropriately trained people and the proper structure is in place.
Cell therapy got its start in lymphoma and leukemia, but it won’t be long until the FDA approves therapies for larger patient populations, according to Maziarz. The process is already underway with this year’s approval of idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) for patients with multiple myeloma, and he predicted that solid tumor indications are likely to follow.
“Potentially, in the not-too-distant future, we're going to have an FDA-approved cell therapy for melanoma and another for squamous cell carcinoma of the cervix,” he said.
“These aren't too far away,” Maziarz added. “We can't do it all as inpatient [but], in the end, outpatient cell therapy is going to be cheaper for all.”
References
Alexander M, et al. Transplant Cell Ther. 2021;doi:10.1016/j.jtct.2021.01.014.
Breyanzi (prescribing information). Bothell, WA: Bristol Myers Squibb; 2021.
Bristol Myers Squibb. U.S. Food and Drug Administration approves Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel), a new CAR T cell therapy for adults with relapsed or refractory large B-cell lymphoma (press release). Available at: https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-Breyanzi-lisocabtagene-maraleucel-a-New-CAR-T-Cell-Therapy-for-Adults-with-Relapsed-or-Refractory-Large-B-cell-Lymphoma/default.aspx. Accessed Dec. 1, 2021.
For more information:
E. Randolph “Randy” Broun, MD, can be reached at randy.broun@usoncology.com.
Leo I. Gordon, MD, FACP, can be reached at l-gordon@northwestern.edu.
Edward J. Licitra, MD, PhD, can be reached at elicitra@regionalcancercare.org.
David G. Maloney, MD, PhD, can be reached at dmaloney@fredhutch.org.
Richard T. Maziarz, MD, can be reached at maziarzr@ohsu.edu.
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