In the early years of its development, CAR-T cell therapy was a story of trade-offs, particularly in its ability to produce high rates of deep, durable responses in blood cancer patients who had otherwise run out of options, but at the cost of extremely high rates of hard-to-manage and potentially fatal side effects. As management of toxicities has improved, and CAR-Ts with fewer side effects have hit the clinic, there is growing talk of using them on an outpatient basis. But while that is certainly more attractive than the prospect of keeping patients in the hospital for days, experts said it is more complex than it might sound.

Most recently, for example, the abstract presented at the American Society of Clinical Oncology’s annual meeting for Johnson & Johnson’s JNJ-4528, a CAR-T that targets the antigen BCMA in multiple myeloma, concluded that its safety profile supported outpatient dosing. Another CAR-T, Bristol-Myers Squibb’s lisocabtagene maraleucel – which targets CD19 and is under Food and Drug Administration review for non-Hodgkin’s lymphoma – has also been used on an outpatient basis.

“Outpatient,” in this case, doesn’t mean something quick and easy like a flu shot. It means that patients who have received their infusions stay within the vicinity of the hospital, but don’t necessarily have to be kept overnight. Whether a CAR-T has potential for such use boils down to its safety profile, and especially the serious side effects most commonly associated with CAR-Ts, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

In the data on JNJ-4528, 93% of 29 patients experienced CRS, while 10% experienced neurological toxicity consistent with ICANS, though events rated as serious or worse – thereby potentially requiring hospitalization – occurred in only 7% and 3% of patients, respectively. Nevertheless, mild toxicity opening up the possibility of outpatient use is one thing. Actually doing it is another.

“None of the products are being used as an outpatient treatment as yet,” said Dr. Noopur Raje, a professor at Harvard Medical School, in a phone interview. She noted that her center had used JNJ-4528 in addition to the most advanced CAR-T for myeloma, Bristol-Myers Squibb and bluebird bio’s bb2121 (idecabtagene vicleucel), while the lymphodepletion performed prior to CAR-T infusion was already being done outpatient. “Once they get a label, I think they will experiment a little more. I do think in a select population, after experience with bb2121, it may be reasonable with [JNJ-4528] to consider outpatient use.”

For BMS’ lisocabtagene maraleucel, also known as liso-cel, a November 2019 paper published in Blood, the American Society of Hematology journal, provided details on 37 patients who had received the CAR-T on an outpatient basis, showing that severe but reversible CRS and ICANS occurred in only two, with 22 requiring hospitalization at any time, while 15 were not admitted within the first 29 days after infusion. Three of the 22 patients hospitalized at any given time were admitted for CRS, and one required a stay in the intensive care unit.

Still, outpatient use of CAR-Ts comes with some hefty infrastructure requirements, such as being able to closely monitor patients and admit them quickly if their CRS or neurotoxicity begins to worsen, said Dr. Amanda Cashen, a hematologist and associate professor of medicine at Washington University in St. Louis, in a phone interview.

“The patient would have to be staying close by to the treatment center so they could be quickly admitted with signs of symptoms,” Cashen said. “At our center we do not have that capacity to monitor patients getting cellular therapy as outpatients.”

Dr. Caron Jacobson, an assistant professor of medicine at the Dana-Farber Cancer Institute in Boston, gave an idea of the kinds of infrastructural requirements – physical as as well as occupational – required, as her center also has not given CAR-Ts outpatient but is in the process of developing the means to do so. Jacobson was the presenter at ASCO of data from the ZUMA-5 study of Gilead Sciences’ Yescarta (axicabtagene ciloleucel) in indolent non-Hodgkin’s lymphomas. While the clinical trial that led to Yescarta’s approval in aggressive lymphoma showed high rates of CRS and ICANS, Jacobson and also Ibrahim Elhoussieny, VP and head of global medical affairs at Gilead subsidiary Kite Pharma, pointed to favorable toxicity in ZUMA-5 as opening the door to outpatient use in that setting.

“Most CAR-T centers are large, academic centers, where space is at a premium, so having the space to do the appropriate follow-up for patients is challenging,” Jacobson said in a phone interview. “On top of that, many of these patients travel to come to us – not everybody is local and can go back and forth to homes. Many of these centers are in large metro urban areas, where hotels are expensive.”

In addition to the scarcity of available space, Jacobson said developing capacity for outpatient CAR-T therapy involves training inpatient nurses, physician assistants and consultant services. “That’s a lot of people who need to be trained, and you have to do that on the outpatient side as well,” she said.

Additionally, ensuring the timely supply of drugs to treat CAR-Ts’ side effects in an outpatient setting is important, particularly as those drugs are administered at Risk Evaluation and Mitigation Strategy (REMS)-certified centers by REMS-certified physicians and pharmacy staff. “Not only do we have to train all those people on the outpatient side, we are also obligated to be able to audit ourselves to make sure we are meeting the REMS requirements and able to do everything the FDA asks of us on the outpatient level,” Jacobson said.

But one potential reason to give CAR-Ts outpatient rather than inpatient is favorable reimbursement given to outpatient therapies relative to inpatient ones.

“That has been a major motivator for some centers to try and do an outpatient program and lean towards products that can potentially be given in the outpatient setting,” Jacobson said.

In addition to the list prices of the CAR-Ts themselves – ranging from $373,000 for Yescarta and Novartis’ Kymriah (tisagenlecleucel) in diffuse large B-cell lymphoma to $475,000 for the latter in acute lymphoblastic leukemia, supportive care can likewise run well into the six figures.

“When a CAR-T cell manufacturer can make the case that their product can be given outpatient, that has benefits for both the patient, who can avoid a longer hospitalization, but also for the finances of the inpatient-outpatient setting where this is occurring,” Cashen said.

Outpatient administration is especially enticing in the context of allogeneic CAR-T therapies made with donor T cells, such as Allogene Therapeutics’ ALLO-501, which also has a much lower degree of toxicity compared with the traditional autologous CAR-Ts. But off-the-shelf CAR-Ts given outpatient will face similar issues in terms of the investment involved, Cashen added.

“The way Kymriah and Yescarta are billed is based on the sticker price of the CAR-T cells, and it goes directly to the CAR-T cell company,” Raje said. “As an institution, we don’t get the same reimbursement for housing these patients for a certain time, so that’s not factored in.”

Add to that the Covid-19 pandemic, which means a lot will have to be redefined and figured out in terms of cost structures, Raje said, such as some form of bundled payment. “I don’t know if that would be the case, but those are the kinds of things we have to start talking about realistically, or it’s going to be impossible to justify the cost of these therapies.”

Photo: CGToolbox, Getty Images



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