What's Keeping CAR T-Cell Therapies From the Outpatient Setting?

Andre Goy, MD

Chimeric antigen receptor (CAR) T-cell therapies have been commercially available for less than 2 years. In that short time, they have fundamentally improved the prognosis for many patients with lymphoma and leukemia. Although these therapies were initially conceived of and developed as inpatient therapies, interest is growing in extending CAR T-cell therapies to the outpatient setting.

Much depends on progress in overcoming the barriers to outpatient administration, which are considerable. In a 2017 survey, 64% of nearly 400 US-based community oncologists, hematologists, and practice administrators indicated that the logistics of administering and following up with patients would be the most challenging elements of adoption and referral for CAR T-cell therapy. Those surveyed said high toxicities such as cytokine release syndrome (CRS) and neurotoxicities (46%), cost of therapy (29%), and lack of knowledge about CAR T-cell therapy (19%) were chief concerns.1 In addition, 61% said patients should be hospitalized for 1 to 2 weeks based on CAR T-cell toxicities, and 21% said this therapy should be an outpatient procedure (Table).¹

Two years later, purely outpatient CAR T-cell therapy has been achieved, although not consistently. Oncologists note that the 4-1BB costimulatory domain CAR T-cell therapy is more easily managed than CD28 CAR T-cell therapy. In a 2018 report on delivery and management of CAR T-cell therapy, Teachey et al posited that with the 4-1BB construct, "patients can…be infused with CAR T cells in the outpatient setting and admitted to hospital at the time of fever development."²

Table. Oncologists' Perceptions About Toxicity and Management of CAR T-cell Therapy

AE indicates adverse effects; CAR, chimeric antigen receptor.

Patients infused still require monitoring for up to a month, and “some patients, especially those with a low disease burden, do not require hospital admission at all,” the authors wrote, adding that the "large majority" of CAR T-cell infusions performed at the Fred Hutchinson Cancer Research Center in Seattle, Washington, and Children's Hospital of Philadelphia in Pennsylvania occur in the outpatient setting. For patients treated with CD28 CAR T-cell therapy, initial hospital stays of up to 7 days have proved necessary. CAR T cells “have not fully moved into the outpatient setting,” agreed Andre Goy, MD, MS, chairman and director of the John Theurer Cancer Center in Hackensack, New Jersey. "It’s an ongoing process."

John Theurer has used both tisagenlecleucel (Kymriah), which incorporates the 4-1BB costimulatory domain, and Axicabtagene ciloleucel (axi-cel; Yescarta), which uses the CD28 costimulatory domain. At John Theurer, treatment may begin as outpatient therapy, progressing to hospital admission if warranted by development of CRS-related fever. Physicians generally can wait up to 72 hours, but for Medicare patients, admission is a requirement. Hospital admissions may decline with advances in care, Goy noted. "It will, hopefully, continue more in this direction." Another issue regarding the outpatient setting is that the magnitude and occurrence of toxicities associated with CAR T-cell therapy vary widely across disease types and patient characteristics such as age, comorbidities, and prior therapy. These factors must be weighed in hospital admission decisions.²

Tisagenlecleucel became the first FDA-approved CAR T-cell drug in August 2017, when it was approved to treat patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.³ Axi-cel received FDA approval in October 2017 for adult patients with large B-cell lymphoma who have progressed on at least 2 prior treatments.⁴ Indications include use in diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. In May 2018, the FDA extended its approval for tisagenlecleucel to include adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Commercial adoption of CAR T-cell therapy has been hindered by payment issues and the complexities of care. In May 2018, IQVIA reported that 60 US sites were doing trials of CAR T-cell therapy but that these trials were in close orbit to academic transplant centers, owing to the demanding treatment requirements of CAR T-cell therapy. In addition, these sites were “overburdened” by requests to host new trials, and not enough patients were available, IQVIA reported. The limited window of opportunity for administering CAR T-cell therapy to patients in need of this treatment and variable CAR T-cell manufacturing times, ranging from a few weeks to 4 or more, were cited as impediments to rolling the treatment out on a larger scale.⁵

“These obstacles will need to be addressed for CAR T therapy to become a mainstream treatment option and for this important research to continue. To get there, we need to expand the number of clinical research sites that can handle these trials, including community-based transplant centers. We also need to implement more innovative strategies for recruiting patients and to scale up T-cell manufacturing services to support the growing need,” Jeff Hodge, vice president of Developmental Solutions for the Oncology Center of Excellence at IQVIA, wrote.

Unresolved payment pathways, including unclear coding for payment by the Centers for Medicare & Medicaid Services (CMS) and slowness by private payers to establish CAR T-cell payment policy, have been cited as obstacles to adoption of this therapy. In addition, oncologists and others have contended that the ancillary costs of care related to the therapy are not sufficiently addressed by CMS payment policy. CAR T-cell therapies carry daunting price tags. Axi-cel—manufactured CAR T cells cost $373,000 per infusion.⁶ Tisagenlecleucel retails for $475,000 per dose.⁷ When the necessary care that accompanies each CAR T-cell dose is added in, the totals can reach 7 figures per patient, particularly if serious complications develop from CRS, infection, or neurotoxicities.

Almost 2 years after the first FDA approval of CAR-T cell therapy, CMS continues to develop coding and payment policies for the treatment. As a condition of coverage, CMS has proposed that every patient be enrolled in a clinical trial or a registry if they are to get Medicare coverage for CAR T-cell therapy, a decision that may leave some without access to the lifesaving cancer treatment. This "would improve access to this therapy while deepening CMS' understanding of how patients in Medicare respond to it so the agency can ensure that it is paying for CAR T-cell therapy for cases in which the benefits outweigh the risks," CMS Administrator Seema Verma, MPH, said in a statement.⁸

Facilitating Outpatient Treatment

CMS opened a 30-day public comment period in mid-February 2019 and will issue a f inal decision on the proposal within 60 days of the comment period’s conclusion. Without a standard coverage amount, private payers are negotiating payment with individual cancer treatment institutions for each patient, tying up administrative resources and adding uncertainty to already-fraught situations.With further refinements, broadening outpatient CAR T-cell therapy should be possible, said Nilanjan Ghosh, MD, PhD, in an interview with OncLive^®. "There have been some centers able to offer outpatient CAR T-cell therapy. What is needed is a good infrastructure for outpatient management where a patient can be seen any day of the week, which means those sites should also have providers available on the weekends to evaluate these patients. Also needed is a way to admit these patients as easily as possible to the inpatient setting if they have any signs of toxicity, such as a fever, which could be a first sign of CRS, or slight confusion or a headache, which could be signs of neurotoxicity." CMS Administrator Seema Verma, MPH, said in a statement.⁸

CMS opened a 30-day public comment period in mid-February 2019 and will issue a f inal decision on the proposal within 60 days of the comment period’s conclusion. Without a standard coverage amount, private payers are negotiating payment with individual cancer treatment institutions for each patient, tying up administrative resources and adding uncertainty to already-fraught situations.

Ghosh, a hematologist with the Hematologic Oncology and Blood Disorders program at Levine Cancer Institute in Charlotte, North Carolina, noted that for CAR T-cell therapy to be successful, it must be possible to move patients between outpatient and inpatient care settings smoothly, and patients must live close to centralized facilities. The lag between observing toxicities and admitting patients must be minimized, he added. To be candidates for outpatient therapy, patients should be stable and have good performance status, a lower disease burden, and good social support systems, Ghosh said. Some physicians go as far as educating local emergency medical technicians to be alert for patients on CAR T-cell therapies so they can be directed to the appropriate facilities in the event of severe toxicity events.

“In addition to giving lectures about CAR Ts to the local paramedics and [emergency department] residents, we email the local fire departments where our CAR T patients live or are staying,” said James H. Essell, MD, medical director of the Blood Cancer Center at The Jewish HospitalMercy Health and medical director of cellular therapies for The US Oncology Network. “The symptoms of neurotoxicity can include aphasia, so we don’t want our patients taken to a stroke center instead of to us. These therapies require a lot of coordination at all levels.”

Physicians at the Bezos Family Immunotherapy Clinic of the Seattle Cancer Care Alliance at Fred Hutch have grown comfortable giving 4-1BB costimulatory domain CAR T cells in the outpatient setting, said David Maloney, MD, PhD, medical director of cellular immunotherapy at Fred Hutch and the Bezos Family Immunotherapy Clinic. “But that’s because we have extensive experience and a very robust clinic wherein we have 24/7 triage and the ability to immediately care for patients in the hospital at the first sign of CRS or other toxicities.”

With 4-1BB CAR T cells, there is a more gradual onset of symptoms, Maloney said. Most patients will present with fevers. They do not require urgent treatment at an intensive care unit (ICU), and there is time to get them admitted to hospital for treatment by an inpatient team if necessary. "With the CD28 CAR, such as axicabtagene ciloleucel, that onset is much quicker, and I do not believe that it is safe to do that in the outpatient setting. Patients require a more urgent evaluation when they become symptomatic with fevers because this can quickly escalate to requiring supportive care, oxygen, fluids, and ICU care for blood pressure support," Maloney noted.

At the University of Kansas, where physicians treat with both axi-cel and tisagenlecleucel, patients are admitted for the first 7 days following infusion. Following that, the standard of care has been to see these patients every calendar day for the rest of the first month. "Most programs around the country continue to follow that policy, although now that we have significant experience with these therapies, we’ve been able to spread it out so that they’re coming in 2 to 3 times per week for that month," Joseph McGuirk, DO, medical director of blood and marrow transplant at the University of Kansas Cancer Center in Kansas City, said.

Guidance for CAR T-cell Therapy Programs

For such treatment to be replicated in the community setting, cancer centers need to be "top-notch" and experienced in both inpatient and outpatient care, Maloney said. It is essential that these physicians are primed to recognize and respond to CRS promptly and effectively. "I don't think there are many community centers available that really have that degree of support to be able to do this yet. It could certainly be done in the future, but it really requires this 24/7 triage, recognition, and an experienced team to take care of the patients," he said.A growing number of resources are available to help interested institutions develop policies and procedures for safe CAR T-cell therapy care. For example, the Foundation for the Accreditation of Cellular Therapies (FACT) has issued the FACT Standards for Immune Effector Cells to provide voluntary minimum performance guidelines for cellular therapy programs, including CAR T-cell therapies.⁹ In January 2018, the CAR T-cell therapy-associated TOXicity (CARTOX) Working Group, which included investigators from multiple institutions and disciplines with experience treating patients with CAR T-cell products, provided recommendations for monitoring grading and managing acute toxicities that occur in patients.¹⁰

Other guidelines are on the way, as a variety of professional organizations are developing methodologies for administering CAR T-cell therapies, including the American Society of Hematology, the American Society for Blood and Marrow Transplant, the American Society of Gene & Cell Therapy, and the International Society for Cellular Therapy. Additionally, the Association of American Cancer Institutes, whose membership comprises 98 cancer centers in the United States and Canada, has launched the CAR T Initiative to address the challenges that institutions encounter in developing their treatment programs.¹¹ The initiative features a steering committee and working groups on administrative barriers, clinical best practices, and CAR T cell—related clinical research. The steering committee, chaired by McGuirk, aims to educate legislators, government agencies, and clinical colleagues about the importance of CAR T-cell therapies and the need to increase patient access to them.

The Institutional Commitment

McGuirk expects a gradual but steady reduction in the need for urgent care. "We all are looking to how we can move these therapies to the outpatient setting in a safe manner, without compromising patient safety and without compromising the effectiveness of these therapies," he said. "We will move in that direction over time, and some centers indeed already have. But I can’t overemphasize the importance of the necessary infrastructure to make that possible in a safe way."Essell summarized the basic institutional requirements for safety and the effective administration of CAR T-cell therapy in the outpatient setting.¹² Institutions must:

• Obtain certification from the CAR T-cell manufacturer and enroll in its Risk Evaluation and Mitigation Strategies program
• Develop cellular therapy policies and procedures
• Form an institutional biosafety committee
• Develop an apheresis unit or coordinate with an apheresis center to collect patients’ cells
• Coordinate care among the outpatient clinical team, including hospital-based specialists in critical care, neurology, and infectious diseases in preparation for any inpatient stays
• Plan and develop dedicated patient care spaces and cell storage facilities
• Train any staff needed for support positions in social work, navigation, records management, and financial services
• Develop detailed educational materials for patients and caregivers
• Ensure that clinical staff with CAR T-cell therapy training will be on call 24/7

Essell’s practice, Oncology Hematology Care in Cincinnati, Ohio, now provides CAR T-cell therapy on an outpatient basis.

The CAR T-cell Therapy Process

"When we started getting ready for this more than a year ago, we met weekly with the hospital’s chief executive officer and chief financial officer, as well as with our clinical team, because of the large burdens placed on the institution," he said. "There has to be a commitment by the entire hospital staff… to take on these patients. Some institutions are just going to say no because they don’t have the technical capabilities and don’t want that around-the-clock responsibility."The CAR T-cell therapy process itself has many parallels with stem cell transplantation, Essell noted:

• Leukapheresis or lymphocyte collection at a blood center, clinic, or infusion center
• Transportation of the collected cells to a laboratory for the cells to be genetically modified
• Cell engineering, which should take 2 to 3 weeks, although Essell said production bottlenecks can lengthen waits to 2 months
• Patient conditioning or lymphodepleting chemotherapy
• Infusion
• Patient monitoring and follow-up

The timing of each step in the process is critical because of patients’ vulnerabilities and the severity and aggressiveness of their disease.

"If you take too long getting all the treatment details worked out, patients will progress and succumb to their disease before you can get them to therapy," McGuirk said, noting that the University of Kansas Cancer Center’s goal is to see referred patients within 24 hours with all pertinent medical records already in hand and insurance approval under way, with help from the center's CAR T-cell therapy coordinators and other team specialists.

"Hours and days are precious in these patients," he noted. Essell agreed. Part of making outpatient oncology work is getting referring physicians to understand that treatment with CAR T cells will be more successful if patients are referred earlier in treatment progression, he said. "Most referring docs are really good, but it’s vital to understand refractory and relapsed lymphoma. There can be this thought that the patient can receive salvage chemotherapy for a few weeks or months and then be referred to us, but it's better to call us once it becomes apparent that your new line of chemotherapy is ineffective so that the patient doesn’t lose precious time."

Looking to the Future

Oncologists who do refer patients for CAR T-cell therapy have a right to expect continued updates, particularly when patients are set to return to the community practice a month or so following infusion, McGuirk said. "It’s not uncommon for patients to return to the referring team with only a partial response. We as the CAR T experts must communicate that patients still might go into complete remission, so they don't insist on additional chemotherapy right away on residual disease, and we can talk through that,” he said.Next-generation CAR T-cell therapies are widely expected to have fewer toxicities, which may expand use of CAR T-cell therapy in the community setting.

One example is Juno's lisocabtagene maraleucel (liso-cel; JCAR017), which has shown promise in early-phase trials. Liso-cel's improved safety profile has led to innovations in clinical trial design that are expected to help shape how the drug will be used if it ultimately gains FDA approval, Essell said. "At The US Oncology Network, we’re working with Juno to be involved in a clinical trial in which the entire treatment will be handled on an outpatient basis, admitting patients only if they have complications," he added.

With the current locus of CAR T-cell administration in centralized facilities, it is estimated that many eligible patients are missing out on this therapy. “We believe that only 10% of the potentially eligible patients in the country are being referred for a CAR T-cell therapy consultation," McGuirk said. He expects to see rapid improvement in the use of these potentially lifesaving therapies. "Compare a 40% chance of curing a patient’s lymphoma with CAR T cells with lymphoma’s natural history of 7% survival, and that means there are thousands of patients dying unnecessarily in our nation from lymphoma right now,” McGuirk said. “The only way to fix that is for us to educate our physician colleagues so that patients can be referred in a timely manner and appropriately to our centers. That is critically important in solving this national crisis."

References

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