CAR-T Cell Program Development: A Tale of Two Institutions

Maxwell A. Brown, PharmD
Clinical Pharmacy Manager, Stem Cell Transplantation
New York–Presbyterian/Weill Cornell Medical Center
New York, NY

Zahra Mahmoudjafari, PharmD BCOP
Clinical Pharmacy Coordinator
Hematology/Bone Marrow Transplantation and Cellular Therapeutics
University of Kansas Health System
Kansas City, KS

With the groundbreaking approval in 2017 of two chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), comes much excitement but also many administrative and logistical obstacles. The therapies involve lymphocyte collection, lymphodepleting chemotherapy, cell infusion, and finally, and perhaps most important, management of unique side effects. This process may seem straightforward, but CAR-T cell administration from start to finish is complex and requires the expertise and input of a multidisciplinary team to ensure success. Below we outline the processes used by two separate institutions with extensive experience implementing a CAR-T cell program.

Don’t Put the CAR-T Before the Horse: Practical Aspects of Implementing Commercial Chimeric Antigen Receptor T-Cell Therapies

Maxwell A. Brown, PharmD

Memorial Sloan Kettering Cancer Center (MSKCC) recently published a review describing its process for establishing and implementing a commercial CAR-T cell therapy program. The authors identified eight workflow tasks that are essential for the development of a successful CAR-T cell therapy program.¹ In this article, I will briefly discuss each workflow component from the perspective of a pharmacist.

Task 1. Patient Referral, Selection, and Evaluation
The demand for CAR-T cell therapy will presumably be high because it has received considerable media attention in both the medical and public sectors. As a result, institutions must develop rigid guidelines for screening, identifying, and selecting patients who are eligible to receive these products. Given that the wholesale cost of the commercial CAR-T cell products ranges from $373,000 to $475,000,² it is crucial for clinicians to ensure that patients meet the U.S. Food and Drug Administration (FDA)–labeled indications to prevent problems with reimbursement. In addition, financial coordinators and other administrative staff members should be involved early in the intake process to conduct insurance preauthorization and coordinate patient intake.

Task 2. Development of a CAR-T Consultation Service
A physician must be registered with the manufacturer as a CAR-T certified physician in order to be able to prescribe commercially available CAR-T cell products. Some institutions have developed a CAR-T cell consultation service consisting of physicians, pharmacists, nurses, and other healthcare providers who have expertise in CAR-T cell therapy. For example, at MSKCC the CAR-T cell consultation service is responsible for selecting appropriate patients for treatment with CAR-T cells, determining the use of commercial versus investigational CAR-T cell products, and providing comprehensive medical care to patients receiving CAR-T cell therapy.¹

Task 3. CAR-T Cell Collection and Production
Patients who receive CAR-T cell therapy must first have autologous lymphocytes collected via leukapheresis. FDA-registered apheresis and cell-processing facilities must undergo a sophisticated contracting and quality assurance process with manufacturers to ensure that collection, manipulation, tracking, and other procedures meet the quality standards developed by each manufacturer. When it has been collected, the apheresis product is shipped to the manufacturer, where it is genetically engineered to express the CAR, and then shipped back to the treating institution.

Task 4. Bridging Treatment Strategies
The average time from apheresis until CAR-T cell infusion varies between products; for example, the median time from leukapheresis to delivery of axicabtagene ciloleucel is 17 days.³ However, administrative delays and issues with cellular manufacturing could lengthen this period to several weeks or months. Patients with aggressive malignancies may require treatment during this time to prevent disease progression, and it is the combined responsibility of the CAR-T cell consultation service and the treating physician to determine the appropriate course of action.

Task 5. CAR-T Cell Infusion
In the days leading up to CAR-T cell infusion, a lymphodepleting chemotherapy regimen is administered to patients to allow for adequate in-vivo CAR-T cell expansion.^4,5 Organizations should consider developing electronic order sets for the lymphodepleting chemotherapy to simplify prescribing. In addition, certain institutions may involve pharmacy in the registration of CAR-T cell products to a given patient. Therefore, institutions should establish a clear process for verification and labeling of the CAR-T cell product prior to infusion. Other institutions may not involve the pharmacy and may instead have the cell therapy laboratory register the CAR-T product, given that CAR-T cells could be considered more a cellular therapy product than a drug product.

Task 6. Immediate Post-Infusion Care (Days 0 through 30)
The FDA mandates that any institution dispensing a commercially available CAR-T cell product must be enrolled in the risk evaluation mitigation strategy (REMS) program for that particular product. The REMS program requirements for tisagenlecleucel and axicabtagene ciloleucel are quite similar and include live on-site REMS training, provision of a patient wallet card prior to CAR-T infusion, and a procedure to ensure that patients will remain within 2 hours of the institution for at least 4 weeks after the CAR-T cell infusion. However, most germane to the pharmacy department is the requirement that the institution maintain a minimum of two doses of tocilizumab for each patient receiving CAR-T cell therapy.^4,5

Tocilizumab is a humanized monoclonal antibody directed against the interleukin (IL)-6 receptor and was approved by the FDA in tandem with tisagenlecleucel for the treatment of cytokine release syndrome (CRS), a potentially deadly complication of CAR-T cell therapy.⁶ As a result of the FDA-mandated REMS program, the pharmacy department will need to develop policies and procedures to ensure maintenance of adequate stock of tocilizumab. Several strategies exist to accomplish this task, including but not limited to ordering and assigning tocilizumab vials to patients or establishment of a par level for tocilizumab in the pharmacy. An additional decision point for pharmacies will be the length of time to “reserve” tocilizumab vials for a given patient, a detail that is conspicuously left out of the FDA REMS program requirements.

Pharmacy staff should be well educated on the REMS program requirements for CAR-T cell therapy, including the purpose behind the 2-hour turnaround time for tocilizumab. Proper in-service training of the pharmacy staff about the detrimental consequences of delayed treatment of CRS and neurotoxicity should engage staff in the treatment of these patients and help ensure timely administration of tocilizumab. Development of electronic order sets to allow swift and painless ordering of anti-IL-6 therapy and other supportive medications will cut down on delays in treating CRS.

Task 7. Late Post-Infusion Care (Day 31 Onward)
Organizations must also develop effective procedures for transitioning the care of patients out of the hospital and into the outpatient clinic. This especially holds true for patients referred from physicians outside the institution performing the CAR-T cell infusion because the risk of CAR-T cell–related toxicities persists for several weeks after infusion.

Task 8. Regulatory and Reporting Requirements
The Foundation for the Accreditation of Cellular Therapy (FACT) and the FDA administer regulations for collection, manufacturing, and chain of custody of the CAR-T cell product. FACT also recommends that CAR-T cell therapy programs collect internal data regarding CAR-T cell therapy and submit their data to the Center for International Blood and Marrow Transplant Research (CIBMTR) database for collective analyses.⁷ As mentioned, the FDA mandates compliance with a REMS program to ensure that the benefits of CAR-T cell therapy outweigh the risk of severe toxicities.

As organizations develop CAR-T cell therapy programs, numerous administrative, financial, and practical obstacles will need to be overcome. To address these challenges, institutions should leverage the experience of specialists from several disciplines. A multidisciplinary approach to the development of a CAR-T cell program infrastructure will allow organizations to incorporate this exciting and novel immunotherapeutic approach into their treatment armamentarium for patients with cancer.

Take-Home Point
I recommend that a pharmacy department within an institution initiating a CAR-T cell therapy program establish straightforward and perspicuous procedures for the ordering, maintaining, and dispensing of tocilizumab stock. Procedures should be documented in a formalized policy with clear assignment of responsibilities to avoid ambiguity and allow for streamlined auditing in the future.

References

1. Perica K, Curran KJ, Brentjens RJ, Giralt SA. Building a CAR garage: preparing for the delivery of commercial CAR T cell products at Memorial Sloan Kettering Cancer Center. Biol Blood Marrow Transplant. 2018 Jun 24;24(6):1135-1141. doi: 10.1016/j.bbmt.2018.02.018. [Epub ahead of print]
2. Rosenberg J. ICER Report: Costs of approved CAR T-cell therapies aligned with clinical benefit. Am J Manag Care [Internet]. 2018 Feb [cited 2018 May 23]. Available from: http://www.ajmc.com/newsroom/icer-report-costs-of-approved-car-tcell-therapies-aligned-with-clinical-benefit.
3. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017; 377:2531-44.
4. Kymriah (tisagenlecleucel) [package insert]. Morris Plains, NJ: Novartis Pharmaceuticals Corporation; 2017.
5. Yescarta (axicabtagene ciloleucel suspension) [package insert]. El Segundo, CA: Kite Pharma, Inc.; 2017.
6. Actemra (tocilizumab) [package insert]. South San Francisco, CA: Genentech, Inc., 2010.
7. Foundation for the Accreditation of Cellular Therapy. Immune Effector Cells Accreditation Manual, First Edition. Available from: http://www.factwebsite.org/Standards/. Accessed May 22, 2018.

Commit-Arrange-Refine-Train: Developing the Foundation for a Successful CAR-T Program—A Pharmacist’s Perspective

Zahra Mahmoudjafari, PharmD BCOP

Commit
Groundwork prior to administering CAR-T therapy includes development of standard operating procedures (SOPs) and order sets. SOPs that must be created include workflows for compliance with the REMS requirements (including training and adverse event reporting), guidelines for when to start lymphodepleting chemotherapy, frequency and methods of monitoring for toxicities (i.e., CRS and neurotoxicity), and planning for how and when patients will be transferred between units when they experience severe side effects.

SOPs for financial workflows, including insurance authorization and billing, should be established to avoid financial toxicity for both the institution and the patient. Because this product is a “medication” but is not stored in the pharmacy, one challenge has been to determine whether it is billed under the pharmacy budget or under another department entirely. Decisions regarding how and when to label the product will be institution-specific. Order sets should be developed for the lymphodepleting chemotherapy that is given prior to the re-infusion of cells, for admission, for the cell infusion itself, and finally for adverse-event management.

At our institution, the admission order set for CAR-T therapy is individualized and titled specifically for CAR-T patients. It contains many of the elements of a hematology/bone marrow transplant admission order set but has specific nuances for CAR-T patients, such as seizure prophylaxis. Additionally, at our institution the cell infusion is incorporated into the order set for the lymphodepleting chemotherapy. These order sets can be written or electronic, or even both. It is also helpful to build a treatment algorithm that addresses the management of the unique side-effect profile of this therapy; this treatment algorithm should be consistent with the order set for adverse-event management and should include monitoring and treatment parameters to ensure consistency. For example, at our institution we have incorporated the CARTOX10 assessment in the electronic medical record, where it can be easily accessed by the multidisciplinary team.¹

Arrange
These agents are extremely expensive; therefore, the pharmacy and therapeutics committee should give careful consideration to their management, and a process to ensure proper insurance verification prior to a patient’s receiving treatment should be established. In addition, the anti-IL-6 receptor antibody tocilizumab that is used in the event of acute toxicity should be considered for inclusion in the formulary if it is not currently readily available. Consideration should also be given to secondary agents such as siltuximab. Because of the high risk of adverse events, the FDA requires the inpatient pharmacy to stock a minimum of two doses of tocilizumab for each patient before CAR-T cell administration and to have it available for immediate administration within 2 hours.^2,3

At our institution, we increased our par levels of tocilizumab in the inpatient pharmacy and have it available at our outpatient cancer location. Furthermore, when a patient is admitted for CAR-T therapy, the patient’s chart documents that a minimum of two doses of tocilizumab have been verified. Processes should be established to ensure that the staff (both pharmacists and technicians) are aware of the acute need for this medication, the location of the product, and the steps that need to be taken when a dose of tocilizumab is ordered for a patient.

One important caveat is to plan how a dose of tocilizumab would be administered during the initial admission in contrast to the workflow for an individual who is currently an outpatient but is later admitted because of delayed toxicities. Our institution, for example, has an “as needed” (PRN) entry of tocilizumab available on the medication administration record that is released at the time of a patient’s admission for cell infusion and is discontinued when the patient is discharged. Because of the delayed risk for toxicities, patients may begin to experience symptoms and must be admitted, so establishing a guideline for how tocilizumab is ordered is critical.

Furthermore, the use of corticosteroids in this patient population can be controversial, and processes should be standardized to ensure that patients do not inadvertently receive corticosteroids during the initial admission or afterward when they are discharged—unless strictly indicated. Tools within the electronic medical record to promote the judicious use of corticosteroids include temporary contraindication or allergy warnings and best-practice advisory alerts.

Refine
Developing these new processes and technological tools is no easy undertaking. Expect to go through several revisions before a final version, and even then,expect it to change again. Quality improvement processes certainly apply to CAR-T therapy. Plan to become close friends with your physician colleagues, leukapheresis staff, nursing team, and information technology (IT) team!

Train
Training staff members to identify and manage side effects of CAR-T therapy is likely one of the most important undertakings of offering this therapy. In compliance with the REMS requirements, all staff members who prescribe, dispense, and administer this therapy must receive direct training. The manufacturer of each product provides the training materials, and this training must be documented and readily available for assessment if requested by the FDA. This education must be completed by the institution’s designated REMS Authorized Representative; this individual can be a pharmacist.

Training involves both the direct hematology/bone marrow transplant and intensive care unit clinical pharmacists taking care of the patient, as well as the central pharmacy staff, including those on the day, evening, and midnight shifts. The central pharmacy staff must be trained to assess appropriate indications for corticosteroids (for instance, familiarizing themselves with the institution’s algorithm and order set for CAR-T toxicity management) and ensure the timely administration of tocilizumab. SOPs, staff competencies, and even e-mail reminders alerting your pharmacy, nurse, and physician teams that a patient is being admitted for CAR-T therapy are essential to making sure that the staff is prepared to mitigate the unique side effects of this treatment.

Patient education should also be taken into consideration. As part of the REMS program, patients are provided a wallet card that lists potential side effects of the therapy and indicates when they should immediately seek medical attention. They should also be educated about the toxicities of the lymphodepleting chemotherapy preceding CAR-T. Their education should include guidance on how close they should stay to the hospital and for how long (for example, patients receiving tisagenlecleucel must be advised to stay within 2 hours of the treatment site for at least 4 weeks).

Despite the complexities involved in administering this novel treatment, this is an exciting time in cancer medicine. Pharmacists have a unique role in promoting the success of CAR-T therapy both now and in the future as we gain experience and as this modality continues to evolve. Developing and maintaining a strong foundation are integral to positive patient outcomes.

Take-Home Points

• Build the team: Engage all key stakeholders (pharmacists, pharmacy technicians, physicians, nurses, apheresis staff, and IT) sooner rather than later.
• Create the path: Develop standardized order sets to manage toxicities.
• Polish for success: Ensure that all pharmacists and technicians receive appropriate training.

References

1. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy-assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47-62.
2. Kymriah (tisagenlecleucel) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; August 2017.
3. Yescarta (axicabtagene ciloleucel) [prescribing information]. Santa Monica, CA: Kite Pharma Inc.; October 2017.