Introduction
Cancer care in the United States is typically delivered within two locations: at an academic or university-based cancer center or at a community cancer center. About 80% of the patients treated for cancer in the United States receive their care in community cancer centers.1 As cancer care evolves with immune stimulating therapies such as chimeric antigen receptors (CARs) and bispecific T-cell engagers (BiTEs), a robust team of health care professionals is required to assess and manage unique adverse events, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Not only are these adverse events a potential concern, but complex methods for medication administration can challenge a smaller community health system. Herein we will review the technical and clinical issues facing community cancer centers and their pharmacy teams delivering these high-tech treatments.
About St. Luke’s Cancer Institute
Located in Boise, Idaho, St. Luke’s Cancer Institute (SLCI; formerly Mountain States Tumor Institute) is a member of the St. Luke’s Health System which serves southern Idaho, northern Nevada and eastern Oregon. We have five full-service cancer centers located within 3 hours of each other within Idaho. Annually our cancer institute sees 20,000 patients with about 5,000 newly diagnosed patients. Oncology pharmacy services provided across centers include pediatric oncology, oral chemotherapy, infusional chemotherapy, autologous and allogenic blood and marrow transplant, CAR T cell therapy and investigational drug services.
BiTE Therapy Planning at a Community Cancer
Center The first FDA approved BiTE therapy, blinatumomab, was approved with accelerated approval for relapsed B-cell acute lymphocytic leukemia (ALL) in December of 2014, with full approval following in 20172 . St. Luke’s Cancer Institute participated with the Children’s Oncology Group protocol AALL1331 evaluating blinatumomab administration for first relapse of childhood B-Lymphoblastic Leukemia (B-ALL). The protocol strongly recommended hospitalization for the first 9 days of blinatumomab administration to evaluate for CRS. The remainder of the 28-day cycle could be infused through a programmable CADD® pump for at home administration. Sounds like a simple transition, right? Outpatient administration of a continuous infusion monoclonal antibody is potentially not an issue when you have a dedicated home care infusion service line at your health care system. But what if these services do not exist? Our first pediatric blinatumomab patient spent both 28-day cycles admitted on the pediatric oncology unit due to lack of dedicated resources to adequately support this patient in the outpatient setting. That is 56 days away from their home, family, friends, and pets. As the efficacy of blinatumomab was confirmed in the first relapse space, pediatric clinical trials began investigating blinatumomab administration at first diagnosis of B-cell ALL for higher risk patients with detectable minimal residual disease (MRD) and are now looking at high throughput sequencing in patients with MRD negative disease. To maintain quality of life for our patients and their families, and ensure we were responding to change in care standards, our efforts needed to focus on how to support in-home administration of blinatumomab. The focus needed to include not only our pediatric patients, but our adult patients as well, both those participating in clinical trials and those obtaining blinatumomab through commercial avenues as blinatumomab became incorporated into the standard of care.
It Takes a Village
A definitive team approach is essential to care for these BiTE eligible patients. Communication and effective processes between pharmacy, nursing, oncology providers, emergency room providers, triage, and patients and/or their families need to be established. Administration challenges with blinatumomab need to be addressed, including prolonged continuous infusion, dedicated intravenous line or access, nursing care for central venous access changes, and technical requirements such as the specific intravenous bags, tubing and need for programmable ambulatory pumps.3 Management challenges with in-home administration also need to be addressed, including processes for continued evaluation for serious adverse events, how to handle interruptions with continuous administration (including a pump malfunction or a pump alerting to warn of an occlusion), and what to do if tubing has been severed or the Port-A-Cath has been accidentally disconnected or de-accessed. The oncology pharmacy team needs to create a compounding strategy to address the need for this complicated technical compound for both clinical trial and commercially treated patients as well as both pediatric and adult patients, as these two service lines are typically distinct from one another. Discharges from inpatient to outpatient administration also take coordination with home health care services if these are involved. Education of pharmacy and nursing staff is also important, particularly with staffing turnover, protocol requirements for documentation of pharmacy training, nursing familiarity with adverse 4 FEATURE events, continuous infusion administration, intravenous line care, and familiarity with battery operated programmable pumps.
Needs and Limitations of CAR T Cell Therapy
Unfortunately, as with many cutting-edge treatment modalities, patient access to CAR T cell therapy is limited by geography and cost. Patients residing in rural areas may be hours away from the tertiary care centers that offer this treatment, often requiring outof-state travel. Due to the high risk of life-threatening toxicities within the early days of therapy, patients must stay within two hours of the facility for the first four weeks after treatment.4,5 For patients without family or friends with whom to reside during this period, lodging must be prepared. Travel and board are logistical barriers patients must tack on to the already mammoth task of undergoing costly and intensive medical care. Additionally, outside referral and travel incur delays in treatment for patients who are already facing several weeks before therapy may be administered, in the setting of relapsed or refractory disease that may not respond to bridging chemotherapy. Patients have died during this referral waiting period at our institution. These obstacles may be ameliorated in part by smaller health systems nearer these patients offering CAR T cell therapy. This presents many challenges on the part of the healthcare system, however. Treatment with CAR T cell therapy is a labor-intensive process and requires substantial multidisciplinary input. Additionally, the financial cost of administering CAR T cell therapy cells is higher than comparable therapies such as blood and marrow transplant (BMT).6 The steps to become an authorized treatment center for CAR T cell therapy vary between manufacturers, but all require various proofs of clinical competence and sufficient resources to offer treatment, in addition to the need to have Risk Evaluation Mitigation Strategy (REMS) enrollment in place. This means a center must have an established history of clinical excellence in treating hematologic malignancies. Due to the resource demands of having a BMT program in place accredited by the Foundation for the Accreditation of Cellular Therapy (FACT), many programs, including our own, begin CAR T cell therapy delivery within the BMT service line, although some centers may choose to offer this through a separate service line.7-9 Within the CAR T cell therapy service line alone, this includes a team of physicians, advanced practice providers, nurses, and pharmacists with training and experience caring for hematology and stem cell transplant patients. Additional education and training of all involved clinical and laboratory staff is essential to managing these patients as well as their subsequent toxicities. Logistically, a treatment center must also be equipped with coordinators and administrative leadership capable of establishing and maintaining the policies, procedures, and other operational standards to meet requirements set by FACT and the Food and Drug Administration (FDA).5,10 A treatment center must also have access to apheresis methods to obtain patient T cells prior to shipping off to processing facilities for CAR generation. Outside of the department providing cellular therapy, providers from related specialty areas must be integrated to provide consultation or intensive care during the eventual management of toxicities after CAR T cell therapy administration, particularly CRS and ICANS. Once a center has decided which CAR T cell therapy products to offer and has satisfied the requirements to establish contracts with the associated manufacturing entities, it must also have a network in place to identify and evaluate patients for eligibility.
Overcoming Barriers
Fortunately, St. Luke’s Health System has long served its surrounding community and has a well-established reputation for oncology treatment through St. Luke’s Cancer Institute. Multiple SLCI clinics are present throughout the state and form a crucial referral network within the system, in addition to community sources of referral from outside SLCI. St. Luke’s has offered autologous BMT services for decades and allogeneic BMT since 2018. This has laid a foundation of clinical staff experienced in the complexities of care for this general patient population. In the context of the wide-ranging medical services available within the St. Luke’s Boise Medical Center, the CAR T cell therapy team is able to take advantage of a well-resourced infrastructure to meet the needs of care delivery to these patients. For patients residing farther from the medical center, a Guest House on campus is able to provide lodging within walking distance to both the hospital and cellular therapy clinic for close outpatient follow-up and easy access in cases of emergency. Having a stable foundation from both a clinical and financial perspective is imperative given the high cost of entry inherent to CAR T cell therapy. Current reimbursement models are inadequate for the initial administration and toxicity management period of CAR T cell therapy patients, so a health system must be able to take the hit upfront to recuperate these losses later in care.11
Looking Forward
BiTEs are here to stay and are an important part of our armamentarium of hematologic malignancies and studies are underway evaluating their potential utility in solid tumors as well. Luckily, many new BiTE therapies in development do not require continuous infusion techniques as the issue of short half-life has been overcome, allowing once weekly dosing. Delivery of complex, high-cost treatment such as CAR T cell therapy is often left to tertiary care referral centers inaccessible to many patients. However, any community cancer center with an FEATURE (continued) “Unfortunately, as with many cutting-edge treatment modalities, patient access to CAR T cell therapy is limited by geography and cost.” FEATURE VOLUME 19 | ISSUE 4 5 FEATURE (continued) established BMT program may be well-poised to take the next steps toward offering this potentially life-saving treatment to its patients, without the sometimes-insurmountable hurdle of referral to an out-of-state medical center. As of this writing, our medical center has recently performed its third CAR T cell therapy infusion, with several more patients slated for treatment in the near future. Each patient receiving CAR T cell therapy cells at our facility represents a patient (and family) that has been able to receive cutting-edge standard-of-care therapy, close enough to home to substantially reduce out-of-pocket travel and lodging costs. Likewise, referral within our health system or local community has allowed for shorter time to treatment in patients whose survival often hinges on receiving this treatment before they can be overcome by disease. As reimbursement models are further delineated and our processes are further refined with experience, our CAR T cell therapy program is expected to grow to meet all the cellular therapy needs of our community. Eventually, all CAR T cell therapy products are expected to be available, and methods of increasing accessibility and decreasing cost, such as outpatient administration, will be explored. Access to novel therapies is unfortunately a barrier to best practice or standard-of-care treatments that not only affect complete remission, overall survival, and disease-free survival rates, but may inadvertently increase risk of adverse events and increase cost of care. Access issues may also potentially influence the sequencing of these novel therapies based on geographic availability. Physicians without “quick” access to CAR T cell therapy may choose to prescribe a BiTE regimen at first relapse because it is easier to obtain through all the necessary channels than CAR T cell therapy, whereas a physician at an academic medical center may choose to pursue CAR T cell therapy at first relapse because the accessibility issues are not a barrier to care. How to best sequence these novel “high-tech” therapies is still under investigation. Hopefully, the discovery of “cleaner” BiTE and CAR T cell therapies with improved administration schedules and fewer potentially life-threatening adverse events will resolve current accessibility issues and no longer be a factor in subsequent treatment options. Special thank you to Robert Mancini and Scott Robison for their contributions!
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