The commercial success and ability of eligible patients to receive chimeric antigen receptor T-cell (CAR-T) therapies depend on optimizing the logistics of delivering this transformational treatment platform. One essential component of this, is site of care and whether patients are best to receive this treatment in an inpatient or an outpatient setting. While there are financial implications to that decision, it is critical to assure that patients receive CAR-T therapy safely in a monitored environment where timely interventions to mitigate potential adverse events are available. We argue that until data on safe outpatient administration are available and mature, CAR-T therapies are best given in the inpatient setting regardless of any financial implications.
In the Viewpoint piece above, “CMS Sets CAR-T Reimbursement Levels—Where Should the Patient Be Treated?”, Dr Wong discusses the Centers for Medicare and Medicaid Services (CMS) decisions on how to reimburse for CAR-T therapy based on the site of infusion: outpatient vs inpatient setting. In agreement with his comments and expanding upon his discussion, we assert that making the decision on site of infusion should first and foremost consider patient safety, which means CAR-T infusion should take place in the inpatient setting.
There is little doubt that CAR-T therapies have improved the prognosis of some refractory hematologic malignancies. The promising results in relapsed/refractory (R/R) diffuse large B-cell lymphoma and acute lymphoblastic leukemia (ALL) have led to 2 CAR-T therapies being approved by the Food and Drug Administration in 2017.1,2 This efficacy came at a high cost of toxicities, with the most severe and potentially lethal toxicities being cytokine release syndrome (CRS) and neurotoxicity. In the phase 2 study that led to the approval of Kymriah for R/R ALL, severe CRS and neurotoxicity occurred in 47% and 15% of treated patients, respectively.3 In the ZUMA-1 trial of Yescarta, severe CRS and neurotoxicity occurred in 13% and 28% of patients, respectively.4 The common theme for these severe toxicities is that they require early identification, laborious monitoring, aggressive in-patient management, and often intensive care nursing. Commonly, these toxicities occur within 1 week of CAR-T infusions but can develop later. Further, fatalities could occur in some patients who develop these toxicities if not managed immediately and appropriately.
In addition to the reported data on efficacy and toxicity, one must pause and acknowledge that patients treated in these studies do not represent typical patients seen in clinical practice. It goes without saying that clinical trial patients are highly selected; they are younger, relatively healthier with few comorbidities, predictably able to tolerate intensive therapies, often of Caucasian populations not representing the diversity of US demographics, and have adequate psychosocial supports, all of which have significant implications for patient management and outcomes for CAR-T therapy. If the toxicities cited above are occurring in the healthiest of patients, it would be fair to assume that one needs to apply a clinical adjustment/correction that accounts for the reasonable difference in risk-stratification between trial and real-world patients.
So, what does this all mean when it comes to deciding on reimbursement, and how can government and commercial payers navigate the data on efficacy and toxicity to make decisions on their share vs patients’ share of incurred costs? To make a fair decision, one must have the foresight of the overall total costs of care while ensuring that patient safety is front and center in every decision. In the outpatient setting, the patient bears more cost; CMS accrues more cost when the infusion is delivered in the inpatient setting. Looking at the economic advantage, CMS might be pushing for CAR-T therapy to be administered on an outpatient basis, but all the data to date suggest that this would compromise patient safety. Notably, clinical trials that have led to the approval of these CAR-T therapies have all been administered in the hospital, and, despite rigorous monitoring in a highly selected patient population, severe toxicities and some fatalities were still observed. So, realistically, how could we change the site of administration as these therapies enter a real-world setting where patients are older, sicker, and have less support? In our view, this is counterintuitive and argues for a critical look at this policy to ensure that patients are not harmed purely because of a financial decision that prioritizes dollars over patients.
We must note also that Kite and Novartis, the manufacturers of Yescarta and Kymriah, respectively, emphasize that patients are treated safely and in the most appropriate setting. In fact, Novartis clearly states on their website that CAR-T treated patients have to be located within 2 hours of the treatment center for up to 4 weeks.5 This seems to underscore that treatment and infusion patients should occur in the inpatient setting. Similar recommendations are provided by the manufacturer of Yescarta.6 Even if economics are the driving forces behind the decision of where to infuse, costs will be incremental to CMS and commercial payers when patients are hospitalized and get transported emergently to emergency rooms when adverse events occur.
Until biomarkers validate which subset of patients can be safely given CAR-T therapy as an outpatient, the decision, in our view, is clear. CAR-T therapy should be infused in the inpatient setting regardless of costs, however, we support ongoing clinical trials that assessing the plausibility of outpatient administration.
To read the initial viewpoint this article references, click here.
References
1. Food and Drug Administration (FDA). Kymriah (tisagenlecleucel). FDA.gov website. https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm573706.htm. Updated May 7, 2018. Accessed July 11, 2018.
2. Food and Drug Administration (FDA). Yescarta (axicabtagene ciloleucel). FDA.gov website. https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approved
products/ucm581222.htm. Updated February 20, 2018. Accessed July 11, 2018.
3. Kymriah [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017.
4. Yescarta [package insert]. Santa Monica, CA: Kite Pharma Inc.; 2017.
5. Novartis Pharmaceuticals Company. Kymriah. https://www.us.kymriah.com/.
Accessed July 11, 2018.
6. Kite Pharma. Yescarta. https://www.yescarta.com/. Accessed July 11, 2018.
