Length of Hospital Stay Key Driver of Costs Associated With CRS Following CAR T Treatment

Health resource utilization data gathered from the TRANSCEND-NHL trial have found that longer stays in the intensive care unit (ICU) have a significant impact on the cost of care due to cytokine release syndrome (CRS) following treatment with chimeric antigen receptor (CAR) T cells. Presenting the results of the study at the 60th American Society of Hematology Annual Meeting & Exposition, being held December 1-4, in San Diego, California, was Tanya Siddiqi, MD, hematologist/oncologist with City of Hope, Duarte, California.¹

CRS is a significant side effect of CAR T treatment. According to David Porter, MD, of the University of Pennsylvania Health System, T cells that have been activated release cytokines that activate other immune cells; this in turn releases more cytokines into the bloodstream. Consequently, the patient can experience high fever, sever flu-like symptoms, and other complications. This potentially fatal syndrome may require use of “pressors,” to improve blood pressure, and patients may need to be cared for in an ICU, Porter told The American Journal of Managed Care^® in an interview.

While symptoms may vary based on the type of CAR T-cell treatment being administered, the TRANSCEND-NHL 001 phase 1 study is evaluating lisocabtagene maraleucel (liso-cel), which are CD19-directed 4-1BB CAR T-cells, in adult patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B, and mantle cell lymphoma.

“Resource use [in CRS management] may differ by product and remains to be evaluated,” Siddiqi said. “We have tried to estimate the cost of CRS management in relapsed/refractory DLBCL,” she said, adding that their analysis focused on dose-finding and dose-expansion cohorts from the trial.

Participants were infused with 1 or more cycles of liso-cel, which includes lymphodepletion followed by 1 or 2 doses of the CAR T-cell infusion. The trial has a follow-up period of 24 months following the first infusion.

The authors looked at the case report forms of patients who experienced CRS to evaluate the health resource utilization (HRU) associated with CRS management, which was assessed using a 2-step micro-costing method. “Data cut-off was May 4, 2018,” Siddiqi said. In the first step, Siddiqi explained, they analyzed HRU for managing each event, including number of inpatient days, number of intensive care unit (ICU) days, procedures, and medications.

“HRU was included if it was within the protocol management guidelines,” she added. The analysis included HRU that occurred within the onset date and resolution date of a treatment-related adverse event. In the second step, cost was attributed to each HRU, which included diagnostic and laboratory testing; hospitalization, procedures, and office visits; and medication costs.

“Our methods were consistent with previous micro-costing efforts in CAR T adverse event management conducted by the Institute for Clinical and Economic Review,” Siddiqi said.

Analyses were stratified by grade and by site of care (inpatient or outpatient) at which the CAR T-cell therapy was administered.

The researchers used the Lee criteria² for grading CRS, which clustered a majority of patients in the current cohort in grade 1 and grade 2. Of the 38 (out of 102) patients treated in the dose-finding/dose-expansion portions of the trial who experienced CRS, 19 (19%) patients experienced grade 1 symptoms, 18 (18%) grade 2, and 1 patient had grade 4 CRS. Total HRU and cost varied based on CRS grades. A higher grade of CRS, not surprisingly, was associated with a longer length of stay (LOS): the mean LOS for grades 1 and 2 were 4 and 7 days, respectively, for inpatient CAR T administration. One patient with grade 4 had a LOS of 34 days. Among those who received outpatient CAR T-cell treatment, the mean LOS was 2 days for grade 1 CRS and 6 days for grade 2 CRS. So, patients in the inpatient setting had longer mean LOS compared to those in the outpatient setting.

While patients with grade 1 CRS did not need ICU admission, the mean ICU LOS for CRS grade 2 patients was 1 day, and 1 patient was in the ICU for 26 days.

Siddiqi highlighted that patients in TRANSCEND-NHL were successfully managed with conservative HRU compared with the trial’s recommended guidelines. For example, only half the patients (9/18) who experienced grade 2 CRS were administered the recommended tocilizumab, she said.

The analyses found that hospitalization had the most impact on overall cost, which was much lower for patients who experienced grade 1 ($11,226) and grade 2 ($25,617) CRS. Hospitalization costs were $10,813 and $21,397, respectively, for the 2 cohorts. The lone CRS grade 4 patient who had a 34-day LOS, 26 of which were spent in the ICU, incurred an estimated total cost of $201,836.

“More so than diagnostics and drugs, hospitalization led to a tremendous cost burden,” she said. The 1 outlier was her own patient, who came in with a large disease burden to start with, and he had CRS as well as neurotoxicity, which is another adverse effect of CAR T-cell treatment. He was on a ventilator as well

Resource use not referenced in the guidelines was largely comprised of medication use and resulted in minimal increases in total cost. Costs due to resource use that were not referenced in the guidelines, mainly medications, ranged from $1698 (grade 1) to $21,055 (grade 4).

Siddiqi highlighted certain limitations of the study, including that grade 3/4 events are not well-represented in their cohort. Additionally, CRS definitions, management, and incidence vary across CAR T-cell therapies. Also, costs were derived from national averages and may not be generalizable across institutions.

She concluded that based on the analysis, hospital and ICU LOS seem to be key drivers of CRS management cost and are mainly associated with managing higher grade CRS. Siddiqi noted, however, that while actual costs may vary between hospitals, CRS management guidelines, which vary across CAR T therapies, will significantly affect both HRU and associated cost differences.

“Improvement of CAR T-cell therapy complications may be achieved through efficient intervention strategies and product engineering,” to reduce the incidence and the grade of CRS, Siddiqi said.

References

1. Siddiqi T, Garcia J, Dehner C, et al. Estimation of the resource utilization and costs of cytokine release syndrome observed in the Transcend-NHL clinical trial: a micro-costing study. In: Proceedings from the American Society of Hematology; December 1-3, 2018; San Diego, CA. Abstract 319.
2. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188-195. doi: 10.1182/blood-2014-05-552729.