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Evidence-Based Oncology January 2019

Cost of Care

Updates from the annual ASH meeting, December 2018.

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

Surabhi Dangi-Garimella, PhD

Health resource utilization data gathered from the TRANSCEND-NHL 001 trial show 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, 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 adverse 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, severe flu-like symptoms, and other complications. This potentially fatal syndrome may require use of vasopressors, medications 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.2

Although 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), comprising 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.3

“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.4 “Data cut-off was May 4, 2018,” Siddiqi said. In the first step, she explained, they analyzed HRU for managing each event, including number of inpatient days, number of 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 microcosting 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 (eg, inpatient or outpatient), where the CAR T-cell therapy was administered.

The researchers used the Lee criteria5 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. Patients in the inpatient setting had longer mean LOS compared with those in the outpatient setting. Although 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 were successfully managed with conservative HRU compared with the trial’s recommended guidelines. Only half (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 alone were $10,813 and $21,397, respectively. The lone patient with CRS grade 4 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,” Siddiqi 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 made up of medication use and resulted in minimal increases in total cost. These costs 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, and 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 although 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.

  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. Dr David L. Porter discusses side effects of CAR T-cell therapy. The American Journal of Managed Care® website. Published April 11, 2017. Accessed December 2, 2018.
  3. Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-cell non-Hodgkin Lymphoma (TRANSCEND-NHL-001). Updated October 12, 2018. December 2, 2018.
  4. Resource use management: principles 6-10. Global Health Cost Consortium website.
  5. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome [erratum in Blood. 2015;126(8):1048]. Blood. 2014;124(2):188-195. doi: 10.1182/blood-2014-05-552729.

Studies at ASH Evaluate Episodic ED Utilization, Adherence, QOL in Sickle Cell Disease

Surabhi Dangi-Garimella, PhD

Patients with sickle cell disease (SCD) typically have episodic emergency department (ED) and inpatient encounters, and innovative interventions are necessary to improve adherence

to hydroxyurea (HU) treatment among youth suffering from SCD. These were the findings of 2 studies presented during an outcomes research session December 1, 2018, at the 60th American Society of Hematology (ASH) Annual Meeting & Exposition, held in San Diego, California.

ED utilization and inpatient admission among patients with SCD are known issues, but utilization can vary among individual patients. A 30-month study that involved 427 patients in 2 institutions in North Carolina, for example, found that 1 cohort of patients with SCD had more hospital admissions and ED encounters while the other cohort had more day hospital encounters.1 Pain associated with SCD is a common reason for ED visits.2,3

The first study, presented at the ASH annual meeting by Susan Paulukonis, MA, MPH, program director, California Rare Disease Surveillance Program, evaluated both high-use and quiescent periods among patients seen in California’s nonfederal hospitals over 12 years.4

“We were seeing peaks and valleys of ED utilization, and we wanted to understand those patterns better,” Paulukonis said.

The data are part of the California Sickle Cell Data Collection project, a statewide effort to use a wide range of administrative, clinical, and other data sources to describe the population living with SCD, their health outcomes, and healthcare utilization patterns. Paulukonis shared analyses of data gathered from inpatient and ED encounters (with or without an associated inpatient stay) from 2005 to 2016. Patient identifiers across data set and year helped link the patient information. A true SCD case was defined as 3 or more occurrences of a SCD-specific International Classification of Diseases code (version 9 or 10) within any 5-year period between 2005 and 2016. Patients who met this definition and had at least a 1-year follow-up were included in the analyses.

Quiescent periods were defined as lengths of time in which a person had zero or near-zero encounters in ED or inpatient settings. Occasional and high-use periods of ED utilization were quantitatively defined by the model.

“Among the 5090 patients who qualified for the study, the median follow-up period was 9.8 years, with a range of 1.0 to 11.0 years. There were over 94,000 stand-alone ED encounters, while over 59,000 ED encounters were associated with an inpatient stay,” Paulukonis said when describing the cohort that was analyzed.

A 3-component model was used to combine predictive power, parsimony, and clinical relevance, including quiescent periods (mean, 0.09 encounters; 88.8% of 4-week periods), occasional-use periods (mean, 1.28 encounters; 10.8% of 4-week periods), and high-use periods (mean, 7.48 encounters; 0.5% of 4-week periods).

All but 2 patients experienced at least 1 quiescent period during the study period, 75.9% experienced at least 1 occasional-use period, and 8.0% experienced at least 1 high-use period. According to Paulukonis, patient age did not influence the occasional- or high-use periods, which lasted a median of 8 weeks; 3.6% of these spells included at least some very high-use. Younger patients (<20 years) had longer durations of quiescent periods compared with older (≥20 years) patients (median, 24 vs 16 weeks, respectively).

Paulukonis concluded that most patients with SCD experience discrete periods during which ED and inpatient hospital encounters are not uncommon, separated by somewhat longer periods with few encounters or none. Additionally, younger patients are more likely to experience these high-frequency episodes. “We will try to tease out if, based on a patient’s status at a particular time, what will happen to the patient 2, 4, or 6 months from that time,” Paulukonis said.

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