Balancing Monitoring and Access: Optimal Duration of Monitoring for CD19 and BCMA CART Recipients for Lymphoma and Myeloma

Abstract

Background: Due to the risks of cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndromes (ICANS), a four-week monitoring period near the authorized treating center (ATC) is a requirement for all currently approved chimeric antigen receptor T cell (CART) therapies, as part of the required Risk Evaluation and Mitigation Strategy (REMS) programs. The purpose of the REMS program is to facilitate prompt administration of tocilizumab within 2 hours in the event of life-threatening adverse events . Most ATCs require patients to stay within a 30-60-minute radius of the ATC and require a dedicated caregiver. While monitoring is essential for safety, the optimal duration of monitoring post-CART has not been studied. It is an area of need as there is a known financial burden of relocation, which may increase gaps in access to care, especially for underserved populations. We evaluated real-world safety outcomes of patients receiving CD19 and BCMA CART for non-Hodgkin lymphoma (NHL) and relapsed refractory multiple myeloma (RRMM). Methods: Patients (pts) with NHL and RRMM who received commercial CD19-directed (axi-cel, tisa-cel, liso-cel, brexu-cel) and BCMA-directed CART (ide-cel, cilta-cel) respectively, from 1/2017 to 1/2023, at the University of Kansas Health System and Medical University of South Carolina were included. Based on each patient's 5-digit zip code, travel distance to the ATC, median household income, and rural or urban residence were estimated. Patients were divided into two groups: those who had either first or recurrent CRS or ICANS occurring at Day 7 or later (Events≥ D7) and the group with no CRS/ICANS ≥ Day 7 (No Events ≥ D7). Chi-square test and proportion tests were calculated. Results: 185 patients (pts) including 127 NHL pts (59% axi-cel, 19% tisa-cel, 13% liso-cel, 8% brexu-cel) and 58 RRMM pts (75% ide-cel and 25% cilta-cel) were included. Most patients (65%) lived beyond 30 minutes of the ATC, and only 23.2% were from rural neighborhoods. (Table 1) 150 pts were in the “No Events ≥ D7” while 35 pts were in the Events≥ D7 group. There were no differences in baseline characteristics of these groups (Table 1). 151 pts (81.6%) and 70 (39%) pts developed new-onset CRS and ICANS respectively on D0-28. Median time to onset for CRS vs ICANS: 2 (IQR 25-75%:1-4) vs 5 (IQR 25-75%:3-8). Median time to CRS vs ICANS resolution relative to infusion was 6 days (IQR 25-75%: 3-7) vs 11 days (IQR 25-75%: 8-15). 137 (91%) had onset of CRS D0-6, 12 (26% of at-risk at D7) developed CRS D7-14. There was no new onset CRS D15 onwards, although one pt (axi-cel recipient) developed CRS recurrence D15-28, and another axi-cel recipient developed CRS recurrence D43. Only these 2 pts had ongoing CRS beyond D14. 45 (64%) had onset of ICANS D0-6, 20 (14% of at-risk at D7) developed ICANS D7-14. Of the 119 at risk, 4 pts (1 axi-cel, 1 tisa-cel, 2 ide-cel) developed ICANS D15-28 and one pt (cilta-cel recipient) experienced new ICANS onset beyond D28. 30 pts had ongoing ICANS beyond D14 and 5 beyond D28. There was no significant association with disease, early vs no early event, product, co-stimulatory domain (CD28 vs 4-1BB), year of infusion (2021 onwards vs prior), or SDOH with CRS or ICANS on multivariate analysis. Resource Utilization: Tocilizumab (toci) was administered in 67% pts, median 2 doses (1-4). Median time to first dose toci was 3 days (0-11) and median time to last dose was 4 days (0-43). 44% pts received steroids, and all had first dose prior to D15. 14 pts had infections requiring admission D15-28. Other outcomes and resource utilization are shown in Table 2. Mortality:There were 15 deaths D0-90, mostly due to progression (9), 4 due to infection, and 1 “other” cause. No deaths were attributable to CRS or ICANS. Of these, one death occurred D0-28 (in an axi-cel recipient) due to progression. Conclusions: Despite differences in patterns of CRS and ICANS with CART products, there is a low incidence of CRS and ICANS onset beyond 2 weeks, but persistent risk of other fatal complications, mostly infectious, even beyond the mandated monitoring period. Our study suggests a flexible monitoring period proximal to the ATC for CRS/ICANS may be safe for select patients and will likely be more feasible especially for disadvantaged populations with limited support. Exploring hybrid models and earlier partnership of referring centers and ATCs for monitoring, may allow personalized continuum of care and improve outcomes.