Feasibility of outpatient administration of axicabtagene ciloleucel and brexucabtagene autoleucel using telemedicine tools: The Vanderbilt experience

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapies such as axicabtagene ciloleucel (axi-cel), and brexucabtagene autoleucel (brexu-cel) are approved by the United States Federal Drug Administration for relapsed or refractory large B-cell lymphoma (LBCL), follicular lymphoma and mantle cell lymphoma (MCL).1-5 Given the risk of significant toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the registrational trials for axi-cel and brexu-cel required hospitalisation for close monitoring. In the TRANSCEND trial (ClinicalTrials.gov Identifier: NCT02631044), only 9% of patients received lisocabtagene maraleucel in the outpatient setting. The rate of hospitalisation among these patients was 72% for toxicity management.6 Hence, outpatient experience with these CAR-T therapies is limited.7 Since the earliest publication of toxicity grading and management, several studies have shown that early initiation of toxicity-specific management may lead to improved outcomes, which is contrary to initial concerns of impairment on CAR-T activity.8 There is limited data on the safety of outpatient administration of axi-cel and brexu-cel. We were particularly interested in these two products because they have the highest response rates, although with a correspondingly high rate of CRS and ICANS. In preparation, we retrospectively analysed the outcomes of 21 serially treated patients who were admitted pre-emptively for CAR-T infusion from February 2016 to October 2019. The median (range) time to CRS was 60 (12–119) h and hospitalisation days were 11 (7–28). Next, we optimised staffing, created a caregiver training module, and incorporated telemedicine tools to remotely monitor these patients in the outpatient setting including reliable calculation of ICANS score. Here we describe the outcomes of outpatient administration of axi-cel and brexu-cel at our centre. A total of 13 serially treated patients (LBCL, nine; MCL, four) received axi-cel (nine) and brexu-cel (four) in outpatient settings from January 2020 to January 2022. In addition to eligibility criteria from ZUMA-1 (ClinicalTrials.gov Identifier: NCT02348216),1 patients were selected for outpatient administration if their baseline tumour sum of product diameters (SPD) was <1000 mm2 and had minimal comorbidities. [Correction added on 29 July 2022, after first online publication: In the preceding sentence, ‘<100 mm2’ was corrected to ‘<1000 mm2’ in this version.] Patients with a high tumour burden receive planned debulking therapy after apheresis. A reliable caregiver was required to be eligible for outpatient administration. Patients received lymphodepleting chemotherapy and CAR-T infusion in the outpatient clinic and were subsequently monitored with twice daily in-person visits and one overnight remote visit via telemedicine through day 14 post-infusion. The patient and caregiver were trained to obtain reliable vital signs and monitor for CRS and ICANS. Caregivers were trained to use the telemedicine devices and had round-the-clock access to a CAR-T provider. Patients were admitted if they develop Grade ≥2 CRS or any grade ICANS. Inpatient admission for any other organ toxicity was allowed at the discretion of the treating physician. The process was established for a direct admission bypassing the Emergency Department for these patients with <1 h from a decision to admit to arrival to a designated bed in the inpatient cellular therapy unit. The inpatient pharmacy verified that at least two doses of tocilizumab per patient were available all the time. We utilised early tocilizumab in the CRS course (persistent Grade 1 or Grade ≥2) to minimise higher grade CRS. Baseline patient characteristics were as follows (Table S1): median (range) age of 64 (44–70) years, with six patients aged ≥65 years; Ann Arbor Stage III–IV, 10 (77%); median (range) prior lines of therapies 3 (2–5); primary refractory disease, eight (62%); and baseline median (range) tumour burden SPD of 923 (28–8568) mm2. Bridging therapy was given to seven (54%) patients and two received prophylactic oral dexamethasone for 3 days starting the day of CAR-T infusion (based on ZUMA 1, cohort 6).9 The median (range) time from apheresis to cell infusion (D0) was 29 (24–54) days and the median (95% confidence interval [CI]) follow-up from D0 was 389 (215–612) days. The median (range) time to CRS onset was 93.5 (11–201) h. The overall incidence of CRS and ICANS was 92% (12 patients) and 54% (seven) respectively. All CRS events were Grade 1 (54%) or 2 (39%) with a median (range) CRS duration of 3 (1–5) days. Tocilizumab was given to nine (69%) patients for CRS management. There were no Grade 3/4 CRS or Grade 4 ICANS events (Table 1). The median (range) inpatient stay was 7 (1–14) days for CRS/ICANS management within 30 days following CAR-T infusion. Three (23%) patients completed therapy with no inpatient stay. At the time of last follow-up, four patients died from relapsed disease, there were no deaths related to treatment toxicity. The estimated 12-month progression-free survival (PFS) was 61.9% (95% CI 32.1%–91.7%) and overall survival (OS) was 60% (95% CI 29.6%–90.4%) (Figure 1). There were no relapse events beyond 100 days from CAR-T infusion at the last follow-up. Our outcomes were favourable compared to the pivotal studies of axi-cel and brexu-cel. In ZUMA-1, Grade ≥3 CRS and ICANS occurred in 13% and 28% of patients who received inpatient axi-cel.1 Similarly in ZUMA-2 (ClinicalTrials.gov Identifier: NCT02601313), the incidence of Grade ≥3 CRS and ICANS was 15% and 31% respectively.10 The possible reasons for this difference are selection of patients with low-disease burden, the use of prophylactic dexamethasone and earlier intervention for toxicity management, which has been shown to reduce the severity of CRS and ICANS without negatively impacting the outcomes of axi-cel-treated patients.9 During the development of our outpatient CAR-T programme, we established processes to ensure appropriate staffing in the clinic for the twice-daily visits, to educate patients and caregivers on performing vital sign evaluation and telemedicine visits, availability of designated beds in case of urgent admission, and ability to deliver tocilizumab in the outpatient setting.11 Apart from the patient preference and improved quality of life, outpatient administration can also bring significant cost reduction to already expensive therapy.12 Our results show that axi-cel and brexu-cel can be safely administered in the outpatient setting with appropriate monitoring and careful patient selection. Utilising technology (telemedicine visits) can be valuable in improving the safety profile of CAR-T and other immune effector cells. We are currently evaluating outpatient axi-cel administration in a prospective study at our centre (ClinicalTrials.gov Identifier: NCT05108805). Bhagirathbhai Dholaria: institutional research funding: Takeda, Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio. Consultancy/Advisor: Jazz, Gamida Cell, MJH BioScience, Arivan Research, BEAM therapeutics. Olalekan O. Oluwole: consultancy and advisory board for: Pfizer, Kite, Gilead, AbbVie, Janssen, TGR therapeutics, Novartis, curio science, Nektar. Institution funding: Kite, Pfizer, Daichi Sankyo, Allogene. Honoraria: Pfizer, Gilead. RJ: None. Rest of the authors have no relevant conflicts of interest to disclose. Please send data requests to the corresponding author. None. Table S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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