Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-cell Lymphoma.

BACKGROUND: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial. OBJECTIVE: ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel. STUDY DESIGN: Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on Days -5 through -3 followed by a single infusion of axi-cel (2 × 106 cells/kg) on Day 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 hours after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines). RESULTS: Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-month minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 months (95% CI, 5.4-not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid. CONCLUSIONS: Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell-related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL.

Impact of debulking therapy on the clinical outcomes of axicabtagene ciloleucel in the treatment of relapsed or refractory large B-cell lymphoma.

Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, was approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the results from pivotal Cohorts 1+2 of ZUMA-1 (NCT02348216). ZUMA-1 was expanded to investigate safety management strategies aimed at reducing the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs). Prospective safety expansion Cohort 5 evaluated the impact of debulking therapy, including rituximab-containing immunochemotherapy regimens and radiotherapy, in axi-cel-treated patients; the CRS and NE management strategy paralleled those in Cohorts 1+2. Among the 50 patients in Cohort 5 who received axi-cel, 40% received ≥3 prior lines of chemotherapy, and 40% had disease that progressed while on the most recent chemotherapy. Forty-eight patients (96%) received debulking therapy, 14 (28%) radiotherapy only, and 34 (71%) systemic immunochemotherapy. Median decrease in tumor burden (per sum of product of diameters of target lesions) relative to screening was 17.4% with R-ICE/R-GDP, 4.3% with other debulking chemotherapies, and 6.3% with radiotherapy only. All patients were followed for ≥8 months. CRS was reported in 43 patients (86%), with 1 patient (2%) experiencing grade ≥3. NEs were reported in 28 patients (56%), with 6 (12%) experiencing grade ≥3. Cytopenias were the most frequent grade ≥3 adverse event (AE); 19 (38%) and 18 (36%) treated patients had any and grade ≥3 prolonged thrombocytopenia, respectively, and 25 (50%) and 24 (48%) patients had any and grade ≥3 prolonged neutropenia, respectively. Overall, patients who received debulking chemotherapy had higher incidences of serious treatment-emergent AEs than those who received radiotherapy only. At the 24-month analysis, objective response rate was 72%, and complete response rate was 56%. Median duration of response, progression-free survival, and overall survival were 25.8, 3.1, and 20.6 months, respectively. These results from exploratory Cohort 5 demonstrate the feasibility of debulking prior to axi-cel, and together with current real-world evidence, suggest that debulking regimens may help minimize the frequency and severity of CRS and NEs in patients with R/R LBCL. The incidence of other AEs observed in Cohort 5 suggest the risk/benefit profile was not improved via the debulking regimens studied here.

Cost-utility analysis of second-line axicabtagene ciloleucel versus standard of care in Japan based on the ZUMA-7 trial.

Aim: To perform a cost-effectiveness analysis comparing axicabtagene ciloleucel (axi-cel) with standard of care (SoC; salvage chemoimmunotherapy, followed by high-dose therapy with autologous stem cell rescue for responders) for second-line (2L) treatment of adults with relapsed or refractory large B-cell lymphoma (r/r LBCL) in the pivotal ZUMA-7 trial data from a Japanese payer perspective. Materials & methods: A three-state partitioned survival model was utilized using population and clinical inputs from the ZUMA-7 trial data over a lifetime horizon. Results: Axi-cel was associated with greater incremental quality-adjusted life-years (2.06) and higher incremental total costs ($48,685.59/¥6.9 million) leading to an incremental cost-effectiveness ratio of $23,590.34/¥3.3 million per quality-adjusted life-years compared with SoC. Conclusion: Axi-cel is a cost-effective treatment alternative to SoC for 2L treatment of adults with r/r LBCL.

[Box: see text].

Cost-effectiveness analysis of mosunetuzumab for treatment of relapsed or refractory follicular lymphoma after two or more lines of systemic therapy in the United States.

AIMS: Mosunetuzumab has received accelerated approval by the US Food and Drug Administration for adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after two or more lines of systemic therapy. We evaluated the cost-effectiveness of mosunetuzumab for the treatment of R/R FL from a US private payer perspective. MATERIALS AND METHODS: A partitioned survival model simulated lifetime costs and outcomes of mosunetuzumab against seven comparators: axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), tazemetostat (taz, EZH2 wild-type only), rituximab plus lenalidomide (R-Len) or bendamustine (R-Benda), obinutuzumab plus bendamustine (O-Benda), and a retrospective real-world cohort (RW) based on current patterns of care derived from US electronic health records (Flatiron Health). Efficacy data for mosunetuzumab were from the pivotal Phase II GO29781 trial (NCT02500407). Relative treatment efficacy was estimated from indirect treatment comparisons (ITCs). Costs included were related to treatment, adverse events, routine care, and terminal care. Except for drug costs (March 2023), all costs were inflated to 2022 US dollars. Costs and quality-adjusted life-years (QALYs) were used to calculate incremental cost-effectiveness ratios (ICERs). Net monetary benefit (NMB) was calculated using a willingness-to-pay (WTP) threshold of $150,000/QALY. RESULTS: Mosunetuzumab dominated taz, tisa-cel, and axi-cel with greater QALYs and lower costs. Mosunetuzumab was projected to be cost-effective against R-Benda, O-Benda, and RW with ICERs of $78,607, $42,731, and $21,434, respectively. Mosunetuzumab incurred lower costs but lower QALYs vs. R-Len. NMBs showed that mosunetuzumab was cost-effective against comparators except R-Len. LIMITATIONS: Without head-to-head comparative data, the model had to rely on ITCs, some of which were affected by residual bias. Model inputs were obtained from multiple sources. Extensive sensitivity analyses assessed the importance of these uncertainties. CONCLUSION: Mosunetuzumab is estimated to be cost-effective compared with approved regimens except R-Len for the treatment of adults with R/R FL.

Cost-effectiveness analysis 3L of axicabtagene ciloleucel vs tisagenlecleucel and lisocabtagene maraleucel in Japan.

Aim: Cost-effectiveness analysis (CEA) was performed to compare axicabtagene ciloleucel (axi-cel) with tisagenlecleucel (tisa-cel) and lisocabtagene (liso-cel) for treatment of relapsed or refractory large B-cell lymphoma in adult patients after ≥2 lines of therapy in Japan. Materials & methods: Cost-effectiveness analysis was conducted using the partition survival mixture cure model based on the ZUMA-1 trial and adjusted to the JULIET and TRANSCEND trials using matching-adjusted indirect comparisons. Results & conclusion: Axi-cel was associated with greater incremental life years (3.13 and 2.85) and incremental quality-adjusted life-years (2.65 and 2.24), thus generated lower incremental direct medical costs (-$976.29 [-¥137,657] and -$242.00 [-¥34,122]), compared with tisa-cel and liso-cel. Axi-cel was cost-effective option compared with tisa-cel and liso-cel from a Japanese payer's perspective.

[Box: see text].

Network meta-analysis of CAR T-Cell therapy for the treatment of 3L+ R/R LBCL after using published comparative studies.

INTRODUCTION: Studies have compared chimeric antigen receptor (CAR) T-cell therapies and salvage chemotherapy in relapsed/refractory large B-cell lymphoma (LBCL) patients, but further evidence of their relative effectiveness is warranted. METHODS: Our systematic review identified studies comparing efficacy and safety outcomes of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) trials to salvage chemotherapy cohorts in LBCL patients with ≥2 prior lines of treatment; and an extended evidence network included indirect comparisons comparing CAR T-cell therapies. We conducted network meta-analyzes using Bayesian hierarchical modeling. RESULTS: Three studies comparing ZUMA-1 (axi-cel), TRANSCEND (liso-cel) and JULIET (tisa-cel) trials to salvage chemotherapy within the SCHOLAR-1 cohort were identified. Axi-cel (odds ratio [OR]:5.63; 95% credible interval [CrI]:2.66-12.42) and liso-cel (OR:4.26; 95%CrI:2.33-7.93) showed a significant increased overall response rate compared to tisa-cel, but not to one-another. Axi-cel demonstrated significant improvements in overall survival relative to liso-cel (hazard ratio [HR]:0.54; 95%CrI:0.37-0.79) and tisa-cel (HR:0.47; 95%CrI:0.26-0.88). Higher rates of grade ≥3 neurological events were observed with axi-cel than with tisa-cel and liso-cel. CONCLUSIONS: We highlight important differences in clinical outcomes between CAR T-cell therapies. Axi-cel demonstrated improved overall survival compared to tisa-cel and liso-cel, and both axi-cel and liso-cel showed higher response rates compared to tisa-cel.

A Comparison of 3-Year Follow-up of ZUMA-5 (Axicabtagene Ciloleucel) With SCHOLAR-5 in Relapsed/Refractory Follicular Lymphoma.

In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory follicular lymphoma patients. SCHOLAR-5 is an external control cohort designed to act as a comparator to ZUMA-5. Here, we present an updated comparative analysis of ZUMA-5 and SCHOLAR-5, using the 36-month follow-up data and the intent-to-treat population of ZUMA-5. Using propensity-score methods, 127 patients in ZUMA-5 were compared to 129 patients in SCHOLAR-5. At this extended follow-up, axi-cel continues to demonstrate clinically meaningful benefits in survival compared to historically available treatments in this population.

Cost-effectiveness of axicabtagene ciloleucel versus tisagenlecleucel for the treatment of 3L + relapsed/refractory large B-cell lymphoma in the United States: incorporating longer survival results.

AIMS: To provide an update on the cost-effectiveness of the chimeric antigen receptor (CAR) T-cell therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL) among patients who have previously received ≥2 lines of systemic therapy using more mature clinical trial data cuts (60 months for axi-cel overall survival [OS] and 45 months for tisa-cel OS and progression-free survival [PFS]). METHODS: A partitioned survival model consisting of three health states (pre-progression, post-progression and death) was used to estimate quality-adjusted life years (QALYs) and costs associated with axi-cel and tisa-cel over a lifetime horizon. PFS and OS inputs for axi-cel and tisa-cel were based on a previously published matching-adjusted indirect treatment comparison (MAIC). Long-term OS and PFS were extrapolated using parametric survival mixture cure models (PS-MCMs). Costs of CAR-T cell therapy drug acquisition and administration, conditioning chemotherapy, apheresis, CAR T-specific monitoring, stem cell transplant, hospitalization, adverse events, routine care, and terminal care were sourced from US cost databases. Health state utilities were derived from previous publications. Model inputs were varied using a range of sensitivity and scenario analyses. RESULTS: Compared with tisa-cel, axi-cel resulted in 2.51 additional QALYs and $50,185 additional costs (an incremental cost-effectiveness ratio [ICER] of $19,994 per QALY gained). In probabilistic sensitivity analysis (PSA), the ICER for axi-cel versus tisa-cel was ≤$50,000/QALY in 99.4% of simulations and ≤$33,500 in 99% of simulations. Axi-cel remained cost-effective versus tisa-cel (assuming a willingness-to-pay threshold of $150,000 per QALY) across a range of scenarios. CONCLUSIONS: With longer-term survival data, axi-cel continues to represent a cost-effective option versus tisa-cel for treatment of r/r LBCL among patients who have previously received ≥2 lines of systemic therapy, from a US payer perspective.

Real-World Outcomes with Chimeric Antigen Receptor T Cell Therapies in Large B Cell Lymphoma: A Systematic Review and Meta-Analysis.

Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently. Here we comprehensively describe clinical outcomes with approved CAR-T therapies in patients with r/r LBCL using available RWE. We systematically searched Embase, MEDLINE, and 15 conference proceedings to identify studies published between 2017 and July 2022 that included ≥10 patients with r/r LBCL treated with commercially available CAR-T therapies. Eligible study designs were retrospective or prospective observational studies. Key outcomes of interest were objective response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Random-effects meta-analyses were used to compare real-world outcomes with those of pivotal clinical trials and to compare clinical outcomes associated with axi-cel and tisa-cel. Study cohort mapping was conducted to avoid including patients more than once. Of 76 cohorts we identified, 46 reported patients treated specifically with either axi-cel or tisa-cel, with 39 cohorts (n = 2754 patients) including axi-cel and 20 (n = 1649) including tisa-cel. No studies of liso-cel that met the inclusion criteria were identified during the search period. One-half of the tisa-cel cohorts were European, compared with 33% of the axi-cel cohorts. Among studies with available data, axi-cel had a significantly shorter median time from apheresis to CAR-T infusion than tisa-cel. Despite including broader patient populations, real-world effectiveness and safety of both axi-cel and tisa-cel were consistent with data from the pivotal clinical trials. Comparative meta-analysis of axi-cel versus tisa-cel demonstrated adjusted hazard ratios for OS and PFS of .60 (95% confidence interval [CI], .47 to .77) and .67 (95% CI, .57 to .78), respectively, both in favor of axi-cel. Odds ratios (ORs) for ORR and CR rate, both favoring axi-cel over tisa-cel, were 2.05 (95% CI, 1.76 to 2.40) and 1.70 (95% CI, 1.46 to 1.96), respectively. The probability of grade ≥3 CRS was comparable with axi-cel and tisa-cel, whereas axi-cel was associated with a higher incidence of grade ≥3 ICANS (OR, 3.95; 95% CI, 3.05 to 5.11). Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL, and that axi-cel is associated with improved OS and PFS and increased risk of grade ≥3 ICANS compared with tisa-cel. Limitations of this study include nonrandomized treatments, potential unknown prognostic factors, and the lack of available real-world data for liso-cel.

A Pharmacovigilance Study on the Safety of Axicabtagene Ciloleucel Based on Spontaneous Reports from the EudraVigilance Database.

During pre-approval clinical trials, the safety of axi-cel, a second-generation CAR-T-cell therapy directed against CD19, which dramatically improved the prognosis of intractable B-cell lymphomas, has been investigated only in about 400 patients. Therefore, additional information on this issue is urgently needed. In the present paper, we evaluated the 2905 ICSRs with axi-cel as the suspected drug that had been uploaded in the EudraVigilance database from 1 January 2018 to 31 December 2022. About 80% of the reported adverse events were serious, and about 20% of them did not fully resolve or caused death. The adverse events most-frequently reported were Nervous system disorders (25.6%) and, among them, immune-effector-cell-associated neurotoxicity syndrome, followed by Immune system disorders (23.1%), General disorders and administration site conditions (12.0%), Blood and lymphatic system disorders (7.2%), and Infections and infestations (5.8%). Disproportionality analysis showed that the frequency of reported adverse events related to the nervous system was higher with axi-cel than with the other approved CAR-T-cells, except brexu-cel. In conclusion, real-world pharmacovigilance data showed that nervous system and immune system disorders are the adverse events most reported in axi-cel-related ICSRs and suggest that axi-cel could be more neurotoxic than other CAR-T-cells.

A phase 2 study of axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma in Japan: 1-year follow-up and biomarker analysis.

Axicabtagene ciloleucel (axi-cel) is an autologous, CD19-targeting chimeric antigen receptor T­cell therapy. We recently reported the 3-month follow-up results of a phase 2, multicenter, open­label, single-arm study of axi-cel in Japanese patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (JapicCTI-183914). Here, we present 1-year efficacy and safety data and biomarker analysis data regarding mechanisms of resistance to axi-cel. Primary and secondary endpoints included investigator-assessed objective response rate (ORR), serious adverse events, and treatment-emergent adverse events. Axi-cel pharmacokinetics were also examined. Biomarker analysis was performed by cytokine measurement, immunohistochemistry, RNA sequencing, and whole-exome sequencing. At a median follow-up of 13.4 months, ORR was 86.7% (13/15 patients), and the complete response (CR) rate improved to 53.3% (8/15 patients) due to response conversion. Seven patients experienced disease progression, and one achieved CR after re-treatment with axi-cel. No new safety concerns were detected. Plausible resistance mechanisms to axi-cel varied among patients but included CD19 downregulation, programmed death-ligand 1 upregulation, and increased macrophage and angiogenesis signatures. The 1-year efficacy and safety of axi-cel were confirmed in Japanese patients with R/R LBCL. Resistance to treatment may involve multiple factors, including target antigen loss and an unfavorable tumor environment.Clinical trial registration: Japan Clinical Trials Information; JapicCTI-183914.

Cost-effectiveness of axicabtagene ciloleucel versus lisocabtagene maraleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the US.

AIMS: This study evaluated from a US payer perspective the cost-effectiveness of two chimeric antigen receptor T (CAR T) cell therapies, axicabtagene ciloleucel (axi-cel) versus lisocabtagene maraleucel (liso-cel), for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) following two or more systemic therapy lines. METHODS: We developed a 3-state (i.e., pre-progression, post-progression, death) partitioned survival model to estimate patients' lifetime outcomes. Mixture cure models were used for survival extrapolation to account for long-term remission. Survival inputs were based on a matching-adjusted indirect comparison (MAIC) that reweighted the ZUMA-1 population (receiving axi-cel) to match patient characteristics in TRANSCEND-NHL-001 (assessing liso-cel). Costs included apheresis, drug acquisition, and administration for conditioning chemotherapy and CAR T therapies, monitoring, transplant, hospitalization, adverse events, routine care, and terminal care, per published literature and databases. Utilities were derived from ZUMA-1 and literature. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, axi-cel was associated with more QALYs (7.76 vs. 5.94) and greater costs overall ($611,440 vs. $597,174) than liso-cel, at $7,843/QALY gained. The incremental costs (+$14,266) were largely driven by higher routine care costs (+$18,596) due to longer survival and hospitalization (+$10,993) but partially offset by reduced costs of CAR T acquisition (‒$11,300) and terminal care (‒$4,025). Sensitivity analyses consistently suggested robustness of base-case results. LIMITATIONS: This study relied on an MAIC in which trial design differences and unobserved confounders could not be accounted for. Future real-world studies for recently approved CAR T are warranted to validate our results. Due to a lack of data, we assumed equivalent use of transplants and treatment for B-cell aplasia between the two therapies based on clinicians' opinions. CONCLUSIONS: In the US, axi-cel is a potentially cost-effective treatment option compared with liso-cel for adult patients with r/r LBCL after two or more systemic therapy lines.

A potential role of preexisting inflammation in the development of acute myelopathy following CAR T-cell therapy for diffuse large B-cell lymphoma.

The event of anti-CD19 chimeric antigen receptor (CAR)-T therapy inducing serious neurotoxicity in patients with diffuse large B-cell lymphoma (DLBCL) is recognized; however, the patterns of symptoms and severity vary greatly from patient to patient. We report an exceptional presentation of acute myelopathy in a refractory DLBCL following successful CAR-T treatment along with grade 3 cytokine release syndrome (CRS) and neurotoxicity. The patient was initiated on high-dose methylprednisolone (MPS) resulting in rapid improvement of neurological symptoms. Yet the myelopathy patient (MP) experienced severe lower limb motor deficit, and a subsequent spinal cord MRI revealed myelopathy with a sensory level at segment T2. Multimodal therapy consisting of MPS, intravenous immunoglobulin and anakinra therapy resulted in complete reversal of myelopathy condition and the patient remained cancer free. The assessment of time trends of serum cytokines at baseline and post CAR-T infusion in MP compared to other 4 DLBCL complete responder patients with varying degree of CRS following CAR-T infusion, suggested pre-existing baseline inflammatory conditions in MP with altered levels of cytokines. These findings, if corroborated by similar case studies, have the potential to generate novel insights into the manifestation of myelopathy following CAR-T therapy and the successful clinical management of such complications.

Quantification of cell-free DNAfor the analysis of CD19-CAR-T cells during lymphoma treatment.

Chimeric antigen receptor (CAR)-T cells are increasingly used for the treatment of hematologic malignancies. Treatment success relies highly upon sufficient expansion of CAR-T effector cells. Accordingly, longitudinal quantification of CAR-T cells during therapy is clinically important. Techniques to quantify CAR-T cells in patient blood samples are based on flow cytometry and PCR. However, cellular kinetics of CAR-T cells are very complex and under current investigation. In this study, feasibility of CAR-T cell quantification by cell-free DNA (cfDNA) was analyzed. cfDNA isolated from 74 blood samples of 12 patients during lymphoma treatment with the anti-CD19 CAR-T cell product axicabtagene ciloleucel (axi-cel) were analyzed. Concentrations of cfDNA specific for the CAR-T gene construct (cfCAR-DNA) and a reference gene were quantified by a newly designed digital-droplet PCR (ddPCR) assay. Detection and quantification of cfCAR-DNA was feasible and reliable for all patients included. Relative quantification of cfCAR-DNA compared to a reference gene, suitable for genomic DNA analysis, was heterogeneous in treatment responders and non-responders. In contrast, parallel analyses of cfCAR-DNA and reference cfDNA in a patient-specific approach gave insight into active lymphoma killing and treatment responses. In summary, plasma cfDNA determination in lymphoma patients is a promising tool for future clinical decision making.

Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel-related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.

Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma.

ZUMA-1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi-cel), an autologous CD19-directed chimaeric antigen receptor (CAR)-T cell therapy, in refractory large B-cell lymphoma. To reduce treatment-related toxicity, several exploratory safety management cohorts were added to ZUMA-1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end-points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days -5 through -3), 2 × 106  CAR-T cells/kg (day 0) and once-daily oral dexamethasone [10 mg, day 0 (before axi-cel) through day 2]. Forty patients received axi-cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty-eight per cent of patients did not experience CRS or NEs within 72 h of axi-cel. With a median follow-up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population.

Droplet digital PCR allows vector copy number assessment and monitoring of experimental CAR T cells in murine xenograft models or approved CD19 CAR T cell-treated patients.

BACKGROUND: Genetically engineered chimeric antigen receptor (CAR) T lymphocytes are promising therapeutic tools for cancer. Four CAR T cell drugs, including tisagenlecleucel (tisa-cel) and axicabtagene-ciloleucel (axi-cel), all targeting CD19, are currently approved for treating B cell malignancies. Flow cytometry (FC) remains the standard for monitoring CAR T cells using a recombinant biotinylated target protein. Nevertheless, there is a need for additional tools, and the challenge is to develop an easy, relevant, highly sensitive, reproducible, and inexpensive detection method. Molecular tools can meet this need to specifically monitor long-term persistent CAR T cells. METHODS: Based on 2 experimental CAR T cell constructs, IL-1RAP and CS1, we designed 2 quantitative digital droplet (ddPCR) PCR assays. By targeting the 4.1BB/CD3z (28BBz) or 28/CD3z (28z) junction area, we demonstrated that PCR assays can be applied to approved CD19 CAR T drugs. Both 28z and 28BBz ddPCR assays allow determination of the average vector copy number (VCN) per cell. We confirmed that the VCN is dependent on the multiplicity of infection and verified that the VCN of our experimental or GMP-like IL-1RAP CAR T cells met the requirement (< 5 VCN/cell) for delivery to the clinical department, similar to approved axi-cel or tisa-cel drugs. RESULTS: 28BBz and 28z ddPCR assays applied to 2 tumoral (acute myeloid leukemia (AML) or multiple myeloma (MM) xenograft humanized NSG mouse models allowed us to quantify the early expansion (up to day 30) of CAR T cells after injection. Interestingly, following initial expansion, when circulating CAR T cells were challenged with the tumor, we noted a second expansion phase. Investigation of the bone marrow, spleen and lung showed that CAR T cells disseminated more within these tissues in mice previously injected with leukemic cell lines. Finally, circulating CAR T cell ddPCR monitoring of R/R acute lymphoid leukemia or diffuse large B cell lymphoma (n = 10 for tisa-cel and n = 7 for axi-cel) patients treated with both approved CAR T cells allowed detection of early expansion, which was highly correlated with FC, as well as long-term persistence (up to 450 days), while FC failed to detect these events. CONCLUSION: Overall, we designed and validated 2 ddPCR assays allowing routine or preclinical monitoring of early- and long-term circulating approved or experimental CAR T cells, including our own IL-1RAP CAR T cells, which will be evaluated in an upcoming phase I clinical trial.

The role of axicabtagene ciloleucel as a treatment option for patients with follicular/marginal zone lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (axi-cel) continues to make its way in the treatment of B-cell lymphomas. Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma. While its prognosis is usually good, the disease is considered incurable and patients still relapse. High-risk subgroups such as high FLIPI score or early relapses (POD24) face poor outcomes. Current treatment options with phosphatidylinositol 3-kinase (Pi3K) inhibitors or other novel agents have clinical activity but short remission with cures remaining elusive. The ZUMA-5 study of axi-cel has shown high response rates with durable remissions with manageable toxicities, particularly in poor risk FL, replicating the outcomes in smaller and earlier studies. Long-term follow up will demonstrate the real impact of axi-cel in relapsed FL.