Steroid Use, Advanced Stage Disease and ≥3 Lines of Prior Chemotherapy Are Associated with a Higher Risk of Infection Following CD19 CAR T-Cell Therapy for B-NHL: Real World Data from a Large UK Center
Authors: Neill Lorna , Mackenzie Strachan C , Marzolini Maria A V , Townsend William , Ardeshna Kirit M. , Cwynarski Kate , De Surjo , Gant Vanya , Mure Lhara , McElduff Sara , Hughes Chantelle , Peggs Karl S , Roddie Claire , O'Reilly Maeve A 
Published: February 2021

Background: Tisagenlecleucel (Tisagen) and Axicabtagene Ciloleucel (Axicel) CD19 CAR T-cell products are licensed in the UK for adults with relapsed/refractory high-grade B-cell Non-Hodgkin's lymphoma (B-NHL). Infection rates for the first 30 days post CAR T range from 23% (Hill et al, Blood 2018) to 42% (Park et al, Clin Infect Dis 2018) with a predominance of early bacterial infections. Infection etiology is multifactorial, including pre-existing immunosuppression, poor marrow reserve, concomitant disease, delayed cytopenias and lymphodepletion. CRS has been shown to be an independent risk factor and associated treatment (Tocilizumab, steroids) may contribute. Risk assessment is limited by heterogenous cohorts in published reports and practice variations in use of prophylactic antibiotics and intravenous immunoglobulin (IVIG).

To determine incidence and outcome of infection with licensed CAR T-cell products, we conducted a retrospective review at UCLH, London, UK.

Methods: Electronic medical records were used to collect data on patients treated with Tisagen/Axicel from May 2019 to July 2020. Infections at ≤28 days and &gt;28days following infusion were recorded. Infections were defined as a positive microbiological/virology result in conjunction with clinical symptoms. Invasive fungal infections were classified according to revised EORTC criteria. Infections were graded as severe (requiring systemic treatment) or life threatening (hypotension/organ support).

Results: Sixty adults with B-NHL received Tisagen (n=19) or Axicel (n=41). Patients did not receive prophylactic antibiotics. IVIG was given for hypogammaglobulinaemia with recurrent infections (n=4).

Within 28 days of infusion, 44 episodes of infection occurred in 28 patients (47%). Post day 28 (range 29-452), 19 episodes occurred in 9 patients (15%). Severe (n=9) and life-threatening (n=7) infection occurred in 15% and 12% of patients respectively, with two infections resulting or contributing to death (3.3%). Infections were bacterial (56%), respiratory viral (24%), other viral (14%) and fungal (6%). Six (10%) developed viral reactivations; CMV (n=1), BK virus in blood or urine (n=2), HHV6 (n=1) or AdV (n=2). PCR proven JC virus causing progressive multifocal leukoencephalopathy was reported in 1 patient at day 116. Only one late COVID-19 infection occurred despite the program remaining operational throughout lockdown.

There was no association between early infection and CRS severity (p=0.43), or use (p=0.94) and dose of Tocilizumab (p=0.54). With regard to pre-treatment variables, advanced disease at time of infusion (≥stage 3) was associated with higher risk of any infection (OR 4.2, 95% CI 1.3- 13.4, p=0.016) and lines of prior therapy (≥3) with higher risk of early infection (OR 3.0, 95% CI 1.0-8.9, p=0.048). Steroid treatment was associated with a higher risk of early (and overall) infection (OR 3.0. 95% CI 1.0-8.6, p=0.048). A diagnosis of ICANS was associated with infection beyond day 30 (p=0.021). In multivariate analyses, steroid use (p=0.03) and ≥3 lines of prior therapy (p=0.021) were associated with infection ≤28 days of infusion. Steroid use (p= 0.049) and stage pre infusion (p=0.023) were associated with higher risk of any infection.

Conclusion: In this real world analysis of B-NHL patients treated with Tisagen or Axicel, 47% developed early infection at ≤28 days. Severe or life-threatening infection occurred in 27% of patients. Multivariate analysis confirms significant association with (1) steroid exposure (2) ≥stage 3 disease and (3) ≥3 lines of previous therapy. There was no overt association with Tocilizumab use or CRS severity. Unlike other centers, our cohort did not receive prophylactic antibiotics or IVIG.

Patients with advanced disease are high risk for CRS, ICANS and infectious complications. Risk modification strategies include bridging optimization to reduce disease burden pre CAR T with infectious prophylaxis from referral until at least 3-6 months post-infusion. In this analysis, steroids represent a significant risk and efforts should be made to wean doses swiftly. The use of steroid sparing agents such as Anakinra may be important (clinical trial results awaited). In ≥ stage 3 disease or heavily pre-treated patients, there may be a role for prophylactic antibiotics but this should be explored within a clinical study with consideration of local antimicrobial resistance patterns.

Disclosures

Neill: Novartis: Other: Funded attendance at academic conferences; Celgene: Other: Funded attendance at academic conferences. Townsend:Roche, Gilead: Consultancy, Honoraria. Ardeshna:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi, Genzyme, AstraZeneca: Speakers Bureau; University College London (UCL)/UCL Hospitals (UCLH) Biomedical Research Unit: Other: Supported by this organisation. Cwynarski:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Peggs:Autolus: Consultancy. Roddie:Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria. O'Reilly:Gilead: Honoraria; Novartis: Honoraria, Other: Travel support.