ABSTRACT
Background. Chimeric antigen receptor (CAR-T) T-cell therapy is a novel immunotherapy for cancer treatment in which patients are treated with targeted, genetically-modified T-cells. Common side effects include cytokine release syndrome, neurotoxicity, hypogammaglobulinemia, and increased susceptibility to infections. Long-term infectious outcomes are poorly characterized. Methods. We retrospectively examined patients who received CAR-T therapy at BIDMC & MGH from July 2016 to March 2020 and evaluated bacterial, fungal, viral, and parasitic infections at 3 months intervals to 1 year following cell infusion. The incidence, timing, and outcomes of the infectious complications were evaluated. Results. In total, there were 47 patients;averaging 61.4 years of age (±12 years). Primary indications for CAR-T therapy included diffuse large b-cell lymphoma (65%) and multiple myeloma (25%), chronic lymphocytic leukemia (2%) and mantle cell lymphoma (2%). Patients had received an average 4 ± 2.9 lines of chemotherapy prior to CAR-T infusion;19 subjects (40%) had a history of prior autologous stem cell transplant. All patients received acyclovir for antiviral prophylaxis and most received either trimethoprim-sulfamethoxazole (24/47;51%) or atovaquone (16/47;34%) for pneumocystis prophylaxis. In the first year, 35/47 (74.5%) of subjects experienced at least one infection with an infection rate of 84.4/10,000 person days. Median time to first infection was 59 days (range 1-338 patient days). 31/47 (66.0%) subjects had at least one bacterial infection, with pulmonary (42/113;37.2%) sources being the most common site of infection. 13/47 (27.7%) of patients had a viral infection (predominantly respiratory viral infections) and 6/47 (12.8%) had a proven or probable fungal infection. Death attributed to infection was noted in 2 subjects (4.3%), both related to COVID-19. Baseline IgG levels were significantly lower in the group with infections (p=0.028), while white blood cell count and absolute neutrophil counts were comparable. Conclusion. Infectious complications, particularly of bacterial etiology, are common in the first year following CAR-T therapy. These data may inform future prophylactic strategies in this patient population.
ABSTRACT
Background: Pts with previously treated R/R aggressive LBCL have compromised health-related QOL (HRQOL). Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In a prespecified interim analysis of TRANSFORM (NCT03575351), a randomized, open-label, pivotal trial, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint of event-free survival and key secondary endpoints (complete response rate and progression-free survival) in adults with R/R LBCL after failure of first-line (1L) immunochemotherapy compared with SOC, with no new safety signals. Here we present results of the pt-reported outcomes (PRO) analysis from TRANSFORM. Methods: Adults (age ≤ 75 yrs) with R/R LBCL (≤ 12 mo after 1L therapy), who were eligible for autologous stem cell transplantation (ASCT), were randomized to receive either SOC (3 cycles of salvage chemotherapy [CT] and BEAM + ASCT for responding pts) or liso-cel after lymphodepletion. Crossover to receive liso-cel was allowed in the SOC arm for pts who failed treatment. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - 30 items (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) were administered at randomization (baseline) and on Days 29 (infusion of liso-cel or 2 cycles of salvage CT), 64 (1 mo post liso-cel or completion of CT), 126 (3 mos post liso-cel or 2 mos post ASCT), and Mo 6 and other prespecified timepoints up to Mo 36 or end of study. No PRO data were collected after crossover. The analysis was based on the PRO-evaluable population (pts with a baseline and ≥ 1 post-baseline assessment). Predefined thresholds determined clinically meaningful changes. Global health/QOL (GH/QOL), physical functioning, cognitive functioning, fatigue, pain, and FACT-LymS were the primary domains of interest based on their relevance to the study population and treatment. A linear mixed model for repeated measures (MMRM) analysis was performed to assess the between-treatment difference in overall least squares (LS) mean change from baseline for each primary domain, using data collected up to Day 126 for visits with a sample size per arm ≥ 10. Proportions of pts with meaningful change from baseline were assessed for each primary domain up to Mo 6. All analyses were descriptive only. Results: Of 184 randomized pts, 90 (49%) and 85 (46%), respectively, were included in the PRO-evaluable population for the EORTC QLQ-C30 (SOC vs liso-cel n=43 vs 47) and FACT-LymS (n=40 vs 45, respectively). The PRO assessment completion rate from baseline up to Mo 6 was ≥ 45%, which was lower than expected primarily due to operational challenges during the COVID-19 pandemic but was comparable for both arms. In the MMRM analysis, the liso-cel arm had more favorable overall LS mean changes from baseline to Day 126 than the SOC arm in most of the EORTC QLQ-C30 domains and FACT-LymS. In particular, the between-treatment differences for cognitive functioning (−2.09 vs 2.21) and fatigue (3.75 vs −1.95) for SOC versus liso-cel, respectively, exceeded the prespecified minimal important difference threshold (Table);in those domains, the SOC arm deteriorated while the liso-cel arm improved. In individual-level analyses, the proportion of pts with meaningful improvement for fatigue and GH/QOL was higher, while deterioration was lower, in the liso-cel arm versus SOC arm from baseline up to Mo 6 (Figure). At Mo 6, a higher proportion of pts experienced worsened fatigue (71% vs 18%) and a lower proportion experienced improved fatigue (29% vs 47%) in the SOC arm compared with the liso-cel arm;for GH/QOL, a higher proportion of pts worsened (57% vs 18%) and lower proportion improved (14% vs 53%), respectively. For the other primary domains, the proportions of pts with improvement or deterioration favored liso-cel or were similar between arms. Conclusions: Compared with SOC, liso-cel sh wed favorable improvement in most primary PRO domains, particularly EORTC QLQ-C30 cognitive functioning and fatigue and more pts showed PRO improvements and fewer showed deterioration by Mo 6 with liso-cel. The results were achieved despite only responders remaining in the SOC arm after salvage CT. HRQOL was either improved or maintained after liso-cel treatment in pts with R/R LBCL after failure of 1L therapy. [Formula presented] Disclosures: Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding;Morphosys: Consultancy;C4 Therapeutics: Consultancy;Kite Pharma: Consultancy;Kymera: Consultancy;Incyte Corporation: Consultancy;Bluebird Bio: Consultancy;Astra-Zeneca: Consultancy;Allogene Therapeutics: Consultancy;Novartis: Consultancy;EMD Serono: Consultancy;Genmab: Consultancy;Seagen Inc.: Research Funding;AbbVie: Consultancy;Karyopharm: Consultancy;Genentech: Consultancy;BeiGene: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy;Roche: Consultancy, Research Funding, Speakers Bureau;Riemser: Research Funding;Kite: Consultancy;Novartis: Consultancy;Helios Klinik Berlin-Buch: Current Employment. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Liu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Braverman: BMS: Current Employment, Current equity holder in publicly-traded company. Guo: Daiichi Sankyo: Consultancy;UCB: Consultancy;Janssen: Consultancy;Gilead: Consultancy;Bristol Myers Squibb: Consultancy;EMD Serono: Consultancy;Evidera: Current Employment. Shi: Bristol Myers Squibb: Consultancy. Kamdar: ADC Therapeutics: Consultancy;Adaptive Biotechnologies: Consultancy;TG Therapeutics: Research Funding;Genentech: Research Funding;AbbVie: Consultancy;KaryoPharm: Consultancy;Kite: Consultancy;AstraZeneca: Consultancy;SeaGen: Speakers Bureau;Celgene: Other;Genetech: Other;Celgene (BMS): Consultancy.