Background Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapy (LOT), remission tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT identified through systematic literature review. Methods Eligible studies included comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT published prior to 31st May 2021. Prior LOT must have included an anti-CD20 monoclonal antibody and an alkylating agent, in combination or separately. Overall response rate (ORR) and complete response (CR) were estimated using inverse-variance weighting with Freeman-Tukey double-arcsine transformations. Kaplan-Meier (KM) curves for progression-free survival (PFS) and overall survival (OS) estimated by reconstructing digitized curves using the Guyot algorithm, and survival analyses were conducted, stratified by ≥2 prior LOT and ≥ 3 prior LOT groups (as defined in the source material). Restricting the analyses to the observational cohorts was investigated as a sensitivity analysis. Results The analysis-set included 20 studies published between 2014 and 2021. Studies were primarily US and/or European based, with the few exceptions using treatments approved in US/Europe. The estimated ORR was 58.47% (95% confidence interval [CI]: 51.13–65.62) and proportion of patients with CR was 19.63% (95% CI: 15.02–24.68). The median OS among those ≥2 prior LOT was 56.57 months (95% CI: 47.8–68.78) and median PFS was 9.78 months (95% CI: 9.01–10.63). The 24-month OS decreased from 66.50% in the ≥2 prior LOT group to 59.51% in the ≥3 prior LOT group, with a similar trend in PFS at 24-month (28.42% vs 24.13%). Conclusions This study found that few r/r FL patients with ≥2 prior LOT achieve CR, and despite some benefit, approximately 1/3 of treated patients die within 24 months. The shorter median PFS with increasing prior LOT suggest treatment durability is suboptimal in later LOT. These findings indicate that patients are underserved by treatments currently available in the US and Europe.

e19548 Background: Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapies (LOT), remission tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT using currently available treatment options. Methods: Electronic databases were searched on June 2, 2020. Eligible studies were comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT. Prior LOT must have included anti-CD20 monoclonal antibodies and alkylating agents, in combination or separately. Overall response rate (ORR) and complete response (CR) were analyzed using inverse-variance weighting with Freeman-Tukey double-arcsine transformations. Kaplan-Meier (KM) analysis for progression-free survival (PFS) and overall survival (OS) were conducted using digitized curves and the Guyot algorithm. Survival analyses were stratified by ≥2 prior LOT and ≥3 prior LOT groups and were restricted to the observational cohorts as a sensitivity analysis. Results: The meta-analysis included 12 studies published from 2014-2020. Sample size for response outcomes was 340, for survival outcomes with ≥2 prior LOT was 1024 and for ≥3 prior LOT was 502. The estimated ORR in the ≥2 prior LOT group was 56.0% (95% confidence interval [CI]: 47.2 – 64.5) and proportion of patients with CR was 12.2% (95% CI: 8.0 – 17.3). The median OS was 54.4 months (95% CI: 45.8 – 76.0) and median PFS was 10.3 months (95% CI: 9.3 – 11.1). The 24-month OS decreased from 66% in the ≥2 prior LOT group to 60% in the ≥3 prior LOT group (Table 1), with a similar trend in PFS at 24-month (28% vs 24%). Conclusions: This study found that few r/r FL patients with ≥2 prior LOT achieve CR, and despite some benefit, approximately 1/3 of patients die within 24 months. The shorter median PFS with increasing prior LOT suggest treatment durability is suboptimal in later LOT. These findings indicate that patients are underserved by current treatments, demonstrating a need for new treatments that can achieve high rates of response that are durable in this disease.[Table: see text]

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Unexpected cardiotoxicity underlies high rates of attrition during drug development, posing a multi-billion dollar burden on the pharmaceutical industry. Over reliance on the use of animals and materials derived from animals in preclinical assays to predict the cardiotoxic effect of new drugs in humans has contributed to this problem. The drug responses in human cardiomyocytes compared to animal-derived primary cardiomyocytes (CM) for in vitro assays is not always the same. Here, we describe a combination of human pluripotent stem cell-derived cardiomyocytes (hiPS-CM) and high content analysis confocal microscopy as a potential solution for this major setback in drug development. Initially human skin fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) by lentiviral transduction and utilization of the following combination of transcription factors: Oct3/4, Sox2, c-Myc and Klf4. The human pluripotent stem cell phenotype of the generated hIPSCs was confirmed. hiPSCs were differentiated into cardiomyocytes and the cardiac cell phenotype was confirmed by immunofluorescence and RT-PCR analysis of cardiac markers i.e. αMHC, cTNT, NKX2.5 and connexin 43. Seventeen known cardiotoxic compounds, as well as controls, were applied to the cells in 384 well format at a dose of 10μM for 48 hours. Then hiPSC-CM underwent confocal microscopy high content analysis to simultaneously evaluate the cell mitochondrial transmembrane potential (using TMRM dye), and plasma membrane permeability (using TOTO-3 dye). All known cardiotoxins showed a significant decrease in mitochondrial transmembrane potential ranging from 74% to 95% and an increase in plasma membrane permeability ranging from 67-327 fold in comparison to the controls. These results showed 100% prediction rate of cardiotoxicity of known cardiotoxins by hiPS-CM. This was compared to only 12% general cytotoxicity prediction rate when these compounds tested on A549 and ACHN cancer cell lines. In conclusion, combining two state of the art technologies 1) hiPSC-CM and 2) confocal microscopy high content analysis, we were able to provide a reliable high throughput method to assess cardiotoxicity of compounds.

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