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•Patients, caregivers, and experts describe similar effects of chimeric antigen receptor T cell (CAR-T) therapy on patients.•CAR-T therapy impacts physical, mental, and social health and finances of patients.•Patients’ social role and activities are most significantly affected by CAR-T therapy.

ABSTRACTAR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer.

Nuclear receptor (NR)-mediated transcriptional activity is a dynamic process that is regulated by the binding of ligands that induce distinct conformational changes in the NR. These structural alterations lead to the differential recruitment of coregulators (coactivators or corepressors) that control the expression of NR-regulated genes. Here, we show that a stretch of proline residues located within the N-terminus of androgen receptor (AR) is a bona fide coregulator binding surface, the disruption of which reduces the androgen-dependent proliferation and migration of prostate cancer (PCa) cells. Using T7 phage display, we identified a novel AR-interacting protein, Src homology 3 (SH3)-domain containing, Ysc84-like 1 (SH3YL1), whose interaction with the receptor is dependent upon this polyproline domain. As with mutations within the AR polyproline domain, knockdown of SH3YL1 attenuated androgen-mediated cell growth and migration. RNA expression analysis revealed that SH3YL1 was required for the induction of a subset of AR-modulated genes. Notable was the observation that ubinuclein 1 (UBN1), a key member of a histone H3.3 chaperone complex, was a transcriptional target of the AR/SH3YL1 complex, correlated with aggressive PCa in patients, and was necessary for the maximal androgen-mediated proliferation and migration of PCa cells. Collectively, these data highlight the importance of an amino-terminal activation domain, its associated coregulator, and downstream transcriptional targets in regulating cellular processes of pathological importance in PCa.

Increased expressions of fatty acid synthase (FASN) and epidermal growth factor receptor (EGFR) are common in cancer cells. De novo synthesis of palmitate by FASN is critical for the survival of cancer cells via mechanisms independent of its role as an energy substrate. Besides the plasma membrane and the nucleus, EGFR can also localize at the mitochondria; however, signals that can activate mitochondrial EGFR (mtEGFR) and the functions of mtEGFR of cancer cells remain unknown. The present study characterizes mtEGFR in the mitochondria of cancer cells (prostate and breast) and reveals that mtEGFR can promote mitochondrial fusion through increasing the protein levels of fusion proteins PHB2 and OPA1. Activation of plasma membranous EGFR (pmEGFR) stimulates the de novo synthesis of palmitate through activation of FASN and ATP-citrate lyase (ACLy). In vitro kinase assay with isolated mitochondria shows that palmitate can activate mtEGFR. Inhibition of FASN blocks the mtEGFR phosphorylation and palmitoylation induced by EGF. Mutational studies show that the cysteine 797 is important for mtEGFR activation and palmitoylation. Inhibition of FASN can block EGF induced mitochondrial fusion and increased the sensitivity of prostate cancer cells to EGFR tyrosine kinase inhibitor. In conclusion, these results suggest that mtEGFR can be activated by pmEGFR through de novo synthesized palmitate to promote mitochondrial fusion and survival of cancer cells. This mechanism may serve as a novel target to improve EGFR-based cancer therapy.

Objective:To determine treatment regimens used in clinical practice and the associated clinical outcomes among third line (3L) follicular lymphoma (FL) patients in the United States (US).

Background: Novel therapies for multiply relapsed follicular lymphoma (FL) are often evaluated in single arm trials with no comparative data on patients receiving usual care. This study (ReCORD-FL) therefore sought to construct a historical control cohort to augment current and future single arm trials in relapsed/refractory (r/r) FL. The analytic aims were to document patient characteristics, treatment patterns and clinical outcomes in a r/r FL population treated with standard therapies in routine practice.

Background:Follicular lymphoma (FL) is the second most frequently diagnosed Non-Hodgkin lymphoma subtype in Western countries. Patients often undergo multiple lines of therapy over many years throughout the course of their disease with worse survival after each successive line of therapy. Recent findings from the ELARA trial showed that tisagenlecleucel, a chimeric antigen receptor (CAR)-T cell therapy, had durable complete response rate of 66.0%, with a probability of 79% (95% CI, 66%-87%) to remain in response ≥6 months (overall response rate 86.2%) in patients with relapsed or refractory (r/r) FL. Prior evidence in patients with r/r diffuse large B-cell lymphoma demonstrated that tisagenlecleucel can be safely infused in an outpatient setting and may reduce healthcare resource utilization (HCRU) (Lyman et al, 2020). we present the first HCRU among patients with r/r FL who received tisagenlecleucel in the ELARA trial.

Glioblastoma (GBM) is the most common and aggressive form of malignant glioma in adults with a median overall survival (OS) time of 16–18 months and a median age of diagnosis at 64 years old. Recent work has suggested that depression and psychosocial distress are associated with worse outcomes in patients with GBM. We therefore hypothesized that the targeted neutralization of psychosocial distress with selective serotonin reuptake inhibitor (SSRI) antidepressant treatment would be associated with a longer OS among patients with GBM. To address this hypothesis, we retrospectively studied the association between adjuvant SSRI usage and OS in GBM patients treated by Northwestern Medicine-affiliated providers. The medical records of 497 GBM patients were analyzed after extraction from the Northwestern Medicine Enterprise Data Warehouse. Data were retrospectively studied using a multivariable Cox model with SSRI use defined as a time-dependent variable for estimating the association with OS. Of the 497 patients, 315 individuals died, while 182 were censored due to the loss of follow-up or were alive at the end of our study. Of the 497 patients, 151 had a recorded use of SSRI treatment during the disease course. Unexpectedly, SSRI usage was not associated with an OS effect in both naïve (HR ​= ​0.81, 95% CI ​= ​0.64–1.03) and adjusted time-dependent (HR ​= ​1.26, 95% CI ​= ​0.97–1.63) Cox models. Ultimately, we failed to find an association between SSRI treatment and an improved OS of patients with GBM. Additional work is necessary for understanding the potential therapeutic effects of SSRIs when combined with other treatment approaches, and immunotherapies in particular, for subjects with GBM.

Abstract 2754

Ph+ CML patients may develop PE, as an adverse event of some tyrosine kinase inhibitors (TKI) drug therapy. PE is characterized by an excessive accumulation of fluid in the fluid-filled space that surrounds the lungs. PE requires medical care, may compromise the course of CML treatment, and have economic consequence beyond the costs of treating PE.To compare healthcare resource utilization and costs between CML patients treated with a TKI who developed PE and their matched PE-free controls.MarketScan and Ingenix Impact databases (2001-2009) were combined to identify adult CML patients (ICD-9CM code 205.1×) who received ≥1 prescription of imatinib, dasatinib, or nilotinib before the index date and had continuous enrollment ≥6 months prior to and after the index date. The index date was defined as 30 days before the first PE diagnosis (ICD-9CM code 511.9×) for patients with PE and was randomly selected among all the eligible calendar dates (i.e., following a prescription for a TKI and a diagnosis for CML) for the PE-free controls. Patients were followed for 6 months after the index date. PE and PE-free patients were matched on a 1:1 ratio using propensity score matching. PE-related (i.e., medical claims with a PE diagnosis) resource utilization (inpatient [IP], outpatient [OP], emergency room [ER] and other medical visits) and costs were estimated for PE patients. To estimate the overall incremental impact of PE, all-cause and CML-related (i.e., medical services associated with a diagnosis code of 205.1×) resource utilization and costs were compared between PE and PE-free controls. All costs were reported in 2009 US dollars. Incidence rate ratios (IRR) for healthcare resource utilization were estimated by Poisson regression models. Incremental costs were estimated using generalized linear models or two-part models. Multivariate regression models controlled for age, gender, treatment duration with tyrosine kinase inhibitor, other chemotherapy, bone marrow or stem cell transplant, CML complexity, Charlson comorbidity index, adverse events, and comorbidities.The study included 179 matched pairs. On average, patients were 63.4 and 63.8 years old with 41% and 49% of the population being female for PE-free and PE patients, respectively. During the study period, PE patients were estimated to have an average of 0.62 PE-related IP admissions, 8.43 IP days, 0.06 ER admissions, and 1.76 OP visits. Compared to PE-free patients, PE patients had more than 7 times as many IP days (IRR=7.23; p<.01), almost 3 times as many IP admissions (IRR=2.96; p<0.01), almost twice as many OP visits (IRR=1.98; p<.01) and ER visits (IRR=1.77; p<.01). Especially, PE patients had almost 10 times as many CML-related IP days (IRR=9.91; p<.01), more than 3 times as many CML-related IP admissions (IRR=3.95; p<0.01), twice as many CML-related OP visits (IRR=2.16; p<.01), and almost 6 times as many CML-related ER visits (IRR=5.60; p<.01). On average, PE-related medical costs were estimated at $11,015 per patient, where 84.2% was accounted for by IP costs. Total costs for all-cause related medical services were estimated at $37,566 for PE patients and $14,841 for PE-free patients. After adjusting for confounding factors, the incremental total medical cost of PE patients was $22,299 (p<.01), mostly due to the incremental OP cost ($12,931; p<.01) and IP cost ($8,737; p<.01). Similarly, PE patients incurred higher CML-related medical costs compared to PE-free patients, with a $15,859 (p<.01) incremental cost.Compared to PE-free patients, PE patients have a substantial economic burden with higher PE-related costs, CML-related costs, and total medical cost.Wu: Analysis Group, Inc.: Employment. Guerin:Analysis Group, Inc.: Employment. Bollu:Novartis: Employment, Equity Ownership. Williams:Novartis: Employment, Equity Ownership. Guo:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Ponce de Leon Barido:Analysis Group, Inc.: Employment. Yu:Analysis Group, Inc.: Employment.

Beaumont: Novartis: Research Funding. Coombs:Novartis: Employment, Equity Ownership. Bollu:Novartis: Employment, Equity Ownership. Woodman:Novartis Oncology: Employment. Cella:Novartis: Research Funding.

Nilotinib and dasatinib are second-generation tyrosine kinase inhibitors (TKI) indicated for the treatment of chronic phase (CP) and accelerated phase (AP) Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) patients resistant to or intolerant of first-line therapy with imatinib. Dasatinib is also indicated for treatment of blast crisis (BC) patients. The recommended dose of nilotinib for treatment of resistant or intolerant Ph+ CML-CP is 400 mg twice daily. The current recommended starting dose of dasatinib for second-line therapy of Ph+ CML-CP is 100 mg once daily, and for Ph+ CML-AP or BC is 140 mg once daily. Some patients may experience treatment-related adverse events at the recommended doses of nilotinib or dasatinib, necessitating a dose reduction or interruption of treatment. Therefore, patients may not be receiving the full approved therapeutic doses. There is no available information comparing dose modifications or interruption of treatment between nilotinib and dasatinib. The objective of this study was to compare the frequency of dose adjustments and treatment interruptions between nilotinib and dasatinib in second-line therapy in CML patients from a clinical practice setting perspective.Two claims databases were combined (MarketScan and Ingenix Impact, 01/2002-12/2008) to identify patients diagnosed with CML (ICD-9 code 205.1x) and who had received ≥1 prescription of nilotinib or dasatinib. Patients were required to have continuous enrollment ≥1 month prior to and after the index date. The index date was defined as the first prescription for nilotinib or dasatinib. Two patient cohorts were created based on patient's index treatment. Dasatinib data prior to the 100 mg once daily approval date were excluded from the analysis. Patients were followed for up to 6 months from the index date to the earliest of the termination of health care plan enrollment, or end of data availability. Dosage characteristics, including any dose changes from index prescription, defined as either an increase or decrease in the delivered dose and average dose were calculated during the study period. A ≥15% dose decrease in average dose is selected for comparison between the two groups as it is the mean of the lowest absolute dose change. Dose adjustments were further characterized in relation to the incidence and frequency of hematological and non-hematological events during the study period.Data were analyzed for 514 patients receiving a second-line TKI (67 nilotinib, 447 dasatinib). Baseline characteristics were similar between the groups. Seven patients (2 nilotinib, 5 dasatinib) were excluded due to missing dosage information. Patients treated with dasatinib had more follow-up days in the study period than nilotinib-treated patients (mean ± standard deviation [SD], 162 ± 39 days versus 143 ± 51 days; P = 0.0003). There were no differences between the number of patients treated with nilotinib or dasatinib who had any dose adjustments over the study period (P = 0.8424). Stratification of the data by percent of adjustment revealed statistically significant differences between the two treatment groups. Eighty-nine (19.9%) patients treated with dasatinib had at least one dose reduction of at least 15% compared with 4 patients (6.0%) treated with nilotinib (P = 0.0057). Dasatinib-treated patients with at least 15% dose reduction experienced a mean ± SD of 0.24 ± 0.52 dose decreases compared with 0.06 ± 0.24 dose decreases for patients who received nilotinib (P = 0.0055). However the time to first dose reduction was longer for dasatinib users than for nilotinib users (15.1 ± 37.5 days vs. 7.5 ± 31.5 days, P = 0.0194). Dose decreases occurred within 30 days of a hematological or non-hematological event in 49.5% of patients.These data demonstrate that more CML patients treated second-line with dasatinib experienced dose reductions of at least 15% than patients treated second-line with nilotinib, and that fewer dose reductions were required by the nilotinib users. Although this study did not assess the specific reasons for dose change, dose reductions are frequently associated with hematological or non-hematological events. Future studies may also investigate the relationship between response to treatment and dose reduction for the two TKIs.Yu: Analysis Group, Inc.: Employment. Guerin:Analysis Group, Inc.: Employment. Bollu:Novartis: Employment. Cloutier:Analysis Group, Inc.: Employment. Williams:Novartis: Employment, Equity Ownership.

The recommended treatment option for patients diagnosed with chronic myeloid leukemia (CML) who do not achieve hematological or cytogenetic response to first-line imatinib therapy is to switch to one of the two new BCR-ABL tyrosine kinase inhibitors, nilotinib or dasatinib. Both drugs appear to be efficacious; however, there are no direct comparisons for treatment adherence between nilotinib and dasatinib. Analysis of adherence may reveal whether these two drugs are being used as intended and how adherence issues may potentially affect clinical outcomes. Previously, higher imatinib adherence was associated with significantly lower utilization of resources and costs. (Wu EQ, et al. Curr Med Res Opin. 2010;26:61-69.) The objective of this retrospective study was to compare adherence associated with second-line nilotinib versus dasatinib in a real-world setting.Two administrative claims databases were combined (MarketScan and Ingenix Impact, 01/2002-12/2008) to identify patients diagnosed with CML (ICD-9 code 205.1x) who had received ≥1 prescription for either nilotinib or dasatinib. Patients were required to have continuous enrollment ≥1 month prior to and after the index date. The index date was defined as the first prescription for nilotinib or dasatinib. Patients were followed for up to 6 months from the index date to the earliest of the termination of health care plan enrollment, or end of data availability. Treatment adherence was measured by the proportion of days covered (PDC) and compared using generalized linear models. PDC was calculated as the sum of the days of supply for nilotinib or dasatinib, divided by the number of calendar days in the study period (i.e., up to 6 months after the index date). Unadjusted average PDCs were compared between nilotinib and dasatinib users using Wilcoxon sum-rank tests. Multivariate regressions were controlled for age, gender, CML disease complexity, any adverse event at baseline, CML year of diagnosis, comorbidities, and bone marrow or stem cell transplant at baseline. Medication possession ratios and discontinuation rates, defined as a treatment gap ≥30 days, were also evaluated.A total of 521 patients receiving a second-line TKI (452 dasatinib and 69 nilotinib) were studied. Patients had a mean age of 57 years, and all other characteristics were similar between the 2 cohorts with the exception that patients in the dasatinib cohort had a longer mean follow-up period compared to those in the nilotinib cohort (161.6 days vs 141.9 days; P = 0.0105). Patients in the dasatinib cohort were less adherent to their therapy compared to nilotinib patients. The PDC (mean ± standard deviation) over the study period was 0.79 ± 0.23 for nilotinib patients and 0.69 ± 0.28 for dasatinib patients. After adjustment, dasatinib patients were estimated to have a 0.096 lower PDC value (approximately 13% lower) compared with nilotinib patients (P = 0.0086). A greater proportion of dasatinib users had a PDC <0.8 and PDC <0.9 (Figure). A statistically significant difference in medication possession ratios at 180 days was also observed; 0.75 ± 0.33 for dasatinib and 0.85 ± 0.27 for nilotinib (P = 0.029). Discontinuation rates were similar between the two drugs with an adjusted hazard ratio (HR) of 1.03 (HR >1 indicates that dasatinib users have a greater discontinuation rate than nilotinib users; 95% confidence interval, 0.63–1.69; P = 0.8981).CML patients treated with second-line nilotinib had significantly better adherence during the 6-month study period than patients treated with second-line dasatinib as defined by the PDC. The medication possession ratio was also greater for nilotinib-treated than dasatinib-treated patients; however, discontinuation rates were similar between the two treatment groups. Although adherence may be related to a greater safety profile as adverse events may disrupt treatment, head-to-head comparisons of the drugs as second-line therapy for CML have not been performed. Further research is necessary to understand and define all factors, including safety, involved in affecting treatment adherence for nilotinib and dasatinib patients.Guerin: Analysis Group, Inc.: Employment. Bollu:Novartis: Employment. Guo:Novartis: Employment. Griffin:Novartis: Consultancy, Research Funding. Yu:Analysis Group, Inc.: Employment. Wu:Analysis Group, Inc.: Employment.