Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models. Our results suggested that KDM1A is highly expressed in GSCs and knockdown of KDM1A using shRNA-reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the cell viability, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSCs-driven tumor progression and improved mice survival. RNA-sequencing analysis showed that KDM1A inhibitors modulate several pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that KDM1A inhibitors induce activation of the unfolded protein response (UPR) pathway. These results strongly suggest that selective targeting of KDM1A using NCL-1 and NCD-38 is a promising therapeutic strategy for elimination of GSCs.
BRAF mutation was noted in 38 tumors (76%). Systemic treatment was administered in 23 patients (51%), including targeted therapy in 13 (56%) and immunotherapy in 3 (13%). Patients with BRAF-mutated tumors received systemic treatment in 22 cases (58%), including targeted therapy in 13 patients (59%). Intrathecal treatment was given in 23 patients (45%). Whole brain radiotherapy was used in 16 patients (31%), 33 patients (65%) had no brain radiotherapy. The combination of systemic and intrathecal treatment (n¼13, 25%) was the most commonly used combination. No specific treatment was given to 11 patients (22%). Median OS for the whole cohort was 1.7 months (IQR: 0.9-5.2). Median OS was 1.5 months (0.8-4.3) in type I LM versus 2.2 months (1.5-8.1) in type II LM; 1.9 months (IQR: 0.9-4.5 months) in BRAF mutated tumors versus 4.6 (IQR:1.4-8.6) in the BRAF non-mutated tumors; and 1.4 (IQR: 0.5-1.6) without versus 2.9 months (IQR: 1-6) with treatment. Conclusions:The prognosis of LM in melanoma patients remains poor despite novel systemic treatment options. New therapeutic approaches are urgently needed in this population.
Introduction : CLL is the most common chronic leukemia in the US, with nearly 20,000 new cases expected annually. Novel agents, such as ibrutinib, idelalisib, and venetoclax, have been approved in recent years and provide oral options for CLL. However, there is limited data regarding real-world treatment patterns with these novel agents. This study describes dose reduction and discontinuation rates, reasons for both, and outcomes, including overall survival (OS) and duration of therapy (DOT), in CLL patients treated with novel agents. Methods : This is an analysis of a large retrospective cohort study of adult patients (≥ 18 years old) with CLL, treated with novel agents in the VHA from 10/01/2013 to 3/31/2018. Historical data were examined for up to 20 years prior to the enrollment period (10/01/1993 to 9/30/2013). Index date was defined as the date of novel agent initiation. The follow-up period was a minimum of 6 months post index date. Variables, collected via a structured EMR database, included patient demographics, and clinical and treatment characteristics. CLL diagnosis, molecular profiles, and reasons for dose reduction and discontinuation were abstracted by chart review. Descriptive statistics were used to summarize baseline characteristics, treatment patterns, and outcomes. Results: A total of 1205 CLL patients were included in this analysis. Of these, in first observed line, 328 (27%) patients received ibrutinib; in relapsed/refractory observed line (r/r), 741(62%) patients received ibrutinib, 49 (4%) patients on idelalisib, and 87 (7%) patients on venetoclax. Ibrutinib patients in first observed line had a median (range) age of 73 (48-96) years and a median follow-up of 23 (3-54) months after treatment initiation. Dose reduction (n=83, 25%) and discontinuation (n=108, 33%) were frequently due to adverse events (AEs) (93% and 64%). Median DOT to ibrutinib discontinuation was 8 months. The most common AEs leading to dose reduction were major bleed (15%) and rash (15%). The most common AEs leading to discontinuation were atrial fibrillation (20%), major bleed (19%), and infection (11%). The calculated median OS from initiation was 31 (14-49) months. R/R ibrutinib patients had a median age of 72 (45-96) years and had 31 (2-85) months of follow-up after treatment initiation. Dose reduction (n=242, 33%) and discontinuation (n=263, 35%) were frequently due to AEs (89% and 63%). Median DOT to ibrutinib discontinuation was 12 months. The most common AEs leading to dose reduction were thrombocytopenia (13%), arthralgia/myalgia (13%), and infection (12%). The most common AEs leading to discontinuation were atrial fibrillation (19%), infection (15%), and major bleed (11%). the calculated median OS from initiation was 39 (9-57) months. R/R idelalisib patients (n=49) had a median age of 72 (55-93) years and had 27 (3-53) months of follow-up after treatment initiation. Dose reduction (n=8, 16%) and discontinuation (n=41, 84%) were frequently due to AEs (100% and 54%). Median DOT to idelalisib discontinuation was 5 months. The most common AE leading to dose reduction was neutropenia (50%). The most common AEs leading to discontinuation were infection (27%) and pneumonia (18%). R/R venetoclax patients (n=87) had a median age of 72 (47-90) years and had 9 (0-35) months of follow-up after treatment initiation. Dose reduction (n=24, 28%) and discontinuation (n=27, 31%) were frequently due to AEs (100% and 41%). Median DOT to venetoclax discontinuation was 5 months. The most common AEs leading to dose reduction were neutropenia (27%) and thrombocytopenia (27%). The most common AEs leading to discontinuation were neutropenia (36%), thrombocytopenia (18%), and infection (18%). There was not enough follow-up time to have a meaningful OS in this cohort. Conclusions: To our knowledge, this is the largest EMR/chart review study among CLL patients initiating treatments in the real-world setting. This study provides evidence regarding patient characteristics, treatment patterns, and outcomes among patients initiating novel agents for the treatment of CLL in the national VHA population. Dose reduction and discontinuation were frequent across all novel agents, with AEs as the most common reason. These data highlight the significant difference in real world data compared with clinical trial data and indicate the unmet need for more tolerable treatment options for CLL patients. Disclosures Frei: AstraZeneca: Research Funding. Le:AstraZeneca: Employment, Other: Stocks. McHugh:AstraZeneca: Employment. Elesinmogun:AstraZeneca: Employment, Equity Ownership. Obodozie-Ofoegbu:UT Austin: Employment.
Sacituzumab govitecan (SG) is an antibody drug conjugate (ADC) that targets Trop-2 for the selective delivery of SN-38 to tumors. SG carries SN-38, a topoisomerase inhibitor active in the nanomolar range for most cells (including TNBC and GBM) and freely cross the blood brain barrier. SN-38 is conjugated to SG by a linker designated CL2A which is sensitive to acidic conditions. SG has since been granted priority review designation by the FDA, with approval anticipated for triple negative breast cancer. Brain metastases is a significant concern in this patient population, but whether this agent is able to target the CNS through the blood brain barrier is unknown. Based upon the characteristics of this specific ADC, including the use of a pH labile linker and a payload with good CNS penetration, it is our specific hypothesis that the SG can achieve intratumoral concentrations of SN-38 sufficient to achieve therapeutic benefit in patients with neoplastic involvement of the brain. We further hypothesize that while total concentration of SN-38 will correlate with expression of trop2, free SN-38 will correlate more strongly with intratumoral hypoxia. To address this, we are performing a non-randomized, prospective study of SG in subjects with CNS involvement and planned surgical resection. SG is given as single dose at 10mg/kg pre-operatively on Day-1. Surgery will be followed by post-operative treatment with sacituzumab govitecan given intravenously with standard dose of 10 mg/kg on day1 and day 8 of 21-day cycle, until disease progression. Approximately 20 patients, 2 cohorts of 10 patients each with GBM and breast brain tumors, will be enrolled. Tumors will be analyzed for total antibody, free SN-38, and total SN-38 (free SN-38 + Antibody-SN38) concentrations in tumor tissue. Correlations will be made to Trop2 expression and hypoxia. Interim results will be presented.
BACKGROUND Currently, the options for treatment of hematologic malignancies continues to expand with resulting positive outcomes in overall survival, but there is still concern that not all populations have the opportunity for cancer treatment due to lack of health insurance. We have taken a cohort of patients with health-insurance related disparities in a majority-minority population whose immigration status often precludes them from standard insurance but can still utilize a payment plan (PP) associated with hospital care. The main objective of our study was to see how insurance status in a majority-minority population affected treatment response. METHODS Doing a retrospective analysis of a cohort of 364 patients with hematologic malignancies at a single center institution, the patients identified received care exclusively with Mays Cancer Center at UT Health San Antonio, between 1998-2017. Variables for each patient measured included age, gender, date of diagnosis, treatment received, date of first treatment, initial response to treatment, stage, > 2 comorbidities, vitality status, HIV status, and insurance status. The patient's insurance status was either identified as funded (to include Medicare, Medicaid, and private insurance), unfunded (self pay) or unfunded-payment plan (PP) associated with the hospital. Statistical significance was assessed with Pearson's Chi-Square, Fisher's Exact test, and a logistic regression model with a generalized logit link with a 3-level response (CR, PR, F) where CR was designated as the referent. For each effect, the Odds Ratio (OR) and its 95% confidence interval (95% CI) are reported. All statistical testing was two-sided with a significance level of 5%. SAS Version 9.4 for Windows (SAS Institute, Cary NC) was used throughout. RESULTS Our patient population (n=346) was shown to have a median of 56, female patients (n=174, 50.3%), males patients (n=172, 49.7%), Hispanics (n=180, 52%), uninsured (n=107, 30.9%), and HIV (n=22, 6%). Diagnoses studied included aggressive lymphomas (Burkitt's, 1ry CNS, Hodgkin's, NHL, PTLD; n=252) and indolent lymphomas (Marginal Zone, Follicular; n=94). The odds of treatment failure (F) and of Partial Response (PR) in Hispanic patients was not significantly different from the odds in non-Hispanic patients (F OR=1.43, 95% CI 0.62 to 3.3, p=0.40, PR OR=1.36, 95% CI 0.73 to 2.54, p=0.33). Despite having a slightly larger insured patient population (68.9%), insurance status did not affect outcome for our patients. Less than 30% of patients used Carelink or had no insurance in this cohort [Carelink CR 58 (24.7%) PR 17 (24.3%) F 10 (24.4%), No insurance CR 15 (6.4%) PR 5 (7.1%) F 2 (4.9%)]. Twenty percent of Hispanic patients (36/180) and 29.5% (49/166) of non-Hispanic patients reported using Carelink. After combining Carelink with no insurance, the odds of treatment failure (F) and of Partial Response (PR) in patients with insurance was not significantly different from the odds in those without insurance (F OR=1.12, 95% CI 0.44 to 2.84, p=0.81, PR OR=0.95, 95% CI 0.49 to 1.85, p=0.89). In an examination of variation in the relation between treatment response and insurance status with ethnicity, we found no overall association between treatment response and insurance after adjustment for ethnicity (p=0.97) and no association between treatment response and insurance status among Hispanic or non-Hispanic patients (p=0.75 and p=0.69 respectively). CONCLUSION This study directly challenges the idea that Hispanic populations are faced with being the least likely to have health insurance of any racial or ethnic group; among those 18-64 years of age, 37% of Hispanics are uninsured compared to 13% of non-Hispanic whites. In an uninsured minority-majority Hispanic patient population with PP firmly established in the community that allows for ready access to healthcare, insurance status and race did not adversely affect outcome. Disclosures No relevant conflicts of interest to declare.
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