ALBERT

Description: Key Points Upon in vitro differentiation, iPSCs obtained from patients with SCID and OS show a similar block in T-cell development. Presence of unresolved single-strand DNA breaks in developing T cells from OS patient-derived iPSCs affects their differentiation.

Description: Introduction: Acute myeloid leukemia (AML) developing secondary after other hematologic diseases, or therapy related after cytotoxic treatment for solid tumors or rheumatologic diseases (s/tAML) is clinically, genetically & prognostically distinct from de novo diseases. Data indicate that s/tAML patients (pts) have inferior outcome compared to de novo cases after chemotherapy & therefore often require consolidation therapy using allogeneic stem cell transplantation (HSCT). Leukemic stem cells (LSC) initiate & maintain AML. They are also believed to exist within the CD34+/CD38- &/or high GPR56 expressing bone marrow (BM) population, which have been shown to impact adversely on outcome. The prognostic impact of LSC markers in de novovs s/tAML after HSCT with non-myeloablative conditioning intensity - where the therapeutic approach also relies on immunological graft-versus-leukemia effects - is unknown. Methods: We analyzed 379 AML pts who received an allogeneic peripheral blood HSCT in complete remission (CR, 82%) or CR with incomplete peripheral recovery (CRi, 18%) between 1999 & 2018 after non-myeloablative (3x30 mg/m2 Fludarabine & 2 Gy total body irradiation) conditioning. At diagnosis, cytogenetic & flow cytometric analyses were performed centrally. For pts with pre-treatment BM available the mutation status of CEBPA, NPM1 & presence of FLT3-ITD by fragment analyses as well as expression levels of GPR56 by qPCR were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated (mut) genes in myeloid malignancies on the MiSeq platform (Illumina). Median follow up after HSCT was 3.7 years. Results: 229 pts (60%) had de novo & 150 pts (40%) had AML secondary to myelodysplastic syndrome (MDS, n=82), myeloproliferative neoplasm (MPN, n=22) or MDS/MPN (n=10), or therapy related after Non-Hodgkin lymphoma (n=9), solid tumors (n=25) or rheumatologic diseases (n=2). At diagnosis, s/tAML pts had lower white blood counts (P=.03), lower blasts in BM (P

Description: Key Points Patient-specific pathways of resistance to venetoclax can be identified by high-content screening of clinical samples with a KI library. Sunitinib may overcome resistance to venetoclax for many patients by downregulating the expression of Bcl-xl, Mcl-1, and A1 in CLL cells.

Description: Background: Recent literature provides conflicting views on whether there is a negative value trend in pharmaceutical oncology treatments. A previous study (J Econ Perspect 2015;29:1) found that the price of pharmaceutical oncology treatments has outpaced the improvements in survival benefits over time, with most treatments developed since 1995 offering marginal improvements in survival with significant increases in costs. In contrast, other literature suggests pharmaceutical oncology treatments have produced significant value. Chimeric antigen receptor t-cell (CAR-T) therapy represents a novel approach for treating particular hematologic cancers-including pediatric acute lymphoblastic leukemia and diffuse large b-cell lymphoma-but a remaining question is whether CAR-T represents a continued trend of low-value innovation, or a significant break from past trends. In this study, we investigate three key questions: (i) what are the trends over the past 10 to 20 years in incremental quality-adjusted life years (QALYs) and incremental cost per incremental quality-adjusted life year (cost/QALY) for newly approved anti-cancer innovations? (ii) how do innovations for hematologic cancers differ from those for other cancers in terms of this value trend? and (iii) how does CAR-T therapy compare with the recent history of innovations for both hematologic and non-hematologic cancers? Methods: We identified all analyses of pharmaceutical treatments for cancer published since 2007 that appear in the Tufts Medical Center Cost-Effectiveness Analysis (CEA) Registry, a comprehensive database focusing on a subset of CEAs called cost-utility analyses (CUAs), which quantify health benefits in terms of QALYs. CUA results on CAR-T therapies came from an analysis conducted by the Institute for Clinical and Economic Review (2018). We limited the CUAs in our study to those conducted in the US context with at least one of the following measures of value: incremental QALYs or cost/QALY, and with intervention/indication approval year 1995 or later. We measured linear trend in the value measures as a function of approval year and compared interventions for non-hematologic cancers with non-CAR-T interventions for hematologic cancers and, in turn, with CAR-T therapy. Regression analysis was used to control for the potential influence of characteristics of a CUA such as discount rate chosen, time horizon, number of years between publication and approval of the intervention for the indication in question, and an indicator for rare diseases as defined by the Genetic and Rare Diseases Information Center of the NIH. Indicators for CAR-T therapy and for non-CAR-T treatments for hematologic cancers were included to test for differences from innovations for other cancer types. Results: 103 incremental QALY and 108 cost/QALY measures met our inclusion criteria. The figures show incremental QALYs and cost/QALY, respectively, by approval year. The regression analysis shows that -- for innovations as a whole -- incremental QALYs gained have declined with approval year by 0.079 per year (95% CI -0.128 to -0.030). Cost effectiveness has worsened somewhat over time although that trend is not statistically significant (cost/QALY increase of $36,147 per year, 95%CI -$29,575 to $101,868). CAR-T is substantially more effective than both pharmaceutical cancer innovations outside of hematology (5.17 more incremental QALYs, 95%CI 4.09 to 6.25) and other innovations within hematology (4.67 more incremental QALYs, 95%CI 3.44 to 5.90). Innovations in hematology other than CAR-T are somewhat more effective than innovations outside of hematology (0.5 more incremental QALYs, 95%CI -0.09 to 1.09), although the difference is not statistically significant. Differences in cost/QALY between CAR-T and other pharmaceutical interventions are not statistically significant. Conclusions: CAR-T therapy improved health outcomes (measured in QALYs) to a greater extent than both treatments for non-hematologic cancers and non-CAR-T treatments for hematologic cancers, with no significant differences in cost/QALY. Those improvements represent a break from a trend previously reported in the literature of negligible incremental effectiveness and rising costs per life-year gained. Disclosures Baumgardner: Precision Health Economics: Employment. Everson:Precision Health Economics: Employment. Brauer:Precision Health Economics: Employment. Zhang:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Liu:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lakdawalla:Precision Health Economics: Consultancy; Novartis Pharmaceuticals Corporation: Other: PHE conducted the research underlying this study with funding from Novartis.; Precision Medicine Group: Equity Ownership.

Description: Introduction: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. Treatment selection in CLL is dependent upon a number of factors, such as patient age and genetic mutations, and can be challenging. A number of novel therapies and combination treatment approaches are now available, making treatment selection and management of adverse events increasingly complex. We sought to determine if a curriculum of online continuing professional education (CPE) activities could improve hematologists/oncologists (hem/onc, H/O), pathologists (path), nurse/NP, and pharmacist knowledge, competence, and confidence related to clinical decision making in patients with CLL. Methods: An expert panel identified educational gaps related to the treatment of patients with CLL. Based on the educational needs identified, the curriculum included 4 activities that were posted online between March 2019-June 2019. The first activity was a 30 minute video lecture (1 faculty) about measurable residual disease (MRD) analysis in CLL. The second activity was 30 minute video roundtable discussion (3 faculty) about treatment initiation and selection in newly diagnosed CLL. The third activity was a text activity focused on relapsed/refractory (R/R) CLL with 2 patient cases. The final activity was a video discussion between a nurse and pharmacist about mitigating side effects and optimizing compliance with oral therapies in CLL. Three activities were certified for physicians and the fourth activity was certified for nurses and pharmacists. Multiple-choice questions were asked before and after participation in each activity A repeated-pairs analysis was conducted where individual learners served as their own controls. Improved indicates an incorrect response pre-activity and a correct response post-activity. Reinforced indicates a correct answer pre- and post-activity. Improved confidence indicates a higher level of confidence post-activity. Results: As of July 2019, there were 356 hem/oncs, 154 pathologists, 178 nurses/NPs, and 504 pharmacists included in this analysis. The curriculum had a large impact on the knowledge and competence of hem/oncs and pathologists. MRD is an indicator of improved progression free survival: 13% H/O and path improved their knowledge, 58% H/O and 36% path reinforced their knowledge. The role for MRD measurement in CLL: 24% H/O and 15% of path improved their knowledge, 51% H/O and 39% path reinforced their knowledge. Selecting therapy for treatment-naïve CLL: 13% H/O and 30% path improved their competence, 57% H/O and 36% path reinforced their competence. Selecting therapy for relapsed/refractory (R/R) CLL: 39% H/O and 42% path improved their competence, 26% H/O and 11% path reinforced their competence. Managing treatment-related side effects in CLL: 11% H/O and 33% path improved their competence, 72% H/O and 31% path reinforced their competence. 10% of nurses/NPs and 11% of pharmacists improved and 30% of nurses/NPs and 38% of pharmacists reinforced their skills counseling patients about adverse event management and drug-drug interactions in R/R CLL. Tailoring frontline therapy in treatment-naïve CLL: 26% H/O and 15% path improved their confidence. Tailoring therapy in R/R CLL: 34% H/O and 31% path improved their confidence. Using MRD in CLL management: 31% H/O and 21% path improved their confidence. Improving patient engagement by using effective interprofessional communication: 25% nurses/NPs and 36% pharmacists improved their confidence. Conclusions: This analysis shows that an online CPE curriculum, utilizing many different formats (video, text, panel discussions) can improve and reinforce the knowledge, competence, and confidence of hem/oncs, pathologists, nurses/NPs, and pharmacists in multiple areas surrounding the treatment of patients with CLL. Results also suggest the following areas warrant further education: knowledge of the role for MRD in CLL management, individualizing therapy selection for treatment-naïve and R/R CLL, and managing treatment-related adverse events of CLL therapies. Acknowledgements: Sameer Bhagavatula contributed to data analysis for this research. Figure Disclosures Allan: Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy, Honoraria; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Gilead: Consultancy. Brander:AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Tolero: Research Funding; DTRM Biopharma: Research Funding; BeiGene: Research Funding; MEI: Research Funding; Acerta: Research Funding; Novartis: Consultancy; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding. Barrientos:Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Consultancy; Genentech: Consultancy.