Time and Personnel Costs Associated with Adverse Event (AE) Management Among Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Acalabrutinib, Ibrutinib, or Venetoclax

Abstract Introduction Guidelines recommend chemoimmunotherapy and novel agents such as Bruton's tyrosine kinase inhibitors and B-cell lymphoma 2 inhibitors for the treatment of CLL. AE profiles differ across therapies, and management of AEs in patients with CLL treated with novel agents incurs burden on healthcare professionals (HCPs) and oncology practices. Time and personnel costs associated with AE management are not well understood for patients with CLL and are overlooked while assessing the value of oncology drugs. To assess practice burden, this study quantified HCP time and personnel costs related to AE management for patients with CLL who received a novel agent, either acalabrutinib, ibrutinib, or venetoclax. Methods HCPs (i.e., oncologists, pharmacists, physician assistants, nurse practitioners, and registered nurses) who actively treated ≥5 patients with CLL during the past year with >1 patient receiving acalabrutinib, ibrutinib, or venetoclax in the past month were recruited through a physician panel vendor to participate in a longitudinal, observational, prospective survey. This study was conducted in two phases (November 2020-January 2021; April-June 2021). Over the 2-month data collection period, HCPs reported on a daily basis the time spent performing AE management activities for CLL patients receiving a novel agent, which included 1) interactions with patients in-person or via remote consultation (telephone, video, or email), 2) interactions with other HCPs, and 3) other management activities that did not include interactions with patients or other HCPs (e.g., recording notes in patient's charts, ordering lab tests). Mean time and personnel costs per AE management activity were summarized using descriptive statistics. Personnel costs (USD) were calculated by multiplying median wage information reported by the ureau of Labor Statistics Occupational Employment Statistics survey by HCP-reported time spent managing AEs. Results Among 49 HCPs enrolled in the survey, 36 (73%; Table 1) reported managing ≥1 AE during a total of 1,106 AE management activities (229 for acalabrutinib; 500 for ibrutinib; 377 for venetoclax) for 421 patients with CLL during the 2-month study period. Among all patients, 108 (26%), 186 (44%), and 129 (31%) received acalabrutinib, ibrutinib, or venetoclax in any line, respectively (Table 2). Anemia was the most frequently managed AE reported among all patients (19%), but differed by treatment: 11%, 19%, and 26% for patients treated with acalabrutinib, ibrutinib, and venetoclax, respectively (Table 2). Other AEs reported among ≥10% of patients with a reported AE management activity also differed by treatment. For acalabrutinib, this included only headache. For both ibrutinib and venetoclax patients, thrombocytopenia, diarrhea, and myalgia were managed in ≥10% of patients. For venetoclax patients, back pain and arthralgia were also managed in ≥10% of patients. Mean (standard deviation [SD]) time spent managing AEs per activity was 11.8 (7.7) minutes (min) overall, 12.1 (7.4) min for acalabrutinib, 11.6 (6.9) min for ibrutinib, and 11.8 (8.9) min for venetoclax (Table 3). Mean time per AE management activity was numerically similar across the three treatments overall and stratified by type of HCP, treatment duration, and line of therapy. We noted differences in the type of HCP managing AEs by treatment, with a lower proportion of oncologists managing acalabrutinib AEs compared to the other two therapies. Corresponding mean (SD) personnel costs per AE management activity were $16.0 ($10.6) overall, and $14.4 ($9.8) for acalabrutinib, $16.3 ($9.8) for ibrutinib, and $16.7 ($11.9) for venetoclax. Conclusions This study demonstrates the importance of accounting for time and labor costs related to AE management, as results suggest that the burden to HCPs related to AE management for patients with CLL treated with acalabrutinib, ibrutinib, and venetoclax is substantial. During the 2-month study period, almost three-quarters of HCPs reported managing ≥1 AEs and an average of 12 AE management days was observed across these HCPs. While mean time and personnel costs were similar, differences in types of AE and types of HCPs managing AEs were observed across treatments. Future research should confirm our observed differences in types of AE and types of HCPs managing AEs by treatment to comprehensively assess the burden of managing AEs for patients with CLL. Figure 1 Figure 1. Disclosures Wahlstrom: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. DerSarkissian: Analysis Group, Inc.: Current Employment. Kunzweiler: Apellis: Other: Employee of Analysis Group, Inc., Research Funding. Castriota: Analysis Group, Inc.: Ended employment in the past 24 months. Chang: Analysis Group, Inc.: Current Employment. Cheung: Analysis Group, Inc.: Ended employment in the past 24 months. Gu: Analysis Group, Inc.: Current Employment. Guo: Analysis Group, Inc.: Current Employment. Duh: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study.. Ryan: AstraZeneca: Current Employment, Current equity holder in publicly-traded company.

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Characteristics and Treatment Patterns of Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Who Received ≥3 Lines of Therapies

Blood ◽

10.1182/blood-2020-140136 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-5

Author(s):

Jipan Xie ◽

Aozhou Wu ◽

Laura Liao ◽

Xiaoyan Du ◽

Ahmed Noman ◽

...

Keyword(s):

Treatment Duration ◽

Therapy Group ◽

B Cell Lymphoma ◽

The Novel ◽

Publicly Traded ◽

Agent Based ◽

Analysis Group ◽

Car T ◽

Novel Agent

Introduction: Treatment options continued to evolve in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), with many novel treatments available in recent years. The current study aimed to describe characteristics and treatment patterns of patients with R/R DLBCL who received ≥3 lines of therapy (LOT) using recent real-world data. Methods: This study used the PharMetrics Plus administrative claims database to identify adult patients who had ≥1 inpatient claim or ≥2 outpatient claims for DLBCL (ICD-10: C83.3) between 10/01/2015 and 09/30/2019. Patients were selected if they had ≥6-months of continuous eligibility before the first DLBCL diagnosis (index diagnosis). To capture newly diagnosed patients, the study excluded patients who had a claim for a possible DLBCL diagnosis and other hematologic malignancies (except hematologic conditions that may transform into DLBCL) before the index diagnosis and those who had stem cell transplantation (SCT) as the first treatment without prior chemotherapy (CT). An algorithm was developed to define LOT. In general, a new LOT was indicated by addition of a new drug or re-initiation of the previous LOT after a gap of ≥90 days. Pharmacologic therapies were categorized as CT or chemoimmunotherapy (CIT) or novel agent-based therapy (including brentuximab vedotin, ibrutinib, venetoclax, lenalidomide, obinutuzumab, nivolumab and pembrolizumab). SCT was counted as consolidation therapy instead of a separate line, while chimeric antigen receptor T cells (CAR-T) was counted as a separate line with preparation included (e.g., leukapheresis, bridging therapy, and lymphodepletion). Patients who received a third LOT (3L) comprised the study population, with the index date defined as the initiation date of 3L pharmacologic therapy or the infusion date of 3L SCT or CAR-T. 3L treatment distribution was described separately before and after the first CAR-T approval for DLBCL (10/18/2017). Treatment duration of 3L pharmacologic therapies was analyzed using Kaplan-Meier (KM) analysis. The proportion of patients initiating 4L during the observed follow-up period were described for all patients receiving a 3L. Due to the limited follow-up time and a high proportion of censoring, the current data was not mature to estimate rates of 4L initiation at different time points based on the KM analysis. All analyses were conducted for the overall study population and by treatment. Results: Among the 3,559 DLBCL patients receiving ≥1L treatment, 92.3% were treated with rituximab-containing regimens and 68.9% with R-CHOP or similar in 1L. There were 160 (4.5%) patients who received ≥3 LOT, with a mean age of 58.5 years and 64.4% male. Before CAR-T approval, 51 patients received 3L: 52.9% received CT/CIT, 33.3% received novel agent-based therapy, and 13.7% received SCT. After CAR-T approval, 109 patients received 3L: 45.9%, 30.3%, 7.3%, and 16.5% received CT/CIT, novel agent-based therapy, SCT and CAR-T, respectively. There were some differences in patient characteristics across treatment groups. Specifically, CAR-T patients had a relatively lower mean Charlson Comorbidity Index (CCI) score (2.9). The novel therapy group had a shorter median time from index diagnosis to index date (10.3 months). SCT patients were younger (mean 56.6 years) but with a relatively higher mean CCI score (4.2). The median follow-up time was 5.0 months and varied across treatments: from 3.9 months for CAR-T to 5.7 months for SCT. Among patients receiving pharmacologic treatments, the median treatment duration was 3.1 months and 2.8 months for the CT/CIT and novel agent-based therapy groups, respectively. During a median follow-up time of <6 months, a total of 51 (31.9%) patients initiated 4L. The proportion was 27.8% in the CAR-T group, 28.6% in the CT/CIT group, 38.0% in the novel therapy group and 33.3% in the SCT group. Conclusions: In patients with R/R DLBCL receiving 3L treatment post CAR-T approval, about 76% were treated with CT/CIT or novel agent-based therapies, though most of the novel agents are not indicated for DLBCL. CAR-T and SCT were used in 17% and 7% of patients, respectively. Treatment duration of 3L CT/CIT or novel agent-based therapies was short. A relatively high proportion of patients moved to the next LOT during a short follow-up period. These findings highlight the unmet need for more effective treatments among R/R DLBCL patients in 3L and later lines. Disclosures Xie: Analysis Group, Inc.: Other: Employee of Analysis Group, Inc., which has received consultancy fees from ADC Therapeutics, Inc.. Wu:Analysis Group, Inc.: Other: Employee of Analysis Group, Inc., which has received consultancy fees from ADC Therapeutics, Inc.. Liao:ADCT: Current Employment, Current equity holder in publicly-traded company. Du:Analysis Group, Inc.: Other: Employee of Analysis Group, Inc., which has received consultancy fees from ADC Therapeutics, Inc.. Noman:Analysis Group, Inc.: Other: Employee of Analysis Group, Inc., which has received consultancy fees from ADC Therapeutics, Inc.. Liang:Analysis Group, Inc.: Other: Employee of Analysis Group, Inc., which has received consultancy fees from ADC Therapeutics, Inc.. Camardo:ADCT: Current Employment, Current equity holder in publicly-traded company. Chen:ADCT: Current Employment, Current equity holder in publicly-traded company.

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Pharmacologic Inhibition of the Histone Methyltransferase SETD2 with EZM0414 As a Novel Therapeutic Strategy in Relapsed or Refractory Multiple Myeloma and Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2021-151147 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1142-1142

Author(s):

Jennifer Totman ◽

Dorothy Brach ◽

Vinny Motwani ◽

Selene Howe ◽

Emily Deutschman ◽

...

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Cell Line ◽

Cell Lines ◽

B Cell Lymphoma ◽

Publicly Traded ◽

The Past ◽

Molecule Inhibitor

Abstract Introduction: SETD2 is the only known histone methyltransferase (HMT) capable of catalyzing H3K36 trimethylation (H3K36me3) in vivo. It plays an important role in several biological processes including B cell development and maturation, leading to the hypothesis that SETD2 inhibition in these settings could provide anti-tumor effects. The normal process of B cell development/maturation renders B cells susceptible to genetic vulnerabilities that can result in a dysregulated epigenome and tumorigenesis, including in multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL). For example, 15%-20% of MM harbors the high risk (4;14) chromosomal translocation, resulting in high expression of the multiple myeloma SET domain (MMSET) gene. MMSET is an HMT that catalyzes H3K36me1 and H3K36me2 formation and extensive scientific work has established overexpressed MMSET as a key factor in t(4;14) myeloma pathogenesis. To the best of our knowledge MMSET has eluded drug discovery efforts, however, since t(4;14) results in high levels of the H3K36me2 substrate for SETD2, inhibiting SETD2 offers promise for targeting the underlying oncogenic mechanism driven by MMSET overexpression in t(4;14) MM patients. In addition, SETD2 loss of function mutations described to date in leukemia and DLBCL are always heterozygous, suggesting a haploinsufficient tumor suppressor role for SETD2. This observation points to a key role for SETD2 in leukemia and lymphoma biology and suggests that therapeutic potential of SETD2 inhibition may also exist in these or similar settings. EZM0414 is a first-in-class, potent, selective, orally bioavailable small molecule inhibitor of the enzymatic activity of SETD2. We explored the anti-tumor effects of SETD2 inhibition with EZM0414 in MM and DLBCL preclinical studies to validate its potential as a therapy in these tumor types. Methods: Cellular proliferation assays determined IC 50 values of EZM0414 in MM and DLBCL cell line panels. Cell line-derived xenograft preclinical models of MM and DLBCL were evaluated for tumor growth inhibition (TGI) in response to EZM0414. H3K36me3 levels were determined by western blot analysis to evaluate target engagement. Combinatorial potential of SETD2 inhibition with MM and DLBCL standard of care (SOC) agents was evaluated in 7-day cotreatment in vitro cellular assays. Results: Inhibition of SETD2 by EZM0414 results in potent anti-proliferative effects in a panel of MM and DLBCL cell lines. EZM0414 inhibited proliferation in both t(4;14) and non-t(4;14) MM cell lines, with higher anti-proliferative activity generally observed in the t(4;14) subset of MM cell lines. The median IC 50value for EZM0414 in t(4;14) cell lines was 0.24 μM as compared to 1.2 μM for non-t(4;14) MM cell lines. Additionally, inhibitory growth effects on DLBCL cell lines demonstrated a wide range of sensitivity with IC 50 values from 0.023 μM to >10 μM. EZM0414 resulted in statistically significant potent antitumor activity compared to the vehicle control in three MM and four DLBCL cell line-derived xenograft models. In the t(4;14) MM cell line-derived xenograft model, KMS-11, robust tumor growth regressions were observed at the top two doses with maximal TGI of 95%. In addition, two non-t(4;14) MM (RPMI-8226, MM.1S) and two DLBCL xenograft models (TMD8, KARPAS422) demonstrated > 75% TGI; with two additional DLBCL models (WSU-DLCL2, SU-DHL-10) exhibiting > 50% TGI in response to EZM0414. In all models tested, the antitumor effects observed correlated with reductions in intratumoral H3K36me3 levels demonstrating on-target inhibition of SETD2 methyltransferase activity in vivo. In vitro synergistic antiproliferative activity was also observed when EZM0414 was combined with certain SOC agents for MM and DLBCL. Conclusions: Targeting SETD2 with a small molecule inhibitor results in significantly reduced growth of t(4;14) MM, as well as non-t(4;14) MM and DLBCL cell lines, in both in vitro and in vivo preclinical studies. In addition, in vitro synergy was observed with EZM0414 and certain SOC agents commonly used in MM and DLBCL, supporting the combination of SETD2 inhibition with current MM and DLBCL therapies. This work provides the rationale for targeting SETD2 in B cell malignancies such as MM, especially t(4;14) MM, as well as DLBCL, and forms the basis for conducting Phase 1/1b clinical studies to evaluate the safety and activity of EZM0414 in patients with R/R MM and DLBCL. Disclosures Totman: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Brach: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Motwani: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Howe: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Deutschman: Epizyme, Inc.: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Lampe: Epizyme, Inc.: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Riera: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Tang: Epizyme, Inc.: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Eckley: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Alford: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Duncan: Epizyme, Inc.: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Farrow: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Dransfield: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Raimondi: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Thomeius: Foghorn Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cosmopoulos: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Kutok: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company.

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A Phase 2/3 Randomized, Placebo-Controlled, Open-Label, Multi-Center Trial of Lenzilumab to Improve the Safety and Efficacy of CAR-T Cell Therapy in Adults with Relapsed or Refractory Large B-Cell Lymphoma (The SHIELD Study)

Blood ◽

10.1182/blood-2021-153987 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1758-1758

Author(s):

Saad S. Kenderian ◽

Cameron Durrant ◽

Dale Chappell ◽

Omar Ahmed ◽

Adrian Kilcoyne

Keyword(s):

Cell Lymphoma ◽

B Cell Lymphoma ◽

Publicly Traded ◽

Inflammatory Cascade ◽

Gm Csf ◽

The Past ◽

Large B Cell Lymphoma ◽

Car T ◽

Optimal Regimen ◽

Large B Cell

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive sub-type of non-Hodgkin's lymphoma(Liu, et al. Am J Hematol 2019). All three approved CD19-directed CAR-T therapies (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) are associated with toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that can be severe, resulting in non-relapse mortality, ICU admission, and significant non-drug related health resource utilization which represent barriers to access and adoption (Nabhan, et al. J Clin. Pathway 2017). Studies have shown that early elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF) levels 1-day post CAR-T infusion correlates with severe ICANS (Rossi, et al. EMA Workshop 2016), which is a negative prognostic factor for overall survival (Karschnia, et al. Blood 2019). It has been proposed that upon contact with the tumor, CAR-Ts produce GM-CSF, which serves as a communication conduit between the specific immune response of CAR-T and the off-target inflammatory cascade produced by myeloid lineage cells, causing myeloid cells to expand and promote the production of other downstream proinflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-1, IL-6), and other markers of systemic inflammation (CRP, Ferritin) (Sterner, et al. Blood 2019). Moreover, IL-6 is predominately released by tumor cells in a contact-independent manner (Barrett et al. Blood 2016), which helps explain why the prophylactic administration of tocilizumab is not effective in reducing the overall incidence of CRS or ICANS, as this cytokine is downstream in the inflammatory cascade. Further, the prophylactic use of tocilizumab has been shown to increase the incidence of all-grades and grade >3 ICANS (Locke, et al. Blood 2017). Lenzilumab is a novel Humaneered ® monoclonal antibody that neutralizes GM-CSF and has demonstrated potential to reduce the hyper-immune mediated cytokine storm induced by SARS-CoV-2 infection and significantly improve the likelihood of survival without ventilation in hospitalized COVID-19 patients, as reported in the LIVE-AIR phase 3 study (Temesgen, et al. medRxiv 2021). Methods: Eligible patients are adults (≥ 18 y) with relapsed or refractory DLBCL or are chemorefractory. Prior therapy must have included an anti-CD20 monoclonal antibody and an anthracycline-containing regimen. Patients will undergo leukapheresis and may receive optional corticosteroid bridging therapy. Patients will then receive lymphodepleting chemotherapy on Days ‒3 to ‒5 followed by infusion of lenzilumab on Day 0, 6-hrs prior to CAR-T infusion. Approximately 40 accredited sites across the U.S. certified to administer the three commercially available CAR-Ts have been engaged to participate in this 2-part study. In Part 1, all patients will receive lenzilumab 1800mg via a single 2-hour infusion prior to CAR-T administration. The objective of Part 1 is to evaluate the optimal regimen and assess whether a second dose of lenzilumab post-CAR-T infusion is required. A translational assessment of GM-CSF axis suppression, levels of CAR-T cells in blood, other inflammatory markers and lenzilumab PK/PD will be evaluated, along with the incidence and severity of CRS and ICANS, objective response rates (ORR) and rates of complete response (CR) by Day 28 to select the optimal regimen to carry forward into Part 2. The objective of Part 2 is to confirm whether lenzilumab can improve the toxicity and tolerance of CAR-T while maintaining or improving efficacy and durability of response. Up to 250 patients will be randomized 1:1 to receive lenzilumab or placebo with CAR-T per standard of care. The primary endpoint of the study is incidence of grade >2 CRS and/or ICANS by Day 28, with a key secondary endpoint of CR at 6-months in patients without grade ≥ 2 CRS and/or ICANS at Day 28 (Toxicity-free CR). This design and sample size yields 90% power to detect a 50% reduction in the primary outcome measure. Secondary endpoints include incidence of all grades and grade >3 CRS and/or ICANS, respectively; ORR and CR at 1, 3, 6, 12 months; durability of CR; progression-free survival, overall survival and health related quality of life using validated patient reported outcome measures. In addition, the study will explore the CRS and ICANS grading criteria that have been utilized with each of the approved CAR-Ts. Disclosures Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding. Durrant: Humanigen, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Chappell: Humanigen Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Ahmed: Humanigen Inc.: Current Employment, Current equity holder in publicly-traded company. Kilcoyne: Humanigen, Inc.: Current Employment, Current equity holder in publicly-traded company.

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The shift in therapies for the treatment of chronic lymphocytic leukemia (CLL) patients in the US Veterans Health Administration (VHA) from 2013-2018.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e19339 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e19339-e19339

Author(s):

Zohra Nooruddin ◽

Hannah Le ◽

Daniel McHugh ◽

Kellie Ryan ◽

Xavier Jones ◽

...

Keyword(s):

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Agent Orange ◽

Novel Agents ◽

Fiscal Year ◽

Veterans Health ◽

Health Administration ◽

Secondary Complications ◽

The Impact ◽

Novel Agent

e19339 Background: The first novel agent for use in CLL was approved in 2014; however, the extent of novel agent uptake in the VHA is largely unknown. Objective: This study described the pharmacoepidemiology of three novel agents (ibrutinib, idelalisib, venetoclax), and traditional chemotherapies/chemoimmunotherapies (CT/CIT) in the VHA. Methods: This was a retrospective study of 26,879 adults with CLL in the VHA from 10/01/2013 to 5/31/2018. All were followed for at least 6 months. Data were extracted from the VHA electronic health record. Patients came from all 18 Veterans Integrated Service Networks, spanning all 50 states and US territories. Descriptive statistics were used to summarize baseline characteristics, CLL treatments, next therapies, and secondary complications. Results: A total of 3670 patients received at least one of 12 CLL therapies of interest. Patients had a median age of 69 years (47% were 65+ and 26% were 75+), a median age-adjusted Charlson comorbidity score of 6, and 6% had a history of exposure to Agent Orange. Ibrutinib accounted for 89% of the novel agent use. Ibrutinib use across all lines of therapy (LOTs) increased sevenfold over the study period (Table). Venetoclax (42%) and idelalisib (30%) were the most common therapies for the next LOT after ibrutinib. Across all LOTs, traditional CT/CIT use declined steadily over the study period. However, in fiscal year (FY) 2018, there were still 17% of patients receiving CT/CIT. Ibrutinib was the most common therapy for the next LOT in these patients (43–74%). Incidence of diffuse large B cell lymphoma post-index was 2–6 times higher in patients on CT/CIT than those on ibrutinib. Other secondary complications were similar between ibrutinib and CT/CIT. Conclusions: To our knowledge, this is the largest study looking at CLL treatment patterns among VHA patients in the real world. There has been a major shift in the treatment of CLL, with fast adoption of novel agents in the VHA from 2013 to 2018. The impact of this shift on healthcare resource use and cost burden in the VHA will need to be examined. [Table: see text]

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Patient Reported Outcomes Among Systemic Mastocytosis (SM) Patients in Routine Clinical Practice: Results from the TouchStone Survey

Blood ◽

10.1182/blood-2020-137480 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Ruben A. Mesa ◽

Erin M. Sullivan ◽

David Dubinsky ◽

Brittany Carroll ◽

Valerie M. Slee ◽

...

Keyword(s):

Mast Cell ◽

Research Funding ◽

Patient Reported Outcomes ◽

Publicly Traded ◽

Ability To Work ◽

The Past ◽

Stomach Pain ◽

Patient Reported ◽

Ed Visits ◽

Mean Time

Introduction: SM is a rare, clonal mast cell neoplasm characterized by uncontrolled proliferation and activation of mast cells driven by the KIT D816V mutation, which leads to severe and unpredictable symptoms. This study evaluated disease and healthcare system burden of SM in a real-world treatment setting in the US. Methods: In this cross-sectional study, SM patients recruited through the Mast Cell Connect Registry completed an online survey. The 100-item survey consists of symptom assessments using the ISM-SAF© and widely used patient-reported outcomes (PRO) measures including the Short Form (SF)-12, Work Productivity and Activity Impairment (WPAI), and questions regarding SM-related medication and physician and emergency department (ED) visits during the past year. Patients ≥18 years with a self-reported diagnosis were included after providing informed consent. Established PRO measures were scored using established scoring algorithms. Data from the first 30 patients enrolled were analyzed using descriptive statistics. Results: Thirty patients completed the survey: 87% female; mean age of 54 years; mean time since diagnosis of 8 years; mean time from symptom onset to diagnosis of 7 years; 80% reported indolent SM, 10% reported aggressive SM, 3% reported smoldering SM, and the remainder (7%) were uncertain of their type. Ninety percent reported ≥10 symptoms during the past year, the most bothersome being abdominal/stomach pain (17%), anaphylactic episodes (13%), diarrhea/loose stools (13%), and fatigue (10%). Most patients indicated they have moderate (43%) or severe (33%) disease. Symptom Burden and Quality of Life (QoL) Impact Mean ± SD mental and physical component summary scores from the SF-12 were 44 ± 1.8 and 43 ± 2.5, respectively, indicating below average health and mental well-being. The mean total symptom score (TSS) from the ISM-SAF was 50, with >28 indicating moderate-severe SM. Nearly all (27/30) patients reported that they strongly agreed (27%), agreed (40%) or somewhat agreed (23%) that SM had a negative impact on their QoL, and 50% (15/30) reported feeling a great deal (17%), quite a bit (10%), or somewhat (23%) depressed or discouraged due to their disease. Use of Healthcare Services & Medications Patients reported encounters with multiple physicians over the course of 1 year (Table). Most patients (90%) reported taking ≥2 over-the-counter (OTC) medications, and 40% of patients reported taking >3 prescription medications to manage SM. Twenty percent of survey respondents visited the ED due to anaphylaxis, with 50% of these patients requiring ED care for anaphylaxis on 3 different occasions. Fifty-seven percent (17/30) of patients reported managing at least 1 anaphylactic episode at home without visiting the ED, with 4 of these patients reporting ≥12 anaphylactic episodes within the past year. Work Impairment Limited activities due to pain attributed to SM were reported by 60% (18/30) of patients, and 56% (17/30) of patients indicated that pain interfered with their ability to work. 17% of respondents reported they were unable to work for pay, 46% of patients reported having to reduce work hours because of SM, and 20% of patients had filed for disability, all due to SM. Conclusions: Despite close management by healthcare providers, and taking prescription and OTC medications, early findings from the TouchStone survey show that the majority of SM patients continue to report significant burden of disease, including inadequate symptom control, negative effects on QoL, reduced ability to work, frequent physician visits to manage SM and multiple, potentially costly, ED visits. These findings suggest high unmet medical need underscoring the value of more effective therapeutic interventions. Disclosures Mesa: LaJolla Pharma: Consultancy; Novartis: Consultancy; Sierra Onc: Consultancy; Abbvie: Research Funding; Celgene: Research Funding; CTI: Research Funding; Genetech: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Samus: Research Funding. Sullivan:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Dubinsky:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Carroll:Blueprint Medicines Corporation: Consultancy, Current equity holder in publicly-traded company. Mathias:Blueprint Medicines Corporation: Other: employed by Health Outcomes Solutions, which received funding Blueprint for providing assistance in developing the Touchstone survey. Castells:Annals of Allergy, Asthma & Immunology: Other: Editorial Board; UpToDate: Other: Author fee; Blueprint Medicines Corporation: Consultancy, Other: Clinical trials: Principle Investigator.

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Neoantigens in Patients with De Novo Follicular Lymphoma: Results from the PRIMA Study

Blood ◽

10.1182/blood-2020-134795 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 25-26

Author(s):

Carsten Henneges ◽

Dexter X Jin ◽

Jeffrey M Venstrom ◽

Sally E Trabucco ◽

Tina G Nielsen ◽

...

Keyword(s):

Follicular Lymphoma ◽

Clinical Outcomes ◽

Prognostic Value ◽

De Novo ◽

Null Model ◽

B Cell Lymphoma ◽

Hazard Ratio ◽

Phase Iii ◽

Publicly Traded ◽

The Past

Introduction: Follicular lymphoma (FL) is a slow growing lymphatic cancer characterized by translocations in and overexpression of BCL-2, which inhibits apoptosis. This pathogenesis may generate neoantigens (NAs) that are recognizable by T-cells as part of a patients' immune surveillance and are unique to specific FL mutations. Tumor mutation burden (TMB), and NA prevalence and prognostic nature, have previously been characterized for diffuse large B-cell lymphoma (DLBCL), identifying that TMB correlated with NA burden (NAB). While TMB did not correlate with outcomes, the presence of a NA, especially BCL2 NA, correlated with outcomes in de novo DLBCL. In addition, the majority of patients were predicted to have ≥1 NA (Paulson, EHA 2019). However, to date, the prevalence of NAs in FL, and their association with clinical outcomes, have not been characterized. The aim of our study was to characterize NA prevalence and evaluate the prognostic value of NA biomarkers, assessed by a targeted, comprehensive genomic profiling (CGP) platform, on progression-free survival (PFS) for patients with de novo FL. Methods: CGP data on 465 genes were available from patients with FL who provided biopsy samples at screening for the Phase III PRIMA trial (NCT00140582; intent-to-treat [ITT] population =1018; patients received rituximab [R] maintenance vs observation after response to initial first-line treatment with R-CVP [cyclophosphamide, vincristine, prednisone], R-CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] or R-FCM [fludarabine, cyclophosphamide, mitoxantrone]). CGP was used to calculate TMB, HLA type (OptiType) and NA prediction (NetMHCpan). The prevalence of NAs at time of screening was analyzed by the number and proportion of patients. The prognostic value of NAs were evaluated against the Cox Proportional Hazards null model for PFS including terms for treatment, country and response to induction treatment. The Akaike Information Criterion (AIC), a likelihood ratio test (LRT) p-value vs the null when including an additional NA term and its associated hazard ratio (95% CI), were calculated. A visualization of the genetic mutational landscape was generated using dimension reduction methods. Results: In total, 247 of the 1202 enrolled patients were assayed with CGP. Baseline characteristics and survival in the biomarker evaluable population (BEP) were consistent with the ITT population. We calculated a median TMB of 6.7 mutations per megabase for the PRIMA cohorts with a median of two predicted NAs per patient. The majority of patients (83%) were predicted to have ≥1 NA. TMB moderately correlated with NAB (0.42 pearson coefficient), Figure A. TMB was not associated with outcomes (hazard ratio [HR] 95% CI: 0.98 [0.94-1.02]) and similarly the presence of a NA was not associated with PFS (HR [95% CI]: 0.90 [0.56-1.44]). The most prevalent predicted NAs (n [patients]; %) were in BCL2 (54; 21.9%), CREBBP (49; 19.8%), EZH2 (14; 5.7%), KMT2D (13; 5.3%), and CARD11 (10; 4.0%). In a pooled analysis of patients from both arms, only presence of EZH2 NA improved the AIC of the null model (AIC=1135.6) to 1134.7 (LRT p=0.09 better than 0.1), Table. The HR (95% CI) of EZH2 NA in this model was 0.46 (0.17-1.25), indicating better survival for the EZH2 NA-negative group. Within each treatment group, HR (95% CI) for EZH2 was 0.27 (0.07-1.13) in the observation group and 1.05 (0.25-4.44) in the R group, Figure B. Inspecting the tSNE mutations by gene, a neighborhood pattern could be seen between EZH2 and BCL2 connected by KMT2D and flanked by CARD11 and CREBBP, Figure C. Conclusions: We observed that similarly to de novo DLBCL, TMB and NAB were also correlated in patients with de novo FL. While NAB was associated with clinical outcomes in de novo DLBCL, we did not observe these associations in FL. In patients with de novo FL,who discontinued R after initial treatment response, the absence of EZH2 predicted neoantigens were associated with PFS. This is consistent with results on EZH2 mutation status reported by Huet, et al.(Blood Cancer J 2017). A caveat to this hypothesis generating analysis is the small number of PFS events in the EZH2 neoantigen group. These insights may inform future personalized strategies in FL. Disclosures Henneges: Genentech (via Syneos Health): Current Employment; University of Wurzburg: Ended employment in the past 24 months. Jin:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Foundation Medicine Inc: Current Employment. Venstrom:Foundation Medicine, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Trabucco:F. Hoffmann-La Roche, Bristol-Myers Squibb Co., BioNTech: Current equity holder in publicly-traded company; Bristol-Myers Squibb Co: Current equity holder in publicly-traded company; BioNTech: Current equity holder in publicly-traded company; Loxo Oncology: Divested equity in a private or publicly-traded company in the past 24 months; Foundation Medicine, Inc.: Current Employment; Patent pending with Foundation Medicine and Genentech: Patents & Royalties: Patent pending. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Penuel:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Salles:Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, Roche, Takeda: Other: Participation to educational events; Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Honoraria; Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Consultancy. Paulson:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company.

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Potent and Orally Bioavailable BCL6 PROTAC TM Degraders Demonstrate Efficacy in Pre-Clinical Models of Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽

10.1182/blood-2021-149654 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2272-2272

Author(s):

Sheryl M Gough ◽

Dan Sherman ◽

Lynn DeCarr ◽

Sarah Eaton ◽

Maja Milanovic ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Publicly Traded ◽

The Past ◽

Large B Cell Lymphoma ◽

Orally Bioavailable ◽

Large B Cell

Abstract The BCL6 transcription repressor (B-cell lymphoma 6, BCL6) protein has been shown to be a key molecular driver of diffuse large B-cell lymphoma (DLBCL). Somatic mutations of the BCL6 gene include gross- or cryptic-chromosome translocations and point mutations that have been shown to result in the deregulation of BCL6 expression. These BCL6 abnormalities also contribute to a subgroup of high-risk (HR) aggressive double- and triple-hit (DH/TH) lymphomas with very poor outcomes. We have developed highly specific, potent and orally bioavailable BCL6 PROteolysis TArgeting Chimera (PROTAC TM) degraders that demonstrate potent in-vitro and in-vivo efficacy in multiple pre-clinical DLBCL models. Ten of 12 germinal center B-cell (GCB) and two of four activated B-cell (ABC) DLBCL cell lines show significant growth inhibition in-vitro with BCL6 PROTAC TM treatment, demonstrating a critical dependence on BCL6. This array of sensitivity across genetically variable cell lines suggests that BCL6-dependence is not just associated with BCL6-mutated DLBCLs. A more advanced BCL6 PROTAC TM, ARVN-71228, achieves >95% BCL6 D max in-vitro at a DC 50 of <1 nM in the OCI-Ly1 model following 24 hr treatment, degrading BCL6 equally well in the nuclear, chromatin-bound and cytosolic cell fractions. BCL6 degradation is associated with dose-dependent G1 cell cycle arrest and elevated apoptosis that increases over time (24 vs 72 hours). In head-to-head BCL6 degradation and growth inhibition studies using OCI-Ly1, the ARVN-71228 BCL6 PROTAC TM demonstrates superior activity compared to recently published BCL6-targeted degraders/inhibitors and heterobifunctional molecules. Importantly, medicinal chemistry efforts have resulted in the successful development of orally bioavailable BCL6 PROTAC TM degraders for in-vivo dosing. Time-course studies show >95% BCL6 loss within four hours which is maintained at 8-, 16- and 24-hours. Genes repressed by BCL6 such as BLIMP1 and PTPN6 are derepressed and show increased protein levels 24 hours post-dose. ARVN-71228 achieves regressions in the GCB OCI-Ly1 CDX model. Future studies plan to look at rational drug combinations with BCL6 PROTAC TM degraders to find collaborative or synergistic pathways to target, especially in the HR-DLBCL subtypes where there is a high unmet medical need. Disclosures Gough: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Sherman: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. DeCarr: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Eaton: Arvinas: Current Employment, Current equity holder in publicly-traded company. Milanovic: Arvinas: Current Employment, Current equity holder in publicly-traded company. Bookbinder: Arvinas: Current Employment, Current equity holder in publicly-traded company. Pizzano: Arvinas: Current Employment, Current equity holder in publicly-traded company. Altieri: Arvinas: Current Employment, Current equity holder in publicly-traded company. Corradi: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Xiao: Arvinas: Current Employment, Current equity holder in publicly-traded company. Gallego: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Soto: Arvinas: Current Employment, Current equity holder in publicly-traded company. Lingamaneni: Arvinas: Current Employment, Current equity holder in publicly-traded company. Chen: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Zhang: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Wang: Arvinas: Current Employment, Current equity holder in publicly-traded company. Dong: Arvinas: Current Employment, Current equity holder in publicly-traded company. Chirnomas: Arvinas: Current Employment, Current equity holder in publicly-traded company. Berlin: Arvinas: Current Employment, Current equity holder in publicly-traded company. Hornberger: Arvinas: Current Employment, Current equity holder in publicly-traded company. Snyder: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Taylor: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months.

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Evolving Paradigms in the Treatment of Newly Diagnosed Multiple Myeloma

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2011.0096 ◽

2011 ◽

Vol 9 (10) ◽

pp. 1186-1196 ◽

Cited By ~ 6

Author(s):

Alessandra Larocca ◽

Antonio Palumbo

Keyword(s):

Multiple Myeloma ◽

Treatment Options ◽

Young Patients ◽

Novel Agents ◽

Immunomodulatory Drugs ◽

Newly Diagnosed ◽

The Past ◽

Treatment Paradigm ◽

Novel Agent

The treatment of multiple myeloma has undergone significant changes in the past few years. The introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, has dramatically improved the outcome of this disease and considerably increased the treatment options available. Several trials have shown the advantages linked to the use of novel agents both in young patients, who are considered eligible for transplantation, and elderly patients, for whom a conventional therapy should be considered. These novel agents may increase the efficacy of autologous stem cell transplantation with deeper and long-lasting response. In the transplant setting, different novel agent combinations have proved to be superior to the traditional vincristine-doxorubicin-dexamethasone. Similarly, novel agents have also changed the treatment paradigm of patients not eligible for transplantation, thus replacing the traditional melphalan-prednisone approach. Preliminary data also support the role of consolidation and maintenance therapy to further improve outcomes. This article provides an overview of the latest strategies, including novel agents used to treat patients with multiple myeloma, both in the transplant and nontransplant settings.

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FRI0177 MULTI-MODALITY IMAGING TO EVALUATE LUPUS NEPHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5012 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 672.2-673

Author(s):

C. Dykas ◽

B. H. Rovin ◽

M. Boesen ◽

O. Kubassova ◽

P. Lipsky

Keyword(s):

Image Analysis ◽

Renal Function ◽

Rank Correlation ◽

Renal Perfusion ◽

Imaging Data ◽

Spearman Rank Correlation ◽

Dce Mri ◽

Analysis Group ◽

Multi Center Study ◽

Mean Time

Background:Lupus nephritis (LN) remains a significant cause of morbidity and mortality in subjects with Systemic Lupus Erythematosus (SLE). The gold standard for evaluation of LN remains the kidney biopsy, whereas renal function is usually evaluated by eGFR and urinary protein:creatinine ratio. More effective and sensitive methodology is needed to assess LN and also the response to treatment. Functional imaging of the kidney using quantitative techniques has great potential, as it can assess kidney function and pathologic changes non-invasively by evaluating perfusion, oxygenation, cellular density and fibrosis.Objectives:The objective of this study was to develop a multi-modality imaging approach for the evaluation of the spectrum of pathologic changes in LN and to determine when imaging data correlated with renal functionMethods:In this multi-center study (NCT03180021), subjects who were having a standard of care renal biopsy for LN were asked to participate in the imaging evaluation. Local Institutional Review Board approval was obtained, and subjects signed an Informed Consent Form. Dynamic contrast enhanced MRI (DCE-MRI) was employed to detect changes in vascularization and perfusion, Diffusion Weighted Imaging (DWI) to assess interstitial diffusion, T2*Map/BOLD to evaluate tissue oxygenation and T1rho to evaluate fibrosis (Figure 1). Regions of interest were identified in the imaged kidneys and imaging parameters were correlated with measures of renal function, including eGFR and urinary protein: creatinine ratio. In DCE-MRI, we specifically focused on mean Maximum Enhancement (ME), mean Time to Peak Enhancement (TTP) and mean Time of Washout (Twashout) as indicators of renal perfusion.Results:Nine subjects have been evaluated to date and their imaging data assessed for quality. Evaluation of mean data from DCE-MRI has shown a significant correlation between renal perfusion and renal function. For example, as shown in the figure, the 24 hour protein concentration negatively correlated with ME (rs=-0.81, p=0.015), TTP (rs=-0.83, p=0.01) and Twashout (rs=-0.81.p=0.01, Spearman rank correlation). In addition, the protein:creatinine ratio also negatively correlated with ME (rs=-0.79, p=0.02), TTP (rs=-0.74, p=0.04) and Twashout (rs=-0.79, p=0.02, Spearman rank correlation).Conclusion:These initial results have established the feasibility of multi-modality imaging as a tool to evaluate LN in a multi-center study. Moreover, changes in perfusion detected by DCE-MRI significantly correlate with proteinuria and urinary protein:creatinine ratio. These results suggest that multiparameter imaging may contribute useful data in the evaluation of subjects with LN.Figure:Disclosure of Interests:Claire Dykas: None declared, Brad H Rovin Grant/research support from: GSK, Consultant of: GSK, Mikael Boesen Consultant of: AbbVie, AstraZeneca, Eli Lilly, Esaote, Glenmark, Novartis, Pfizer, UCB, Paid instructor for: IAG, Image Analysis Group, AbbVie, Eli Lilly, AstraZeneca, esaote, Glenmark, Novartis, Pfizer, UCB (scientific advisor)., Speakers bureau: Eli Lilly, Esaote, Novartis, Pfizer, UCB, Olga Kubassova Shareholder of: IAG, Image Analysis Group, Consultant of: Novartis, Takeda, Lilly, Employee of: IAG, Image Analysis Group, Peter Lipsky Consultant of: Horizon Therapeutics

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Cost-utilization of peripheral intravenous cannulation in hospitalized adults: An observational study

The Journal of Vascular Access ◽

10.1177/1129729820901653 ◽

2020 ◽

Vol 21 (5) ◽

pp. 687-693 ◽

Cited By ~ 1

Author(s):

Fredericus HJ van Loon ◽

Tina Leggett ◽

Arthur RA Bouwman ◽

Angelique TM Dierick-van Daele

Keyword(s):

Catheter Insertion ◽

International Standards ◽

Personnel Costs ◽

Peripheral Intravenous Catheter ◽

Nurses And Physicians ◽

Supply Costs ◽

Cost Utilization ◽

The Cost ◽

Hospital Protocols ◽

Mean Time

Aim: In modern healthcare there is increased focus on optimizing efficiency for every treatment or performed procedure, of which reduction of costs is an important part. With this study, authors aimed to calculate the cost of peripheral intravenous cannulation including all components that influence its price. Methods: This observational cost-utilization study was conducted between May and October 2016. Hospitalized adults were included in this study, who received usual care. Peripheral intravenous cannulation was carried out according to current hospital protocols, based on international standards for peripheral intravenous catheter insertion. Device costs were assumed equal to the number of attempts multiplied by the fixed supply costs and applicable costs for additional attempts, whereas personnel costs for both nurses and physicians were based on their hourly salary. Results: A total of 1512 patients were included in this study, with a mean of 1.37 (±0.77) attempts and a mean time of 3.5 (±2.7) min were needed for a successful catheter insertion. Adjusted mean costs for peripheral intravenous cannulation were estimated to be €11.67 for each patient, but costs increase as the number of attempts for successful cannulation increases. The cost for patients with a successful first attempt was lower, at approximately €9.32 but increased markedly to €65.34 when five attempts were needed. Conclusion: Prevention of multiple attempts may lower the costs, and furthermore, additional technologies applied by nurses to individual patients based on predicted difficult intravenous access will make the application of these additional technologies, in turn, more efficient.

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