Citations

Introduction: Most induction regimens for multiple myeloma (MM) contain bortezomib. In most clinical trials, bortezomib has been prescribed either intravenously or subcutaneously twice per week in 21-day or 28-day cycles. However, several retrospective single-center studies have shown that once-weekly bortezomib has comparable efficacy and less peripheral neuropathy compared to twice-weekly bortezomib ( Sidana et al, PLoS One 2017; Cook et al, AJH 2021). These findings have also been confirmed by a secondary analysis of data from three prospective Phase 3 randomized studies ( Mateos et al, Haematologica 2014). As such, many clinicians have adopted once-weekly bortezomib regimens in routine care in the past decade. However, the real-world (RW) prevalence and efficacy of once-weekly vs twice-weekly bortezomib regimens in a larger population have not yet been characterized. Methods: This study used US nationwide longitudinal Flatiron Health electronic health record-derived de-identified data. We included patients aged 18-70 years with newly diagnosed MM between 2017-2022 with ≥ 6 months of follow-up and ≥ 2 clinical visits who were treated with a first-line (1L) bortezomib-containing regimen. Patients aged >70 were excluded a priori given the likelihood of altered practice patterns and more frequent comorbidities. Twice-weekly bortezomib was defined as patients for whom the most frequent interval between two doses of 1L bortezomib within a cycle was 3.0-4.9 days, while once-weekly bortezomib was defined as a corresponding interval of 5.0-9.9 days. We used multivariable logistic regression to assess demographic and clinical factors associated with once-weekly vs twice-weekly (reference) bortezomib. RW progression free survival (rwPFS) and RW overall survival (rwOS) from 1L treatment initiation were estimated using the Kaplan-Meier method. Outcomes were compared using Cox proportional hazards model including transplant as a time-varying covariate and adjustment for other demographic and clinical factors. Results: Of 2,522 patients included, 927 (36.8%) received twice-weekly while 1,522 (63.2%) received once-weekly bortezomib. Approximately half of patients (50.3%) were non-Latinx White, 21.7% non-Latinx Black, and 8.0% Latinx. Most patients were treated in the community setting (78.8%). Rates of once-weekly bortezomib administration were 66.2% and 62.1% among patients treated at academic and community practices, respectively. The frequency of weekly bortezomib use increased over time, from 58.0% between 2017-2019 to 68.8% between 2020-2022. In multivariate analysis, ECOG PS ≥ 2 (odds ratio [OR] 1.50; [95% CI 1.14 to 1.99] vs ECOG PS 0), and more recent year of diagnosis (OR 1.14; [95% CI 1.08 to 1.20] per year) were associated with higher odds of receiving once-weekly bortezomib. Conversely, Latinx patients vs non-Latinx White (OR 0.60 [95% CI 0.44 to 0.82]) and patients with ≥ 2 high-risk cytogenetic abnormalities (HRCA) vs 0 HRCA (OR 0.66 [95% CI 0.48 to 0.91]) had lower odds of receiving once-weekly bortezomib administration. No significant associations were found between gender, ISS stage, practice setting, insurance category, or baseline creatinine. There was no statistically significant difference in rwPFS among patients receiving once-weekly (median 37.3 months, 95% CI 33.8 to 42.5) vs twice-weekly bortezomib (median 39.2 months, 95% CI 32.9 to 42.8) (HR 0.87 [95% CI 0.77 to 1.00]) (Figure 1A). Similarly, there was no statistically significant difference in rwOS with median 25.5 months follow-up (Figure 1B). Median rwOS was not reached in either group (hazard ratio 0.89 [95% CI 0.75 to 1.07]). Discussion: We evaluated US bortezomib prescribing patterns for the first time in the modern era using a large nationwide RW-study. Whereas prescribing patterns have shifted towards once-weekly bortezomib over time, over 30% of patients diagnosed in the last three years received twice-weekly bortezomib. Importantly, once-weekly and twice-weekly bortezomib performed comparably with regard to rwPFS and rwOS. While our study did not analyze neuropathy or patient quality of life, once-weekly bortezomib is known to be associated with less neuropathy and less time in clinic. These data further support the conclusion that once-weekly bortezomib should be considered the standard of care for newly diagnosed patients with MM.

Background: Chemotherapy in combination with radiotherapy (RT) is the standard for early-stage (ES) Hodgkin lymphoma (cHL). Despite high cure rates (12-year overall survival (OS) >93%), there is room to improve short and long-term outcomes for children and adults with ES cHL. Incorporation of immunotherapy (IO) into front line treatment of ES cHL is an opportunity to both improve progression-free survival (PFS) and maintain OS, while minimizing long-term morbidity and mortality by reducing exposure to RT and high-dose chemotherapy. Study Design and Methods: HL leaders of the NCTN groups, expert HL researchers and physicians, and representatives from the Cancer Therapy Evaluation Program (CTEP) formed a working group in April 2020 with the goals of harmonizing treatment approaches for ES cHL across pediatric and adult patients and reaching consensus regarding the optimal study design for incorporating IO therapy into frontline treatment. Study champions identified from each of the North American cooperative groups [Children's Oncology Group (COG), SWOG, ECOG-ACRIN, Alliance, NRG] and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes (PROs) were included. The resulting COG-led clinical trial, AHOD2131, represents the largest ES cHL trial in the history of North American cooperative groups and the first to enroll patients across the age continuum. AHOD2131 (NCT05675410; Figure) is a randomized, phase 3 trial enrolling patients ages 5 to 60 years with newly diagnosed, previously untreated stage I and II cHL and will investigate the addition of the CD30-antibody drug conjugate brentuximab vedotin (Bv) with PD-1 blockade (nivolumab) compared to standard chemotherapy +/- RT. Since the April 2023 activation, 97 North American sites have activated the trial, and 21 participants have enrolled. Target enrollment is 1875 patients over 5 years of accrual, for an estimated 1782 eligible and evaluable patients. The primary objective is to compare the 3-year PFS of patients with ES cHL treated through a response-adapted, superiority design with either standard therapy or with an IO approach (BV + nivolumab). All patients will be stratified as favorable or unfavorable based on disease risk features at enrollment. Based on initial response assessment by PET/CT (via central review) after 2 cycles of ABVD, patients were classified to PET2 positive (SER, defined as 5 Point Score 4 or 5, ~15% of patients) and PET negative (RER). Those who are PET positive will receive involved site RT (ISRT). The SER and RER patients will be randomized to standard chemotherapy vs. IO therapy respectively. In addition to the primary outcome of PFS, there are 11 secondary and 10 exploratory aims. The secondary aims focus on OS, PFS of subgroups, and event-free survival at 12 years, physician-reported treatment-related adverse event (AE) rates, patient-reported AE using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the capture of representation by self-report and the use of electronic PRO data collections. The exploratory aims include the assessment of imaging central review as compared to local institutional review and the use of convolutional neural networks through artificial-intelligence machine learning. The study will examine the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and OS for up to 12 years. The study will compare patient self-report and provider AE reports and evaluate the associations of self-reported race/ethnicity and social determinants of health (SDOH)and post-progression/post-relapse OS. AHOD2131 strengthens the effort between the North American cooperative groups to conduct collaborative clinical trials and aims to harmonize an improved standard of care for ES cHL across the age continuum.

*Drs. Yifan Zhai and Sikander Ailawadhi are co-corresponding authors Background R/R MM is an incurable condition, with virtually inevitable relapse. AL amyloidosis is a rare disease that may cause serious illness and even death. Lisaftoclax is a novel, potent, selective BCL-2 inhibitor under clinical development for treatment of patients with hematologic malignancies or solid tumors, and has shown clinical antitumor benefits. In a previous study on chronic lymphocytic leukemia, lisaftoclax was shown to require only a short (daily vs weekly) dose ramp-up to mitigate tumor lysis syndrome and was associated with a low incidence of adverse events (AEs) (Ailawadhi et al. J Clin Oncol 2021;39:abstract 7502; Davids et al. Blood 2022;140[suppl 1]:2326-2328). Methods This multicenter study evaluated lisaftoclax combined with pomalidomide and dexamethasone (Arms A and C) or daratumumab, lenalidomide, and dexamethasone (Arm B) in patients with R/R MM (Arm A and B) or R/R amyloidosis (Arm C). Eligible patients had an ECOG performance status ≤ 2; ≥ 1 prior line of therapy; and adequate organ function. Patients with R/R amyloidosis also needed confirmed symptomatic organ involvement, in addition to purpura and/or carpal tunnel syndrome. Lisaftoclax was administered orally daily (QD) at 5 dose levels (400, 600, 800, 1,000, and 1,200 mg) without ramp-up in repeated 28-day cycles. Pomalidomide, daratumumab, and lenalidomide were administered per label use. Dexamethasone 40 mg (20 mg for patients aged > 75 years) was administered on Days 1, 8, 15, and 22 of 28-day cycles. Study objectives were safety and efficacy assessments of the combination treatments. Results As of July 3, 2023, a total of 30 patients were enrolled: 22 in Arm A at dose levels of 400 (n = 3), 600 (n = 4), 800 (n = 3), 1,000 (n = 6), and 1,200 mg (n = 6); 3 in Arm B at 600 mg; and 5 in Arm C at 400 (n = 1) and 600 mg (n = 4). A total of 66.7% of patients were male, and the median (range) age was 70.5 (24-88) years, with 66.7% of patients above the age of 65. The median (range) lines of prior therapies was 4 (1-19), and median (range) time from diagnosis to first dose was 5.2 (1-29) years. The median (range) number of treatment cycles was 4 (1-19). A total of 18 patients were triple-class-exposed, 7 had received pomalidomide, and 3 harbored t(11;14) at baseline. A total of 19 patients reported experiencing any-grade lisaftoclax treatment-related adverse events (TRAEs), including neutropenia or nausea (16.7% each); and thrombocytopenia, leukopenia, abdominal distension, constipation, or diarrhea (6.7% each). Seven patients experienced grade ≥ 3 TRAEs, including neutropenia (10%) and febrile neutropenia, iron deficiency anemia, thrombocytopenia, prolonged electrocardiogram QT interval, and acute kidney injury (3.3% each). Two patients experienced lisaftoclax-related serious AEs, of which 1 was febrile neutropenia and 1 acute kidney injury. In Arm B, 1 patient experienced a dose-limiting toxicity (prolonged QT interval). A total of 12 patients discontinued treatment because of disease progression (n = 8), an AE (n = 1), noncompliance (n = 1), and investigator/patient decision (n = 2). In Arm A, 21 patients with R/R MM were evaluable, of whom 9 experienced a partial response (PR) and 5 a very good PR (VGPR). The overall response rate (ORR [PR or better]) was 66.7%, with a median (range) time to response of 1.2 (1-3) months. After a median (range) time to response of 1.4 (1-2) months, 2 patients with R/R MM in Arm B achieved a PR (n = 1) or VGPR (n = 1). In Arm C, 3 patients with R/R amyloidosis achieved a hematologic VGPR; the ORR was 60%; the median (range) time to response was 0.9 (1-1) month; and 1 patient experienced organ function improvement. Conclusion Lisaftoclax, combined with novel therapeutic regimens, was well tolerated and has demonstrated preliminary antitumor activity in patients with AL amyloidosis or R/R MM. Internal study identifier: APG-2575-MU101; clinical trial registration: NCT04942067.

Introduction: Waldenström macroglobulinemia (WM) is a rare B-cell lymphoma that may be preceded by an asymptomatic IgM-monoclonal gammopathy of undetermined significance (MGUS). The mechanisms underlying the progression from IgM-MGUS to WM remain to be fully elucidated; however, the stepwise accumulation of genomic abnormalities has been suggested as a potential driver. Currently, the role of epigenetic regulation of DNA remains underexplored in this disease spectrum. Aberrant DNA methylation is a hallmark of oncogenesis that plays an important role in hematologic malignancies. The aim of this study was to assess differential DNA methylation in WM compared to IgM-MGUS and identify hyper- and hypomethylated pathways that may alter key cellular functions. Methods: This study included 15 patients with WM and 6 with IgM-MGUS. Bone marrow samples were prospectively collected and CD19+ and/or CD138+ B cells were positively selected. Subsequently, genome-wide DNA methylation analysis was performed. CpG methylation ratios were segmented into 200-bp regions and differentially methylated regions (DMRs) comparing WM to IgM-MGUS were identified. DMRs with a Q-value <0.05 and absolute methylation difference of ≥20% were considered significant and utilized for analysis. DMRs were annotated according to genomic regions of interest (promotors, 3'UTR, 5'UTR, introns, exons, CpG islands, CpG shores). Next, genes with significant promotor hyper- or hypomethylation were assessed using the Ingenuity Pathway Analysis. Pathways with a corrected p-value<0.05 were considered statistically significant and a Z-value was calculated based on the degree of differential methylation. Results: Genome-wide DNA methylation analysis revealed a significant number of DMRs (n= 15691, hyper: 8248; hypo: 7443) in WM compared to IgM-MGUS. Assessing genomic regions, promotors (hyper: 1379; hypo: 2403), introns (hyper: 1548; hypo: 2292), CpG shores (hyper: 587; hypo: 849) and 3'UTR (hyper: 66; hypo: 193) regions were observed to have a significantly greater number of hypomethylated DMRs (all comparisons, p<0.001) in WM compared to IgM-MGUS (Figure A). While exons (hyper: 1686; hypo: 1378), CpG islands (hyper: 2128; hypo: 82), and 5'UTR (hyper: 854; hypo: 246) regions had a significantly greater number of hypermethylated DMRs (all comparisons, p<0.001) (Figure A). Next, promotor methylation-based pathway analysis revealed differential methylation of multiple cellular pathways important in WM pathogenesis (Figure B). These included pathways involved in intracellular signaling and the regulation of cellular proliferation, such as the STAT3 and CXCR4 pathways which were hypomethylated, and the PTEN signaling pathway which was hypermethylated. Of interest, we have previously demonstrated the transcription factor, STAT3, to have an increased expression in WM and to be implicated in IgM secretion (Elsawa, 2011). Next, multiple cytokine signaling pathways were observed to be hypomethylated in WM compared to IgM-MGUS including members of the interleukin (IL) family (IL-1, IL-8, IL-15, IL-23), VEGF, and TGF-β. Of relevance, previous studies have demonstrated the elevation of IL-8, IL-15, and increased expression of angiogenic cytokines, including VEGF, in patients with WM (Lewicki, 2010; Anagnostopoulos, 2007). Furthermore, our group has also shown miRNA-based epigenetic regulation of IL-8 and IL-15 in WM compared to IgM-MGUS (Chohan, 2023). Lastly, several pathways critical in the regulation of the cell structure and the extracellular matrix (ECM) were found to be hypomethylated including the FGF, actin cytoskeleton, PAK, and FAK signaling pathways. Of note, the FGF/FGFR axis has been demonstrated to be dysregulated in WM, and its targeting has been shown to halt WM cell growth (Sacco, 2021). Conclusions: This study demonstrates differential DNA methylation of key genomic regions in WM compared to IgM-MGUS. Promotor methylation-based analysis reveals hypomethylation of several important cellular pathways involved in cytokine signaling, cell structure/ECM, and intracellular signaling. These results underscore the influence of epigenetics in the IgM-gammopathy disease spectrum and suggest the potential role of aberrant DNA methylation underlying the malignant progression from IgM-MGUS to WM.

Introduction: Treatment options for multiple myeloma (MM) are evolving rapidly with recent introduction of BCMA-targeting CAR-T (Ide-cel, Cilta-cel) and bispecific antibody (Bi-Ab; Teclistamab) alternatives. These are complex, logistically demanding therapies, and patient awareness/knowledge can affect treatment decisions. There are traditionally underserved patients in MM, and awareness among them must be investigated to uncover disparities which may impact their access to and choice of novel therapies, contributing to disparate outcome. Methods: The study involved an anonymous 25-question online English language survey covering basic demographics, understanding of available T-cell directed MM treatments (CAR-T, Bi-Ab), and preferences for these agents. MM patients within the Mayo Clinic database and members of International Myeloma Foundation's MM support groups were sent a link to the voluntary survey. The survey was active from March 30 until July 12, 2023. Descriptive statistics were calculated with R language (Bluesky Statistics, V7.40), and categorical variables among outcome demographic groups were compared using Pearson Chi-square test (p-value ≤0.05 considered statistically significant). Multiple model logistic regression was used for multivariate analysis amongst statistically significant outcomes. Results: The survey had 2370 respondents with median age 68 years (range: 30-95) and median age at MM diagnosis 62 years (range: 18-88). Time since diagnosis was <5 years in 59.5%. Majority of the respondents (89.4%) were non-Hispanic Whites (NHW). Maximum education categories were high school (10.9%), some college but no degree (18.1%), associate/bachelor (39.7%), and master's/professional (32.3%). Geography and type of residence were reported as: West (24%), Midwest (46.2%), Northeast (3.3%), South (24.8%), outside U.S. (1.7%), and rural (26.7%), urban (21.4%), suburban (51.9%). The goals of MM treatment in order of reported importance were complete remission (66.1%), longer survival (55.3%) and low symptom burden (43.3%). Only 6.5% and 2.6% of respondents had received CAR-T and Bi-Ab, respectively, while 27.9% and 70.5% had never heard of CAR-T and Bi-Ab, respectively. A high proportion of respondents did not understand the risks/benefits of CAR-T (65.5%) or Bi-Ab (90.7%). Given a preference among CAR-T products, 5.4% would prefer Cilta-cel, 1.9% Ide-cel and 92.7% were not sure/no preference. Amongst only those who reported understanding the risks/benefits of CAR-T, the majority (73%) said they would prefer Cilta-cel. The majority (87.5%) were not sure of any differences between the two CAR-T products while some reported different targets (6.3%), response rate (5.9%), response duration (6.2%), side effects (4.9%), and manufacturing time (2.7%). The biggest concern for both CAR-T and Bi-Ab was side effects. Majority (89.4%) were not sure that Teclistamab Bi-Ab targeted BCMA, and nearly 70% felt that CAR-T was superior to Bi-Ab for treating MM. Reported sources of knowledge about MM treatment were healthcare team (82.6%), online resources (43.6%) and other patients/support groups (37.9%). Several demographic characteristics that significantly affected patient's responses to different questions in the survey. Selected questions and respondent categories with statistically significant results in multivariate analysis are shown in Table 1. Generally, higher education, living in northeast U.S., urban or suburban residency, and >5 years since MM diagnosis were associated with better awareness/understanding of CAR-T and Bi-Ab. Respondents with >70-year age were less likely to be aware of these agents or understand their risks/benefits. Race-ethnicity had no statistically significant associations in this cohort of predominantly NHW. Conclusions: This large cross-sectional study identifies lack of adequate awareness regarding CAR-T and Bi-Ab and provides a glimpse of current understanding of these complex therapies. There are disparate groups including rural, less educated, elderly and those with recent diagnosis of MM who have significantly lesser awareness. Some better-informed respondents had preferences among these treatments. Targeted awareness campaigns should be developed so that knowledge gaps can be bridged and patients across all sociodemographic groups are better equipped to take informed decisions about MM treatment.

Background CV mortality has been recognized as the preventable cause of death in most cancers. However, there is a scarcity of data exploring CV mortality in adults diagnosed with leukemia. Hence, understanding the timing, and quantifying the magnitude of CV mortality can facilitate strategies to reduce the burden of mortality in these patients. Methods Surveillance, Epidemiology, and End Results (SEER) database (2004-2018) was queried to obtain CV mortality (defined as deaths due to heart diseases, hypertension, cerebrovascular diseases, atherosclerosis, and aortic aneurysm and dissection) in adults (>18 years of age) diagnosed with leukemias including acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Standardized mortality ratios (SMRs) were calculated. SMR was defined as the observed deaths from each category divided by the expected number of deaths in the age-matched US population for the same period. SMR >1 indicated increased while <1 indicated decreased mortality. SMR was presented by latency periods of <2, 2-5, and >5 years after the initial diagnosis of leukemias and stratified by age (<50 years, 50-70 years, >70 years), race (White, Black, Asian/Pacific Islander, Native American), ethnicity (Hispanic, Non-Hispanic), and marital status (married vs single/divorced/widowed). Results This analysis included 120,193 leukemia patients. Of which, 61,763 had lymphocytic leukemia and 58,430 were diagnosed with myeloid leukemia. In overall population, a significant increase in mortality was observed in adults diagnosed with leukemia (SMR: 1.34, 95% CI: 1.27-1.40). The risk of CV death was highest <2 years of initial diagnosis (1.94, 1.87-2.01) as compared to the population who died 2-5 years (1.17, 1.11-1.23) and >5 years (1.07, 1.01-1.14) after the initial diagnosis. In terms of different subgroups, patients aged <50 years observed the highest risk of CV mortality within < 2 years (9.35, 6.54-13.38) compared to patients aged 50-70 years (2.73, 2.45-3.04), and aged >70 years (1.80, 1.73-1.88). Similarly, regarding race, Asians/Pacific islanders had the highest risk of CV mortality (4.41, 3.70-5.26) followed by Blacks (2.58, 2.26-2.94), and Whites (1.85, 1.78-1.92) within <2 years of initial diagnosis. There was a significant increase in observed mortality in Hispanic (2.83, 2.47-3.23) as well as in non-Hispanic (1.90, 1.83-1.97) population within <2 years of initial diagnosis. However, the magnitude was relatively higher in Hispanic as compared to non-Hispanics. The risk of CV death was observed to be higher in single/divorced/widowed patients (2.30, 2.00-2.20) compared to those who were married (1.81, 1.71-1.91). The CV mortality risk remained consistent for all subtypes of leukemias (ALL, CLL, AML and CML) in overall patient population and among subgroups of interest over different latency periods of <2, 2-5, and > 5years after the initial diagnosis. Small sample size in Native Americans precluded any meaningful statistics. Conclusions: Risk of CV mortality among adults with leukemia is observed to be highest among younger (<50 years), Asians, Hispanics, and single/divorced/widowed patients, especially within 2 years of initial diagnosis. A risk-adapted approach may be warranted for cardiovascular care in these patients. Targeted cardio-oncological strategies should be aimed at improving CV mortality in patients who are at the highest risk of death.

Introduction: Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are the most prevalent types of leukemia in the United States. Given the emergence of novel CLL/SLL therapies, it is important to understand real-world treatment characteristics and unmet needs. The objectives of this retrospective cohort study were to examine patient characteristics, treatment patterns, and associated outcomes for patients with CLL/SLL, overall, and by CLL and SLL, respectively. Methods: A retrospective study was conducted using Symphony Integrated Dataverse (IDV ®), a comprehensive, longitudinal, open-claims database, and integrated electronic medical record data. Patients aged ≥18 years with ≥1 diagnosis for CLL or SLL and who initiated a first-line or second-line treatment between January 1, 2020, and December 31, 2022 (index period) were included in the study. Index date was defined as the date of treatment initiation. Patients were required to be continuously enrolled for 365 days prior to the index date and ≥90 days following the index date. Patient data were included until patients were lost to follow-up or to the end of the study period (March 31, 2023). Treatment patterns were examined with the following treatment regimens and stratified by line of therapy: chemotherapy (including bendamustine-based and other chemotherapy), anti-CD20-based, Bruton tyrosine kinase inhibitors (BTKiibrutinib- and acalabrutinib-based), and venetoclax-based therapy. Zanubrutinib use was not captured in the BTKi treatment category as its CLL/SLL indication approval date (January 19, 2023) was outside the index period. Discontinuation rate was defined as the percentage of patients who discontinued their current treatment regimen within 90 days. Healthcare resource utilization was measured by number of outpatient visits, inpatient visits, and other medical/hospital services per patient per month (PPPM) during the treatment regimen. Results:There were 17,748 and 5,667 patients with CLL/SLL who initiated a first-line or second-line treatment regimen during the index period, respectively. The most frequently used treatment regimens in first line were BTKi (49.9%), followed by anti-CD20 (26.1%), venetoclax (15.4%), and chemotherapy (8.6%). BTKi continued to be the predominant treatment (49.6%) in second line, followed by venetoclax (30.9%), chemotherapy (10.4%), and anti-CD20 (9.2%). First-line patients treated with BTKi regimens were older and Medicare-insured when compared with patients receiving venetoclax-based regimens (65+ years: 77.1% vs 66.9%, P-value <0.001; Medicare: 61.7% vs 53.0%, P-value <0.001). Patients receiving BTKi had significantly lower discontinuation rates compared with other treatment regimens during both first and second lines of therapies (Figure 1). Mean PPPM outpatient visits, inpatient visits, and other medical/hospital services were less frequent with BTKi therapies vs other treatment regimens across both lines of therapy (Table 1). Of the 17,748 patients initiating first line of therapy, 13.3% had SLL while the remaining 86.7% had CLL. The proportion of patients with SLL vs CLL decreased in second line and second line or later (8.0% vs 92.0% and 6.8% vs 93.2%, respectively). Treatment discontinuation rate in SLL patients was higher than that in CLL patients in first line (32.41% and 25.08%, respectively); however, discontinuation rates became comparable with later lines of therapy. Across all lines of therapy, healthcare resource utilization was significantly higher in SLL patients than CLL patients. Median PPPM outpatient visits were 1.02 for SLL and 0.67 for CLL. Median PPPM for other medical/hospital services was 0.7 for SLL and 0.23 for CLL. Conclusions: BTKi therapy, the primary treatment regimen across first- and second-line therapies, has significantly lower discontinuation rate and healthcare resource utilization compared with other treatment regimens. Further studies are needed to evaluate real-world clinical outcomes of CLL/SLL regimens to support evidence-based treatment decisions.

Introduction: Telemedicine has been widely utilized in the healthcare marketplace since the beginning of the COVID-19 pandemic. Over the last 3 years, virtual care has been widely employed in the care of patients with polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) at Mayo Clinic. These rare disorders have few experts; therefore, telemedicine becomes an optimal approach for patients receive expert care even when they are not close to the medical center. 1 Additionally, telemedicine reduces financial burden for the patients. We aim to estimate potential cost savings to patients utilizing telemedicine. Methods: We identified patients with MPN seen at Mayo Clinic, Arizona who have had at least 2 visits (1 or more virtual visits) between March 2020 and June 2022. We extracted retrospective data from electronic medical records (EMR) including sociodemographic data, disease related data and number of visits - both virtual and in person - of the patients identified. The address recorded from the EMR was assumed to be the patient's location at the time of virtual visit. Driving distances were determined using zip codes in Google Maps and the patients were stratified into quartiles based on round trip travel distances. Patients in quartiles 1 through 3 were assumed to have driven while patients in quartile 4 were assumed to have traveled by plane. Patients in quartile 1 were assumed to have 1 travel day including the follow-up visit and no accommodation, patients in quartile 2 were assumed to have 2 travel days including the follow up visit and 1 night of accommodation whereas patients in quartiles 3 and 4 were assumed to have 2 travel days, 1 day for the follow up visit and 2 nights of accommodation. Mileage rate costs were based on US Internal Revenue Service (IRS) standard mileage rates for medical or moving purposes for 2021. 2 Owing to extreme variability in flight costs, flying costs were assumed to be equal to the driving costs. Per diem costs for accommodation and meals and incidentals were based on the US General Services Administration (GSA) 2021 rates for Phoenix 3 with the cost being 75% of the full per diem rate on traveling days via GSA formulaic approach. Results: One hundred and eight patients having 282 virtual visits were identified. Patients ranged from 30 - 87 years with the mean and median age of 65 years and 67 years respectively. Majority of the patients were female (62%) and white (98%) with gender distribution varying by distance. Descriptive statistics of the estimated out-of-pocket costs for patients by distance quartiles are summarized in Table 1a. Mean estimated cost savings ranged from $46.8 to $877.3 with the savings of $43.8 - $1372.2 at extremes. The total cost savings by all patients was $90,306.7. The breakdown of costs by category for each quartile is shown in Table 1b which shows that the majority of costs saved by patients in quartile 1 were due to avoiding costs spent on meals and incidentals (~90% of mean costs) whereas costs saved due to meals and incidentals for patients in quartile 4 were only ~16% of the mean costs. Conclusions: Our research highlighted telemedicine as a cost-effective approach for patients with MPN who received virtual care from March 2020 - June 2022. Study limitations included not weighing costs for childcare or accompanying individuals and using driving costs instead of flying costs, however, these considerations potentially underestimate the actual cost savings to the patient. Additionally, since the median age of this population was 65, we didn't include loss of wages to the analysis, which may further underestimate the costs. Despite concerns over billing, reimbursement, and state licensure, virtual care is being established as a critical part of medicine moving forward. 1. Doolittle, G.C. and A.O. Spaulding, Providing Access to Oncology Care for Rural Patients via Telemedicine. Journal of Oncology Practice, 2006. 2(5): p. 228-230. 2. Internal Revenue Service. Standard mileage rates for 2021. Available at: https://www.irs.gov/tax-professionals/standard-mileage-rates 3. US General Services Administration. Per diem rates. Available at: https://www.gsa.gov/travel/plan-book/per-diem-rates/per-diem-rates-results?action=perdiems_report&fiscal_year=2021&state=AZ&city=&zip=85054

Introduction Acute chest syndrome (ACS) is a clinical presentation of fever, chest pain, pulmonary symptoms, and new infiltrates on lung imaging. It affects nearly 50% of patients with sickle cell disease during their lifetime and often leads to hospitalization. The mortality rate is variable ranging from 3 to 9 %. and depends on several factors. We aimed to identify the clinical and epidemiological characteristics of patients admitted with ACS on a national scale and factors affecting clinical outcomes in inpatient setting. Methods: We utilized the National Inpatient Sample (NIS) database 2019 for the purpose of this study. Using this database, we identified patients with a principle diagnosis of ACS using International Classification of Diseases (ICD-10) codes. Data on demographic characteristics such as age, sex, race, insurance type were collected. Additionally, we selected clinically significant medical comorbidities such as asthma, chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD), chronic kidney disease (CKD), heart failure, hypertension, diabetes mellitus (DM), sepsis, obesity, and others. The primary endpoint of this study was to identify factors influencing all-cause mortality, while the secondary endpoint was to identify factors influencing mechanical intubation, in-patient blood transfusion, and length of stay. We used multivariate logistic regression analysis to adjust for confounders. A p value of ≤0.05 considered statistically significant. Results: Baseline Characteristics Our analysis consisted of 22,459 patients who were admitted with principal diagnosis of ACS. 49.5% were female and 50.5% were male. Mean age was 30.5 years. African American race was predominant (92%) with sickle cell Hb-SS disease (87%). Major insurance payer was Medicaid (47%) followed by Medicare (27%) and then private insurance (21%). Asthma was the most common comorbidities (24%) and majority of patient had Charlson Comorbidity Index (CCI) score of zero (55%). The details of clinical and epidemiological characteristics are shown in Table 1. Clinical outcomes and factors influencing mortality Only 0.89% patient died of ACS. Average length of stay was 6.86 days. 34% of the patient required packed red blood cell (pRBC) transfusion. 3.2% needed mechanical ventilation. In multivariate analysis, factors associated with mortality included age of patient, CCI and sepsis. Younger patient had higher odds of mortality however this was not statistically significant. There was no difference in mortality with sex, race and insurance status of the patients. Factors affecting inpatient transfusion, mechanical ventilation and length of stay Female, higher CCI score and sepsis on admission were associated with higher needs of inpatient pRBC transfusion. Within race, White (OR 3.16, CI 1.44-6.93, P <0.01) and Hispanics (OR 2.68, CI 1.59-4.51, P<0.01) had higher odds of receiving transfusion compared to African Americans (OR 1.84, CI: 1.17-2.89, P <0.01). Similarly patient with sepsis, supraventricular tachycardia had more odds of needing mechanical ventilation. Patient's insurance status was also related to increased odds of intubation. Comorbidities such as asthma and CAD were not associated with need of mechanical ventilation and in fact our study shows they had less odd of needing mechanical ventilation. Length of stay was influenced by several of epidemiological and clinical comorbidities. Females had less odds of longer length of stay compared to male (OR: 0.65, P <0.01). Comorbidities such as asthma, heart failure, CAD, DM2 and hypertension did not increase the length of stay while patients with sepsis and high CCI score had higher odds of hospitalization for extended period of time. The details are in Table 2. Conclusion We found mortality was 0.89% in patients admitted with ACS compared to 3 to 9% previously reported. Sepsis and CCI were one of the predictors for odds of having higher mortality, need of blood transfusion, mechanical ventilation and increased length of stay in patient with ACS. Female, White and Hispanic had higher odds of needing transfusion then African Americans. Comorbidities such as asthma, heart failure, CAD, DM 2 and hypertension did not increase the odds of prolonged hospital stay.

INTRODUCTION: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. In prior studies, LUX has been shown to suppress aberrant proliferative signaling in B cell malignancies and acute myeloid leukemia (AML) via regulation of BTK, LYN, SYK, AKT, ERK, and MAPK. LUX is cytotoxic to primary AML cells insensitive to other FLT3 inhibitors and to malignant B-cells insensitive to ibrutinib, at pM and nM concentrations, respectively. AIMS: The primary objectives of these studies are to assess the safety, tolerability, and pharmacokinetics (PK) of LUX and determine recommended phase 2 doses for relapsed or refractory (R/R) AML and B cell malignancy patients. METHODS: In two studies (NCT04477291; NCT03893682), LUX (original formulation, G1) was administered continuously as oral capsules BID in 28-day cycles of ascending cohorts (relapsed or refractory de novo, secondary, or therapy-related AML or higher risk myelodysplastic syndrome (MDS), and relapsed and refractory for B cell lymphoma and chronic lymphocytic/small lymphocytic leukemia). A novel generation 3 (G3) formulation of LUX designed to increase bioavailability was tested at a single-dose (sub-study) for relative bioavailability (RBA), followed by continuous dosing in subsequent R/R AML patients. RESULTS: In the B-cell study (as of 15 th May 2023), LUX has been administered to 36 patients at dose levels from 150 mg to 900 mg BID in patients with a median of 3 lines of prior treatment, with 47.2% having received a BTK-inhibitor. Only one (2.8%) patient had a DLT of hypertension and 14 (38.9%) experienced at least one drug related ≥Grade3 treatment emergent adverse event (TEAE). Two patients (900 mg) are currently on study with no DLT and no ≥Grade 3 related TEAEs. A Follicular lymphoma patient is at cycle 28, and achieved a best response as partial response (PR) with a decrease in lesion size of 76.2%; an SLL patient is at cycle 13, and achieved stable disease (SD) showing a decrease in lesion size of 43.1% (Figure A). The overall best response achieved among the 17 patients who have been on treatment for more than 12 weeks are stable disease (SD) (n=11), partial response (PR) (n=3), minor response (n=2) and complete response (CR) (n=1). As of 5 th June 2023, in the AML trial, a total of 40 patients (16 (40%) FLT3-ITD, 21 (52.5%) FLT3-WT, 2 (5.0%) FLT3-TKD, and 1 (2.5%) unknown mutations) with a median of 3 prior treatments (range, 1 - 10) have been treated with LUX G1 formulation at dose levels from 450 mg - 900 mg BID (n=34) or with 50 mg BID of G3 formulation (n=6). Four (10%) experienced drug related SAE and 7 (17.5%) had a drug related grade ≥3 TEAEs. The most common related TEAEs were lymphocyte count decrease, platelet count decrease, and anemia (n=2; 5% patients each). One (2.5%) patient at 450 mg dose, reported complete remission without minimum residual disease (CRmrd) and remained on study for 56 weeks. In the RBA sub-study, G3 (50 mg) produced comparable exposures to G1 (450-900 mg range) (Figure B) and was, therefore, selected as the starting dose for use in the R/R AML study. Six patients were treated with a continuous dosing of 50 mg BID G3; with plasma levels of 274 ng/mL and 195 ng/mL LUX observed by the end of C1D15 and C1D22 respectively. No drug related Grade ≥3 TEAEs or DLTs were observed in 50 mg BID G3 LUX treated patients; with no new safety signals observed for the G3 formulation. Based on these findings and expected exposures for higher dose levels, the cohort safety review committee has approved escalation of G3 dosing to 200 mg BID at which dosing is ongoing. CONCLUSIONS: LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting.