bluuebunny/crossref_metadata_2025 huggingface dataset:
Racial/ethnic disparities in serious illness communication for patients with cancer.
Authors: Frydman Julia L. , Gelfman Laura P. , Morillo Jose , Allen Olivia S. , Bickell Nina A. , Kwon Deukwoo , Pollak Kathryn I. , Smith Cardinale B.
Published: June 2022

6540

Background: Racial/ethnic disparities in serious illness communication exist between patients with cancer and their oncologists. Our prior work has shown that goals of care discussions are three minutes shorter with racial/ethnic minority patients. In this study, we sought to compare oncologist's use of serious illness communication skills, patient participatory behavior, and overall communication quality during encounters with patients with advanced cancer of different self-reported races/ethnicities. Methods: We analyzed baseline recordings from a two-arm multisite randomized controlled trial to test a coaching model of communication skills training for solid tumor oncologists and their newly diagnosed advanced cancer patients. We audio recorded post-imaging patient-oncologist encounters for patients receiving systemic cancer treatment and coded transcripts for oncologist's use of serious illness communication skills (coded as count/encounter): open-ended questions, reflections, empathic responses to patient empathic opportunities, empathic statements, “sorry” statements, and elicitation of questions. We also assessed global codes of oncologist communication (assessed on 5-point Likert scales): flow, concerns addressed, attention, warmth, and respect. Finally, we coded patient participatory behavior (coded as count/encounter): asking questions and assertive responses. We compared the skills and behaviors by race/ethnicity of the patient using the non-parametric Kruskal-Wallis test. Results: We included the 56 (38%) recordings with oncologists who did not receive the intervention. The patients in these encounters were 25 (45%) female; 32 (57%) over the age of 65; 23 (41%) White Non-Hispanic, 20 (36%) Black Non-Hispanic, and 11 (20%) Hispanic. Overall, oncologists responded empathically to patients’ emotions only 19% of the time. Oncologists used fewer reflective statements with Black Non-Hispanic patients (mean 0.3 statements/encounter) as compared to White Non-Hispanic patients (1.1) and Hispanic patients (1.1), p = 0.02. Furthermore, coders rated oncologists as being less likely to address concerns of Black Non-Hispanic patients (mean Likert scale 3.1) as compared to White Non-Hispanic (3.8) and Hispanic (3.4) patients, p = 0.04. Finally, coders rated oncologists as having less warmth with Black Non-Hispanic patients (mean Likert scale 2.9) as compared to White Non-Hispanic (3.8) and Hispanic (3.3) patients, p = 0.04. Conclusions: In this diverse sample of patients with advanced cancer, oncologists used fewer reflective statements, were less attentive to concerns, and expressed less warmth with Black Non-Hispanic patients. Interventions are needed to overcome these striking racial/ethnic disparities in serious illness communication for patients with cancer.
Evaluation of inpatient chemotherapy among patients with cancer.
Authors: Petrone Giulia , Chowdhury Nobel , Handa Shivani , Anderson Justine , Kwon Deukwoo , Bhardwaj Aarti Sonia , Jain Priya , Smith Cardinale B. , Berger Natalie S
Published: June 2022

6566

Background: Administration of inpatient chemotherapy (IC) is associated with more aggressive end of life care, reduced use of palliative care (PC) and decreased quality of life (QOL). This study aims to identify risk factors associated with overutilization of IC. Methods: We conducted a retrospective chart review of all admissions where IC was administered at an academic center between January 2016 and December 2017. Patients (pts) were stratified by solid tumors (ST) versus hematologic malignancies (HM) and urgency for IC was assessed. We evaluated other variables which can impact patient care such as length of stay (LOS), reason for admission and for IC. Descriptive statistics and odds ratios (OR) were estimated from logistic regression models with mixed-effect taking into account correlations from multiple admissions per patient. All tests were two-sided and statistical significance was considered when p<.05. Results: We analyzed 880 admissions (17% ST). Table 1 summarizes outcomes. HM pts required frequent direct admission for IC compared to ST. ST pts (p<.0001), pts >65 years (p=0.004) and pts with KPS ≤50% (p<.0001) were most likely admitted for cancer complications rather than for IC. LOS (>7 days) was significantly longer in HM admissions (p=0.0001), among pts with stage 4 cancer (p=0.014) and KPS ≤50% (p=0.0001). ST (p=0.006) and pts with KPS ≤50% (p=0.0001) received IC for a non-urgent indication significantly more often than HM. In 20% of ST admissions, pts received IC because the admission coincided with a non-urgent planned cycle compared to 3% of HM. In the adjusted analysis, tumor type was the most important factor correlated with urgency of IC (OR 0.42, 95% CI: 0.25-0.72; p=0.001). ST pts (p=0.0001), older pts (p=0.004) and pts with KPS ≤50% (p=0.0001) were less likely to respond to chemotherapy. Only 15% of HM admissions and 46% of ST admissions had a PC consult. 60-day mortality was significantly higher in ST pts than HM (p=0.002). Conclusions: IC is associated with poorer outcomes for pts with advanced stage ST, pts with poor functional status and pts admitted for acute indications. Additionally, ST pts have a higher mortality after IC compared to HM. Utilization of IC should be standardized to account for different patient characteristics and to reduce the incidence of non-urgent administration. Based on this data, we created a standardized protocol to better assess the appropriateness of IC to improve patient care, QOL, and reduce chemotherapy and healthcare utilization at the end of life. [Table: see text]
Real-world trends of PARPi maintenance treatment uptake and progression-free survival (PFS) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) in the United States.
Authors: Chan John K , Liu Jinan , Song Jinlin , Xiang Cheryl , Wu Eric Q. , Kalilani Linda , Hurteau Jean , Thaker Premal H.
Published: June 2022

6580

Background: Since 2018, the FDA has approved 2 PARP inhibitors (PARPi), niraparib and olaparib, for first-line (1L) maintenance therapy for OC. Using real-world population data, we assessed trends of 1L PARPi maintenance treatment uptake and PFS of pts with newly diagnosed AOC. Methods: Pts diagnosed with AOC between January 1, 2017, and June 30, 2021, who completed 1L chemo were identified from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. We calculated descriptive statistics describing pt demographics, clinico-pathological characteristics, and 1L treatment patterns. The use of PARPi or active surveillance (AS) was identified during a 120-day period after the last dose of 1L chemo. The end of the 1L treatment identification period was defined as the index date. Time to next treatment was used as a proxy for PFS and was defined as time from the index date to the next therapy, last clinical activity, end of study period, or death. Kaplan-Meier methods and Cox models were used to analyze the PFS endpoint. Results: A total of 705 pts were included in the study; 166 received PARPi monotherapy (PARPi mono) and 539 underwent AS after completion of 1L chemo. Median age was 68 y for AS vs. 65 y for PARPi mono (Table). Median time from last chemo to initiation of PARPi mono was 48.5 d. Median follow-up was 20.6 mo for AS and 10.9 mo for PARPi mono. In the overall group, median PFS (mPFS) was 9.53 mo for AS vs. not reached (NR) for PARPi mono. In those with BRCA mutations ( BRCAm), corresponding mPFS was 11.4 mo vs. NR and for BRCA wild type ( BRCAwt) was 9.1 mo vs. 13.5 mo. On multivariate analysis, 1L PARPi maintenance was an independent predictor for improved PFS when compared to AS in all pts (HR, 0.47; 95% CI, 0.34-0.63), BRCAm (HR, 0.17; 95% CI, 0.07-0.41) and BRCAwt (HR, 0.50; 95% CI, 0.35-0.72). Stage IV at initial diagnosis, no debulking surgery, residual disease, and BRCAwt status were associated with poorer PFS. Trends analysis over the 4-year study period showed PARPi mono use increased from 6% in 2017 to 53% in 2021. Conclusions: This real-world analysis shows that adoption of PARPi mono in the 1L maintenance setting in pts with newly diagnosed AOC has increased to 53% in 2021. PARPi use, when compared with AS, was associated with significantly improved mPFS in both pts with BRCAm and BRCAwt. [Table: see text]
Cost effectiveness of reduced intensity conditioning and transplantation of unrelated umbilical cord blood versus HLA haploidentical related bone marrow for adults with hematologic malignancies.
Authors: Steuten Lotte Maria Gertruda , Bansal Aasthaa , Li Li , Brunstein Claudio G , O'Donnell Paul V. , Eapen Mary , Sangaralingham Lindsey R. , Thao Viengneesee , Roth Joshua A. , Wright Winona E , Ramsey Scott David
Published: June 2022

6591

Background: BMT CTN 1101 was a Phase III randomized controlled trial evaluating the comparative effectiveness of unrelated umbilical cord blood (UCB) versus HLA-haploidentical related donor bone marrow (haplo-BM) cell sources for hematopoietic cell transplantation (HCT) in patients with high-risk hematologic malignancies (leukemias, lymphomas). We report results of an economic evaluation conducted as part of the clinical trial. Methods: 368 patients (90% of planned accrual) enrolled from 33 centers in the U.S. were randomly assigned to unrelated UCB (n=186) or haplo-BM (n=182) transplant. Healthcare utilization and costs were estimated using propensity-score matched cohorts of BMT patients in the OptumLabs Data Warehouse for trial participants <65 years, and Medicare claims for trial participants ≥65 years. Cost-effectiveness was calculated from payer perspectives (commercial, Medicare) over a 20-year time horizon from time of transplant. Weibull models (best fit based on AIC/BIC) were used to extrapolate survival from 5-year trial follow-up data. Trial participant surveys (EQ-5D) were used to derive health state utilities for estimating Quality-Adjusted Life Years (QALYs). One-way and probabilistic sensitivity analyses were conducted to assess uncertainty in results. Outcomes were discounted at 3% annually. Results: At 5-year follow-up, overall survival was 42% for haplo-BM versus 36% for UCB (P=.06). Over a 20-year time horizon, haplo-BM is expected to be more effective and more costly for <65 year-olds and in ≥65 year-olds it is expected to be more effective and less costly. In one-way uncertainty analyses, for persons <65, the cost/QALY result was most sensitive to life years and health state utilities. For persons ≥65, life years were more influential than costs and health state utilities. Using probabilistic sensitivity analysis, for persons <65 there was a 43% chance that haplo-BM was cost-effective using a willingness to pay threshold of $150k/QALY and 52% at a $200K/QALY threshold. Conclusions: Results from a large national clinical trial indicate that compared to UCB, haplo-BM was moderately cost-effective for patients aged <65 years, and less costly and more effective for persons ≥65 years. Haplo-BM is a fair value choice for commercially insured patients with high-risk leukemia and lymphoma who require HCT. For Medicare enrollees, haplo-BM is a preferred choice when considering costs and outcomes. [Table: see text]
A quantitative analysis of escalating antineoplastic medication price increases.
Authors: Alevizakos Michail , Bockorny Bruno
Published: June 2022

6592

Background: Established antineoplastic medication prices are overall increasing, yet the yearly trend and additive cost of such increases relative to overall antineoplastic spending is often unclear. Methods: We accessed the yearly reimbursement files from Medicare Part B for parenteral antineoplastic agents (codes J8501-J9999) for the years 2010-2020 and adjusted all values to 2020 USD to account for inflation. We calculated an initial inflation-adjusted price-per-claim for every medication at the time of medication entry to the database and compared that price with the yearly price-per-claim that Medicare reimbursed. For medications whose price had increased beyond the initial inflation-adjusted price, we multiplied the annual differences with the total annual claims of the medication reimbursed in order to calculate the additional cost accrued by Medicare for every affected year. We only included medications with total annual cost >10 million USD/yr in our analysis. Results: Price increases were noted in 70.9% of already established medications annually (median 74.5%, range 52.17-81.48%). This led to an average additional extra cost of 311 million USD (range 156-492 million USD) annually, for a total of 3.1 billion USD over the 10 years of observation. This extra cost represented 4.6-9.3% of the total Medicare Part B spending for antineoplastic medications annually and this percentage rose yearly by a statistically significant 0.43% (95% CI 0.14%-0.73%, P = 0.01; R2 0.59) in absolute terms (Table). Rituximab (1,003 million USD), trastuzumab (421 million USD), and bevacizumab (326 million USD) accumulated the highest extra costs. Conclusions: The majority of established parenteral antineoplastics are affected by escalating price increases beyond the rate of inflation. Year-by-year, these increases occupy a progressively larger part of overall Medicare Part B spending. Since Medicare does not negotiate medication price nor receives rebates but rather relies on average market prices, these increases likely affect other U.S. markets as well.[Table: see text]
Systematic performance status assessment by primary care providers in patients with advanced cancer and its impact on referral to palliative care and cost in a value-based practice.
Authors: Ochoa Roberto Enrique , Salomon Say , King Alexandra , Hosein Peter Joel , Prats Leon Ernesto , Gilbert Candace , Guerra Daniel , Chen Christopher James , Tromanhauser Scott , Chen James
Published: June 2022

6595

Background: Value Based (VB) Care model has been growing in the primary care (PrC) Medicare population, its role in oncology and integration with VB PrC has not been well defined. Key initiatives in VB include reducing hospitalizations by multidisciplinary management of chronic conditions. Earlier Palliative Care (PaC) has shown to favorably impact outcomes. Eastern Cooperative Oncology Group Performance Status (ECOG-PS) is a validated tool used for decision making. Poor PS is associated with worse outcomes and futile end of life care; Guidelines recommend using ECOG-PS to decide on involvement of PaC in patients (pts) with metastatic cancer (mCa). ECOG-PS is subject to significant variability among oncologists and rarely used by PrC providers (PCPs). We created a standardized system for ECOG-PS documentation and monitoring by PCPs in a VB model in a large Medicare Advantage (MA) population with the goal of increasing earlier PaC referrals. Methods: Pts with mCa managed by PCPs in a multi-state MA practice were identified via EMR from February 2021 to September 2021. At every visit, an automated alert asked PCPs to determine pts’ ECOG-PS and for those ≥ 2, recommendation to refer to PaC. PCPs were trained on use of the tool and were given a script to discuss with pts the role of PaC. Hospital admissions as well as total cost of care was measured in pts comanaged by PCP’s & PaC versus those managed by PCPs &Oncology without PaC. Statistical analysis between the groups was done using Pearson's Chi-squared test with Yates' continuity correction. Results: An ECOG-PS was measured in a total of 565 pts with mCa during the study period. Median age was 73 years, 40% were ≥75 yrs. 55% were female. Breast, Prostate, Lung, Colorectal and Gyn ca accounted for 75% cases. ECOG was documented in 97% of patients; 250 (44%) had ECOG ≥ 2, 124 (22%) had ECOG ≥ 3. Of those PaC referral was done by the PCP in 70%, in total 69 patients were comanaged by PC vs 181 who did not. Pts that had PaC involvement were 43% less likely (RR 0.57 [95%CI 0.33,0.98 p = 0.043]) to be admitted compared to patients without PC. Pts without PaC that were admitted had 238% higher admission days per 1,000 pts compared to pts comanaged by PaC. Total medical costs of pts comanaged by PaC was 86% lower after PaC involvement $18,541 3-months prior vs $2,742 3-months after PaC involvemen, driven by lower part A and part B costs (p=0.001) Conclusions: ECOG PS monitoring of pts with mCa by PCPs was very successful, easy to perform and implement in a PrC. Poor PS is common in this medicare advantage population. PaC involvement in pts with poor ECOG-PS was associated with lower admission rates at the end of life, and significantly lower total medical costs. [Table: see text]
Efficacy and safety of intramuscular (IM) recombinant Erwinia asparaginase in acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL): The Children’s Oncology Group (COG) AALL1931 study.
Authors: Maese Luke Devon , Loh Mignon L. , Choi L. Mi Rim , Lin Tong , Aoki Etsuko , Zanette Michelle , Agarwal Shirali , Silverman Jeffrey Alan , Silverman Lewis B. , Raetz Elizabeth A. , Rau Rachel E.
Published: June 2022

7001

Background: The inability to receive L-asparaginase (ASNase) therapy due to hypersensitivity is associated with inferior outcomes in patients with ALL or LBL. JZP458, a recombinant Erwinia-derived ASNase from a Pseudomonas fluorescens expression platform, is approved by the FDA for patients with ALL/LBL who have developed hypersensitivity to E. coli–derived ASNase. Here, we report the efficacy and safety of IM JZP458 from COG AALL1931, a phase 2/3, open-label, multicenter, pharmacokinetic (PK) study. Methods: Eligible patients with ALL/LBL had a grade ≥3 allergic reaction or silent inactivation to a pegylated E. coli–derived ASNase. Each remaining dose of pegylated E. coli–derived ASNase was replaced with 6 doses of IM JZP458 on Monday/Wednesday/Friday (M/W/F) over 2-weeks. Three dosing cohorts were enrolled: Cohort 1a, 25 mg/m2 M/W/F; Cohort 1b, 37.5 mg/m2 M/W/F; Cohort 1c, 25 mg/m2 M/W and 50 mg/m2 F. Efficacy was assessed by the proportion of patients who achieved the last 72-hour (primary endpoint) or 48-hour (key secondary endpoint) nadir serum asparaginase activity (NSAA) levels ≥0.1 IU/mL in the first treatment course. A population PK (PPK) model was developed based on SAA data from AALL1931 to characterize the PK of JZP458 and to inform dosing decisions. Results: 167 patients were enrolled for IM dosing (Cohort 1a, n = 33; Cohort 1b, n = 83; Cohort 1c, n = 51). The median (range) age was 10 (1, 25) years. The median (range) of JZP458 courses received was 5 (1, 14) for Cohort 1a, 5 (1, 15) for Cohort 1b, and 4 (1, 11) for Cohort 1c. Mean (95% CI) SAA levels (IU/mL) at 72-hour were 0.16 (0.12, 0.19) for Cohort 1a, 0.33 (0.27, 0.39) for Cohort 1b, and 0.47 (0.35, 0.59) for Cohort 1c; and 0.45 (0.37, 0.53), 0.88 (0.76, 1.01), and 0.66 (0.54, 0.77), respectively, at 48-hour. Simulated data from the PPK model matched the observed data well. For Cohort 1c, the proportions of patients (95% CI) achieving NSAA levels ≥0.1 IU/mL at the last 72- and 48-hour in Course 1 were 90% (81%, 98%) and 96% (90%, 100%), respectively, based on observed data; and were 92% (91%, 93%) and 94% (93%, 95%) based on modeled data. The Table shows the rates of treatment-related adverse events (TRAEs; all grades) of interest per cohort. Overall, TRAEs leading to discontinuation included pancreatitis (6%), drug hypersensitivity (4%), anaphylactic reaction (2%), increased alanine aminotransferase (1%), and hyperammonemia (1%). There were no TRAEs leading to death. Conclusions: The totality of the results from AALL1931 demonstrate the positive benefit-risk profile of the IM JZP458 dosing regimen of 25 mg/m2 M/W and 50 mg/m2 F with a safety profile consistent with other asparaginases. Clinical trial information: NCT04145531. [Table: see text]
Risk-adjusted safety analysis of pacritinib (PAC) in patients (pts) with myelofibrosis (MF).
Authors: Pemmaraju Naveen , Scott Bart L. , Savona Michael R. , Oh Stephen T. , Harrison Claire , Vannucchi Alessandro M. , Palandri Francesca , Al-Ali Haifa Kathrin , Sobas Marta , McMullin Mary Frances , Gupta Vikas , Mesa Ruben A. , Buckley Sarah , Roman-Torres Karisse , Verstovsek Srdan , Yacoub Abdulraheem
Published: June 2022

7058

Background: PAC is a novel JAK2/IRAK1 inhibitor that has shown significant activity in pts with MF, including those with platelet (plt) counts <50×109/L. Recently, JAK inhibitors have come under increased scrutiny due to specific, emerging toxicities with drugs in this class. This safety analysis focuses on these toxicities of interest for pts treated with PAC 200 mg BID and best available therapy (BAT), including ruxolitinib (RUX), on the Phase 3 PERSIST-2 and Phase 2 PAC203 studies. Data are presented as risk-adjusted incidences to account for differential time at risk for adverse events (AEs) between arms due to cross-over. Methods: Pts treated with PAC 200 mg BID on PERSIST-2 and PAC203, and those treated with BAT on PERSIST-2, were included. Risk-adjusted AEs, representing event rate per 100 patient-years (pt-yrs), were calculated for overall and fatal AEs, bleeding AEs (determined by Standardized Medical Dictionary for Regulatory Activities Query [SMQ]), cardiac AEs (by SMQ), major cardiac events (per major adverse cardiovascular events [MACE] classification), infections, thromboses, and secondary malignancies. Results: A total of 160 pts were analyzed as the pooled PAC group (n=106 in PERSIST-2; n=54 in PAC203) and 98 pts in the BAT group (44 on RUX). At baseline, median plt count was 57×109/L; 61% had prior JAK2 inhibitor therapy. The rate of AEs was higher on PAC versus BAT, while the rate of fatal AEs was lower (Table). Both bleeding and cardiac events occurred at slightly lower rates on PAC compared to BAT. There were no MACE events on PAC, whereas there were on BAT. Malignant neoplasms occurred at similar rates on PAC and BAT, though rate of non-melanoma skin cancers was lower in pooled PAC (3/100 pt-yrs) versus BAT (7/100 pt-yrs), including RUX (11/100 pt-yrs). Infection occurred more frequently on PAC, though fungal and viral infections occurred less frequently, as did herpes zoster reactivation (pooled PAC: 0/100 pt-yrs vs BAT: 2.4/100 pt-yrs, including RUX: 5.5/100 pt-yrs). Thrombosis occurred at similar rates on PAC and BAT. Conclusions: Risk-adjusted analysis demonstrates that the safety profile of PAC 200 mg BID is comparable or superior to BAT, including RUX. PAC 200 mg BID may represent a full-dose therapeutic option for pts with MF, including those with thrombocytopenia. Clinical trial information: NCT02055781; NCT04884191. [Table: see text]
Subcutaneous epcoritamab with rituximab + lenalidomide (R2) in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): Update from phase 1/2 trial.
Authors: Falchi Lorenzo , Leppä Sirpa , Wahlin Bjorn E. , Nijland Marcel , Christensen Jacob Haaber , De Vos Sven , Holte Harald , Linton Kim M. , Abbas Aqeel , Wang Liwei , Dinh Minh , Elliott Brian , Belada David
Published: June 2022

7524

Background: R/R FL is associated with poor prognosis and less frequent, shorter responses with each line of treatment (Tx). Although R2 is an effective regimen in R/R FL with an acceptable safety profile, FL remains incurable; thus, better Tx options are needed. Subcutaneous epcoritamab is a bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells. In the dose-escalation part of the phase 1/2 EPCORE NHL-1 trial, single-agent epcoritamab (0.76–48 mg) resulted in an overall response rate of 90% and a complete response rate of 50% in R/R FL. The distinct mechanisms of action of epcoritamab and R2 may combine to increase antitumor response, with generally non-overlapping toxicity profiles. We present updated data for epcoritamab with R2 in R/R FL (EPCORE NHL-2 arm 2; NCT04663347). Methods: Adults with R/R CD20+ FL received epcoritamab + R2 for 12 cycles (C) of 28 d; epcoritamab was administered at 24 or 48 mg in dose escalation and 48 mg in expansion. During C1, step-up epcoritamab dosing and corticosteroids were required to mitigate CRS. Response was assessed by PET-CT. The epcoritamab regimen for these pts was: Q1W, C1–3; Q2W, C4–9; Q4W, C≥10 up to 2 y. Results: As of December 1, 2021, 30 pts (median age, 68 y) had received epcoritamab + R2 (24 mg, n=3; 48 mg, n=27), 21 pts (70%) had stage IV disease, and 20 pts (67%) had FLIPI scores 3–5. Median (range) number of prior lines of therapy was 1 (1–5), 30% had primary refractory disease, and 40% had disease progression within 24 mo after starting first-line Tx (20% within 24 mo after starting immunochemotherapy). At a median (range) follow-up of 5.1 mo (0.8–12.3), 25 pts (83%) remained on Tx; 5 pts discontinued Tx due to progression (n=2), AEs (n=2), or consent withdrawal (n=1). Common Tx-emergent AEs (TEAEs) of any grade (G) included infections (57%), injection-site reactions (50%), constipation (37%), fatigue (37%), and neutropenia (37%). CRS was seen in 15 pts (50%; G1/2 43%, G3 7%), with most events in C1. All CRS events resolved with standard management, including tocilizumab in 3 pts, and 1 pt discontinued Tx due to CRS. One pt experienced G2 ICANS. No fatal TEAEs occurred. Antitumor activity is shown in the Table. As of the data cut, all responders remained in response, with the longest duration of response being 7.0+ mo and ongoing. Conclusions: Subcutaneous epcoritamab+ R2 exhibits promising efficacy, including a high CMR rate, in pts with R/R FL. The safety profile was consistent with prior data, and CRS events were generally low grade and in C1. Updated data with an additional 30 pts will be presented. Clinical trial information: NCT04663347. [Table: see text]
Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk, transplant-eligible patients with newly diagnosed myeloma: Results of the phase 2 study IFM 2018-04.
Authors: Touzeau Cyrille , Perrot Aurore , Hulin Cyrille , Manier Salomon , Macro Margaret , Caillot Denis , Karlin Lionel , Decaux Olivier , Jacquet Caroline , Tiab Mourad , Leleu Xavier , Planche Lucie , Avet-Loiseau Herve , Moreau Philippe
Published: June 2022

8002

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02, STAMINA). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is evaluating an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensive strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n = 20, 40%), t(4;14) (n = 26, 52%) or t(14;16) (n = 10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to severe adverse event (COVID-19 infection, n = 1 ; drug-induced hepatitis, n = 1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related adverse event ( > 5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-vein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Overall response rate was 96%, including 92 % > very good partial response. Among 37 (/46) evaluable patients post induction, Minimal Residual Disease negativity rate (NGS, 10-5) was 62%. Conclusions: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to evaluate safety and efficacy of the overall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients. Clinical trial information: NCT03606577.
Phase I open-label single arm study of GPRC5D CAR T-cells (OriCAR-017) in patients with relapsed/refractory multiple myeloma (POLARIS).
Authors: Huang He , Hu Yongxian , Zhang Mingming , Ding Xiaomin , Tang Yu , He Xiaowen , Chen Siye , Yang Yue
Published: June 2022

8004

Background: GPRC5D, a type-C 7-pass transmembrane receptor protein, is predominantly expressed on malignant plasma cells from MM patients. The autologous GPRC5D-directed CAR-T cell (OriCAR-017), owning to an additional proprietary Ori element, is the 2nd generation CAR-T cell with improvement in expansion and durability. Methods: The primary objective of this study was to evaluate safety and tolerability of OriCAR-017. Key enrolment criteria included measurable MM adults, R/R or intolerant to established therapies. Patient received lymphodepleting chemotherapy with fludarabine 30mg/m2/d and cyclophosphamide 300mg/m2/d for 3 days followed by a single infusion of OriCAR-017. The trial followed 3+3 design with 1×106/kg, 3×106/kg and 6×106/kg CAR+ T cells cohorts. Results: Eleven patients were enrolled and underwent apheresis during June 9, 2021 and January 31, 2022. 9pts have completed infusion and 8pts available for efficacy and safety evaluation, the 9th pt completed infusion at January 23, 2022. 2 pts were suspended infusion due to rapid disease progression. Of the 9 infused pts, median age 65 years (range41-71) and a median of 6 (range3-17) prior therapy lines; 3 (33.0%)/1 (11.0%) triple-class/penta-drug exposed; 2 (22.0%)/1 (11.0%) triple-class/penta-drug refractory; 4 (44.0%) prior BCMA CART therapy. Five out of 6pts had high-risk cytogenetic profiles including 2pts with del(17p). No dose-limiting toxicities occurred. The most common TEAEs were neutropenia (G3/4 100%), thrombocytopenia (G3/4 100%), leukopenia (G3/4 100%), lymphopenia (G3/4 100%) and anemia (G3/4 87.5%). All pts experienced CRS with 7pts in G1, 1pt in G2. All CRSs were rapidly relieved after conventional intervention(tocilizumab and steroids). The median onset time was 3 days (range0-8), median duration 6 days (range5-8). No neurologic toxicities were reported. No nail disorders were reported. 8pts avaliable for efficacy evaluation, median follow up time was 109.5 days (range32-195 days). A 100.0% ORR were observed with 3pts CR/sCR, 2pts VGPR, 3pts PR. Three out of 4pts with prior BCMA CAR-T therapy were available for efficacy evaluation-1sCR, 1VGPR, 1PR. After infusion, 8pts were MRD negative in the bone marrow by flow cytometry (10-5) at day 28, 5pts continued at month 3 and 1pt at month 6. Robust OriCAR-017 expansion in peripheral blood by using qPCR for 8pts, median peak was 507,463.6copies/ml (range152093.7 – 1121996.9), median time to peak expansion was 10 days (range7-14). Conclusions: In this phase I study, OriCAR-017 was showed safe and impressive efficacy in RRMM patients. Majority of AEs were transient and manageable. 100% ORR and 100% MRD negative rate, along with favorable safety support OriCAR-017 to be a competitive therapy for RRMM. Furthermore, patients who had relapsed from BCMA CAR-T therapy may still benefit from OriCAR-017. Clinical trial information: NCT05016778.
Retrospective review of outcomes of patients with multiple myeloma with COVID-19 infection (two-center study).
Authors: Ehsan Hamid , Britt Alec , Voorhees Peter M. , Paul Barry , Bhutani Manisha , Varga Cindy , Chiad Zane , Ragon Brittany K. , Shahid Zainab , Shahoud Moussa , Abdallah Al-Ola A. , Ahmed Nausheen , Atrash Shebli
Published: June 2022

8048

Background: Coronavirus-2 has profound effects on patients (pts) with Multiple myeloma (MM). At the beginning of the pandemic, COVID-19 infection resulted an overall mortality around 54% (cook et al. BMJ 2020). Here, we report an updated morbidity and fatality for MM. Methods: After obtaining IRB approvals from each participating institute, retrospectively, between January 1, 2021 and August 30, 2021, we identified pts with MM and COVID-19 in two myeloma centers (Levine Cancer Institute (LCI) & the University of Kansas medical center (KUMC). Results: We identified 162 MM pts who had COVID-19 (LCI n=132, UKMC n=30), including 57% males, with median age of 64 years. Current or former smoking reported in 40% of pts. Most pts have associated comorbid conditions: hypertension (45%), hypogammaglobulinemia (32%), CKD (30%), DM (22%), obesity (16.6%), CHF (14%), and CAD (13.5%). Within 3 months prior to infection, treatment included immunomodulatory combinations in 35%, proteasome inhibitors in 28 %, and Daratumumab in 26.5%. Symptoms are summarized in table. 69% had Mild symptoms (no need for hospitalization), 20 % had moderate symptoms (requiring hospitalization), and 9.8% had severe symptoms (ICU level of care). The 18% of pts required oxygen: 6 pts required invasive oxygenation and 3 pts needed vasopressors. The 32% of pts had RRMM, 29.5% on maintenance, and 12% was getting induction. Regarding MM response: >VGPR in 45% and PD in 18%. The 78 pts had ASCT prior to COVID-19 infection: only 3 pts < 1 year and 3 pts < 6 months. MM response or ASCT did not affect hospitalization or mortality.The case fatality rate (CFR) was 6%. In the univariate analysis, CKD, DM, HTN and hepatic dysfunction were associated with an increased risk of hospitalization. However, in multivariate analysis, only CKD, hepatic dysfunction, and Hypogammaglobulinemia significantly increased the risk of admission with only age and lymphopenia were associated with increased COVID-19 related fatatlity. Conclusions: With implementation of center-specific disease control measures and universal screening, pts might have lower case severity and fatality rate than was initially reported. [Table: see text]
Impact of second primary malignancy post-autologous hematopoietic stem cell transplantation on outcomes of multiple myeloma: A CIBMTR analysis.
Authors: Ragon Brittany K. , D'Souza Anita , Estrada-Merly Noel , Fraser Raphael , George Gemlyn , Gowda Lohith , Shah Nina , Qazilbash Muzaffar H. , Kumar Shaji , Horowitz Mary M. , Usmani Saad Zafar , Shah Mithun Vinod
Published: June 2022

8057

Background: Following autologous hematopoietic stem cell transplant (auto HCT), maintenance therapies improve survival, reduce relapse risk in multiple myeloma (MM), and are the de facto standard-of-care. However, clinical trials have shown an increased risk of second primary malignancies (SPM) with maintenance therapy, including second hematological malignancies (SHM). We examined data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to evaluate the impact of SPM on progression-free (PFS) and overall survival (OS) and the utilization of allogeneic HCT in patients with therapy-related myeloid neoplasms (t-MN). Methods: Adult patients (pts) with MM who underwent first auto HCT in the United States with a melphalan conditioning regimen from 2011-2018 and subsequently received maintenance therapy were included (N=3948). The primary endpoint of interest was the impact of SPM and SHM on OS. Multivariate analytic (MVA) modelling was applied, accounting for competing risks while integrating significant covariates to determine the impact of SPM on PFS and OS. Finally, we studied the utilization and survival following allogeneic HCT for SHM. Results: Baseline characteristics were similar between the two groups. Maintenance regimens used were lenalidomide (2836, 72%), bortezomib (370,9 %) or lenalidomide + bortezomib (372, 9%) based combinations. At a median follow up of 37 months, 175 (5%) pts developed SPM, including 112 (64%) solid 36 (21%) myeloid, and 27 (15%) lymphoid cancers. In MVA, the development of SPM and SHM was associated with an inferior PFS (HR 2.62, P<0.001 and HR 5.01, P<0.001, respectively) and OS (HR 3.85, P<0.001 and 8.13, P<0.001, respectively). The two commonest causes of death were MM (42%) and SPM (30%) for those developing SPM. Similarly, MM (53%) and SHM (18%) were the two commonest causes of death for those developing SHM. Nine (14%,5 t-MDS and 4 t-AML) of 63 patients with SHM underwent an allogeneic HCT. Patients undergoing allogeneic HCT were more likely to have Karnofsky score ≥90 (100% vs. 50%, P=0.02) compared to those who did not. One year survival from allo SCT was 66.7% (CI 34.6-92%). Conclusions: The three-year cumulative incidence of SPM was 3.3 (2.6-4)% in this large contemporaneous CIBMTR cohort. Disease relapse remains the primary cause of death in MM patients who develop SPM or SHM. Given the median OS for MM is now > 10 years, longer follow-up is needed to assess the SPM and SHM risks with maintenance therapy post-auto HCT.
Clinical features of patients with multiple myeloma harboring t(4;14) and impact on long-term survival.
Authors: Joseph Nisha , Hofmeister Craig C. , Heffner Leonard T. , Gupta Vikas Anand , Kaufman Jonathan L. , Dhodapkar Madhav V. , Lonial Sagar , Nooka Ajay K. , Boise Lawrence
Published: June 2022

8062

Background: Translocation (4;14) is a known adverse prognostic factor in myeloma. However, utilization of proteasome inhibitors (PIs) in myeloma has abrogated the negative impact of t(4;14) in myeloma, and some investigators question whether t(4;14) still needs to be considered a high-risk marker. Here, we present a retrospective analysis of 142 patients with t(4;14) and describe disease characteristics, treatment patterns, and long-term outcomes. Methods: From January 2007 to August 2016, 42 patients with newly diagnosed myeloma and t(4;14) were identified. Demographics, clinical characteristics, and outcomes data for the patients were obtained from our institutional review board-approved myeloma database. Responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 59.6 years (range 33-78). Notable patient characteristics include: W/AA/Asian 25.9%/23.6%/50%; ISS I/II/III 36.4%/22.9%/24.1%; R-ISS I/II/III 0%/27.8%/25.8%. Median lab values at diagnosis include: Hgb 10.4 g/dL, Hct 30.8%, Cr 1.01, and Ca 9.4, Frequency of concurrent cytogenetic abnormalities include del(17p): 19.7%; del(13): 44.4%, and +1q21: 46.5%. A majority of patients (86.7%) were induced with either triplet or quadruplet regimens, with 88% of these regimens including a proteasome inhibitor. 78.9% of patients underwent ASCT. Of those responses captured, 75.3% achieved ≥VGPR (sCR 4.8%, CR 30.5%, VGPR 40%, PR 20%). Post-transplant, 88% achieved ≥VGPR (sCR 35.1%, CR 30.9%, VGPR 22.3%), and 82% received maintenance therapy. The most common maintenance regimens included revlimid (34.8%), bortezomib (16.5%), and RVD (11.3%); one-third of patients received triplet maintenance regimens. With a median follow up of 99.5 months, the overall mPFS and mOS for this cohort of t(4;14) patients was 47.6 m (95% CI 32.3-62.8) and 108.5 months (95% CI 87.9-129.2). In patients with both t(4;14) and del(17p), the mPFS was 20.8 months and mOS was 89.6 months; for concurrent t(4;14) and +1q21, the mPFS was 32.0 months and 89.6 months. In patients that received maintenance therapy versus no maintenance, the mPFS and mOS was 54.9 months (95% CI 47.4-62.4) and 115.3 months (95% CI 96.3-134.3) versus 14.7 months (95% CI 13.1-16.3) and 34.3 months (95% CI 10.1-58.5), respectively. Conclusions: Overall, the prognosis of t(4;14) myeloma patients significantly improved compared to the pre-proteasome inhibitor era. In particular, maintenance therapies (predominantly PI- based) have made a clear survival impact (doubling of mPFS to 4.5 years and mOS to 9.5 years) compared to patients that did not receive maintenance therapy. However, presence of other concomitant cytogenetic abnormalities such as +1q21 and del(17p) continues to confer poorer outcomes, and innovative approaches are needed to obtain better outcomes for this subgroup of patients.
Intraoperative quality metrics and association with survival following lung cancer resection.
Authors: Heiden Brendan , Eaton Daniel B. , Chang Su-Hsin , Yan Yan , Schoen Martin W. , Meyers Bryan F. , Kozower Benjamin D. , Puri Varun
Published: June 2022

8502

Background: Surgical resection remains the preferred treatment for functionally fit patients with clinical stage I non-small cell lung cancer (NSCLC). Process-based intra-operative quality metrics (QMs) are important for optimizing long-term outcomes following curative-intent resection. We sought to characterize overall survival using a novel surgical quality score. Methods: We performed a retrospective cohort study using a uniquely compiled dataset of US Veterans with clinical stage I NSCLC receiving definitive surgical treatment. Based on contemporary treatment guidelines, we defined five surgical QMs: timely surgery (within 12 weeks of diagnosis), minimally invasive approach, anatomic resection via lobectomy, adequate nodal sampling (≥10 nodes), and negative margin. Using a multivariable Cox proportional hazards model, we developed a surgical quality score reflecting the relationship between these QMs and overall survival (OS). We also examined the relationship between this score and disease-free survival (DFS). Results: The study included 9,628 Veterans undergoing surgical treatment between 2006 and 2016. QMs were met as follows: timely surgery (n=6,633, 68.9%), minimally invasive approach (n=3,986, 41.4%), lobectomy (n=6,843, 71.1%), adequate nodal sampling (n=3,278, 34.1%), and negative surgical margin (n=9,312, 96.7%). The median (IQR) follow-up was 6.2 (2.5-11.4) years. A normalized score from 0 (no QMs met) to 100 (all QMs met) was constructed, with higher scores reflecting progressively improved risk-adjusted OS (Table). The median (IQR) OS was 86.8 (37.8-149.6) months in the highest score quintile versus 25.3 (7.1-45.8) months in the lowest score quintile. Recurrence was detected in 2,268 (23.6%) patients. Higher surgical quality score was associated with improved DFS (multivariable-adjusted hazard ratio, aHR 0.494, 95% CI 0.245-0.997). Conclusions: Adherence to intra-operative QMs is associated with markedly improved overall and disease-free survival. Efforts to improve adherence to surgical QMs can dramatically improve patient outcomes following curative-intent resection of early-stage lung cancer. [Table: see text]
Targeting genomic instability in extrapulmonary small cell neuroendocrine cancers: A phase II study with ATR inhibitor berzosertib and topotecan.
Authors: Takahashi Nobuyuki , Desai Parth Anil , Sciuto Linda , Nichols Samantha , Steinberg Seth M. , Thomas Anish
Published: June 2022

8518

Background: Extra-pulmonary small cell neuroendocrine cancers (EP-SCNC) are rare cancers with no standard treatments at relapse that share molecular similarities with small cell lung cancer (SCLC). Concurrent inhibition of ataxia telangiectasia and Rad3 related (ATR) and topoisomerase 1, key enzymes for maintaining genomic stability, exacerbated replication stress in SCLC cells and produced durable antitumor responses in patients with relapsed SCLC (Cancer Cell 2021; PMID: 33848478). Methods: Combination of berzosertib and topotecan was evaluated in patients with relapsed EP-SCNC (NCT02487095). Berzosertib was administered at 210 mg/m2 on days 2 and 5 and topotecan 1.25 mg/m2 on days 1-5 in 21-day cycles. Whole exome sequencing (WES) and transcriptome analyses were performed to assess the genomic features associated with response. Results: Fifteen patients with EP-SCNC involving various primary sites were enrolled [three each: cervix, transformed SCLC; two each: bladder, breast, prostate; one each: gallbladder, ovary, rectum]. Two patients (13.3%: breast and rectum) achieved a confirmed partial response (PR; -72.2% and -48.5% tumor reduction in size) lasting 6.9 and 5.8 months. Responses occurred irrespective of platinum-sensitivity or prior treatment with topotecan or immunotherapy. Pre-treatment tumor gene expression profiles of EP-SCNC patients who achieved clinical benefit revealed enrichment of neuroendocrine differentiation (normalized enrichment score and p-value of a gene set enrichment analysis: 2.1 and 2.1 x 10-4). Principal component analysis showed convergent gene expression profiles of both SCLC and EP-SCNC patients who achieved PR. Pre-treatment tumor of a breast small cell cancer patient who achieved durable response revealed amplifications of multiple genes driving replication stress such as KRAS and CCND1. Longitudinal tumor sampling of the patient through treatment course revealed increasing intra-tumor heterogeneity as a potential resistant mechanism. Conclusions: Combination of berzosertib and topotecan is a novel therapeutic paradigm for patients with EP-SCNCs. Both SCLCs and EP-SCNCs responding to this approach show a similar transcriptional phenotype characterized by high replication stress. Clinical trial information: NCT02487095.
Driver coexistence characteristics of ALK-fusion in Chinese patients with lung cancer.
Authors: Gao Min , Fang Yu , Zhang Xiaoyan , Wang Bin , Wang Meng , Hua Li , Ma Tonghui
Published: June 2022

8530

Background: ALK fusions and other driver mutations are usually mutually exclusive. With the widespread application of genetic testing techniques, the coexistence of ALK fusions and other driver mutations could be detected, such as ALK fusion and EGFR driver mutations. However, there were no systematical studies about the coexistence of ALK fusions and other driver mutations. Here, we retrospectively investigated the coexistence of ALK fusions and other driver mutations. Methods: Samples with ALK fusions were extracted from a Chinese lung cancer cohort, which from OncoPanscan (Genetron Health) based sequencing of tissue. Driver mutations of EGFR, ROS1, RET, NTRK1/2/3, BRAF, MET, KRAS and ERBB2 could be detected. Results: In the cohort, 692 samples with ALK fusions contained the intact kinase domain. These samples could be classified into three forms: canonical fusions (only EML4 partner, n = 601), single non-canonical fusions (only non- EML4 partner, n = 51) and complex non-canonical fusions (two or more partners, n = 40). Among the 692 samples, only 20 samples (20/692, 2.89%) coexisted with other driver mutations, which indicated that the driver coexistence were rare. 70% (14/20) of driver coexistence were happened on canonical fusions ( EML4-ALK) samples. They were coexisting with EGFR L858R (3), EGFR L858R plus ROS1 fusion (1), EGFR L858R plus MET amplification (1), KRAS G12C/D/V (3), MET amplification (3), MET Exon14 skipping (1), ERBB2 amplification (1), and MET amplification plus ERBB2 amplification (1), respectively. 20% (4/20) of driver coexistence samples were single non-canonical ALK fusions coexisting with EGFR 19del (1) or 20ins (1) or L858R (1) or MET amplification (1). Another 10% (2/20) samples were complex non-canonical ALK fusions coexisting with EGFR G719S (1) or RET fusion (1). Most co-mutations have corresponding targeted inhibitors, maybe these patients can be treated by combined or sequential therapies. Among canonical fusions, single non-canonical fusions and complex non-canonical fusions of ALK, the frequency of the samples without coexistence of driver mutations was respectively 97.67% (587/601), 92.16% (47/51), 95.00% (38/40), without significant difference (P = 0.056). Maybe single/complex non-canonical fusions are also strong drivers as canonical fusions. Conclusions: In this cohort, very few of ALK fusion patients coexisted with other driver mutations. Among the co-existence samples, ALK fusion were mainly coexisting with the site mutations of EGFR and KRAS, amplifications of MET and ERBB2, fusions of ROS1 and RET. These samples maybe obtain more effective outcomes by combined or sequential therapies.