bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular disease monitoring in patients with relapsed/refractory B-cell non-Hodgkin lymphoma receiving anti-CD19 CAR T-cell therapy.
Authors: Colton Meryl D. , Purev Enkhtsetseg , Haverkos Bradley , Bair Steven Michael , Jasem Jagar , Schliekelman Mark Jason , Kamdar Manali K. 
Published: June 2022

7531 Background: Chimeric antigen receptor (CAR) T-cell therapy has improved the historically poor outcomes for relapsed and refractory (R/R) B-cell non-Hodgkin’s lymphoma (NHL). However, nearly 60% of patients will either fail to respond or relapse after CAR T-cell therapy. Currently, PET/CT scans are used to assess response. Cell-free circulating tumor DNA (ctDNA) is released by tumor cells into the peripheral blood and can be measured for minimal residual disease (MRD) assessment. Methods: In this retrospective, IRB approved pilot study, archived lymphoma tissues and ctDNA from peripheral blood samples on day 0, 14, 28, 56, 80, 180, and 365 after CAR T-cell infusion from 10 patients with R/R NHL were collected for next-generation sequencing (NGS) of clonal variable-diversity-joining (VDJ) rearrangements [Adaptive biotechnologies (Seattle, WA)]. Response was assessed by PET/CT on days 30, 60, 90, 180 and 365 and graded according to the Lugano 2014 criteria. The primary endpoint was to determine the feasibility of detecting ctDNA to monitor disease response after anti-CD19 CAR T-cells. The secondary endpoint was to compare the sensitivity/specificity of MRD assessment from ctDNA to PET/CT imaging. Results: Nine out of 10 patients with a trackable sequence [median age 69 (range: 56-76); 55.6% male; median LDH 224], were included in this study. Each received tisagenlecleucel CAR T-cell therapy after median two prior treatments (range: 2-4). 7/9 patients had R/R diffuse large B-cell lymphoma (DLBCL), and 2/9 had transformed follicular lymphoma. At a median follow up of 12.7 months (range: 1.5-30 months), four patients were alive. By day 90, three patients (33.3%) achieved a radiographic complete response (CR) whilst six patients (66.6%) had progressive disease (PD). MRD and radiographic response are outlined in the Table. Detectable MRD on day 14 or day 28 had 83% sensitivity and 100% specificity for radiographic progression at any time before one year. For patients with PD, the median (interquartile range) MRD at day 0, 14, and 28 were 17.31 (1.01, 96.84), 9.12 (0.30, 18.8), and 23.77 (8.01, 137.53) copies per milliliter (mL), respectively. For patients with detectable MRD at day 28, mOS and mPFS were 205 and 38 days, respectively. Conclusions: Our pilot study demonstrated that monitoring MRD was a sensitive and specific method to detect disease response and relapse. In addition, MRD can be monitored more frequently, thus allowing for earlier detection of relapse. MRD and PET/CT identified progressive disease (PD) or complete response (CR) by day 90 in nine patients (A-I) with R/R NHL post CAR T-cell infusion.[Table: see text]
Cost-effectiveness of CD19 chimeric antigen receptor T-cell (CAR-T) therapy versus autologous stem cell transplantation (ASCT) for high-risk diffuse large B-cell lymphoma (DLBCL) in first relapse.
Authors: Kelkar Amar Harry , Cliff Edward Robert Scheffer , Jacobson Caron Alyce , Abel Gregory A. , Redd Robert , Dijk Stijntje , Krijkamp Eline , Hunink M. G. Myriam , Cutler Corey S. 
Published: June 2022

7537 Background: The recently reported ZUMA-7 and TRANSFORM trials demonstrate superior event-free survival among patients with primary refractory or early relapsed DLBCL compared to salvage chemotherapy with ASCT. However, given a cost of >$370,000, it is not known whether second-line CAR-T is cost-effective compared to ASCT. Thus, we developed a state-transition microsimulation model to simulate clinical outcomes and costs associated with therapy for DLBCL patients in first relapse, using ZUMA-7 and TRANSFORM data. Methods: The model begins at initiation of second-line therapy comparing salvage chemotherapy with ASCT or CAR-T therapy. We examined a three-year time horizon, including crossover to the alternative strategy therapy in the third line, as well as subsequent lines of therapy, using open-source Amua 0.3.0 software. Base case analysis was performed using 1000 first-order Monte Carlo simulations and probabilistic sensitivity analysis (PSA) was performed with 1000 simulations to test model uncertainty. Conditional probabilities of survival and disease progression were extracted from Kaplan-Meier curves from pivotal clinical trials using the WebPlotDigitizer tool. Costs were estimated from public sources in US Dollars ($) and effects were estimated in quality-adjusted life years (QALY) using published utility values. Results: Median overall survival was 15 months (95% confidence interval [CI] 13-19 months) with ASCT and 21 months (95% CI 17-29 months) with CAR-T. The PSA demonstrated costs and effectiveness per patient of $243,581 and 1.06 QALYs with ASCT and $470,150 and 1.22 QALYs with CAR-T with an incremental cost-effectiveness ratio (ICER) of $1,383,320/QALY. Incremental net monetary benefit of CAR-T versus ASCT, based on a willingness-to-pay (WTP) threshold of $200,000/QALY, was -$193,812. The break-even price for CAR-T and all subsequent therapies, based on a one-way sensitivity analysis, was $170,489. Conclusions: The model demonstrated improved survival and QALYs for the second-line CAR-T therapy, but was not cost-effective, as the ICER exceeded $1,000,000/QALY, which is higher than most accepted WTP thresholds. A limitation of these early data is that they only assess outcomes over three years. To estimate the full effect of these therapies, we will extrapolate the Kaplan-Meier curves for additional analyses. Clinical outcomes of second-line CAR-T are promising, but prices would need to be considerably lower to enable equitable access and affordability.[Table: see text]
Asia subpopulation analysis from the phase III POLARIX trial.
Authors: Song Yuqin , Jin Jie , Tilly Herve , Zhang Huilai , Cao Junning , Feng Jifeng , Zhang Liling , Rai Shinya , Goto Hideki , Terui Yasuhito , Kim Won Seog , Shin Ho-Jin , Gau Jyh-Pyng , Tsai Cheng-Hong , Sharman Jeff Porter , Bu Lilian , Hirata Jamie , Lee Calvin , Izutsu Koji , Zhu Jun 
Published: June 2022

7558 Background: In the pivotal Phase III POLARIX trial, Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP, with a similar safety profile in patients with previously untreated DLBCL (Tilly et al. 2022). An Asia subpopulation analysis was included as part of the trial design; patients enrolled in Asia were analyzed for the purpose of registration in China of POLARIX (NCT03274492). Methods: Patients from mainland China, Hong Kong, Japan, South Korea, and Taiwan (enrolled during the global phase), and from the China extension cohort were included in the Asia subpopulation. POLARIX methods were previously described (Tilly et al. 2022). Briefly, patients with untreated DLBCL were randomized 1:1 using the same stratification factors to receive six cycles of Pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The purpose of this analysis was to evaluate consistency of PFS (defined as ≥50% risk reduction in PFS) in the Asia subpopulation with the global population. Results: Overall, 281 patients (intent-to-treat population; 150, 85, 31 and 15 patients in mainland China, Japan, South Korea and Taiwan, respectively) were analyzed (141 received Pola-R-CHP and 140 received R-CHOP); 160 patients from the global population and 121 from the China extension cohort. Median age was 63 (range 19–79) years, and most patients had an International Prognostic Index of 3–5 (61.9%). At the data cut-off of June 28, 2021, (median follow-up of 24.2 months) PFS was superior with Pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.40–1.03) and met the consistency definition with the global population. The 2-year PFS rate was 74.2% (95% CI: 65.7–82.7) with Pola-R-CHP vs 66.5% (95% CI: 57.3–75.6) with R-CHOP. Other key efficacy results were similar to the global study results (Table). The safety profile was generally comparable for Pola-R-CHP vs R-CHOP, including rates of grade 3–4 adverse events (AEs; 72.9% vs 66.2%), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to discontinuation of any study treatment (5.0% vs 7.2%), and incidence of peripheral neuropathy (all grades, 44.3% vs 50.4%), respectively. Key efficacy results. CR, complete response. Conclusions: The results from the Asia subpopulation of POLARIX were consistent with the global study, with a clinically meaningful improvement in PFS (risk of disease progression, relapse or death reduced by 36%) following treatment with Pola-R-CHP vs R-CHOP, and a comparable safety profile in Asian patients with previously untreated DLBCL. Clinical trial information: NCT03274492. [Table: see text]
Association of socioeconomic status with adherence to oral agents in patients with multiple myeloma.
Authors: Rutter Wilbur , Prakash Shivaani , Cavers William , Avalos-Reyes Elisea , Johnson Kjel Andrew , Bernal-Mizrachi Leon 
Published: June 2022

8023 Background: The introduction of novel oral immunomodulatory drugs has improved the overall survival rates of patients with multiple myeloma (MM). Poor adherence to oral therapies may lead to drug resistance, poor response to treatment and other downstream effects. It is unknown if socioeconomic status (SES) mediates adherence to oral MM agents. Methods: This is a retrospective review of newly diagnosed adult patients with MM with drug coverage through a large pharmacy benefit manager (PBM) who received oral MM agents between September 1, 2016 and September 1, 2020. Patients were excluded if they were not eligible for PBM benefits for the 6 months prior to or the 12 months after the index date and if they had a stem cell transplant based on a proxy signal. Adherence was defined as an annual medication possession ratio between 0.8 and 1.2. An SES composite index was developed using ZIP code level factors in a K-means clustering algorithm. Multivariable logistic regression for adherence was conducted using the SES-index and controlled for other patient-specific demographics. Results: In total, 6,602 patients were enrolled in the study, of which, 4,211 (64.5%) were defined as adherent. There were significant unadjusted differences in age (67.89 vs 64.06, p<0.00001), ZIP code-based SES index (p=0.00049), census region (p<0.00001) and insurance plan type (p<0.00001). Results from multivariable logistic regression are shown in table. Patients residing in Very Low SES ZIP codes were significantly less likely to be adherent to oral MM agents compared to those residing in Very High SES locations. Odds of adherence increased as patient’s age increased. Increasing polypharmacy was negatively associated with oral MM agent adherence. Conclusions: Aside from patients residing in Very Low SES ZIP codes, ZIP code-based SES measures were not associated with worse adherence. Other mediating factors include younger age and number of co-prescribed medications. Further investigations of adherence to oral MM agents with clinically relevant outcomes are warranted. [Table: see text]
Subcutaneous (SC) isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM): Interim phase 1b study results.
Authors: Quach Hang , Parmar Gurdeep , Ocio Enrique , Prince H. Miles , Oriol Rocafiguera Albert , Tsukada Nobuhiro , Sunami Kazutaka , Bories Pierre , Karanes Chatchada , Madan Sumit , Semiond Dorothee , Inchauspe Marlene , Macé Sandrine , Musholt Petra B. , Suzan Florence , Moreau Philippe 
Published: June 2022

8025 Background: Intravenous (IV) isatuximab (Isa) + Pd is approved for the treatment of RRMM patients (pts). SC delivery would optimize convenience of administration. Prior results showed that SC Isa administered by syringe pump has efficacy and safety profiles comparable to IV Isa; the recommended Phase 2 dose (RP2D) was 1400 mg (IMW21 P-207). Methods: This multicenter Phase 1b study evaluated safety, PK and efficacy of SC vs IV Isa + Pd in RRMM pts after ≥2 prior treatment lines. Pts were randomized 2:1 to SC1000 mg or IV 10 mg/kg and to SC1400 mg or IV. An expansion cohort was later implemented with SC Isa administered at the RP2D via OBDS, a wearable bolus injector applied to the abdomen by a healthcare professional. Primary endpoints (EPs) were safety, including injection site reactions (ISRs), and PK. Main secondary EPs were overall response rate (ORR) and progression-free survival (PFS). Results: 56 pts were randomized and treated: 12 Isa IV, 12 Isa SC1000, 10 Isa SC1400 and 22 OBDS pts. At study entry, ISS stage II–III was 67% in IV, 33% in SC1000, 60% in SC1400 and 50% in OBDS pts. On Jan 20, 2022, 33% IV, 25% SC1000, 50% SC1400 and 86% OBDS pts remained on treatment. Due to sequential accrual, median follow-up (FU) was longer in IV (20.6 mo) and SC1000 (23.8 mo) than SC1400 (18.1 mo) and OBDS (6.5 mo) pts. Infusion reactions (IRs) were infrequent (≤10% in each cohort, all Grade [G] 2), only at first IV or SC infusion/injection, with no IRs in OBDS. Local tolerability of OBDS was very good, with 5 (22.7%) pts experiencing 7 ISR episodes, all G1, out of 305 administrations (2.3%): 5 injection site erythemas, 1 injection site hemorrhage, and 1 injection site induration. Median duration of OBDS injection was 10 min. Incidence of G4 neutropenia was lower in SC1000 (42%) vs the other cohorts (55–60%). The lower % of ≥G3 treatment-related AEs in OBDS (77%) vs the other cohorts (≥80%) may be due to shorter FU. Best overall responses are shown in table; longer FU is needed for OBDS pts. Median PFS was 22 mo in IV, 12.5 mo in SC1000 and not reached in SC1400 and OBDS pts. PK and CD38 receptor occupancy results in OBDS pts are consistent with those observed in SC1400 with pump. Conclusions: SC Isa administered by OBDS shows a safety profile consistent with IV administration with no IRs and excellent local tolerability. Efficacy in the SC cohorts was comparable to the Phase 3 ICARIA results. Isa SC administration by OBDS is well tolerated, requires a short duration of injection and provides a convenient hands-free option. Clinical trial information: NCT04045795. [Table: see text]
Safety and efficacy of daratumumab use in patients with renal impairment and hemodialysis.
Authors: Niewinski Mateusz , Chin-Hon Jamie , Akerman Meredith , Davies Faith , Morgan Gareth , Braunstein Marc Justin 
Published: June 2022

8026 Background: Targeting CD38 in multiple myeloma (MM) using daratumumab-based regimens can prolong remission in both the newly diagnosed and relapsed settings. However clinical trials have excluded patients with creatinine clearances (CrCl) <30 mL/min, warranting real-world analysis of daratumumab use in MM patients with renal insufficiency. Methods: Following IRB approval, we performed a retrospective chart review of relapsed MM patients at our institution who had reduced CrCl and received at least one dose of either daratumumab between October 2018 and January 2022. All subjects received IV daratumumab, 52% went on to receive SQ. Outcomes included change in CrCl during treatment, adverse events, and survival. Survival was estimated using product-limit estimates. CrCl groups at daratumumab initiation of more or less than 30 were compared using the chi-square test or Fisher’s exact test, as deemed appropriate, for categorical variables and the two-sample t-test or Mann-Whitney test for continuous data (SAS Institute Inc., Cary, NC). Results: 101 MM patients were included, with median age of 74 (54-92); 46 (45.5%) were female. 14% were on hemodialysis. Patients had a median of 2 prior lines of therapy. Distribution of R-ISS stages were I (20%), II (35%), and III (45%). High-risk cytogenetics were present in 20%. A median of 23 daratumumab infusions (1-60) were delivered over a median of 18 months (median IV=16, SQ=10). Daratumumab regimens included DRD (32%), DPD (35%), DKD (13%), and DVD (35%). Median CrCl at MM diagnosis and at daratumumab initiation was 45 (7.3-101) and 40 (5.3-107), respectively, with 33% having CrCl <30. Following 3, 6, and 12 months (n = 95, 89, 69) on daratumumab-based regimens, median CrCl were 45, 43, and 41, respectively. There were no differences in renal function in patients who went on to receive SQ daratumumab. 16 patients had died at the time of data collection, and the median survival was 63 months. Of the 101 patients, 16 subjects were deceased at the time of data collection, and 23% of subjects had gone on to subsequent treatments. Analysis showed that there was a progression-free survival of 54% at 5 years. The most common adverse events reported were anemia (37%) and neutropenia (15%). Infusion-related reactions were reported in 19% of patients. Conclusions: This is the largest real-world assessment of outcome for MM patients treated with daratumumab-containing regimens in the setting of renal insufficiency. There was no significant impact of the treatment on renal function at 12 months. Compared to published data on patients treated with CrCl>30, there does not appear to be a detriment to survival or an increase in adverse events when using daratumumab regimens in patients with more advanced renal insufficiency.
Subgroup analyses in patients with relapsed/refractory multiple myeloma (RRMM) receiving real-life current standard of care (SOC) in the LocoMMotion study.
Authors: Einsele Hermann , Moreau Philippe , De Stefano Valerio , Dytfeld Dominik , Angelucci Emanuele , Benjamin Reuben , Goldschmidt Hartmut , van de Donk Niels W.C.J. , Besemer Britta , Scheid Christof , Vij Ravi , in ’t Groen-Damen Ester , Semerjian Maria , Strulev Vadim , Schecter Jordan Mark , Roccia Tito , Nesheiwat Tonia , Wapenaar Robert , Weisel Katja , Mateos Maria-Victoria 
Published: June 2022

8031 Background: Patients (pts) with RRMM who are triple-class exposed (proteasome inhibitor [PI], immunomodulatory drug [IMiD], and anti-CD38 monoclonal antibody [mAb]) have an urgent and currently unmet clinical need. LocoMMotion (NCT04035226) is the first prospective multinational study of real-life SOC in triple-class exposed pts with RRMM. Here we present efficacy in subgroups of pts treated with SOC therapies in the LocoMMotion study. Methods: LocoMMotion is a noninterventional study across 76 sites (63 European; 13 US). Eligible pts had received ≥3 prior lines of therapy (LOT) or were double refractory to a PI and an IMiD; received a PI, an IMiD, and anti-CD38 mAb; and had disease progression during/after their last LOT. Real-life SOC treatments were defined as those used in local clinical practice. Responses and disease progression were assessed by response review committee, per IMWG criteria. Subgroups were defined by baseline (BL) characteristics: age, Eastern Cooperative Oncology Group performance status (ECOG PS), renal function, ISS stage, presence of extramedullary plasmacytoma, LDH level, % of bone marrow plasma cells, number of prior LOT, triple-class or penta-drug exposure, and refractoriness. Results: As of May 21, 2021 (median follow-up 11.0 mo), 248 pts were enrolled and treated with median 4.0 (range, 1–20) cycles of SOC therapy. Evaluation of efficacy outcomes in subgroups demonstrated that refractoriness to 3 classes of antimyeloma therapy, presence of extramedullary plasmacytomas, high LDH, and ECOG PS ≥1 were associated with generally worse outcomes, compared with pts who did not have these characteristics (Table). Overall response rate (ORR) ranged from 20.0–43.1% across all subgroups. Age and number of prior LOT did not have an impact on efficacy outcomes. Conclusions: Subgroup analyses of this first prospective study of real-life SOC tx in triple-class exposed pts with RRMM indicate that specific pt and disease characteristics were associated with poor outcomes. Triple-class refractory and non-triple-class refractory pts had poor outcomes, although the latter had longer median progression-free survival (PFS). These findings should be considered when planning bridging strategy for CAR-T therapy. Clinical trial information: NCT04035226. [Table: see text]
Demographic disparities in genomic data and clinical trials for multiple myeloma.
Authors: Aggarwal Nidhi , Ahluwalia Pankaj Kumar , Kolhe Ravindra B. , Cortes Jorge E. 
Published: June 2022

8043 Background: There are considerable outcome disparities among patients with multiple myeloma (MM). African-Americans have higher risk of developing MM, earlier age at diagnosis, and higher mortality compared to Whites. While outcomes have multifactorial socioeconomic etiologies, race and ethnicity (R&E) correlate with genomic ancestry, and any role of genetics should be explored. This requires equitable representation in biological databases like The Cancer Genome Atlas (TCGA). Here, we characterize disparities in MM cases of TCGA and clinical trials (CT). Methods: MM incidence was obtained from North American Association of Central Cancer Registries (NAACCR) for R&E, sex and age ( < 50, 50-64, 65+ years). Race includes White, Black, and Asian, along with Hispanic ethnicity, as TCGA MM is limited to these groups. Genes with oncogenic potential and > 5% mutation were stratified by R&E and age. TCGA MM cases are from USA, Canada, Italy, and Spain. On ClinicalTrials.gov, completed MM CT limited to these countries were identified. Student’s t-test and chi-square test were used to analyze disparities and gene mutations. Kaplan-Meier curve was generated to evaluate survival. Results: TCGA MM representation is in Table, calculated as (demographic TCGA cases divided by total TCGA cases) divided by (demographic incidence divided by total incidence). Race was not reported in 20% of TCGA, 4% of CT, and 3% of NAACCR. Of cases reporting R&E, Hispanics are underrepresented by 26% in TCGA and 47% in CT relative to incidence, Blacks by 22% in TCGA and 41% in CT, and Asians by 40% in TCGA and 10% in CT. Whites are overrepresented, by 8% in TCGA and 7% in CT. More men are in TCGA than women, in all R&E. Less than 25% of patients age < 50 relative to incidence are in TCGA, in all R&E. BCL7A is mutated more in Blacks age < 50 (n = 20, 50%) than Whites (n = 39, 10%) (p < 0.01). FAT4 is mutated in Whites age 65+ (n = 31, 10%) but not Blacks. In all ages, KRAS is mutated more in Blacks than Whites (31-35% vs. 20-25%, p < 0.05). Black patients have lower survival than Whites (p < 0.02). In patients age 65+, KRAS mutation is associated with 10% lower 4.5-year survival. Conclusions: Substantial disparities in Black, Hispanic, women, and age representation exist for MM cases in TCGA and CT. This stratification by R&E and age offers new insight on BCL7A, FAT4, and KRAS mutation in MM. Mutation status is associated with survival in older patients. Equitable demographic representation should be pursued to improve quality of available data and access to medical resources for all populations. [Table: see text]