bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with manufacturing failure of commercial CD19 CAR-T cell products for large b cell lymphoma (LBCL).
Authors: Patel Romil , Gurumurthi Ashwath , Feng Lei , Westin Jason , Nastoupil Loretta J. , Nair Ranjit , Iyer Swaminathan P , Torres Janet M. , Nieto Yago , Kebriaei Partow , Hawkins Misha , Chihara Dai , Malpica Luis , Adkins Sherry , Shpall Elizabeth J. , Ramdial Jeremy L , Strati Paolo , Hosing Chitra M. , Neelapu Sattva Swarup , Ahmed Sairah 
Published: June 2024

7044 Background: As CD19 chimeric antigen receptor T-cell (CAR-T) therapy has shown curative potential in patients (pts) with relapsed/refractory (R/R) LBCL, indications for treatment are expanding. The reported manufacturing failure rate was 1-13% in clinical trials, but there is poor understanding of out-of-specification (OOS) products and CAR-T products on 2nd apheresis. This study aims to characterize factors associated with successful manufacturing. Methods: This study includes pts with R/R LBCL who underwent apheresis for CAR-T product between 12/2017 and 2/2023. Baseline variables were obtained at time of apheresis. OOS product is defined as not meeting eligibility for a commercial product but suitable for infusion on expanded access protocol. 2nd apheresis was performed due to initial manufacture failure. Progression-free survival (PFS) is the time from CAR-T conditioning to disease progression or death, whichever occurs first. Overall survival (OS) is defined as time from conditioning to death or last follow-up. A chi-square test or Fisher’s exact test was used for comparison of 2 categorical variables. Results: 319 pts underwent apheresis; 261(78%) were axicabtagene ciloleucel, 26(8%) were tisagenlecleucel and 47(14%) were lisocabtagene maraleucel 284(85%); products were in-specification (in-spec) on 1st apheresis, 8(2%) in-spec on 2nd apheresis, 27(8%) OOS, and 15(4%) manufacturing failures. Comparison of variables are in the table. OOS rates were 10/250(4%) for axicabtagene, 4/23(17.4%) for tisagenlecleucel and 13/46(28.3%) for lisocabtagene. Reason for OOS product were low viability:14, high interferon:4, internal manufacturing issue:2, CD4 lineage purity:2, high transduction:1, low transduction:2, and low vector copies:2. No association was found with clinical factors and OOS. Factors associated with OOS were advanced stage (P=0.012), IPI score >3 (p=0.001), extranodal involvement (P=0.012) and older age (p= 0.002). In-spec product on 1st apheresis had greater OS (p= 0.011) and PFS (p=0.043) than 2nd apheresis. Conclusions: Factors predictive of OOS product include older age, advanced disease, extranodal involvement and high IPI. Pts requiring 2nd apheresis had worse survival. Lisocabtagene had higher likelihood for OOS product. Outcomes for OOS products are not well described. Failure to manufacture an eligible product is a barrier for LBCL pts to receive CAR-T therapy. [Table: see text]
Genomic profiling in a subgroup analysis of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and extranodal (EN) sites of involvement in the phase 3 Pola-R-CHP versus R-CHOP (POLARIX) study.
Authors: Lue Jennifer Kimberly , Morschhauser Franck , Tilly Herve , Lenz Georg , Jardin Fabrice , Herrera Alex Francisco , Sharman Jeff Porter , Flowers Christopher , Friedberg Jonathan W. , Trneny Marek , Herbaux Charles , Yan Mark , Jiang Yanwen , Hirata Jamie , Batlevi Connie Lee , Sahin Deniz , Leung Wilfred , Harris Will , Salles Gilles A. , Sehn Laurie Helen 
Published: June 2024

7061 Background: The prognosis and survival outcomes of pts with EN involvement remain a challenge for DLBCL management. In the Phase 3 POLARIX study (NCT03274492), Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP in previously untreated DLBCL (Tilly et al. 2022). This retrospective analysis assessed clinical outcomes and genomic patterns of pts with DLBCL and EN disease. Methods: POLARIX methods were previously described (Tilly et al. 2022). Using a data cutoff of June 15, 2022, this analysis assessed pts with EN involvement as determined by investigators. Additional outcomes and genomics analyses were performed on pts whose EN status was confirmed from documented radiographic lesions or bone marrow biopsy with denotation of EN disease sites. Hazard ratios (HRs) for investigator-assessed PFS were adjusted for age (≤60 vs >60) and sex. Cell of origin (COO) by NanoString, mutation analysis by whole exome sequencing, and global gene expression profiling by RNAseq were performed centrally. Results: In POLARIX, 616/879 pts (70%) had identified EN involvement. After a median follow-up of 39.7 months, pts showed improved PFS with Pola-R-CHP vs R-CHOP (HR 0.72, 95% confidence interval [CI]: 0.55–0.96), with a 2-year PFS of 75% vs 66%. A total of 556 pts (Pola-R-CHP, n=279; R-CHOP, n=277) had confirmed sites of EN involvement, defined as pts with EN radiographic lesions or bone marrow disease. In these pts, PFS favored Pola-R-CHP vs R-CHOP but the difference was not statistically significant (HR 0.84, 95% CI: 0.63–1.13). Of pts with confirmed EN disease, 429 had COO results (activated B-cell, 145 [34%]; germinal center B-cell, 223 [52%]; unclassified DLBCL, 61 [14%]). Mutation data and frequencies of select clinically relevant mutations (Ptashkin, 2023) across EN sites were available for 364 pts (Table). Gene expression data were available for 418 pts; genes involved in proliferation (E2F or PI3K signaling targets and checkpoint genes) and regulated by IRF4, OCT2 and XBP1, were commonly upregulated in pts with EN disease. Conclusions: Results in pts with DLBCL with EN involvement suggest superior PFS with Pola-R-CHP vs R-CHOP. Ongoing analyses will further assess the independent impact of EN status on outcome. POLARIX represents the largest cohort of pts with annotated EN disease and systematic genomic analysis, providing new insights into the genomics of these pts. Clinical trial information: NCT03274492 . [Table: see text]
Updated efficacy and safety results of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).
Authors: Lasica Masa , Ailawadhi Sikander , Fu Chengcheng , Thomas Sheeba K. , Wu Depei , Yi Shuhua , Siddiqi Tanya , Yin Qingsong , Allan John N. , Chen Wenming , Matous Jeffrey V , Feng Ru , Chen Zi , Yu Min , Li Mingyu , He Zicong , Ahmad Mohammad , Wang Hengbang , Chanan-Khan Asher Alban Akmal , Zhai Yifan 
Published: June 2024

7078 Background: Lisaftoclax is a novel, oral, highly selective, potent BCL-2 inhibitor in development. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax + ibrutinib has a strong synergistic effect. This report provides updated efficacy and safety data of lisaftoclax-based therapies (including combinations with ibrutinib) in pts with WM. Methods: In this global, open-label, phase 1b/2 multicenter study, pts with WM were enrolled in 3 arms: Arm A (lisaftoclax) included BTKi-resistant/intolerant pts; Arm B (lisaftoclax + ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax + rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high risk of tumor lysis syndrome (TLS). Objectives were efficacy, safety, and pharmacokinetics (PK) assessments (responses assessed per IWWM criteria). Results: As of January 25, 2024, 46 pts were enrolled and treated at doses of up to 1,000 (Arm A), 1,200 (Arm B), and 800 mg (Arm C; Table). The median (range) treatment duration was 11 (1-28; Arm A), 23.5 (1-34; B), and 11.5 (5-33; C) months. Objective response rates (PR, VGFR, CR) were: 41.7% (Arm A), 90.9% (B), and 37.5% (C). In Arm A, pts with wild-type CXCR4 (n = 7) had better overall response to lisaftoclax than the CXCR4mut group (n = 3). No significant difference was observed between pts with/without CXCR4mut in Arms B and C. In Arm B, 1 DLT (grade 3 clinical TLS due to preexisting renal impairment) was reported at 1,200 mg; 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmia was not observed. One pt required dose reduction because of neutropenia. The MTD was not reached. Lisaftoclax + ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential drug-drug interactions. Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. (CT.gov: NCT04260217; Internal ID: APG2575WU101) *Co-first authors: ML and SA. Clinical trial information: NCT04260217 . [Table: see text]
Ciltacabtagene autoleucel vs standard of care in patients with functional high-risk multiple myeloma: CARTITUDE-4 subgroup analysis.
Authors: Costa Luciano J. , Weisel Katja C , van de Donk Niels W.C.J. , Sidana Surbhi , Cohen Yaël C , Purtill Duncan , Touzeau Cyrille , Fernandez de Larrea Carlos , Martinez-Lopez Joaquin , Lendvai Nikoletta , Slaughter Ana , Lonardi Carolina , Zhao Man , Li Katherine , Vogel Martin , Koneru Mythili , Patel Nitin , Florendo Erika , Costa Filho Octavio , Mateos Maria-Victoria 
Published: June 2024

7504 Background: Functional high-risk (FHR) multiple myeloma (MM) is associated with poor prognosis. In CARTITUDE-4, a single ciltacabtagene autoleucel (cilta-cel) infusion significantly improved progression-free survival (PFS) vs established standard of care (SC; hazard ratio [HR], 0.26 [95% CI, 0.18–0.38]; P<.0001) in patients (pts) with lenalidomide (len)-refractory MM after 1–3 prior lines of treatment (tx; LOT). This post hoc subgroup analysis of CARTITUDE-4 reports outcomes for pts who received cilta-cel vs SC as second-line tx, including pts with FHR MM. Methods: Pts randomized to cilta-cel underwent apheresis, received PVd or DPd bridging tx, and then cilta-cel infusion (target dose, 0.75×106 CAR+ viable T cells/kg) 5–7 d after the start of lymphodepletion. Pts randomized to SC received PVd or DPd until progressive disease (PD). FHR was defined as PD within 18 mo after receiving autologous SCT or the start of initial frontline tx. Efficacy was assessed in randomized pts (intent to treat) and safety in pts who received any part of study tx. Results: 136 pts received cilta-cel (n=68) or SC (n=68) as second-line tx. Of these, 79 had FHR MM (cilta-cel, n=40; SC, n=39). Median PFS was longer among pts who received cilta-cel vs SC as second-line tx including the subset who had FHR MM (Table). Overall survival was immature at the time of this analysis. A greater proportion of pts who received cilta-cel vs SC as second-line tx had an overall response, complete response (CR) or better, minimal residual disease (MRD) negativity, and longer median duration of response (DOR), with similar observations among the FHR subset. Proportion of pts with grade ≥3 TEAEs who received cilta-cel vs SC as second-line tx was comparable (96% vs 96%) including the subset with FHR MM (100% vs 97%). Among pts who received second-line tx, 22 died (cilta-cel, n=11; SC, n=11), 16 of whom had FHR MM (n=7; n=9). Conclusions: In pts with len-refractory FHR MM after 1 prior LOT, cilta-cel improved outcomes vs SC and had a safety profile consistent with the known mechanism of action of CAR-T tx, suggesting cilta-cel may overcome the poor prognosis associated with FHR MM. Clinical trial information: NCT04181827 . [Table: see text]
Class comparison of BCMA-directed therapies in relapsed multiple myeloma.
Authors: Rees Matthew J. , Mammadzadeh Aytaj , Bolarinwa Abiola , Elhaj Mohammed E , Bohra Arwa , Ailawadhi Sikander , Parrondo Ricardo , Chhabra Saurabh , Lin Yi , Binder Moritz , Hayman Suzanne R. , Dispenzieri Angela , Buadi Francis , Dingli David , Warsame Rahma M. , Bansal Radhika , Kapoor Prashant , Gertz Morie A. , Muchtar Eli , Kumar Shaji 
Published: June 2024

7515 Background: BCMA directed CAR T cells, antibody drug conjugates (ADCs), and T cell engagers (TCEs) each have distinct strengths and weaknesses. While these agents have shown unprecedented response rates and survival outcomes, no head-head comparisons exist. We assessed the relative efficacy of different BCMA-therapies in relapsed myeloma, with a focus on high-risk subgroups. Methods: Retrospective study of MM patients treated at Mayo Clinic with commercial or investigational BCMA targeted therapies between April 2018-June 2023. Results: 385 patients (ADC=59, TCE=134, CAR T=192) with a median follow up of 20-months. The median time from diagnosis was 6.1 years. The table shows disease, and treatment characteristics. Amongst ADCs and TCEs recipients, the median treatment duration was 1.9 and 3.5 months respectively, disease progression (64% and 79%) and intolerance (22% and 10%) were the most common reasons for discontinuation. The overall response rates were 27, 50, and 86% for ADCs, TCEs and CAR T, respectively. Compared to ADCs, CAR T was associated with improved PFS (adjusted HRPFS=0.29, 95%CI=0.20-0.43) and OS (aHROS=0.28, 95%CI=0.18-0.44) when adjusting for age, R-ISS, double hit high risk cytogenetic abnormalities (HRCAs), extramedullary disease (EMD, excluding paraskeletal plasmacytomas), triple class refractoriness, and the number of lines of therapy (LOTs) received in the preceding 1 year. Likewise compared to ADCs, TCEs were associated with superior PFS (aHRPFS=0.59, 95%CI=0.40-0.86) and OS (aHROS=0.60, 95%CI=0.39-0.93). Amongst patients with plasma cell leukemia (PCL) or EMD at the time of BCMA therapy (n=123), median PFS was poor irrespective of the therapeutic class at 1.3, 1.7 and 6.1 months for ADCs, TCEs and CAR T, respectively. Equally, for patients previously treated with BCMA therapy (n=58), median PFS was poor regardless of class at 1.9, 2.4 and 3 months for ADCs, TCEs and CAR T, respectively. Of 229 relapses the mode of relapse was known in 192 cases (84%), with 101 (52%) having EMD at relapse. Conclusions: While contingent on myriad other factors, patients able to receive BCMA-directed CAR T therapy experience superior survival compared to ADC and TCEs. EMD, PCL and BCMA-exposed populations are recalcitrant to BCMA-directed immunotherapy, and EMD is a common means of relapse. [Table: see text]
Supplement use habits and perceptions in patients with plasma cell disorders.
Authors: Leyfman Yan , Schach Eliana , Derkach Andriy , Castro Francesca , Hurtado Martínez Jorge Arturo , Sahagun Sanchez Aldana Ana M. , Flores Pérez Patricia Alejandra , Malik Maria , Ahlstrom Jennifer M. , Hydren Jay R , Usmani Saad Zafar , Mao Jun J. , Chimonas Susan , Shah Urvi A 
Published: June 2024

7526 Background: Dietary supplement usage is prevalent among cancer patients in the United States (US), estimated at 70% (Du et al., 2020). For patients with plasma cell disorders (PCDs), there is a strong interest in supplement use. Our 23-question survey aims to understand the perceptions, habits, and knowledge surrounding specific supplements — Vitamin D, omega-3 fatty acids, turmeric/curcumin, and probiotics. Methods: From September 2023 to January 2024, 480 survey responses were collected via HealthTree Cure Hub. Deidentified demographic and survey data were retrieved, and summary statistics were used to evaluate responses. Results: Survey participants were predominantly female (58%), white (78%), aged ≥65 (61%), with a college degree or above (67%), and from the US (90%). While most patients (71%) used supplements pre-diagnosis, there was a 46% increase in supplement use post-diagnosis, where95% used supplements. Most patients obtained supplement information online — including medical media (45%) and myeloma education websites (28%)— and from physicians, such as oncologists (46%) or primary care providers (34%). Patient’s goals for supplement use included immune support (70%), prevention of nutritional deficiencies (54%), or halting cancer progression (38%). Of patients, 63% discussed their supplement use with their physician, with 74% preferring their oncologist’s recommendations. Overall, 91% of patients expressed interest in research on the risks and benefits of supplement use. Conclusions: This survey underscores the unmet need for research on supplements. Despite limited evidence, most survey participants reported an increase in supplement use after being diagnosed with a PCD, primarily interested in their oncologist's recommendations. [Table: see text]
Patient-reported outcomes (PROs) from the DREAMM-7 randomized phase 3 study comparing belantamab mafodotin, bortezomib, and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma (RRMM).
Authors: Hungria Vania , Robak Pawel , Hus Marek , Fu Chengcheng , Zherebtsova Vera , Ward Christopher , de Almeida Ana Carolina , Ho P. Joy , Hajek Roman , Cerchione Claudio , Pirooz Nicholas , McKeown Astrid , Baig Hena , Eccersley Lydia , Pompilus Farrah , McNamara Simon , Lin Chee Paul , Roy-Ghanta Sumita , Opalinska Joanna , Mateos Maria-Victoria 
Published: June 2024

7543 Background: Belantamab mafodotin(belamaf), a first-in-class antibody-drug conjugate targeting B-cell maturation antigen, acts through a multimodal mechanism including direct cell killing and immune-mediated mechanisms. The global, phase 3, open-label, randomized, DREAMM-7 trial (NCT04246047) met its primary endpoint of demonstrating statistically significant progression-free survival benefit favoring BVd vs DVd in patients with RRMM who had received ≥1 prior line of therapy; here, we report PRO findings for BVd vs DVd. Methods: Patients were randomized (1:1) to receive BVd or DVd and completed electronic PRO measures at baseline and every 3 weeks (Q3W) during treatment. PRO measures included EORTC-QLQ-C30, EORTC-QLQ-MY20 disease symptoms (pain), PRO-CTCAE patient-reported tolerability, and OSDI vision-related functioning (Q3W up to the sixth dose of belamaf, then Q6W). Each domain was summarized using descriptive statistics. Results: Among 494 patients (BVd, n=243; DVd, n=251), adherence to PRO assessments was >90% for most study visits. There was no difference in EORTC QLQ-C30 global health status/quality-of-life assessments between the study arms over time. Similarly, role functioning, physical functioning, fatigue, and pain were stable (change from baseline in EORTC score was within 10 points) over time and consistent between arms. Most symptomatic adverse events evaluated by PRO-CTCAE were reported at no to low severity, frequency, and interference (PRO-CTCAE ratings ≤2) in both arms throughout the study. The severity and interference of blurred vision and frequency of watery eyes were reported at higher levels (PRO-CTCAE ratings ≥3) in the BVd arm. Among patients in the BVd arm with a clinically meaningful deterioration in vision-related functioning (a change from baseline of ≥12.5 points), EORTC-QLQ-C30 global health status, role functioning, and physical functioning were comparable to the DVd arm over time. Conclusions: Overallquality of life, role functioning, physical functioning, fatigue, and pain were comparable in patients treated with BVd vs DVd. In patients treated with BVd who reported a clinically meaningful deterioration in vision-related functioning, overall quality of life was consistent with the DVd arm.
Effect of daratumumab on light chain reduction in newly diagnosed multiple myeloma with light chain cast nephropathy.
Authors: Velez-Hernandez Juan Esteban , Mejia Saldarriaga Mateo , Bustoros Mark , Pearse Roger Niles , Niesvizky Ruben , Monge Urrea Jorge 
Published: June 2024

7554 Background: Light chain cast nephropathy (LCCN) is present in 16-31% of patients (pts) in newly diagnosed multiple myeloma (NDMM). In pts with an involved serum free light chain (iFLC) >150mg/dL and predominant LC proteinuria, the probability of LCCN is high enough for a clinical diagnosis without the need for kidney biopsy. Early mortality is higher in pts with renal impairment (RI) who did not achieve a renal response (RR), and a rapid reduction in iFLC may predict RR. While the use of bortezomib and dexamethasone (Vd) in upfront therapy has led to marked improvements in outcomes, the optimal regimen is unclear. Methods: We included pts with NDMM and RI (creatinine >2 mg/dL or eGFR <40 ml/min/1.73m2) and a diagnosis of LCCN (iFLC >150mg/dL and light chain proteinuria) at a single center from 2005-2023. Pts with >10% albuminuria or a diagnosis of MGRS or amyloidosis were excluded. Primary outcome was FLC response (iFLC <50mg/dL and >90% reduction, FLC-R) at day 30 (d30). Other outcomes included hematologic response (partial response or better) at d30 and RR (minimal response or better) at d90, based on International Myeloma Working Group criteria. Results: We included 51 pts with characteristics depicted in the table. All pts received therapy with Vd, adding cyclophosphamide (VCd) in 26 (51%), daratumumab (dara, DVd) in 13 (25%), both (DVCd) in 6 (12%) and alone in 6 (12%). At d30, 11 pts (58%) in dara-containing regimens (DVd, DVCd) and 10 pts (31%) in non-dara-containing regimens (Vd, VCd) achieved a FLC-R (p=0.08); dara was associated with higher odds of achieving a FLC-R at d30 (OR 2.9, p=0.03) after adjusting for age, stage and eGFR at diagnosis. At d90, pts receiving dara had a higher rate of RR than those who did not (69% vs 58%, p=0.5); dara was associated with higher odds of a RR at d90 (OR 1.6, p=0.5). After adjusting for age, stage and eGFR at diagnosis, achieving a FLC-R at d30 was associated with higher odds of a RR at d90 (OR 8.9, p=0.02). Conclusions: Prompt reduction of iFLC is an important objective during the early treatment of LCCN in order to achieve a RR, and dara increases the odds of achieving a FLC-R. The use of dara led to higher odds of a RR at d90, but not statistically significant. We confirmed that achieving a FLC-R at d30 was associated with achieving a RR at d90. Our results suggest that the role of a dara should be explored in prospective studies for the upfront treatment of LCCN in NDMM. [Table: see text]