bluuebunny/crossref_metadata_2025 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]
Outcomes of myeloma cast nephropathy in the era of anti-CD38 monoclonal antibody-based frontline therapy: A retrospective cohort study.
Authors: Hughes Michael Sang , Balev Metodi , Radhakrishnan Jai , Bhutani Divaya , Mapara Markus Y. , Eisenberger Andrew , Lentzsch Suzanne , Chakraborty Rajshekhar
Published: June 2024

7555

Background: Myeloma cast nephropathy (MCN) has been a well-known negative predictive marker in newly diagnosed multiple myeloma (NDMM). Anti-CD38+ monoclonal antibodies (mAb) have improved outcomes, but little is known about their impact in patients with MCN. We performed a retrospective cohort study to investigate the outcomes of patients with MCN in the era of anti-CD38+ mAb-based frontline therapy. Methods: 115 NDDM patients received frontline anti-CD38+ mAb from 11/15/18 to 1/24/23. MCN was defined as evidence of light chain casts on biopsy, serum creatinine of >2mg/dL, or 2021 CKD-EPI eGFR of <40mL/min/1.73m2; ≥1g/d proteinuria; and involved FLC ≥50mg/dL. 23 had MCN; 92 were contemporary controls. We obtained data regarding clinical course. Results: 6 MCN patients needed hemodialysis (HD) at diagnosis. MCN patients had similar R2-ISS to controls. Median proteinuria in MCN patients was 5.7g/d more than in controls; serum creatinine (Cr) was 3.2mg/dL higher; and median hemoglobin was 1.5g/dL less. More MCN patients received quadruplet regimens (86.9% vs 62.0%, p = 0.010); similar proportions were transplanted. At 1, 3, and 6 months, serum Cr was higher in MCN patients (p < 0.001, p = 0.002, p = 0.002). Urine protein:creatinine ratios trended toward difference at 1 month (2.04 vs 0.15g/g MCN vs controls, p = 0.061) but were similar at 3 and 6 months. Response rates at 6 months did not differ. 4 MCN patients still required HD after 6 months. Median follow-up was 23.0-23.5 months. 4 MCN patients died, 1 due to progressive disease. No significant difference in disease-free survival (DFS; HR = 0.58, 95% CI 0.20-1.64, p = 0.295), time to next treatment (TTNT; HR = 0.53, 95% CI 0.20-1.39, p = 0.191), or overall survival (OS; HR 0.610, 95% CI 0.19-1.98, p = 0.406) was seen at any point between MCN and control cohorts. 1 year DFS, TTNT, and OS were: 87.0% MCN, 94.5% control; 77.2% MCN, 91.7% control; 87.9% MCN, 96.1% control. By statistical equivalence testing, MCN DFS and TTNT were within 6 months of control DFS and TTNT (p = 0.038, p = 0.032); MCN OS was within 5 months of control OS (p = 0.034). Conclusions: Patients with NDMM and MCN who receive upfront anti-CD38+ mAb therapy experience prolonged survival compared to prior findings. Anti-CD38+ mAb may substantially reduce, though not fully eliminate, the negative survival impact of MCN. Multiple mechanisms, including time to proteinuria resolution, may be involved. Further study is warranted. [Table: see text]
Long term follow up of monoclonal gammopathy of undetermined significance (MGUS) in US Veterans: Racial differences and associations with other malignancies.
Authors: Ma Helen , Gupta Pankaj
Published: June 2024

7573

Background: Monoclonal gammopathy of undetermined significance (MGUS) is associated with lymphoid malignancies such as lymphoma and myeloma, but the association with other malignancies has not been described in the US veteran population. Methods: Veterans diagnosed with MGUS from 1991-2023 were identified from the US Veteran Affairs Central Cancer Registry (VACCR). Age at the diagnosis of MGUS was divided into four categories of <60, 60-69, 70-79, 80+. Variables collected included demographic factors and the diagnosis of other cancers. Differences were analyzed using the Chi Square test. Results: There were 3975 veterans who met the criteria. Most patients were male (96.7%) with a median age at diagnosis of MGUS of 70.5 (IQR 65.4-76.0). Almost 1/3 of patients were Black and were diagnosed with MGUS at a younger age compared to White veterans (Table, p<0.0001). Over the 32-year period included in this study, 2/3 of patients remained with a diagnosis of MGUS (62.3%) alone whereas 29.4% had 1 additional malignancy diagnosed and 8.3% had 2 or more additional malignancies. Black veterans with MGUS were more likely to have additional malignancies than white patients (41.4% vs 35.9%, p=0.016). MGUS was diagnosed prior to other cancers in 52% of patients and afterward in 48%. The most common cancers diagnosed in patients with MGUS were prostate (31%), lymphomas (13%), GI (12.5%), lung (12.0%), and skin (6.8%). CLL (3.4%), LPL (3.0%). Among lymphomas, CLL (3.4%) and LPL (3.0%) were most common. Of note, multiple myeloma or plasmacytoma was diagnosed in 6.5% of patients. The proportion of patients with MGUS and additional malignancies was comparable in the 4 age cohorts (p=0.072), indicating that younger patients with MGUS were as likely to be diagnosed with additional malignancies as older patients. Conclusions: In US veterans, nearly 1/3 of those diagnosed with MGUS were Black. These patients were younger when diagnosed with MGUS and were more likely to develop additional malignancies compared to White veterans. Over the 32 years of this study, a considerable proportion of veterans with MGUS developed various solid tumors. Further investigation is warranted to understand the racial, genetic, and other factors that may be contributing to the development of cancers in patients with MGUS. [Table: see text]
Real-world effectiveness and safety of PD-1 inhibitors combined with recombinant human endostatin and chemotherapy in refractory, recurrent/metastatic nasopharyngeal carcinoma.
Authors: Huang Shuang , Cao Caineng , Qiang Mengyun , Hua Yonghong , Jin Qifeng , Jin Ting , Chen Xiaozhong
Published: June 2024

e18007

Background: Nasopharyngeal carcinoma(NPC) is one of the most common head and neck malignancies with a high overall survival rate. However, the treatment of refractory, recurrent or metastatic NPC is complicated. This study aimed to evaluate the safety and effectiveness of GEP (Gemcitabine combined with recombinant human endostatin (Rh-endostatin) and anti-PD-1 antibody) in patients with refractory, recurrent or metastatic NPC that cannot be treated locally in the real-world setting. Methods: Patients with refractory, recurrent or metastatic NPC (Refractory patients were defined as those unsuitable for local treatment due to extensive tumor recurrence/metastasis or necrosis of ulcers) treated in our hospital from December 2022 to October 2023 were retrospectively reviewed and analyzed. with the GEP regimen. Patients received 1-6 cycles of GEP therapy, including Gemcitabine (1.0 g /m2 ond1 and d8) combined with Rh-endostatin (180-210 mg/continuous intravenous pump 72-120h) and PD-1 antibody, Objective response rate (ORR) and disease control rate (DCR) were determined by Clopper-Pearson's method. The incidence of adverse events (AES). Results: A total of 25 patients who completed ≥ 2 cycles of treatment and at least one efficacy assessment were included in the efficacy analysis. The median age was 59 years (range: 33-75 years), 36% of patients ≥ 65 years. There was significant liquefaction necrosis in 17 cases (68%). 68% of the patients were treated with second-line or above GEP. 32% (8/25) of patients had tumor progression after anti-vascular therapy, and 44% (11/25) had disease progression after immunotherapy. Based on RECIST 1.1, the ORR was 44.00% (95%CI: 26.67%, 62.93%), and DCR was 92.00% (95%CI: 70.04%, 95.83%). The history of immunotherapy was a significant influence factor on ORR. 30 patients who received at least one course of GEP therapy were included in the safety analysis. Grade 3 AEs were observed in 7 patients (20%), with hematological toxicity (6/7) and hypertension (1/7). Other AEs with more than 20% incidence were hematological toxicity (93.0%), weight loss (67.0%), abdominal distension and constipation (47.0%), hypertension (47%), infection (33.0%), liver dysfunction (27.0%), nausea and vomiting (23.0%), and infusion reaction (20.0%). The recurrent lesions of 15 patients with recurrent NPC were accompanied by significant liquefaction necrosis and ulcers. The ORR was 46.7%, and DCR was 100%. Among them, 5 patients had grade 1 nosebleed, and the other grade 2 or above AEs were hematological toxicity, and there were no grade 4 treatment-related AEs. Conclusions: Real-world data demonstrated that GEP was well-tolerated, safe and effective in patients with refractory, recurrent or metastatic NPC.
Clinical prognostic factors to guide treatment strategy for HPV-positive oropharyngeal cancer from treatment outcomes of induction chemotherapy: A real-world experience.
Authors: Bang Hyun Jin , Kim Hyeon-Jong , Lee Seung Hyuk , Shim Hyun Jeong , Hwang Jun Eul , Bae Woo Kyun , Chung Ik-Joo , Cho Sang Hee
Published: June 2024

e18014

Background: The role of induction chemotherapy (IC) in locally advanced oropharyngeal cancer (OPC) remains a topic of debate and suitable candidates for de-escalation treatment in these patients have not been fully identified. This study aimed to identify high-risk groups for HPV-positive OPC by analyzing patients who underwent IC followed by chemoradiotherapy (CRT) to guide optimal treatment strategies. Methods: Between 2004 and 2020, we reviewed patients with OPC diagnosed with stage III-IVA who underwent a treatment regimen comprising a minimum of two cycles of IC followed by CRT.In this study, all patients were re-staged according to the American Joint Committee on Cancer (AJCC) 8th edition, and we analyzed the overall response rate and survival outcomes associated with clinical factors based on HPV status by utilizing univariate and multivariate analyses. Results: This study analyzed 105 patients with a median age of 60 years (range: 40–76 years). Among 105 patients, 40 (38.1%) were HPV-negative, and 65 (61.9%) were HPV-positive. Through a median follow-up of 60.0 months (range, 5–60 months), no significant differences in progression-free survival (PFS) (p = 0.172) and overall survival (OS) (p = 0.064) were observed based on HPV status, regardless of no differences in relative dose intensity of IC and cumulative dose of radiation and cisplatin in CRT. In all patients, survival outcomes were notably poorer in patients aged ≥ 60 years ( p = 0.006) and those who did not achieve complete response (non-CR) post-CRT ( p < 0.001), irrespective of HPV status. All have received sufficient IC with a median RDI of 80% or more in both age < 60 years and age ≥ 60 years. Unlike HPV-negative OPC, where age and T stage showed no significant correlation, in HPV-positive OPC, age ≥ 60 years ( p = 0.011) and T4 stage ( p = 0.019) emerged as substantial poor prognostic factors for survival outcomes despite IC and CRT. Utilizing these results, we categorized HPV-positive OPC patients into three groups based on the number of clinical risk factors at diagnosis (age, T4 stage), the PFS and OS showed significant stratification across each group as the number of clinical risk factors increased. Conclusions: This study revealed that age and T stage significantly influenced on prognosis in HPV-positive OPC but not in HPV-negative OPC. Considering our result, HPV-positive OPC exhibiting these risk factors requires a careful treatment strategy, and combined treatments, including immunotherapy, may be considered to enhance treatment outcomes for these patients.
Primary tracheal cancer: Demographics, histology, and treatment outcomes in the United States from 2000-2018.
Authors: Armel Kristen , Stamey Taylor , Ju Andrew W. , Speicher James E. , Burke Aidan Michael , Navaid Musharraf , Larkins Michael Casmer , Bhatt Arjun
Published: June 2024

e18060

Background: Primary tracheal cancers (PTC) account for 0.2% of all respiratory malignancies and have an estimated incidence of 2.6 new cases per one million people in the US. Given the rarity of these cancers and paucity of data in the literature, we sought to determine the demographic and treatment patterns of PTC in the US. Methods: A retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results (SEER) database sponsored by the National Cancer Institute (NCI) was conducted for patients with a diagnosis of PTC between 2000 and 2018. Univariate, multivariate, and survival analyses were performed using 95% confidence intervals [CI] and a p-value < 0.05 indicating significance. Results: 689 patients with PTC were identified, with 53% of these cases being squamous cell carcinoma (SCC) and 17% being adenoid cystic carcinoma (ACC). Comparison of five-year overall survival (OS) stratified by treatment modality, disease stage, and histology can be found in the table. Multi-factor analysis demonstrated significance with only disease histology (p=0.005). Asian patients with SCC had decreased five-year OS compared to White or Black patients (n=12; hazard ratio (HR)=0.19 and 0.20, and p=0.003 and 0.006, respectively). Patient age < 65 years was associated with increased survival (hazard ratio (HR)=0.48; p<0.001); no difference in survival based on sex or marital status was seen (sex: HR=1.03; p=0.733, marital status: HR=1.07; p=0.568). Conclusions: Patients with tracheal ACC had greater five-year OS compared to patients with tracheal SCC. Those with local or regional SCC that received surgery or RT saw survival benefit; patients with regional SCC had survival benefit with chemotherapy. Patients with ACC had no survival benefit from any treatment modality regardless of stage. Patients aged < 65 years had increased survival and Asian patients with SCC had decreased survival. Further investigation into the potential differences in survival among various chemotherapeutic regimens and socioeconomic factors is warranted.[Table: see text]
Utilizing stereotactic body radiation therapy in combination with tyrosine kinase inhibitors for therapeutic benefit in thyroid cancer.
Authors: Kaur Sundeep , Gui Bin , Ghaly Maged , Seetharamu Nagashree
Published: June 2024

e18065

Background: Tyrosine kinase inhibitors improve overall survival (OS) and progression free survival (PFS) in metastatic thyroid cancer. Additionally, studies have shown success of hypo-fractionated radiotherapy in controlling local disease not responsive to systemic therapies. However, there is limited data assessing the combined benefits of radiation therapy (RT) and systemic therapy. This study aimed to determine the effects of adding radiation to tyrosine kinase inhibitors (TKIs) for symptomatic locoregional/metastatic iodine-refractory thyroid cancer. Methods: 21 patients with metastatic/loco-regionally advanced thyroid cancer were treated with radiation to areas of symptomatic disease alone or along with continuation of oral TKIs between March 2016 and December 2023. 18 were treated with RT + TKIs, while 3 were treated with RT only. Response to treatment was assessed 3 months post- RT treatment via imaging and clinical examination. The primary endpoint was assessing overall response rate as per RECIST 1.1. Secondary endpoints included local control, adverse effects, progression-free survival, and overall survival. Results: Median age of patients was 70. 12 patients were male, 14 patients had distant metastases. Histologic types include 12 papillary thyroid cancers, 4 anaplastic, and 5 others. 18 patients (85.7%) received treatment to thyroid mass, others were treated for nodal, soft tissue, and/or bone metastases. Most patients (90.5%) received stereotactic body radiation therapy (SBRT), while 2 patients received intensity-modulated radiation therapy (IMRT) due to insurance denial. The regimen that was frequently used (52.4%) was SBRT 800cGy in 5 fractions. 5 patients were treated with lenvatinib, 5 with dabrafenib/trametinib, and 4 with cabozantinib. 4 patients developed severe AEs requiring discontinuation or change in treatment plan. 74% of patients had documented response at 3 months post-treatment. 19 patients had additional follow up imaging and at median follow up of 16 months, 14 patients had continued clinical response with 9 complete responses (47.4%) and 5 partial responses (26.3%). The median duration of disease control at the site of RT was 23.4 months. Treatment was well-tolerated in general. 13/20 (65%) patients completed treatment without any interruptions or delays. Conclusions: SBRT can be effectively and safely administered to achieve durable disease control in patients with aggressive thyroid cancer histology when combined with tyrosine kinase inhibitors. This strategy warrants evaluation in prospective clinical trials.
Epidemiological analysis and overall survival of thyroid cancer in a developing Middle Eastern Country over 18 years.
Authors: Abdulelah Zaid A. , Abdulelah Ahmed A. , Alhajahjeh Abdulrahman Ahmad , Al-Dqour Mohammad , Saadeh Aseel , Abdel-Razeq Hikmat
Published: June 2024

e18071

Background: The significance of thyroid cancer lies not only in the resulting morbidity and mortality, but in its prevalence as the most commonly encountered endocrine malignancy in the Middle East and globally. Given that thyroid cancer epidemiology in the Middle East is not sufficiently evaluated, the establishment of epidemiological characteristics of thyroid cancer in the Middle Eastern population is of substantial importance for the introduction of effective interventions, especially in scarcely resourced countries and populations. Methods: Comprehensive data on 4,362 patients of various nationalities residing in Jordan diagnosed with thyroid cancer during the period 2000-2018 were retrieved from the Jordan Cancer Registry, the official institutionalized reporting body for cancer epidemiology in Jordan. Epidemiological analysis including Kaplan-Meier analysis and regression models was performed to establish the epidemiological features of thyroid cancer in a Middle Eastern population. Results: A total of 4,362 patients with a mean age of 43.5 ± 29.6 years old and a significant female predominance of 74.9% were included in the analysis. 7.97% of the enrolled patients were smokers at the time of diagnosis. Thyroid carcinoma was found in the right and left thyroid lobes almost equally the same, with only 1.28% having involvement in both lobes. Localized thyroid carcinoma was encountered in 28.8% of the sample, while 6.65% had systemic involvement and distant metastasis. The observed overall survival rate was determined to be 94.7%, 94.7%, 94.1%, 88.2%, and 86.6% at 1-year, 2-year, 3-year, 4-year, and 5-year interval, respectively. There is a statistically significant incline in the crude incidence of thyroid cancer in Jordan over the 18 years with a crude incidence estimated effect of 0.19 (P-value<0.001). Conclusions: Over 18 years, thyroid cancer in Jordan has been progressively increasing in incidence with a worrisome uptrend that carries significant socioeconomic and health burden. Ensuring preventative measures such as reduced exposure to radiation and early detection of thyroid nodules are warranted to achieve better outcomes.
Imaging and clinical characteristics of incidental abnormal thyroid uptake on PSMA PET/CT.
Authors: Yilmaz Burcak , Trone Kristin , Chalker Cameron , Sun John , Lim James Y , Sokolova Alexandra , Mallak Nadine
Published: June 2024

e18077

Background: To investigate the incidence, features, and clinical characteristics of unexpected prostate-specific membrane antigen (PSMA) uptake within the thyroid gland of patients with prostate cancer (PCa) who underwent F-18 DCFPyL PSMA PET/CT. Methods: We retrospectively reviewed a cohort of 1148 PCa patients who underwent PSMA PET/CT at our institution between 11/2021 - 09/2023. Scans with abnormal thyroid uptake were identified. Clinical data included patient demographics, PCa history, Gleason score, prostate specific antigen (PSA), ultrasonography (US), fine needle aspirate (FNA) / thyroidectomy, histopathology, and history of neck radiation or prior malignancy. Each scan was further analyzed with lesion-specific iso-contour method (42% cutoff) to obtain PET parameters (most prominent nodule SUVmax, SUVmean, PSMA volume, tumor lesion PSMA, contralateral gland SUVmax, SUVmax-nodule / SUVmax-contralateral gland ratio, most prominent PCa lesion SUVmax), PCa tumor distribution, and tumor volume. CT-related variables (nodule number, dominant nodule size, short/long axis ratio, CT-HU, integral total value) were also collected. Pearson's chi-square testing and Kruskal-Wallis testing was performed for categorical and nonparametric data respectively. Receiver operating characteristic (ROC) curves with area under curve (AUC) value were determined using IBM SPSS (version 29.0). Results: Of the 1148 PSMA PET/CTs, 60 (5.2%) had abnormal thyroid uptake (nodular: 58, diffuse: 2). Diffuse uptake was found to represent thyroiditis in both patients. 43 (56.7%) had an US, 20 (33%) were biopsied (11 benign, 5 indeterminate, 4 malignant), and 5 (8.3%) pursued thyroidectomy (3 malignant, 2 benign). 22 patients (36.7%) had histopathology data and 5 malignancies (2 PCa, 1 CLL, 2 primary thyroid) were identified. Nodule size was larger in those who had an US relative to those who did not. Among those with US data, no significant differences in clinical or histopathological parameters were seen. SUVmax (p: 0.01; AUC: 0.876, 95%CI: 0.731-1.0) and SUVmean (p:0.01; AUC: 0.871, 95%CI: 0.722-1.0) were higher in the malignant group. Nodule SUVmax/contralateral gland SUVmax ratio showed borderline significance (p = 0.05). Conclusions: Incidental PSMA PET uptake in the thyroid gland is seen in approximately 5% of patients. Focal uptake should prompt consideration of US and FNA due to the possibility of prostate cancer metastasis and thyroid cancer. SUVmax/mean is higher in malignant lesions.
Safety outcomes in adult patients with AML who achieved their first complete remission with GO prior to HSCT.
Authors: Bejanyan Nelli , Ho Vincent , Perales Miguel-Angel , Kebriaei Partow , Kaur Manmeet , Zhang Mei-Jie , D'Amico Paul G. , Purcell Simon , Dorman Stephanie , Vandendries Erik , Asomaning Kofi , Saber Wael
Published: June 2024

e18504

Background: Gemtuzumab ozogamicin (GO) is approved in the US for the treatment of newly diagnosed and relapsed/refractory (R/R) CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients of 1 month and older and 2 years and older, respectively. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most adult patients with AML in first complete remission (CR1). Clinical studies have linked GO with hepatotoxicity and hepatic veno-occlusive disease (VOD); the risk of these events may be further elevated in patients receiving HSCT. This study aimed to characterize the toxicity after HSCT in adult patients with AML who were treated with GO prior to HSCT. These analyses look at outcomes in patients who were in CR1 at the time of HSCT. Methods: This non-interventional post-authorization safety study used de-identified healthcare data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Data were collected from adult patients in the US with newly diagnosed AML treated with GO prior to proceeding with HSCT. Data collection began on 01 September 2017, data cutoff was 04 July 2023. Results: We present data of 84 patients receiving HSCT for AML in CR1 from 19 centers with a median follow-up of 23.9 months (range, 3.0-49.7). Median age was 54.2 y (range, 18.7-74.5); 55% male. Total cumulative GO dose was 1-3 mg/m2 in 15 (18%), 4-6 mg/m2 in 15 (18%), 7-9 mg/m2 in 28 (33%) and ≥10 mg/m2 in 8 (12%) patients. Measurable residual disease (MRD) was undetectable in 50% (n=42) of patients after GO and 51% (n=43) of patients at the time of HSCT. Most patients (58%; n=49) received myeloablative conditioning and 57% (n=48) received HLA matched unrelated donor HSCT. Non-fatal VOD was reported in 6 (7%) patients, most cases were mild (n=5; 83%). Cumulative incidences of transplant-related mortality (TRM) were: 6 months, 7% (95% CI, 3-14); 2 years, 15% (95% CI, 7-25). The 2-year relapse rate was 26% (95% CI, 16-36%). Kaplan-Meier probabilities of leukemia-free survival (LFS) outcomes at 1 and 2 years were, 68% (95% CI, 57-78) and 59% (95% CI, 47-71), respectively. There were 22 deaths during the study, 10 (46%) from relapse of AML, no VOD-related deaths were observed. Conclusions: The use of GO prior to allogeneic HSCT appears to be safe with low rates of posttransplant VOD observed in patients with AML in CR1. TRM and survival outcomes are similar to historically reported rates. Clinical trial information: B1767034.