bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of racial and ethnic identity on overall survival in patients with chronic lymphocytic lymphoma.
Authors: Vardell Victoria , Ermann Daniel Arthur , Shah Harsh , Fitzgerald Lindsey , Hu Boyu , Stephens Deborah Marie 
Published: June 2022

7508 Background: Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and results in highly variable clinical outcomes. Epidemiologically, CLL occurs in White ethnicity more frequently and thus, CLL outcomes among underrepresented minorities are not well studied. We sought to examine differences in treatment patterns and survival outcomes based on racial identity of CLL patients and how these have changed over time. Methods: The National Cancer Database was used to identify CLL patients diagnosed from 2004-2018. Demographic and treatment characteristics were compared between White, Black, Asian, Hispanic and other minority groups. Kaplan Meier and adjusted Cox regression survival analysis were used to compare overall survival (OS) between races. Survival analysis was repeated by year of diagnosis in Black and White populations. Results: Of 97,804 CLL pts identified, 90.7% of patients were White, 7.6% Black (N = 7,391), 2.6% Hispanic (N = 2,487), 0.6% Asian (N = 613), and 1.1% were other. Compared to White pts, Black pts were younger at diagnosis (median age 66 years [interquartile range 61-79] vs. 70 years [range 58-75], more likely to have ≥1 comorbidity (27.9% vs. 21.3%), and be uninsured (6.6% vs. 2.1%) (all p < 0.001). Black pts were more likely than White pts to have CLL directed treatment immediately after diagnosis (35.9% vs 23.6%; p < 0.001). With a median follow-up of 4.3 years, median OS for all CLL patients was 9.0 years (CI 8.9-9.1 years). Black pts had a shorter median OS of 7.0 years (CI 6.7-7.3 years) compared to White pts (9.14 years [CI 9.0-9.3]), p < 0.001), as well as inferior OS at 5-years (61% vs. 69%) and 10-years (36% vs. 46%), p < 0.001. On multivariate analysis adjusted for age and Charlson-Deyo score, Black race was independently associated with shorter OS (HR 1.51 [CI 1.46-1.57], p < 0.001). While OS lengthened with successive year of diagnosis for all races, the relative survival of Black compared to White pts did not improve over the observed time period. Referenced to the White population, Black pts diagnosed between 2004-2006 had a HR of 1.64 (CI 1.52-1.76) for mortality, and those diagnosed between 2016-2018 had a HR of 1.64 (CI 1.44-1.85). Conclusions: We present the largest study to date describing racial disparities in CLL. Black pts have significantly shorter OS compared to White pts, which is sustained when adjusted for the higher prevalence of comorbidities in the Black CLL population. Unfortunately, the survival gap between White and Black patients has not improved since 2004, highlighting the need for targeted research directed at improving survival in Black pts with CLL. [Table: see text]
Four-year follow-up from a phase 2 study of obinutuzumab, ibrutinib, and venetoclax in CLL.
Authors: Rogers Kerry Anne , Huang Ying , Abruzzo Lynne , Bhat Seema Ali , Doong Tzyy-Jye , Kittai Adam , Lozanski Arletta , Lozanski Gerard , Lucas Margaret , Maddocks Kami J. , Mao Charelen , Nussbaum Megan , Sass Ellen J , Suresh Swetha , Byrd John C. , Woyach Jennifer Ann 
Published: June 2022

7540 Background: Targeted agent combinations for chronic lymphocytic leukemia (CLL) have resulted in safe regimens with improved progression-free survival (PFS) compared to chemoimmunotherapy. The optimal regimen and long-term outcomes remain unknown. We conducted a phase 2 study of obinutuzumab (OBIN), ibrutinib (IBR), and venetoclax (VEN) in relapsed/refractory (RR) and treatment-naïve (TN) CLL patients (pts) and report extended follow up on two previously reported cohorts (RR, TN 1) and a new cohort of identically treated TN pts (TN 2). Methods: Pts with TN or RR (≥1 prior treatment) CLL requiring treatment were eligible. Treatment was given for 14 28-day cycles (C). OBIN was started C1, IBR C2, and VEN C3 with standard dose escalation. Response was assessed 2 months (mos) after C14 (EOT) by iwCLL 2008 criteria. Minimal residual disease (MRD) was measured by 10-color flow cytometry with a cutoff of < 1x10-4. The primary endpoint was complete remission (CR) with undetectable MRD (uMRD) in blood and bone marrow at EOT. A sample size of 25 pts per cohort achieves 90% power to test the null hypothesis of 10% against 30% with 1-sided α of 10%. The Kaplan-Meier method was used to estimate PFS and overall survival (OS). Results: 75 pts were treated in 3 cohorts (Table). Data are as of 1/3/2022. In the TN 2 cohort, the overall response rate (ORR) at EOT was 96% (95% CI: 80-100) and CR with uMRD was 20% (95% CI: 7-41). The ORR for TN 1 and TN 2 combined was 90% (95% CI: 78-97) and CR with uMRD was 24% (95% CI: 13-38). Median follow up was 56 (0-65), 57 (7-63), and 30 (24-35) mos, respectively, for RR, TN 1, and TN 2. There were 3 deaths (RR = 1, TN 1 = 1, TN 2 = 1) and 6 disease progressions (RR = 4, TN 1 = 2, TN 2 = 0). Estimated 48-month PFS for TN 1 and RR cohorts were both 96% (95% CI: 72-99) and OS was 85% (95% CI: 60-95) and 100%, respectively. The estimated 24-month PFS and OS for TN 2 were both 96% (95% CI: 75-99). The most frequent adverse events were neutropenia (95%, 73% grade ≥3), leukopenia (95%, 45% grade ≥3), lymphopenia (93%, 40% grade ≥3), and thrombocytopenia (91%, 28% grade ≥3). The only grade ≥3 non-hematologic toxicity occurring at ≥20% was hypertension (85%, 39% grade ≥3). Atrial fibrillation occurred in 11% of pts. Conclusions: At extended follow-up, remissions remain durable after fixed duration OBIN, IBR, and VEN. The efficacy and acceptable safety justify further study and are being compared to IBR and OBIN in 2 phase 3 US cooperative group trials. Clinical trial information: NCT02427451. [Table: see text]
Survival outcomes in patients with chronic lymphocytic leukemia treated at academic centers.
Authors: Vardell Victoria , Ermann Daniel Arthur , Shah Harsh , Fitzgerald Lindsey , Hu Boyu , Stephens Deborah Marie 
Published: June 2022

7544 Background: Chronic lymphocytic leukemia (CLL), the most prevalent leukemia in western countries, is associated with highly variable clinical outcomes. This study aims to evaluate whether patients with CLL treated at Commission on Cancer accredited academic centers (ACs), which offer high clinical volume, clinical trial access, and postgraduate physician education, have improved survival compared to non-academic centers (NACs). Methods: The National Cancer Database (NCDB) was used to identify CLL patients diagnosed between 2004-2018. Demographic and treatment characteristics were compared between center categories with binary logistic regression for odds of receiving CLL treatment at an AC. Survival analysis was completed with Kaplan Meier and multivariate Cox regression, adjusted for the only available disease-related characteristics in the NCDB, age and Charlson-Deyo comorbidity score, to compare overall survival (OS). Results: Of the 98,186 patients identified, 33.3% were treated at ACs. Patients treated at ACs were younger than those treated at NACs (median age 67 vs. 71 years, p<0.001). ACs were more likely to treat Black and other minority patients, with Black patients representing 9.7% vs. 6.3% of AC vs NAC patients (p<0.001). ACs were more likely than NACs to treat privately insured (39.1% vs. 30.3%), uninsured (3.2% vs.2.0%) and patients on Medicaid (4.1% vs. 2.9%) (p<0.001), as well as patients from the highest quartiles of income (OR 1.46), and education (OR 1.12), when referenced to lowest quartiles (p<0.001). ACs were more likely to manage patients with surveillance versus NACs (53.7% vs. 45%, p<0.001). With a median follow up of 4.3 years, median OS at ACs was significantly improved when compared to NACs, with a median OS of 11.0 years (CI 10.5-11.3) vs. 8.2 years (CI 8.1-8.3), respectively (p<0.001). Survival benefit was maintained at both 5-years (73% vs. 66%) and 10-years (53% vs. 43%) (both p<0.001). On multivariate analysis adjusted for age and comorbidity, management of CLL patients at ACs was an independent factor for improved OS (HR 0.87, CI 0.85-0.89, p<0.001). Conclusions: In this study of a large population of CLL patients, there is significant demographic and socioeconomic variation between CLL patients treated at ACs and NACs. While our study is limited by the available disease and treatment level data available, the improved OS benefit of CLL patients managed at ACs suggests possible differences in treatment and clinical trial availability, and supportive care management. Further investigations into the factors contributing to such disparities would be beneficial to help standardize care and improve outcomes. [Table: see text]
Phase 1 dose escalation study of MH048, a novel and non-covalent BTK inhibitor in patients with relapsed or refractory B-cell malignancies.
Authors: Cao Guoqing , Jin Zhengming , Li Yuhua , Zhang Liling , Shi Junwei , Jin Jie 
Published: June 2022

7547 Background: Despite impressive clinical response of covalent Bruton’s tyrosine kinase (BTK) inhibitors in multiple B cell malignancies, treatment failure often occurs through drug resistance most commonly due to BTK cysteine-481 (C481) mutation or intolerance due to off-target toxicities. We evaluated the safety, pharmacokinetics (PK) and preliminary antitumor efficacy of MH048, an orally bioavailable, potent, and reversible inhibitor of both wild type and C481S-mutant BTK, in selected patients with relapsed or refractory (R/R) B-cell malignancies. Methods: Eligible patients with R/R B-cell malignancies were enrolled in a Phase 1, multicenter, open-label, dose escalation study. The primary objectives were to assess the safety and tolerability of MH048, and to determine the maximal tolerated dose (MTD) and the recommended dose for expansion. The secondary objectives were to assess the PK profile and preliminary evidence of anti-tumor activity. Results: Twelve patients were treated with MH048 across six dose levels (5 mg, 15 mg, 45 mg, 90 mg, 135 mg, 200 mg QD) in fast state. No dose-limiting toxicities were observed and the MTD was not reached. The most common drug-related TEAEs (Any grade) that occurred in > 2 patients were platelet count decrease (n=5), anemia (n=4), neutrophil count decrease (n=4), lipase increase (n=3), and white blood cell count decrease (n=3). Drug-related grade 3 TEAEs included platelet count decrease, neutrophil count decrease, lipase increase, and hypertension (one patient for each). Plasma exposure of MH048 and its active metabolite (M3) increased in a dose-proportional manner from 5 to 200 mg dose levels. Sign of efficacy was observed starting from 15 mg. Among eleven efficacy-evaluable patients (one patient in 200 mg cohort is yet to be evaluated), one complete response (CR) and four partial responses (PRs) were achieved in ≥90 mg cohorts, including patients with MZL (n=1, CR), MCL (n=2), SLL (n=1) and DLBCL (n=1). Of the two MCL patients with PRs, one was heavily pretreated including ibrutinib prior to the enrollment. The recommended doses for expansion were selected as 135 and 200 mg. Conclusions: MH048 was well-tolerated and efficacy in heavily pre-treated patients with B-cell malignancies was observed. Pharmacokinetics studies suggest once-daily dosing. The dose expansion study is ongoing at 135 and 200 mg QD for CLL and MCL patients. Clinical trial information: NCT04689308.
Acalabrutinib in patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL): Results of a phase 2, multicenter, open-label trial.
Authors: Budde L Elizabeth , Coleman Morton , Stevens Don A. , Ma Shuo , Patti Caterina , Levy M. Yair , Lossos Izidore S. , Geethakumari Praveen Ramakrishnan , Lam Selay , Calvo Roser , Higgins Kara , Strati Paolo 
Published: June 2022

7549 Background: MZL is a rare indolent B-cell malignancy considered incurable at recurrent stage. Bruton tyrosine kinase (BTK) inhibitors have produced durable responses in patients (pts) with R/R MZL. Acalabrutinib (acala) is a potent next-generation BTK inhibitor with high selectivity for BTK. We report data for acala monotherapy from the R/R MZL cohort (phase 2) of a phase 1b/2 clinical trial (NCT02180711). Methods: Pts with histologically confirmed MZL, ECOG performance status ≤2, and ≥1 prior therapy (including ≥1 CD20-directed regimen) received oral acala 100 mg twice daily until disease progression or unacceptable toxicity ± R. The primary objective was overall response rate (ORR; Lugano criteria as assessed by the investigator). Secondary objectives were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively (no formal hypothesis testing). Results: Forty-two pts received acala (median age 69 y [range 42–84]; median 2 prior systemic regimens [range 1–4]). MZL subtypes were extranodal (43%), nodal (31%), and splenic (26%). At data cutoff (Oct 15, 2021), median follow-up duration was 10.7 mo (range 0.4–42.8). Sixteen (38%) pts discontinued acala, most commonly due to disease progression (26%). Among pts evaluable for response (n = 37; 3 pts had not reached the first assessment timepoint and 2 pts exited the study without response assessment), ORR was 54% (95% CI 37%–71%) with 6 complete (16%) and 14 partial (38%) responses; 17 (46%) pts had stable disease. ORRs in extranodal, nodal, and splenic subtypes were 65%, 44%, and 45%, respectively. Median time to initial response was 3.0 mo; median DOR was 19.3 mo (95% CI 8.4–not estimable). Median PFS was 27.4 mo with a 12-mo PFS rate of 66%. Four pts died (disease progression, n = 2; transformation to diffuse large B-cell lymphoma after stopping treatment, n = 1; adverse event [AE], n = 1 [septic shock unrelated to treatment]); median OS was not reached. Treatment was well tolerated with most AEs being grade 1 or 2. Sixteen pts (38%) had grade ≥3 AEs, most commonly (in ≥2 pts) anemia, dyspnea, neutrophil count decrease (n = 3 each), fatigue, thrombocytopenia, and neutropenia (n = 2 each). AEs led to treatment discontinuation in 2 pts (grade 3 hypotension and grade 1 myalgia). Among AEs of clinical interest, hypertension was reported in 2 pts (both grade 2); no cases of atrial fibrillation/flutter or major hemorrhage were reported. Conclusions: These early results indicate that acala is efficacious and well tolerated in pts with R/R MZL. The AE profile is consistent with the known safety profile of acala. Clinical trial information: NCT02180711.
Methylated DNA markers in early detection of lymphoma: Discovery, validation, and clinical pilot.
Authors: Witzig Thomas E. , Taylor William R. , Mahoney Douglas W. , Bamlet William R. , Foote Patrick H. , Burger Kelli , Doering Karen A. , Devens Mary E. , Arndt Jacquelyn R. , O'Connell Maria , Berger Calise K. , Novak Anne , Cerhan James Robert , Hennek Jacquelyn , Katerov Viatcheslav E. , Allawi Hatim T. , Jevremovic Dragan , Dao Linda N , Graham Rondell P. , Kisiel John B. 
Published: June 2022

7562 Background: Lymphoma is the 6th most common cancer and a top 10 cause of cancer deaths. To date, there are no blood test approaches to population screening, and accurate surveillance markers are limited. Methylated DNA markers (MDMs) are broadly informative for early detection of cancer but have not been extensively studied for lymphomas. We sought to discover and validate MDMs in DNA extracted from lymphoma tissue, then test these MDMs in archival blood plasma specimens. Methods: Reduced representation bisulfite sequencing (RRBS) was performed on DNA extracted from a discovery set of frozen tissues of classic Hodgkin lymphoma (CHL, n=24), non-Hodgkin lymphoma (NHL, n=78: T-cell-TCL (8); diffuse large B-cell-DLBCL (18); follicular-FL (12); mantle cell-MCL (20); marginal zone-MZL (15)), and lymphoma cell line samples (27); controls included benign lymph node (n=11) and healthy donor buffy coat (n=30). 30 MDMs were ranked by fold-change and AUC and used to design methylation-specific PCR assays for biological validation on independent DNA samples extracted from FFPE tissue from 13 normal lymph node and 63 lymphoma samples and 36 buffy coats from healthy patients. Target enrichment long-probe quantitative-amplified signal assays were developed for 16 MDMs and then assayed in plasma-extracted, bisulfite-converted DNA samples from 390 independent treatment-naïve lymphoma patients (100 CHL and 290 NHL:100 DLBCL, 73 FL, 41 MCL, 41 MZL, 35 TCL), and 210 controls without cancer. Lymphoma plasma samples and 159 controls were provided by the Lymphoma SPORE (CA97274); 51 controls came from a 7-county population archive. Classification of lymphoma cases vs controls was modeled with random forest method and cross-validated across 500 bootstrap samples of each dataset. Results: For MDMs tested in DNA from independent biological validation samples, cross-validated random forest models identified 60/63 cases (95% sensitivity) and 12/13 normal controls (92% specificity). In plasmas, a panel of 16 MDMs ( ZNF503, VWA5B1, HOXA9_5195, GABRG3, ITGA5, MAX_chr17_793, BNC1_2407, CDK20, MAX_chr4_184, TPBG, DNAH14, SYT2, CACNG8, FAM110B, and NRN1) detected 78% (95% CI, 74-82%) of lymphoma cases at 90% specificity. Excluding MZL and TCL, sensitivity increased to 84% (80-88%) including 26/49 (53% (38-67%)) of stage I and 59/71 (83% (71-90%)) of stage II cases. Conclusions: MDMs show promise to detect lymphoma. These markers could be evaluated as part of multicancer early detection testing and could also be evaluated as response markers to treatment and subsequent surveillance.[Table: see text]
Daratumumab (DARA) + lenalidomide, bortezomib, and dexamethasone (RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM): A post hoc analysis of sustained minimal residual disease (MRD) negativity from GRIFFIN.
Authors: Rodriguez Cesar , Kaufman Jonathan L. , Laubach Jacob , Sborov Douglas W. , Reeves Brandi , Chari Ajai , Silbermann Rebecca Wang , Costa Luciano J. , Anderson Larry D. , Nathwani Nitya , Shah Nina , Bumma Naresh , Jakubowiak Andrzej J. , Orlowski Robert Z. , Pei Huiling , Cortoos Annelore , Patel Sharmila , Lin Thomas S. , Richardson Paul G. , Voorhees Peter M. 
Published: June 2022

8011 Background: In the primary analysis of the phase 2 randomized GRIFFIN study, DARA + RVd (D-RVd) improved the stringent complete response (sCR) rate by end of consolidation for transplant-eligible NDMM (42.4% vs 32.0%; 1-sided P = 0.068). With longer follow-up (median, 38.6 mo), D-RVd vs RVd improved MRD-negativity (10–5) rates in clinically relevant subgroups (ISS stage III, 71% vs 36%; high cytogenetic risk, 44% vs 29% [del17p, t(4;14), or t(14;16)]; revised high cytogenetic risk, 55% vs 32% [del17p, t(4;14), t(14;16), t(14;20), or gain 1q]). Here we present a post hoc analysis of sustained MRD negativity (median follow-up, 38.6 mo) in the same subgroups and in patients (pts) with ≥CR. Methods: Transplant-eligible NDMM pts were randomized 1:1 to 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and 2 years of maintenance therapy with lenalidomide (R) ± DARA. For induction/consolidation (21-day cycles), pts received R (25 mg PO Days [D] 1-14), V (1.3 mg/m2 SC D1, 4, 8, 11), and d (40 mg PO weekly) ± DARA (16 mg/kg IV D1, 8, 15 of Cycles 1-4 and D1 of Cycles 5-6). In maintenance (28-day cycles), pts received R (10 mg PO D1-21; if tolerated, 15 mg in Cycles 10+) ± DARA (16 mg/kg IV Q8W/Q4W or 1800 mg SC per protocol amendments). The primary endpoint was sCR rate by end of consolidation. Results: The following features were balanced among randomized pts (D-RVd, n = 104; RVd, n = 103): high cytogenetic risk (16; 14), revised high cytogenetic risk (42; 37), gain 1q (34; 28), and ISS stage III (14; 14). Sustained MRD-negativity rates at 10–5 lasting ≥6 and ≥12 months were higher for D-RVd vs RVd among all high-risk subgroups (Table). D-RVd was superior to RVd for rates of sustained MRD negativity lasting ≥12 months for pts with ≥CR (53.7% vs 20.3%) and sCR (59.1% vs 17.4%; Table). Among all pts with sustained MRD negativity, only 1 D-RVd pt subsequently had disease progression, and 1 RVd pt died. Additional data on MRD at 10–6 and PFS will be presented. Conclusions: MRD data in GRIFFIN show that the addition of DARA to RVd induction/consolidation and R maintenance may lead to durable MRD-negativity (10–5) rates in pts with transplant-eligible NDMM with high cytogenetic risk, ISS stage III, and those who achieve ≥CR or sCR, however larger studies are needed. Clinical trial information: NCT02874742. [Table: see text]
Correlative analysis to define patient profiles associated with manufacturing and clinical endpoints in relapsed/refractory multiple myeloma (RRMM) patients treated with idecabtagene vicleucel (ide-cel; bb2121), an anti-BCMA CAR T cell therapy.
Authors: Rytlewski Julie , Fuller Jaymes , Mertz David R. , Freeman Ciara , Manier Salomon , Shah Nina , Campbell Timothy Brandon 
Published: June 2022

8021 Background: The anti-BCMA autologous CAR T cell therapy ide-cel has achieved deep and durable responses in RRMM patients (Munshi, N Engl J Med 2021). Prior studies have described the correlation between patient characteristics and clinical outcomes from CD19 CAR T cell therapy (Finney, J Clin Invest 2019; Fraietta, Nat Med 2018). We sought to define patient profiles correlated with manufacturing and clinical endpoints in RRMM patients treated with ide-cel in clinical trials using unsupervised clustering and multivariate machine learning across multiple key variable domains. Methods: Clinical and manufacturing data were harmonized across 164 RRMM patients treated with ide-cel in KarMMa (NCT03361748) and KarMMa-2 cohort 1 (NCT03601078). Based on individual multivariate importance, 10 selected peripheral blood mononuclear cell (PBMC), drug product (DP), and in-process cell growth variables were used to define patient clusters. Random forest classifiers were generated to identify patient characteristics associated with manufacturing and clinical endpoints. Wilcoxon rank sum and Kruskal-Wallis tests were used to compare 2 and 3+ categorical groups; Cox proportional hazards were used to compare groups with time-to-event data. Results: Using an unsupervised method, 4 patient clusters were identified that represented 10%, 57%, 15%, and 18%, respectively, of the total 164 patients. Cluster 4 was the most favorable and was characterized by a higher frequency of T cells in PBMCs; increased T-cell size during manufacturing; higher DP T-cell transduction, potency, and vector copy number; and ultimately a > 3-fold higher CAR T cell yield compared with the least favorable cluster 1. Cluster 2 contained most patients and was associated with intermediate manufacturing endpoints. Patients in cluster 4 had a higher complete response rate, longer progression-free survival, and were defined by lower tumor burden, higher absolute lymphocyte count (ALC), and longer washout period after alkylator treatment, among others (Table). Conclusions: The current study identified patient profiles in RRMM using accessible laboratory or medical history data that correlated with longitudinal outcomes. These findings may inform patients likely to achieve improved outcomes with CAR T cell therapy. Clinical trial information: NCT03361748. [Table: see text]