bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Pomalidomide, bortezomib, and dexamethasone in lenalidomide-pretreated multiple myeloma: A subanalysis of OPTIMISMM by frailty.
Authors: Oriol Rocafiguera Albert , Dimopoulos Meletios A. , Schjesvold Fredrik , Beksac Meral , Yagci Münci , Larocca Alessandra , Guo Shien , Mu Yutian , Hong Kevin , Dhanasiri Sujith , Richardson Paul G. , Weisel Katja
Published: June 2022

8024

Background: Patients (pts) with multiple myeloma (MM) are likely to be older adults, and advanced age is associated with lower survival rates, in part due to comorbidities and frailty. Results from the phase 3 OPTIMISMM trial (NCT01734928) demonstrated that pomalidomide (P) in combination with bortezomib + dexamethasone (Vd) significantly improved progression-free survival (PFS) in lenalidomide (LEN)-pretreated pts with relapsed/refractory MM (RRMM) vs Vd, irrespective of age and Eastern Cooperative Oncology Group performance status (ECOG PS). Here, we report results from a post hoc analysis assessing outcomes of PVd vs Vd in pts with RRMM by frailty status. Methods: Pts with MM and 1–3 prior lines of therapy (including a LEN-containing regimen) who had been randomized 1:1 to PVd or Vd were assessed for frailty. Frailty scores were calculated using age (≤ 75 yr = 0; 76–80 yr = 1; > 80 yr = 2), the Charlson Comorbidity Index (≤ 1 = 0; > 1 = 1) and ECOG PS (0 = 0; 1 = 1; ≥ 2 = 2). Pts were classified as non-frail (NF; combined score: 0 or 1) or frail (F; combined score: ≥ 2). PFS, overall response rate (ORR), and safety outcomes were assessed by treatment group and frailty status. Results: In the intent-to-treat population (N = 559) (data cutoff Oct 26, 2017), 93/281 (33.1%) pts who received PVd and 93/278 (33.5%) who received Vd were frail. Baseline characteristics were similar between treatment groups within each frailty subgroup. Median PFS was longer with PVd vs Vd in NF ( P = 0.001) and F ( P = 0.006) subgroups (Table). ORR was higher with PVd vs Vd in NF ( P < 0.001) and F ( P < 0.001) subgroups. Incidence of grade ≥ 3 (G3) treatment-emergent adverse events (TEAEs) was higher with PVd vs Vd in NF (88.1 vs 61.3%) and F (96.8 vs 87.9%) subgroups; peripheral neuropathy, acute renal failure, and hypertension were the most common. Treatment discontinuation due to G3 TEAEs was greater with PVd vs Vd in NF (19.2 vs 18.5%) and F (30.1 vs 20.9%) subgroups. PVd had a longer median treatment duration vs Vd in NF (8.8 vs 5.7 mo) and F (8.9 vs 4.3 mo) subgroups. Conclusions: Frail pts with RRMM who received PVd had longer PFS and higher ORR than pts who received Vd, consistent with the overall OPTIMISMM results. Frail pts experienced more G3 TEAEs and treatment discontinuations with PVd vs Vd, but treatment duration was longer with PVd vs Vd. Clinical trial information: NCT01734928. [Table: see text]
Characteristics of long-surviving patients with multiple myeloma: Over 12 years of follow-up in the Connect MM Registry.
Authors: Terebelo Howard R. , Omel James , Wagner Lynne I. , Hardin James W. , Rifkin Robert M. , Ailawadhi Sikander , Durie Brian G. , Narang Mohit , Toomey Kathleen , Gasparetto Cristina J. , Joshi Prashant Ramesh , Yu Edward , Flick E. Dawn , Chung Weiyuan , Lee Hans C. , Abonour Rafat , Jagannath Sundar
Published: June 2022

8027

Background: The Connect MM Registry is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed multiple myeloma (NDMM) and one of the largest, longest running MM registries. Long-term survivors (LTS), defined as patients (pts) who have ≥ 8 years of follow-up, comprise a large portion of the Connect MM Registry. The purpose of this analysis was to assess LTS demographic and clinical characteristics. Methods: Adult pts with NDMM (N = 3011) were enrolled from 250 community, academic, and government sites: Cohort 1 from 2009 – 2011 and Cohort 2 from 2012 – 2016. As 99% of LTS were enrolled in Cohort 1, only pts from Cohort 1 were included in this analysis. Pt data were unevaluable if there were missing treatments, disease assessments, or large gaps in activity during follow-up (n = 28). Baseline characteristics, treatment patterns, and quality of life (QoL) form completion rates were examined. Results: At data cutoff (5/17/21), of the 1493 pts in Cohort 1 with evaluable data, 279 were LTS and 1186 were non-LTS. LTS were generally younger and had better performance status at enrollment (Table). Most (66%) LTS received stem cell transplants and few experienced progression within the first 6 months (3%). Top first-line (1L) regimen for LTS was lenalidomide/bortezomib/dexamethasone (31%) vs bortezomib/dexamethasone (22%) in non-LTS. At data cutoff, 73% of LTS were still on treatment at their most recent visit. LTS underwent disease assessments more frequently (2.0 vs 1.3 per year) and had a higher QoL completion rate by year 5 (58% vs 46%). This analysis showed an estimated 8-year survival of 36% vs an observed 8-year survival of 39% from the SEER database. Additional analyses are ongoing. Conclusions: LTS were younger and healthier than non-LTS. Most LTS received triplets at induction, stem cell transplants in 1L, and were less likely to relapse within the first 6 months of treatment than non-LTS. These findings are consistent with what has been observed in MM clinical trials. Further, this analysis demonstrates the value of longitudinal data in the CONNECT MM Registry and provides insights on long surviving pts with MM. Clinical trial information: NCT01081028. [Table: see text]
Circulating tumor DNA analysis and association with relapse in patients with primary refractory multiple myeloma receiving secondary salvage therapy.
Authors: Mithraprabhu Sridurga , Reynolds John , Turner Rose , Kalff Anna , Bergin Krystal , Quach Hang , Khong Tiffany , Durie Brian G. , Spencer Andrew
Published: June 2022

8037

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy with a 5 year-median overall survival (OS) in newly diagnosed (ND) patients. Real-world data reveals that 23% of transplant eligible (TE) ND MM patients relapse within 12 months of starting first-line bortezomib (1LB) based therapy and of these ̃50% will fail secondary therapy and die within 18 months. It is currently impossible to identify these high-risk patients and genomic studies could potentially inform alternative secondary therapeutic options. We propose that circulating tumour DNA (ctDNA) analysis could provide a more holistic approach to determine genomics of high-risk patients than bone marrow (BM) tumour DNA analysis in this genetically heterogenous multi-site malignancy. Methods: Peripheral blood plasma and BM samples (n = 186) were obtained at baseline, cycle 3 day 1 (C3D1), end of the study (EOS) and/or relapse, whichever appeared earlier, from a Phase II multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 TE ND MM patients who were refractory or registered suboptimal response to 1LB (Australasian Leukaemia and Lymphoma Group - MM17 trial). Somatic variants were identified in BM or ctDNA with ultra-sensitive targeted amplicon sequencing of 22-genes known to be mutated in MM. Mutational spectrum was correlated to standard MM risk factors including International Staging System (ISS), response to 1LB and KTd, cytogenetics/FISH, lactate dehydrogenase (LDH) levels, progression-free survival (PFS) and OS. Results: Our initial analysis of ctDNA mutational proportions between patients who did not or did experience relapse on KTd revealed a significantly higher proportion of RAS/RAF (3% vs 25%), or ATM/ATR/TP53 (17% vs 41%; p < 0.0001), respectively, in relapse patients. Subsequently, we correlated ctDNA RAS/RAF and/or ATM/ATR/TP53 mutational presence to standard MM risk factors. We identified a shorter PFS and OS for ISS Stage 2 and 3 compared to Stage 1 patients (p = 0.002 and p = 0.02, respectively) and a significantly higher proportion of RAS/RAF or ATM/ATR/TP53 mutations in patients with refractory as compared to sub-optimal response to 1LB therapy (p = 0.0002). Patients with RAS/RAF or ATM/ATR/TP53 mutations in ctDNA at the time of starting salvage therapy also had a shorter PFS and OS on KTd (p = 0.003 and p = 0.02, respectively). Sequential ctDNA analysis discovered that in 87.5% of patients, one or more of the dominant mutations present at the time of relapse were already present at the start of salvage therapy. Conclusions: Our analysis reveals that RAS/RAF and ATM/ATR/TP53 mutations in ctDNA could be prognostic biomarkers of response to secondary salvage therapy in primary refractory patients thus providing the opportunity to design targeted salvage treatment paradigms in high-risk MM patients.
Prevalence of ocular comorbidities in patients with multiple myeloma: An analysis of U.S. claims data.
Authors: Ailawadhi Sikander , Ma Qiufei , Jalbert Jessica J. , Zhou Mo , Zhou Zheng-Yi , Downes Nathaniel , Briggs Allison , Chi Lei , Hampp Christian , Song Xue , Noguera-Troise Irene , Weyne Jonathan , Kroog Glenn Scott , Rodriguez-Lorenc Karen
Published: June 2022

8038

Background: Multiple myeloma (MM) predominantly affects older patients (pts) (median age at diagnosis 69 yrs) in whom comorbidities must be considered to manage the disease appropriately. Some anti-MM therapies can be associated with ocular toxicities and require careful attention when used among pts with pre-existing ocular comorbidities (OC). In 2018, 41% of Medicare enrollees had OC. Despite the potential implication on treatment decisions, information on pre-existing OC (e.g., disorders of lens, glaucoma) in MM pts is limited. This study aims to describe the prevalence of OCs among real-world pts with MM in 2011-2020 in the US. Methods: Adults with newly diagnosed MM (NDMM) with or without treatment, with 1L systemic therapy, and with relapsed/refractory MM (RRMM) who received up to 4 lines of systemic therapies (LOT) for MM were identified in the IQVIA PharMetrics Plus data. The index date was the date of initial MM diagnosis or a LOT initiation date. The prevalence of OC in each group was defined as the presence of any OC ICD 9/10 diagnosis codes in the 12 months prior to the index date. OCs (e.g., disorders of conjunctiva, lens, choroid, retina, glaucoma) were considered a potentially MM-related disease manifestation or MM treatment-related toxicity based on published literature and clinical expert opinion. Results: The median age at initial MM diagnosis was 64 yrs overall (N=49,814), and 63 yrs among treated pts (N=22,963). The median age was 63 yrs at 1L initiation and 64 yrs at 2L, 3L, and 4L initiation. The prevalence of OC at initial MM diagnosis was 39.0% overall and 35.2% among treated pts (Table). The OC prevalence was 35.8% prior to 1L initiation and higher in RRMM pts (42.1%, 44.9%, and 45.7% prior to 2L, 3L, and 4L initiation, respectively). This trend was observed across all OC categories, among MM-related OCs, and across all age groups. The prevalence of OC by MM stage was stable over the years. Conclusions: Approximately 40% of NDMM pts have a pre-existing OC, and the prevalence increases with the number of LOT in RRMM. While some OC may be due to aging, the impact of OC on treatment decisions for MM should be explored. [Table: see text]
Idecabtagene vicleucel (Ide-cel) chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma (RRMM): Real-world experience.
Authors: Hansen Doris K. , Sidana Surbhi , Peres Lauren , Shune Leyla , Sborov Douglas W. , Hashmi Hamza , Kocoglu Mehmet H. , Atrash Shebli , Simmons Gary , Kalariya Nilesh , Ferreri Christopher J. , Afrough Aimaz , Kansagra Ankit J. , Voorhees Peter M. , Alsina Melissa , McGuirk Joseph , Locke Frederick L. , Patel Krina K.
Published: June 2022

8042

Background: Ide-cel, a BCMA directed CAR T-cell therapy, was FDA approved 3/26/2021 for the treatment of RRMM after 4 prior lines of therapy. We evaluated the real-world outcomes of patients treated with standard of care ide-cel under the commercial FDA label. Methods: Ten US academic centers contributed data to this effort independent of the manufacturer. As of 1/10/2022, 138 patients were leukapheresed with overall manufacturing failure in 6 (4%). 108 patients were infused ≥ 30 days prior to data-cut off and constitute the study population for this retrospective analysis. Results: Table describes the study population compared to the pivotal KarMMa-1 trial (Munshi et al, NEJM 2021). Patients in our study were less likely to have ECOG PS of 0/1 (77%) and more likely to be penta-refractory (41%). 67% of patients would not have met eligibility criteria for KarMMa. Common reasons for ineligibility (> 1 reason in 22% patients) were co-morbidities (28%), cytopenias (22%), prior therapy with alloSCT/CAR-T/other BCMA therapy (19%), CNS myeloma/non-measurable disease/plasma cell leukemia (13%), and fitness (12%). 81% of patients received bridging therapy. Toxicity was comparable to that seen in KarMMa-1. Cytokine release syndrome (CRS) was seen in 82% (> grade 3: 4%) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 15% (> grade 3: 5%) of patients, respectively. Tocilizumab and steroids were used in 72% and 25% of patients, respectively. Infections were seen in 34% of patients. Day 30 response was evaluable in 104 patients. Response rates were: ≥ partial response, 83%; ≥ very good partial response, 64%; and ≥ complete response (CR), 34%. 11% of patients have died by data cut-off, 7 due to disease progression and 5 due to other causes (1 grade 5 CRS, 1 hemophagocytic lymphohistiocytosis, 1 progressive neurological weakness, 2 COVID-19). Conclusions: This multicenter retrospective study delineates the real-world outcomes of ide-cel CAR T-cell therapy for RRMM. Despite more patients being penta-refractory and less fit compared to the pivotal KarMMa trial, safety and 30-day responses in the real-world setting (overall response rate: 83%, CR: 34%) are comparable to the clinical trial population. Follow-up is ongoing and updated data will be presented. [Table: see text]
A patient perspective on cure in multiple myeloma: A survey of over 1,500 patients.
Authors: Mohyuddin Ghulam Rehman , Ahlstrom Jennifer M. , Chmielewski Cynthia , Sweeney Nathan W. , Molina Thomas H. , Cheung Christian S. , Ballard Emily Watabe , Seng Felicia , Godara Amandeep , McClune Brian , Sborov Douglas W.
Published: June 2022

8046

Background: As treatments advance in multiple myeloma (MM) and increasingly deeper and longer responses are achieved, the definition of what a cure is becomes increasingly relevant. While many physicians quote that patients may achieve a “functional cure”, understanding the patient perspective on the concept of cure has yet to be explored. Methods: HealthTree Cure Hub by the HealthTree Foundation represents an online portal for patients with plasma cell dyscrasias to help navigate their disease. It is the largest single database of patients with multiple myeloma with over 10,200 patients as of January 2022. Using this platform, we surveyed patients online from November 11th 2021 to Feb 7th 2022. Varying scenarios incorporating toxicity, disease status, and being on/off treatment were presented, and participants were asked to rate them from 1-5, with 5 being an ideal cure. Patient awareness of the term functional or operational cure was also. Results: A total of 1525 participants completed the survey. Table lists characteristics of the patients who completed this survey. The majority of the patients were female (55.5%), college educated (88.5%) and non-Hispanic White (70.7%). Most patients rated being off treatment permanently and having no evidence of disease as a cure (1116/1469, 75.5%), with a median score of 5 amongst respondents, indicating an ideal version of cure. Continuing to take the same pill or injection with significant toxicity and no evidence of disease had a median score of 1, a score lower than either “continuing to take same pill or injection without significant toxicity even in the evidence of disease” (median score 2) or “stopping treatment permanently even with some detectable disease” (median score 2). The majority of patients (76.3%) reported being unfamiliar with the term functional or operational cure. Conclusions: In the first study of patients with plasma cell dyscrasias in which patients were asked about their perceptions of what a cure is, our results highlight that drug toxicity and being on treatment profoundly impacts patient's perception of cure. Furthermore, most patients are not familiar with the term functional or operational cure. Future efforts should recruit more diverse patient populations and incorporate patient preferences in approaches to defining cure in myeloma, as well as explaining cure in easily comprehensible terms to patients. [Table: see text]
COVID vaccine immune response in patients with plasma cell dyscrasia: A systematic review.
Authors: Faizan Unaiza , Nair Lakshmi G. , Evans James , Anwer Faiz
Published: June 2022

8067

Background: The defective immune system in plasma cell dyscrasia places patients at a higher risk of developing a severe infection, which is one of the leading causes of death in such patients. In an era of a global pandemic, it is essential to protect them against COVID-19, but fewer effective plasma cells lead to a suboptimal response to vaccines. There is still a lack of evidence whether the seroconversion is truly clinically relevant and if patients with plasma cell disorders would benefit from frequent boosters to maintain antibody levels. Methods: Online databases including PubMed, CINAHL, Ovid, and Cochrane were searched (January 11th, 2022), following the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. Only articles published in the English language were included. Abstracts, case reports, and case series were excluded. Out of 40 studies, 5 articles were selected for a systematic review. Results: In all 5 studies (N=654), seroconversion post-vaccination was used as a positive response to COVID-19 vaccination. Although patients with plasma cell disorders had a lower seroconversion rate compared to controls, the overall percentage was substantial and ranged between 23-95.5%. Amongst patients on active therapy, lower seroconversion rates were seen in patients on a CD-38 inhibitor, ranging from 20.2-92.1% (N=174). Also, a significantly lower percentage was recorded in patients above 65 years and those who have been treated with multiple therapies previously. Better seroconversion rates were seen in mRNA vaccines compared to J&J. Conclusions: Variable seropositive rates are seen in patients with plasma cell dyscrasias, lower rates are reported in patients on active therapy, CD-38 targeting therapy, and elderly patients. Hence, these patients should receive a 4 shot series. [Table: see text]
Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for patients with stage III-N2M0 non-small cell lung cancer (NSCLC): A population-based study.
Authors: Akhdar Marah , Syaj Sebawe , Alser Osaid , Elshami Mohamedraed , Hamouri Shadi
Published: June 2022

8503

Background: Stage III-N2 non-small cell lung cancer (NSCLC) is a heterogeneous disease with controversial management options. Induction therapy as part of multimodal treatment is the standard of care for Stage III-N2 NSCLC. We aim to investigate the effect of adding radiotherapy to neoadjuvant chemotherapy on survival outcomes. Methods: All adult NSCLC patients diagnosed between 2004 and 2015 were identified in the Surveillance, Epidemiology, and End Results (SEER) database using ICD-O-3 histologic type coding. Inclusion criteria involved stage III NSCLC patients with ipsilateral lymph node involvement (N2), of any T stage, and with no known distant metastasis (M0). Our main sub-cohorts were patients who either underwent chemoradiotherapy (CRT) or chemotherapy (CT) in neoadjuvant settings. Our primary outcomes were overall survival (OS) and cancer-specific survival (CSS) in months. Cox proportional hazards model was used to analyze the effect of each treatment modality on OS and CSS in univariate and multivariate fashions. Multivariate analysis was adjusted for age, sex, marital status, T stage, resected lymph node status, tumor histology, primary site, laterality, and surgical procedure. Inverse probability treatment weighting (IPTW) was applied to create weighted samples based on study covariates. Results: Our analysis included 1175 patients; 799 (68.0%) underwent neoadjuvant CRT and 376 (32.0%) underwent neoadjuvant CT. Sample median age was 63 (IQR:56-69) years. T2 stage was the most prevalent (N =561, 47.7%), followed by T4 (N=243, 20.7%), T1 (N=228, 19.4%), and T3 (N=143, 12.2%). The main tumor histology was non-squamous cell carcinoma in 773 (65.8%) patients. The upper lobe was the most common primary tumor site (N =788, 67.1%). Patients underwent lobectomy (N=917, 78.0%), pneumonectomy (N=184, 15.7%), or sub-lobar resection (N=69, 5.9%). Adding radiotherapy to chemotherapy showed a slightly higher median OS than chemotherapy alone in neoadjuvant settings (51 vs. 47 months, respectively), and a higher median CSS (75 vs. 59 months, respectively). However, these differences were not statistically significant for OS or CSS (HR = 1.08, 95% CI: 0.91-1.28 and HR = 1.04, 95% CI: 0.89-1.21, respectively). After adjustment, age, T3-T4 stage, non-squamous histology, lower lobe primary site, positive resected lymph nodes, and pneumonectomy were all significant independent predictors for worse OS and CSS. IPTW analysis showed no remarkable survival advantage for CRT patients (HR = 1.15, 95% CI: 0.95-1.40 and HR= 1.12, 95% CI: 0.90-1.39) for OS and CSS, respectively. Conclusions: Adding radiotherapy to neoadjuvant CT did not result in significant survival benefits. Multiple prognostic factors should be taken into consideration when identifying the optimal choice and sequence of multimodal treatment for stage III-N2M0 NSCLC patients.
Spatial meta-transcriptomics reveal intratumor bacterial association with lung cancer cells showing a distinct oncogenic signature.
Authors: Zhao Chen , Wong-Rolle Abigail , Dong Qiang , Zhu Yunhua , Divakar Prajan , Hor Jyh Liang , Kedei Noemi , Wong Madeline , Tillo Desiree , Conner Elizabeth A. , Rajan Arun , Schrump David S. , Jin Chengcheng , Germain Ronald N.
Published: June 2022

8531

Background: The lung intratumor microbiome influences lung cancer tumorigenesis and treatment responses, but detailed data on the extent, location, and effects of microbes within lung tumors is missing, information needed to improve treatment outcomes and prognosis. Methods: To address this gap, we developed a novel spatial meta-transcriptomic method simultaneously detecting the expression level of 1,811 host genes and three microbe targets (16S rRNA, 28S rRNA and CMV). After rigorous validation, we analyzed the spatial meta-transcriptomic profiles of tumor cells, T cells, macrophages, other immune cells, and stroma in tumor samples from 12 patients with early-stage lung cancer. Results: Bacterial burden was significantly higher in tumor cells compared to T cells, macrophages, other immune cells, and stroma. This burden increased from tumor-adjacent normal lung and tertiary lymphoid structures to tumor cells to the airways, suggesting that lung intratumor bacteria derive from the latter route of entry. Expression of oncogenic β-catenin and epithelial-mesenchymal transition pathway genes was strongly correlated with bacterial burden, as were tumor subtypes, mutation profile, histology and smoking history. Conclusions: Intratumor bacteria were enriched with tumor cells and associated with multiple oncogenic pathways, supporting a rationale for reducing the local intratumor microbiome in lung cancer to optimize clinical outcomes. This research was supported in part by the Intramural Research Programs of the NCI and NIAID. Other funding sources included ASCO Young Investigator Award, SITC-AstraZeneca Immunotherapy in Lung Cancer (Early Stage NSCLC) Clinical Fellowship Award, NIH Bench-to-Bedside and Back Program (BtB), NCI R00 award (CA226400), Emerson Collective Cancer Research fund, Lung Cancer Research Foundation (LCRF) pilot grant and W.W. Smith Trust Foundation award. This study was approved by NCI institutional review board (NCT00242723 and NCT02146170) and Animal Use and Care Committee at the University of Pennsylvania (#806875).
Analysis of circulating tumor DNA in the phase 2 BTCRC LUN 16-081 trial of consolidation nivolumab with or without ipilimumab after chemoradiation in stage III non–small cell lung cancer.
Authors: Jun Soyeong , Shukla Nikhil , Durm Greg Andrew , Hui Angela B. , Cao Sha , Kunder Christian , Alizadeh Ash A. , Hanna Nasser H. , Diehn Maximilian
Published: June 2022

8534

Background: The current standard of care for patients with inoperable stage III non-small cell lung cancer (NSCLC) includes chemoradiation (CRT) followed by up to 1 year of checkpoint inhibitor (CPI) therapy. However, many patients are not able to complete 1 year of treatment and the optimal duration of consolidation therapy remains unknown. Identifying minimal residual disease (MRD) via detection of circulating tumor DNA (ctDNA) may help inform the optimal duration of treatment. Here we report the results of a preplanned correlative study evaluating the association between detectable ctDNA and survival outcomes from the BTCRC LUN 16-081 phase 2 trial of consolidation nivolumab or nivolumab plus ipilimumab following CRT in patients with unresectable Stage III NSCLC (NCT03285321). Methods: Following CRT, patients with unresectable stage IIIA/B NSCLC were randomized 1:1 to receive nivolumab 480 mg IV Q4weeks for up to 6 cycles or nivolumab 240 mg IV Q2weeks plus ipilimumab 1 mg/kg IV Q6weeks for up to 4 cycles. Plasma samples for ctDNA analysis were collected after completion of CRT, prior to C2D1 of CPI, and at the end of treatment or withdrawal from the study. Tumor genotyping and ctDNA analysis were performed using CAPP-Seq with a panel targeting 260 genes recurrently mutated in NSCLC. Patient-specific tumor variants were identified using tumor tissue or baseline plasma and matched leukocyte DNA samples. Tumor variants were then monitored in plasma samples using a tumor mutation-informed bioinformatic strategy. Results: Thirty-nine patients received either nivolumab (n = 25; cycles: median = 6, range 1-6), or nivolumab plus ipilimumab (n = 14; cycles; median = 2, range = 1-6). Patients with detectable ctDNA MRD after completion of CRT demonstrated significantly inferior progression free survival (PFS) than patients who were MRD-negative (12-month 29% vs 76%, 24-month 29% vs 68%, P = 0.003), prior to C2D1 of CPI (12-month 0% vs 85%, 24-month 0% vs 72%, P < 0.0001) and at the end of CPI (12-month 14% vs 90%, 24-month 14% vs 79%, P < 0.0001). Patients with undetectable ctDNA MRD at the end of CPI (median cycles = 5.5; range 1-6) demonstrated 24-month overall survival of 91%. Additionally, patients with decreasing or undetectable ctDNA levels after one cycle of CPI had improved outcomes compared to patients with increasing ctDNA levels (24-month PFS 73% vs 0%, P < 0.0001). Progression of disease occurred within 10.8 months of starting CPI in all patients with increasing ctDNA levels at C2D1. Conclusions: Detectable ctDNA before, during, and after consolidation CPI is strongly associated with inferior survival outcomes. Furthermore, less than 12 months of CPI consolidation can result in MRD negativity and high rates of long term PFS. Clinical trial information: NCT03285321.
Molecular characteristics of ERBB2-activating mutations in Chinese patients with NSCLC.
Authors: Xu Fan , Li Qingshan , LI Wenxin , Zhang Shenglin , Zhao Yaping , Guo Didi , Lu Zhongyu , Chen Siqi , Lu Guanghua , Bu Fanfeng , Ding Ran , Deng Wanglong
Published: June 2022

8546

Background: Activating mutations in the ERBB2 gene were shown to play an oncogenic role similar to that of ERBB2 amplification. Thus, ERBB2 mutations have emerged as therapeutic targets in non-small cell lung cancers (NSCLC). However, Activating ERBB2 mutations have not been described in detail like other driver gene mutations, such as epidermal growth factor receptor (EGFR)-activating mutations. Methods: In this study, we retrospectively analyzed activating ERBB2 mutations using next-generation sequencing(NGS). From May 2019 to January 2022, 21745 patients who were diagnosed with NSCLC were detected. Results: A total of 686 activating ERBB2 mutations were found, and 12 patients carried double ERBB2-activating mutations. In this cohort, the average age of patients was 58 years (range, 13-90 years). 59.6% of the patients were female and 88.2% were diagnosed with lung adenocarcinoma.A total of 47 ERBB2-activating mutation subtypes were defined in 674 patients. The most common activating mutations were Y772_A775dup (55.0%, 371/674), followed by G776delinsVC (8.3%, 56/674), S310F (7.7%, 52/674), G778_P780dup (5.6%, 38/674) and V659E (4.1%, 28/674). All other mutations occurred in 14 or fewer patients. ERBB2-activating mutations occurred most frequently in the tyrosine kinase domain（TKD） (80.1%), which included mutations in exon 20 (76.2%), exon 19 (3.0%), and exon 21 (1.2%),In addition, 13.2% of activating ERBB2 mutations occur in the extracellular domain, and 5.5% in the Transmembrane domain. 23.1%(156/674) patients with ERBB2 activating mutations could be evaluated for concurrent mutations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Among these patients, ERBB2-activating mutations were most frequently co-mutated with TP53(54/156) and EGFR(21/156). The frequency of EGFR mutations was much higher in non-TKD mutation patients than in TKD mutation patients (56.7% vs. 3.2%, P < 0.001), but no difference was observed for TP53. All these patients were microsatellite stable (MSS) and low TMB ( < 10 mutations/megabase). Conclusions: We report mutational landscape and characteristics of ERBB2 in Chinese NSCLC patients.The prevalence of activating ERBB2 mutations was 3.1% in Chinese NSCLC patients. 80.1% of ERBB2 activating mutations were in TKD and 19.9% were in the non-TKD. The non-TKD mutations might also be used as a therapeutic target in ERBB2-directed target therapy.