Citations

Mayo Clinic

Clear

28 citation(s) found for "Kuzma, L".

Climate stressors and impact on cardio-oncology burden in the united states: nationwide and geographically matched analyses
Hassan, I, Kurasz, A, Aldalaeen, R, Alhammouri, H, Alasmar, R, Saif, R, Ibrahim, M, Alghzlawi, I, Shehab, M, Rafaat, K, Kuzma, L, Abohashem, S, Hassan, Ibrahim , Hassan, Ibrahim, Kurasz, Anna , Aldalaeen, Raneem, Al-Asmar, Rahmeh , SAIF, RIYADH, Alghzlawi, Ibrahim , Raafat, Kareem Wael , Kuzma, L, Abohashem, Shady

European Journal of Preventive Cardiology | June 11, 2026 | Volume: 33 | Issue: Supplement_2 | Pages: No page available

10.1093/eurjpc/zwag249.289 Get It

Abstract Background Climate-related stressors such as heat, wildfires, and extreme weather are increasingly recognized as determinants of cardiovascular and oncologic health. However, their joint impact on overlapping cancer–cardiovascular disease (CVD) burdens remains unknown. We developed a Cardio-Oncology Burden Index (COBI) to quantify the co-prevalence of cancer and CVD at the community level and examined its association with climate vulnerability across U.S. census tracts. Methods We conducted a cross-sectional ecological analysis of 82,679 census tracts (328,683,841 residents) using the CDC PLACES database. COBI was derived using principal component analysis of age-adjusted prevalence of cancer, coronary artery disease, and stroke. The Climate Burden Index (CBI, 0–1 percentile) integrates multiple climate-related exposures, including extreme temperature, wildfire frequency, and severe weather events. Population-weighted mixed-effects regression models with county-level random effects estimated associations between CBI and COBI, adjusting for region, rurality, and environmental justice indicators. β coefficients represent percentage-point differences in COBI per unit (or category) increase in climate burden. Exposure–response relationships were examined using restricted cubic splines (RCS). Robustness was assessed via geographically matched (<50 km) and fully matched (region, rural–urban commuting area, and environmental justice) analyses. Results Marked spatial heterogeneity was observed in both CBI and COBI across the U.S. (Fig. A–B). Higher climate burden was consistently associated with greater cardio-oncology burden (Fig. C), demonstrating a dose–response relationship: second vs lowest quartile β=0.92 (95% CI, 0.61–1.24); third vs lowest quartile β=1.61 (95% CI, 1.30–1.92); highest vs lowest quartile β=3.44 (95% CI, 3.11–3.76). The RCS model revealed a significant non-linear association (p_non-linear<0.001), with a plateau at moderate exposures and a steep rise at the highest CBI levels (Fig. D). Results remained robust in sensitivity analyses (β=4.17 [95% CI, 3.62–4.71] for geographically matched; β=4.39 [95% CI, 4.10–4.69] for fully matched tracts; Table). Conclusions Greater climate burden is independently associated with higher cardio-oncology burden across U.S. communities, with disproportionate effects in the most climate-vulnerable areas. This novel, population-level linkage between climate stress and onco-cardiovascular disease burden, highlights an emerging syndemic at the intersection of environment, cancer, and CVD. Targeted mitigation and prevention strategies integrating environmental resilience into chronic disease prevention are urgently needed.For image description, please refer to the figure legend and surrounding text.
Abstract PS3-01-30: Change in mammographic density (MD) with metformin use: Alliance A211201, A companion study to NCIC study MA.32
Wood, Marie , Elsaid, M. I., Grimm, L. J., Liu, H., Oswold, C., Kuzma, C. S., Bedrosian, I., Ligibel, J. A., Goodwin, P. J., Elsaid, Mohamed I , Grimm, Lars J. , Kuzma, Charles, Goodwin, P. J.

Clinical Cancer Research | February 17, 2026 | Volume: 32 | Issue: 4_Supplement | Pages: PS3-01-30-PS3-01-30

10.1158/1557-3265.sabcs25-ps3-01-30 Get It

Abstract Background: Metformin may impact tumorigenesis directly, through effects on AMP kinase, and indirectly, through reduction in circulating growth factors such as insulin. To examine the potential preventive effects of metformin, we analyzed MD, a known risk factor for breast cancer, in participants enrolled in the NCIC MA.32 trial, a randomized, placebo-controlled trial investigating the effects of 5 years of metformin on invasive disease-free survival in women with early breast cancer. The primary aim of this companion to MA.32 (Alliance A211201) was to examine the effects of 1 year of metformin vs placebo on MD in women treated for estrogen receptor negative (ER-) breast cancer. Methods: Eligible women were enrolled on MA.32, had ER- breast cancer, had >25% MD at baseline, and had an unaffected contralateral breast. MD was calculated on the contralateral breast using Cumulus software and analyzed at baseline, 1 and 2 years. The aim was to achieve a sample size of 274 (137 per arm), which would have at least 85% power to detect a 4% difference between study arms, i.e., 5% change from baseline to one year of treatment for metformin vs. 1% for placebo, using a two-sided two-sample t-test at a significance level of 5%. The current study was activated in the United States on 8/22/2012. Enrollment was halted on 10/13/2017 with 177 participants enrolled. Results: 146 women were evaluable (66 on metformin and 80 on placebo). The mean age of evaluable women was 53.6 years (standard deviation [SD] 9.4), 88.4% were white, 31.5% had a body mass index greater than or equal to 30 kg/m2, 99.3% of participants received chemotherapy. The proportions of white women and HER2+ participants in the metformin group were higher compared to placebo ([white 92.4% vs. 85.0%] and [HER2+ 21.2% vs. 11.3%], respectively). The mean MD at baseline was 22.7% (SD 14.1%) for the group as a whole (24.5% (SD 14.5%) for the metformin group and 21.2% (SD 13.6%) for the placebo group. This is lower than the eligibility criteria (>25%MD), due to difference in methods of calculation of MD (BIRADs for eligibility and Cumulus for study analysis). At 1 year, MD decreased by 0.7% (SD 7.6%) in the metformin group and 0.2% (SD 7.3%) in the placebo group (p = 0.58). At 2 years, MD decreased by 0.7% (SD 8.0%) in the metformin group and 0.8% (SD 7.1%) in the placebo group (p=0.60). Conclusions: In a cohort of women with early ER- breast cancer, there was no significant difference in the change in MD in women treated with metformin vs. placebo. There was a non-significant trend toward decreased MD while on metformin after 1 year of treatment. The arms were well balanced, though with more white and HER2+ participants in the metformin arm. The sample size for this study was about half of what was intended thus limiting power to detect a significant difference. Additional limitations include low mean MD, which may have limited our ability to detect the benefit in those at the highest risk, and further, the Cumulus method of MD determination can be imprecise. Interestingly, trends toward decreased MD with metformin were seen in Alliance A211102, and it might be reasonable to consider further study of metformin in a select population (highest MD or atypical hyperplasia). Support: UG1CA189823, U10CA180863, CCS 707213; https://acknowledgments.alliancefound.org.Clinicaltrials.gov ID: NCT01666171. Citation Format: M. Wood, M. I. Elsaid, L. J. Grimm, H. Liu, C. Oswold, C. S. Kuzma, I. Bedrosian, J. Ligibel, P. J. Goodwin. Change in mammographic density (MD) with metformin use: Alliance A211201, A companion study to NCIC study MA.32 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-30.
Abstract PS3-11-04: Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients with HER2+ Breast Cancer - Results from the ATOP Study
Freedman, R. A., Heiling, H., Ruddy, K. J., Rogak, Lauren , Sedrak, M., Dueck, A., Liu, H., Fraettarelli, A., Atanasov, S., DeMeo, M. K., Lange, Paulina, Glen, A. Perilla, Sinclair, S., Dillon, D., Mortimer, J., Fenton, Mary Anne , Walsh, J., Spring, L. M., Muss, H., Sinclair, Natalie, Hamilton, E., Dang, C., Giordano, S., Faggen, Meredith, Lo, SS, Kuzma, Charles S., Lemke, Steffen , Stella, P., Mowat, Rex B., Wilkinson, Mary, Rauch, J., Tayob, Nabihah, Winer, E., Freedman, Rachel A. , Ruddy, Kathryn J. , Sedrak, Mina S. , Dueck, A., Fraettarelli, Ashton, DeMeo, Michelle K. , Perilla-Glen, Adriana, Sinclair, S., Spring, L.M., Muss, H., Dang, Catherine, Kuzma, Charles, Lemke, S.

Clinical Cancer Research | February 17, 2026 | Volume: 32 | Issue: 4_Supplement | Pages: PS3-11-04-PS3-11-04

10.1158/1557-3265.sabcs25-ps3-11-04 Get It

Abstract Purpose: There are limited prospective data on the efficacy, tolerability, and functional impact of treatments for older and frail adults with HER2+ early breast cancer. We report the first-ever, US-based adjuvant trial dedicated to this population. Methods: We conducted a single arm, phase II, multicenter, investigator-initiated study of adjuvant ado-trastuzumab emtansine (T-DM1) in patients aged 60 and older with stage I-III HER2+ breast cancer who either declined standard adjuvant therapy or were deemed by their physician not to be candidates for standard treatment for any reason. Protocol therapy included postoperative administration of T-DM1 (3.6 mg/kg) every 21 days for one year (17 cycles). The primary endpoint was 5-year invasive disease-free survival (iDFS) with a 2-sided 90% confidence interval. Secondary endpoints presented here are toxicity and 3-year iDFS, invasive breast cancer-free survival (iBCFS), and overall survival (OS). All survival analyses were evaluated using Kaplan Meier methods and began at the time of C1D1 of T-DM1. Results: ATOP enrolled 111 evaluable patients during 2015-2020; median follow-up is 4.9 years (IQR 4.2-5.5). The median age was 71 (range 60-88); 50.4% were aged >70 and 11.7% were aged >80. Overall, 69.4% had stage I, 26.1% had stage II, and 4.5% had stage III disease; 70.3% had hormone receptor-positive tumors. The 5-year iDFS = 84.2% (90% CI 77.1-92.0%). The 3-year iDFS = 91.2% (90% CI 85.9%, 96.9%) and iBCFS = 94.1% (90% CI 89.7-98.8%) (see Table for event details); 3-year OS = 96.1% (90% CI 92.4-99.9%). In total, there were 3 distant recurrences and 2 breast cancer-related deaths. Overall, 82% reported grade 2+ toxicity during treatment; the most common grade 2+ events were fatigue (30.6%) and peripheral sensory neuropathy (19.8%). The most frequent grade 3 events were liver function abnormality, anemia, decreased neutrophil count, and neuropathy (<5% for each); one patient (0.9%) had grade 4 thrombocytopenia. Sixty-five (58.6%) completed all 17 cycles of protocol therapy; 27 (24.3%) completed 10-16 cycles, and 19 (17.1%) completed 1-9 cycles. Reasons for early treatment discontinuation in the remaining 41.4% included toxicity (28.8%), patient withdrawal (6.3%), other (3.6%), disease progression (0.9%), death on study (0.9%, deemed unrelated to treatment), and other complicating disease (0.9%). Conclusions: The ATOP trial demonstrated a favorable 5-year iDFS and manageable toxicity among older adults with early stage HER2+ breast cancer. Although iDFS was numerically worse than historical controls (i.e., 5-year iDFS in the ‘ATEMPT’ trial by Tolaney et al. J Clin Oncol, 2024 was 97% [95% 95.2-98.7]), ATOP’s participants had higher-risk cancers, advanced age, and more competing non-breast cancer events. Future endpoints will include in-depth analyses of patient-reported outcomes, biomarkers of aging, and longitudinal functional status. Citation Format: R. A. Freedman, H. Heiling, K. J. Ruddy, L. Rogak, M. Sedrak, A. Dueck, H. Liu, A. Fraettarelli, S. Atanasov, M. DeMeo, P. Lange, A. Perilla Glen, S. Sinclair, D. Dillon, J. Mortimer, M. Fenton, J. Walsh, L. Spring, H. Muss, N. Sinclair, E. Hamilton, C. Dang, S. Giordano, M. Faggen, S. Lo, C. Kuzma, S. Lemke, P. Stella, R. Mowat, M. Wilkinson, J. Rauch, N. Tayob, E. Winer. Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients with HER2+ Breast Cancer - Results from the ATOP Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-04.
The GA4GH Categorical Variation Representation Specification: A Unified Computational Framework for Reasoning over Genomic Variant Categories
Puthawala, Daniel , Reardon, Brendan , Babb, Lawrence , Kuzma, Kori , Stevenson, James , Goar, Wesley , Dolin, Robert H , Freimuth, Robert R. , Procknow, Catherine, Pitel, Beth A. , Kundu, Parijat , Rampersad, Akash , Allen, Eliezer M Van, Babb, Lawrence , Kuzma, Kori , Stevenson, James S , Goar, Wesley A , Pitel, Beth A , Van Allen, Eliezer M , Wagner, Alex H , Freimuth, Robert R , Wagner, Alex H.

No container title available | February 12, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available

10.64898/2026.02.10.705161 | PMID 42094490 Get It

Abstract Categorical variants, or sets of genomic alterations constrained by shared properties, are pervasive across clinical, regulatory, and research domains in the biomedical ecosystem, yet their inconsistent and non-computable representation hinders data interoperability and clinical interpretation. We surveyed genomic knowledgebases spanning regulatory approvals and the biomedical literature and found that categorical variants underpin a substantial proportion of clinical genomics knowledge, but are largely described using incompatible bespoke models. To address this, we developed the GA4GH Categorical Variation Representation Specification (Cat-VRS), a constraint-based framework that provides a unified computable representation for both precise and intentionally broad categories across molecular and systemic variant domains. Cat-VRS enables harmonization of genomic knowledgebases, computable category-based search, and automated matching between assayed variants and categorical entities in clinical and research contexts. By providing a principled, extensible model for categorical variation, Cat-VRS enables computable reasoning over genomic variant categories and establishes a foundation for the standardized representation and exchange of genomic knowledge.
Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL
Woyach, Jennifer A. , Burbano, Gabriela Perez , Ruppert, Amy S. , Heerema, Nyla A. , Zhao, Weiqiang , Wall, Anna, Brander, Danielle M. , Rogers, Kerry A. , Stephens, Deborah M. , Brown, Jennifer R. , Lozanski, Gerard , Nattam, Sreenivasa, Litzow, Mark R. , Luger, Selina M. , Owen, Carolyn , Kuzma, Charles, Little, Richard F. , Dinner, Shira, Stone, Richard M. , Uy, Geoffrey L. , Mandrekar, Sumithra J. , Byrd, John C. , Perez Burbano, Gabriela , Barr, Paul M , Rogers, Kerry A , Parikh, Sameer A , Stephens, Deborah M , Blachly, James , Larson, Richard A , Erba, Harry Paul , Litzow, Mark R. , Abramson, Jeremy S , Little, Richard F , Uy, Geoffrey , Byrd, John C , Miller, Cecelia , Ding, Wei , Bartlett, Nancy L. , Barr, Paul M. , Parikh, Sameer A. , Blachly, James S. , Larson, Richard A. , Abramson, Jeremy S. , Stock, Wendy

Blood | January 12, 2024 | Volume: 143 | Issue: 16 | Pages: 1616-1627

10.1182/blood.2023021959 | PMID 38215395 Get It

Abstract A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.
Development and application of a computable genotype model in the GA4GH Variation Representation Specification
Goar, Wesley , Babb, Lawrence , Cline, Melissa , Kuzma, Kori , Lee, Jennifer , Nelson, Tristan , Smith, Anastasia , Stahl, Kathryn , Bratulin, Anastasia L. , Babb, Lawrence , Chamala, Srikar , Freimuth, Robert R. , Hart, Reece K. , Prlić, Andreas , Riehle, Kevin P. , Yates, Andrew , Rehm, Heidi L. , Wagner, Alex H.

Biocomputing 2023 | November 24, 2022 | Volume: No volume available | Issue: No issue available | Pages: 383-394

10.1142/9789811270611_0035 Get It

Abstract 1177: Introduction of the GA4GH Variation Representation Specification (VRS) and supporting tools for discovery and exchange of clinical genomic and cytogenomic knowledge in cancers
Kuzma, Kori , Stevenson, James , O'Sullivan, Colin, Chaudhari, Bimal P. , Brush, Matthew , Nelson, Tristan , Cline, Melissa , Walsh, Brian , Cannon, Matthew V. , Liu, Jiachen , Freimuth, Robert R. , Baudis, Michael , Griffith, Obi L. , Griffith, Malachi , Babb, Lawrence , Liu, Xuelu, Wagner, Alex H.

Cancer Research | June 15, 2022 | Volume: 82 | Issue: 12_Supplement | Pages: 1177-1177

10.1158/1538-7445.am2022-1177 Get It

Abstract Precision oncology is the practice of interpreting the clinical significance of observed molecular changes in patient neoplasms, potentially impacting medical decision making and care. This process is labor-intensive and (among other challenges) involves accurately translating between variation representation conventions from one resource to the next. For example, differences in representations of Copy Number Variation (CNV) from genomic regions, cytogenomic bands, or gene features create challenges in knowledge matching due to lack of standards covering all of these modalities of observed variation.The Global Alliance for Genomics and Health (GA4GH; ga4gh.org) is an international collaborative of genomic data sharing initiatives (Driver Projects) developing genomic data sharing standards within a human rights framework. GA4GH recently published the Variation Representation Specification (VRS; pronounced “verse”), a standard for the computational representation of biomolecular variation. VRS is a terminology, schema, and associated conventions for creating uniquely identifiable and federatable representations of molecular variation. VRS has formal data classes well-suited to differentiating between variation on a single molecule (e.g. tandem duplications) from variation measured at a systemic level (e.g. genome-wide copy number variation). In addition to molecular sequence variation, VRS also supports variation on cytogenetic coordinate systems and genes, making it well-suited to representing variation associated with cancer biomarkers.We demonstrate the use of VRS to model reported gene-associated CNVs from the AACR Project GENIE cohort, to aid in the computational discovery of evidence from clinico-genomic knowledgebases with genomic or cytogenomic CNV representations. We highlight the use case of knowledge matching to the Atlas of Genetics and Cytogenetics in Oncology and Haematology (“the Atlas”; atlasgeneticsoncology.org), a cytogenetics resource historically driven by user website navigation. Using VRS search tools we developed for the Variant Interpretation for Cancer Consortium (VICC; cancervariants.org) GA4GH Driver Project, we found that 64% of GENIE samples with reported CNVs matched clinically relevant knowledge in the Atlas. This work was enabled by programmatic search tools leveraging standard VRS object structures, demonstrating how VRS enables collection of real-world evidence across more resources without manual interpretation or custom normalization methods. We conclude with a survey of open-source tools supporting this analysis as well as search of other clinico-genomic knowledgebases with VRS, including CIViC (civicdb.org), BRCA Exchange (brcaexchange.org), and the Molecular Oncology Almanac (moalmanac.org). Citation Format: Matthew Cannon, Kori Kuzma, James Stevenson, Jiachen Liu, Colin O'Sullivan, Bimal P. Chaudhari, Matthew Brush, Robert R. Freimuth, Tristan Nelson, Michael Baudis, Obi L. Griffith, Malachi Griffith, Lawrence Babb, Melissa S. Cline, Xuelu Liu, Brian Walsh, Alex H. Wagner. Introduction of the GA4GH Variation Representation Specification (VRS) and supporting tools for discovery and exchange of clinical genomic and cytogenomic knowledge in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1177.
CALGB 40603 (Alliance): Long-Term Outcomes and Genomic Correlates of Response and Survival After Neoadjuvant Chemotherapy With or Without Carboplatin and Bevacizumab in Triple-Negative Breast Cancer
Shepherd, Jonathan H. , Ballman, Karla, Polley, Mei‐Yin C. , Campbell, Jordan D., Fan, Cheng, Selitsky, Sara, Fernández-Martínez, Aranzazu , Parker, Joel S., Hoadley, Katherine A. , Li, Yan, Soloway, Matthew G., Spears, Patricia A., Singh, Baljit, Tolaney, Sara M. , Somlo, George, Port, Elisa R. , Cynthia, X. , Kuzma, Charles, Mamounas, Eleftherios, Golshan, Mehra, Bellon, Jennifer R. , Hahn, Olwen M., Hudis, Clifford A. , Hyslop, Terry, Perou, Charles M. , Sikov, William M. , Hyslop, Terry , Hu, Zhiyuan , Tolaney, Sara , Port, Elisa R , Ma, Cynthia , Bellon, Jennifer R , Collyar, Deborah , Hudis, Clifford , Winer, Eric , Partridge, Ann H , Carey, Lisa A , Perou, Charles M , Sikov, William M , Hoadley, Katherine A , Shepherd, Jonathan H. , Ballman, Karla, Polley, Mei-Yin , Campbell, Jordan D., Fan, Cheng, Selitsky, Sara, Fernandez-Martinez, Aranzazu , Parker, Joel S., Li, Yan, Soloway, Matthew G., Spears, Patricia A., Singh, Baljit, Somlo, George, Kuzma, Charles, Mamounas, Eleftherios, Golshan, Mehra, Hahn, Olwen M.

Journal of Clinical Oncology | January 19, 2022 | Volume: 40 | Issue: 12 | Pages: 1323-1334

10.1200/jco.21.01506 | PMID 35044810 Get It

PURPOSE CALGB 40603 ( NCT00861705 ), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points. PATIENTS AND METHODS The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing. RESULTS Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS. CONCLUSION Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.
Long-Term Results of Alliance A041202 Show Continued Advantage of Ibrutinib-Based Regimens Compared with Bendamustine Plus Rituximab (BR) Chemoimmunotherapy
Woyach, Jennifer A. , Ruppert, Amy S. , Heerema, Nyla A. , Zhao, Weiqiang , Booth, Allison M., Ding, Wei , Brander, Danielle M. , Rogers, Kerry A. , Lozanski, Gerard , Nattam, Sreenivasa, Litzow, Mark R. , Owen, Carolyn , Kuzma, Charles, Brown, Jennifer R. , Little, Richard F. , Smith, Scott E. , Stone, Richard M. , Mandrekar, Sumithra J. , Byrd, John C. , Byrd, John C. , Ding, Wei , Bartlett, Nancy L. , Barr, Paul M. , Parikh, Sameer A. , Coutré, Steven , Larson, Richard A. , Erba, Harry Paul , Blachly, James S. , Abramson, Jeremy S. , Byrd, John C

Blood | November 23, 2021 | Volume: 138 | Issue: Supplement 1 | Pages: 639-639

10.1182/blood-2021-153146 Get It

Abstract Introduction: Alliance for Clinical Trials in Oncology A041202 is a NCI National Clinical Trials Network phase 3 study (NCT01886872) comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy (CIT) in terms of progression-free survival (PFS), and whether rituximab adds benefit to ibrutinib therapy. Initial results showed that ibrutinib-containing regimens had superior PFS to CIT, and that rituximab added to ibrutinib did not improve PFS over ibrutinib alone. Pts and Methods: Eligible pts on A041202 were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl &gt; 40 mL/min, bilirubin &lt; 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified on Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. Pts on Arm 1 who progressed could cross over to Arm 2. Here we present an updated analysis after the third planned interim analysis of Arms 2 and 3 versus Arm 1, and at the second planned interim analysis for Arms 3 vs 2. PFS and OS were estimated using the Kaplan-Meier method and corresponding hazard ratios with p-values were estimated using Cox proportional hazards models. These data encompass patient visits through April 2020 and were locked 15 February 2021. Results: Between 12/9/2013 and 5/16/2016, 547 pts were randomized (Arms 1: 183, 2: 182, and 3: 182). Baseline characteristics have previously been reported; briefly, median age was 71 years, 53% had unmethylated Zap-70, 61% were IGHV unmutated (performed in 66% of patients), 6% had del(17p) and 20% del(11q) by central FISH. Stimulated karyotype was performed centrally and revealed ≥ 3 abnormalities in 27%, and ≥ 5 in 11% of patients. With median follow-up of 55 months (mo), median PFS was 44 mo (95% CI 38-54) in Arm 1 and has not been reached in Arms 2 or 3 [Arm 2 vs 1 hazard ratio (HR): 0.36, 95% CI 0.26-0.52, p&lt;0.0001; Arm 3 vs 1 HR 0.36, 95% CI 0.25-0.51, p&lt;0.0001; Arms 3 vs 2 HR 0.99, 95% CI 0.66-1.48, p=0.96]. 48-month PFS estimates were 47%, 76% and 76% in Arms 1, 2, and 3 respectively (Figure 1). At this time, there are no significant differences in overall survival (OS) among arms (p=0.49). 48-month OS estimates were 84%, 85%, and 86% in Arms 1, 2, and 3, respectively (Figure 2). The benefit of ibrutinib regimens over CIT, with no additional benefit of rituximab when combined with ibrutinib, was consistent for all subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and IGHV (Figure 3). No significant interaction effects were observed between treatment arm and del(11q), complex karyotype, or IGHV. However, greater benefit of ibrutinib regimens over CIT was observed among patients with TP53 abnormalities than without (p&lt;0.001). Thus in Arm 1, PFS was significantly worse for those with TP53 abnormalities vs without (HR 5.32, 95% CI 3.05-9.27, p&lt;0.0001), but in Arms 2 and 3 combined, there was no significant difference in PFS by presence/absence of TP53 abnormalities (HR 0.99, 95% CI 0.51-1.91, p=0.98). Notable adverse events with ibrutinib include atrial fibrillation or flutter (afib) and hypertension (HTN). All grade afib was seen in 11 pts on BR (6%) and 67 pts on ibrutinib (19%). All grade HTN was seen in 95 pts on BR (54%) and 263 pts on ibrutinib (73%). Conclusions: This update of the A041202 trial continues to show that ibrutinib regimens prolong PFS over BR for older patients with treatment-naïve CLL. With longer follow-up, these benefits continue to be seen across subgroups, including those associated with higher risk disease. Strikingly, within the ibrutinib arms, there does not appear to be inferior PFS for patients with abnormalities in TP53, the highest risk feature seen in CLL, and a predictor of inferior PFS with ibrutinib in relapsed CLL. This differentiates ibrutinib (and perhaps BTKi in general) from other targeted therapy paradigms for treatment-naïve CLL. Similar to prior studies, rates of afib and HTN continue to increase with time on therapy. These data support the use of ibrutinib as initial therapy in CLL, and strengthen the rationale for use of ibrutinib for high risk disease. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org, Pharmacyclics, Inc Figure 1 Figure 1. Disclosures Woyach: Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy. Ruppert: Telios Pharma: Consultancy. Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bartlett: ADC Therapeutics: Consultancy, Research Funding; Roche/Genentech: Consultancy; Seagen: Consultancy, Research Funding; Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; LOXO: Research Funding; TG Therapeutics: Consultancy, Research Funding; MEI Pharma: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; DTRM: Research Funding; BeiGene: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Novartis: Research Funding. Barr: Seattle Genetics: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Rogers: Pharmacyclics LLC: Consultancy; Innate Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals, Inc: Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Coutre: Acerta: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Erba: AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Owen: Genentech: Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Servier: Honoraria; Incyte: Honoraria; Pharmacyclics: Research Funding. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding. Stone: Onconova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Jazz: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Innate: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.
Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel
Kunkle, Brian W. , Schmidt, Michael A. , Klein, Hans‐Ulrich , Hamilton‐Nelson, Kara L., Larson, Eric B., Evans, Denis A., Jager, Phil L. De, Crane, Paul K. , Buxbaum, Joseph D. , Ertekin‐Taner, Nilüfer , Barnes, Lisa L. , Fallin, M. Daniele , Go, Rodney C.P., Obisesan, Thomas O. , Bennett, David A. , Hall, Kathleen, Goate, Alison , Foroud, Tatiana M., Martin, Eden R. , Wang, Li‐San , Byrd, Goldie S. , Haines, Jonathan L. , Schellenberg, Gerard D., Mayeux, Richard , Pericak‐Vance, Margaret A. , Reitz, Christiane, Perrie, M. Adams, Roger, L. Albin, Liana, G Apostolova, Steven, Eschrich, Craig, S , Clinton, T. Baldwin, Robert, C. Barber, Barral, Sandra, Thomas, Gunther, James, T., Gary, W. Beecham, Eileen, H. Bigio, Thomas, D., Blacker, Deborah, Bradley, F. Boeve, James, D. Bowen, Boxer, Adam, James, R. Burke, Jeffrey, Morris, Nigel, J Cairns, Cynthia, M. Carlsson, Regina, M. Carney, Minerva, M. Carrasquillo, David, Hugh-Jones, Dick, Malcom, Dickson, Dennis, W., Doody, Rachelle S., Duara, Ranjan , Kelley, M. Faber, Thomas, Jaya , Kenneth, B., David, W. Fardo, Martin, Roger, Matthew, P. Frosch, Douglas, R. Galasko, Gearing, Marla , Daniel, Hervé, Gilbert, John, R., Robert, C. Green, John, Harding, Ronald, L. Hamilton, Hardy, John , Lindy, E. Harrell, Lawrence, Steve, Ryan, Mary, Matthew, J. Huentelman, Christine, M Hulette, Gail, P. Jarvik, Jin, Lee‐Way, Karydas, Anna, Mindy, J. Katz, John, S., Joel, H. Kramer, James, J. Lah, Andrew, Peter, Richard, B., Constantine, G. Lyketsos, Malamon, John , Daniel, Chammiran , Martiniuk, Frank , Masliah, Eliezer , Wayne, C. McCormick, Susan, M, Andrew, Nesbit M, McDonough, Stefan, Ann., Canfield, Mesulam, Marsel, Bruce, L. Miller, Carol, A. Miller, Thomas, J. Montine, Amanda, J. Myers, John, M. Olichney, Joseph, E. Parisi, Peskind, Elaine R. , Pierce, Aimee, Wayne, W. Poon, Joseph, F. Quinn, Raj, Ashok , Raskind, Murray A. , Reisch, Joan, S., John, M. Ringman, Erik, D. Roberson, Howard, J. Rosen, Donald, R. Royall, Mark, A. Sager, Julie, A. Schneider, Lon, Su, William, W. Seeley, Small, Scott A. , Sonnen, Joshua, A., Robert, Aiko, Rudolph, E. Tanzi, Juan, Caballero, Debby, W. Tsuang, Vivianna, M. Van Deerlin, Badri, Nabeel, Harry, Vanessa, Vonsattel, Jean Paul, Weıntraub, Sandra , Kathleen, A Welsh-Bohmer, Kirk, C W, Thomas, SubinVarghese, Randall, Linnell B., Wu, Chuang‐Kuo, Steven, G. Younkin, Yu, Lei , Yu, Chang‐En , Graff‐Radford, Neill R. , Martinez, Izri, Ayodele, Temitope , Cantwell, Laura B., Jean‐Francois, Melissa, Kuzma, Amanda , Adams, Lonnie D., Chung, Jaeyoon , Jun, Gyungah , Hendrie, Hugh C. , Reiman, Eric M. , Kowall, Neil W. , Golde, Todd E. , Saykin, Andrew J. , Starks, Takiyah D. , Albert, Marilyn S. , Petersen, Ronald , Sano, Mary , Wısnıewskı, Thomas , Vassar, Robert , Kaye, Jeffrey A., Henderson, Victor W. , DeCarli, Charles , LaFerla, Frank M. , Brewer, James B., Miller, Bruce L. , Swerdlow, Russell H. , Paulson, Henry L. , Trojanowski, John Q. , Chui, Helena C., Rosenberg, Roger N., Craft, Suzanne , Grabowski, Thomas J. , Asthana, Sanjay , Morris, John C. , Strittmatter, Stephen M. , Kukull, Walter A. , Asthana, Sanjay , Jarvik, Gail P. , Cribbs, David H. , Sonnen, Joshua A. , Bennett, David A. , Saykin, Andrew J , Miller, Bruce L , Jarvik, Gail P , Paulson, Henry L , Hardy, John , Morris, John C , Goate, Alison M , Sonnen, Joshua , Barnes, Lisa L , Naj, Adam Christian , Hamilton‐Nelson, Kara L. , Manly, Jennifer J. , Kamboh, M. Ilyas , Farrer, Lindsay A. , Abner, Erin L. , Atwood, Craig, S., Becker, James, T., Eileen, H Bigio, Blacker, Deborah , Cao, Chuanhai , Cruchaga, Carlos , Dickson, Dennis, W., Duara, Ranjan , David, W. Fardo, Farlow, Martin, R., Ferris, Steven H. , Geschwind, Daniel, H., Ghetti, Bernardino , Gilbert, John, R., Håkonarson, Håkon , Honig, Lawrence, S., Huebinger, Ryan, M., Matthew, J Huentelman, Kauwe, John, S.K., Keene, C. Dirk , Kim, Ronald, Leung, Yuk Yee , Li, Ge , Lipton, Richard, B., Marson, Daniel, C., McDavid, Andrew, N., Mesulam, Marsel M. , Bruce, L Miller, Mukherjee, Shubhabrata , O’Bryant, Sid, E., Potter, Huntington , Qu, Liming , Raj, Ashok, Reisberg, ‌Barry , Reisch, Joan, S., Rogaeva, Ekaterina A. , Julie, A Schneider, Schneider, Lon, S., William, W Seeley, Spina, Salvatore , George‐Hyslop, Peter St , Valladares, Otto , Vardarajan, Badri, N., Wilhelmsen, Kirk, C., Williamson, Jennifer , Wingo, Thomas, S., Woltjer, Randall, L., Steven, G Younkin, Zhao, Yi Chen , Logue, Mark W. , Adams, L.D., Vance, Jeffery M. , Cuccaro, Michael L. , Mez, Jesse , Lunetta, Kathryn L. , López, Oscar L. , Leverenz, James B. , Levey, Allan I. , Hyman, Bradley T. , Kaye, Jeffrey A., Eldik, Linda J. Van , Chui, Helena C.

JAMA Neurology | October 19, 2020 | Volume: 78 | Issue: 1 | Pages: 102

10.1001/jamaneurol.2020.3536 | PMID 33074286 Get It