Welcome to Dana-Farber's Research News
May 15, 2024
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: Michael_buller@dfci.harvard.edu.
Blood
Crombie JL, Abramson JS, Armand P
Bispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in patients with heavily pretreated disease, and 3 drugs have so far received regulatory approvals in various countries. However, BsAbs can potentially lead to severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy has been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies, yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3×CD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3×CD20 BsAb-related toxicities.
Blood
How I Use Genomics and BTK Inhibitors in the Treatment of Waldenström Macroglobulinemia
Treon SP, Sarosiek S, Castillo JJ
Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those previously treated. Mutated MYD88 activates hematopoietic cell kinase that drives Bruton tyrosine kinase (BTK) prosurvival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants show greater resistance to BTK inhibitors. Covalent BTK inhibitors (cBTKi) produce major responses in 70% to 80% of patients with WM. MYD88 and CXCR4 mutation status can affect time to major response, depth of response, and/or progression-free survival (PFS) in patients with WM treated with cBTKi. The cBTKi zanubrutinib shows greater response activity and/or improved PFS in patients with WM with wild-type MYD88, mutated CXCR4, or altered TP53. Risks for adverse events, including atrial fibrillation, bleeding diathesis, and neutropenia can differ based on which BTKi is used in WM. Intolerance is also common with cBTKi, and dose reduction or switchover to another cBTKi can be considered. For patients with acquired resistance to cBTKis, newer options include pirtobrutinib or venetoclax. Combinations of BTKis with chemoimmunotherapy, CXCR4, and BCL2 antagonists are discussed. Algorithms for positioning BTKis in treatment naïve or previously treated patients with WM, based on genomics, disease characteristics, and comorbidities, are presented.
Blood
“Treatment with Curative Intent”: The Emergence of Genetic Therapies for Sickle Cell Anemia
Benz EJ, Silberstein LE
The root cause of sickle cell anemia has been known for 7 decades, yet no curative therapies have been available other than allogeneic bone marrow transplantation, for which applicability is limited. Two potentially curative therapies based on gene therapy and gene editing strategies have recently received US Food and Drug Administration approval. This review surveys the nature of these therapies and the opportunities and issues raised by the prospect of definitive genetically based therapies being available in clinical practice.
Cell
Lampson BL, He L, Hegde M, Koduri V, Pfaff JL, Hanna RE, Shirole NH, He Y, Doench JG, Kaelin WG Jr
Nuclear factor ?B (NF-?B) plays roles in various diseases. Many inflammatory signals, such as circulating lipopolysaccharides (LPSs), activate NF-?B via specific receptors. Using whole-genome CRISPR-Cas9 screens of LPS-treated cells that express an NF-?B-driven suicide gene, we discovered that the LPS receptor Toll-like receptor 4 (TLR4) is specifically dependent on the oligosaccharyltransferase complex OST-A for N-glycosylation and cell-surface localization. The tool compound NGI-1 inhibits OST complexes in vivo, but the underlying molecular mechanism remained unknown. We did a CRISPR base-editor screen for NGI-1-resistant variants of STT3A, the catalytic subunit of OST-A. These variants, in conjunction with cryoelectron microscopy studies, revealed that NGI-1 binds the catalytic site of STT3A, where it traps a molecule of the donor substrate dolichyl-PP-GlcNAc2-Man9-Glc3, suggesting an uncompetitive inhibition mechanism. Our results provide a rationale for and an initial step toward the development of STT3A-specific inhibitors and illustrate the power of contemporaneous base-editor and structural studies to define drug mechanism of action.
Journal of Clinical Oncology
Burstein HJ
ASCO Rapid Recommendation Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only).
JAMA
Aspirin vs Placebo as Adjuvant Therapy for Breast Cancer: The Alliance A011502 Randomized Trial
Chen WY, Partridge AH, Briccetti FM, Holmes MD
IMPORTANCE: Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking.
OBJECTIVE: To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023.
INTERVENTIONS: Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [?30 vs >30], stage II vs III, and time since diagnosis [<18 vs ?18 months]) to receive 300 mg of aspirin (n?=?1510) or placebo once daily (n?=?1510) for 5 years.
MAIN OUTCOMES AND MEASURES: The primary outcome was invasive disease-free survival. Overall survival was a key secondary outcome.
RESULTS: A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease-free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease-free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups.
CONCLUSION AND RELEVANCE: Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02927249.
New England Journal of Medicine
Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma
Choueiri TK, McDermott DF
BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain.
METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point.
RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy.
CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).
American Journal of Bioethics
Establishing and Defining an Approach to Climate Conscious Clinical Medical Ethics
Hantel A, Marron JM, Abel GA
Applied Clinical Informatics
Wang L, Zupanc S, Penumarthy A, Laurentiev J, Lamey J, Farah S, Lipsitz S, Jain N, Bates DW, Zhou L, Lakin J
Blood Advances
Davids MS
Blood Advances
Nikiforow S, Whangbo JS, Prockop SE
Breast Cancer Research and Treatment
Leonard S, Jones AN, Freedman RA, Mayer EL, Mittendorf EA, King TA, Kantor O
Cancer
Oppegaard KR, Hammer MJ
Cancer Prevention Research
Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata
Kipnis LM, Breen KM, Koeller DR, Levine AS, Yang Z, Jun H, Tayob N, Stokes SM, Hayes CP, Ghazani AA, Hill SJ, Rana HQ
Cancer Research
ASPSCR1::TFE3 Drives Alveolar Soft Part Sarcoma by Inducing Targetable Transcriptional Programs
Sicinska E, Kerfoot JA, Taddei ML, Al-Ibraheemi A, Church AJ, Landesman-Bollag E
Cancer Research Communications
A Phase II study of ERK inhibition by ulixertinib (BVD-523) in Metastatic Uveal Melanoma
Buchbinder EI, Cohen JV, Tarantino G, Lian CG, Liu D, Haq R, Hodi FS, Lawrence DP, Giobbie-Hurder A, Sullivan RJ
Cell Reports
The MYCN 5' UTR as a Therapeutic Target in Neuroblastoma
Volegova MP, Banerjee U, Sharma B, Kennedy A, George RE
Circulation
Lin AE, Bapat AC, Xiao L, Niroula A, Ye J, Wong WJ, Agrawal M, Hergott CB, McConkey M, Flores-Bringas P, Shkolnik V, Natarajan P, Libby P, Ellinor PT, Ebert BL
Contemporary Clinical Trials
Amonoo HL, Newcomb R, Psenka R, Holmbeck K, Farnam EJ, Tse A, Waldman LP, El-Jawahri A
European Urology Oncology
Sentana-Lledo D, Chu X, Morgans AK
Hematology Oncology Clinics of North America
Introduction to the Thalassemia Syndromes: Molecular Medicine’s Index Case
Benz EJ
Hematology Oncology Clinics of North America
Benz EJ, Sankaran VG
Journal of Pain and Symptom Management
"At Least I Can Push this Morphine":PICU Nurses' Approaches to Suffering Among Dying Children
Broden EG, Eche-Ugwu IJ, DeCourcey DD, Wolfe J, Snaman J
JCO Oncology Practice
Prostate Cancer Survivorship and Global Health-Related Quality of Life
Nguyen PL
Lancet Digital Health
The Effect of Using a Large Language Model to Respond to Patient Messages
Chen S, Guevara M, Moningi S, Hoebers F, Elhalawani H, Kann BH, Chipidza FE, Leeman J, Aerts HJWL, Miller T, Savova GK, Celi LA, Mak RH, Bitterman DS
Lancet Haematology
O'Donnell E, Mo C, Yee AJ, Nadeem O, Laubach J, Rosenblatt J, Munshi N, Midha S, Cirstea D, Horick N, Richardson PG, Raje N
Leukemia and Lymphoma
Patel KK, Stahl M, Zeidan AM
Nature Reviews Genetics
Genome Assembly in the Telomere-to-Telomere Era
Li H
Nature Reviews Molecular Cell Biology
Targeted Protein Degradation: From Mechanisms to Clinic
Tsai JM, Nowak RP, Ebert BL, Fischer ES
NPJ Breast Cancer
Morganti S, Jin Q, Vincuilla J, Buehler R, Ryan S, Stokes S, Parker T, Mittendorf EA, King TA, Weiss A, Partridge AH, Bychkovsky BL, Tayob N, Lin NU, Garber JE, Tolaney SM, Lynce F
NPJ Breast Cancer
Bardia A, Tolaney SM
Oncologist
Saad E, Semaan K, Eid M, Saliby RM, Labaki C, Xie W, Choueiri TK
Statistics in Medicine
Optimal Ensemble Construction for Multistudy Prediction with Applications to Mortality Estimation
Nunez RA, Parmigiani G
Tobacco Induced Diseases
Nayak MM, Mazzola E, Jaklitsch MT, Drehmer JE, Nabi-Burza E, Bueno R, Winickoff JP, Cooley ME
Translational Behavioral Medicine
Improve Accessibility to Evidence-Based Treatment for Insomnia Disorder
Zhou ES
Transplantation and Cellular Therapy
Bone Marrow Harvest: A White Paper of Best Practices by the NMDP Marrow Alliance
Murakami MA, Spitzer T
Turkish Journal of Haematology
Advancements in the Management of Follicular Lymphoma: A Comprehensive Review
Merryman R, LaCasce A