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1. LNK/SH2B3 as a novel driver in juvenile myelomonocytic leukemia

Author

Wintering, Astrid, Hecht, Anna, Meyer, Julia, Wong, Eric B, Hübner, Juwita, Abelson, Sydney, Feldman, Kira, Kennedy, Vanessa E, Peretz, Cheryl AC, French, Deborah L, Maguire, Jean Ann, Jobaliya, Chintan, Vasquez, Marta Rojas, Desai, Sunil, Dulman, Robin, Nemecek, Eneida, Haines, Hilary, Hammad, Mahmoud, El Haddad, Alaa, Kogan, Scott C, Abdullaev, Zied, Chehab, Farid F, Tasian, Sarah K, Smith, Catherine C, Loh, Mignon L, and Stieglitz, Elliot

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Cancer, Childhood Leukemia, Hematology, Pediatric Cancer, Stem Cell Research - Nonembryonic - Human, Stem Cell Research - Nonembryonic - Non-Human, Genetics, Pediatric, Stem Cell Research, Stem Cell Research - Induced Pluripotent Stem Cell, Rare Diseases, 2.1 Biological and endogenous factors, Humans, Leukemia, Myelomonocytic, Juvenile, Adaptor Proteins, Signal Transducing, Male, Female, Infant, Child, Preschool, Mutation, Intracellular Signaling Peptides and Proteins, Child, Signal Transduction, Pyrazoles, Nitriles, Pyrimidines, Immunology
Abstract

Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.

Published
2024

3. Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia

Author

Peretz, Cheryl A. C., Kennedy, Vanessa E., Walia, Anushka, Delley, Cyrille L., Koh, Andrew, Tran, Elaine, Clark, Iain C., Hayford, Corey E., D’Amato, Chris, Xue, Yi, Fontanez, Kristina M., May-Zhang, Aaron A., Smithers, Trinity, Agam, Yigal, Wang, Qian, Dai, Hai-ping, Roy, Ritu, Logan, Aaron C., Perl, Alexander E., Abate, Adam, Olshen, Adam, and Smith, Catherine C.

Published
2024
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4. Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML

Author

Popescu, Bogdan, Stahlhut, Carlos, Tarver, Theodore C, Wishner, Sydney, Lee, Bianca J, Peretz, Cheryl AC, Luck, Cuyler, Phojanakong, Paul, Serrano, Juan Antonio Camara, Hongo, Henry, Rivera, Jose M, Xirenayi, Simayijiang, Chukinas, John A, Steri, Veronica, Tasian, Sarah K, Stieglitz, Elliot, and Smith, Catherine C

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Pediatric Cancer, Childhood Leukemia, Rare Diseases, Cancer, Pediatric, Orphan Drug, Hematology, 5.1 Pharmaceuticals, Good Health and Well Being, Humans, Cell Line, Tumor, Apoptosis, Leukemia, Myeloid, Acute, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-bcl-2, fms-Like Tyrosine Kinase 3, FLT3, SHP2, acute myeloid leukemia, apoptosis, cancer, drug synergy, targeted therapies, Biomedical and clinical sciences
Abstract

Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

Published
2023

5. Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target

Author

Mandal, Kamal, Wicaksono, Gianina, Yu, Clinton, Adams, Jarrett J, Hoopmann, Michael R, Temple, William C, Izgutdina, Adila, Escobar, Bonell Patiño, Gorelik, Maryna, Ihling, Christian H, Nix, Matthew A, Naik, Akul, Xie, William H, Hübner, Juwita, Rollins, Lisa A, Reid, Sandy M, Ramos, Emilio, Kasap, Corynn, Steri, Veronica, Serrano, Juan Antonio Camara, Salangsang, Fernando, Phojanakong, Paul, McMillan, Melanie, Gavallos, Victor, Leavitt, Andrew D, Logan, Aaron C, Rooney, Cliona M, Eyquem, Justin, Sinz, Andrea, Huang, Benjamin J, Stieglitz, Elliot, Smith, Catherine C, Moritz, Robert L, Sidhu, Sachdev S, Huang, Lan, and Wiita, Arun P

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Hematology, Orphan Drug, Gene Therapy, Rare Diseases, Pediatric Cancer, Pediatric, Childhood Leukemia, Genetics, Immunotherapy, Biotechnology, 5.2 Cellular and gene therapies, 5.1 Pharmaceuticals, Humans, Receptors, Chimeric Antigen, T-Lymphocytes, Integrins, Immunotherapy, Adoptive, Leukemia, Myeloid, Acute, Oncology and carcinogenesis
Abstract

Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture 'structural surfaceomics'. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin β2 as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.

Published
2023

6. Microfluidics-free single-cell genomics with templated emulsification

Author

Clark, Iain C, Fontanez, Kristina M, Meltzer, Robert H, Xue, Yi, Hayford, Corey, May-Zhang, Aaron, D’Amato, Chris, Osman, Ahmad, Zhang, Jesse Q, Hettige, Pabodha, Ishibashi, Jacob SA, Delley, Cyrille L, Weisgerber, Daniel W, Replogle, Joseph M, Jost, Marco, Phong, Kiet T, Kennedy, Vanessa E, Peretz, Cheryl AC, Kim, Esther A, Song, Siyou, Karlon, William, Weissman, Jonathan S, Smith, Catherine C, Gartner, Zev J, and Abate, Adam R

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Cancer, Bioengineering, Human Genome, Biotechnology, Cancer Genomics, Generic health relevance, Humans, Animals, Mice, Microfluidics, High-Throughput Nucleotide Sequencing, Single-Cell Analysis, Genomics, Transcriptome
Abstract

Current single-cell RNA-sequencing approaches have limitations that stem from the microfluidic devices or fluid handling steps required for sample processing. We develop a method that does not require specialized microfluidic devices, expertise or hardware. Our approach is based on particle-templated emulsification, which allows single-cell encapsulation and barcoding of cDNA in uniform droplet emulsions with only a vortexer. Particle-templated instant partition sequencing (PIP-seq) accommodates a wide range of emulsification formats, including microwell plates and large-volume conical tubes, enabling thousands of samples or millions of cells to be processed in minutes. We demonstrate that PIP-seq produces high-purity transcriptomes in mouse-human mixing studies, is compatible with multiomics measurements and can accurately characterize cell types in human breast tissue compared to a commercial microfluidic platform. Single-cell transcriptional profiling of mixed phenotype acute leukemia using PIP-seq reveals the emergence of heterogeneity within chemotherapy-resistant cell subsets that were hidden by standard immunophenotyping. PIP-seq is a simple, flexible and scalable next-generation workflow that extends single-cell sequencing to new applications.

Published
2023

7. Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia.

Author

Daver, Naval, Perl, Alexander E, Maly, Joseph, Levis, Mark, Ritchie, Ellen, Litzow, Mark, McCloskey, James, Smith, Catherine C, Schiller, Gary, Bradley, Terrence, Tiu, Ramon V, Naqvi, Kiran, Dail, Monique, Brackman, Deanna, Siddani, Satya, Wang, Jing, Chyla, Brenda, Lee, Paul, and Altman, Jessica K

Subjects
Humans, fms-Like Tyrosine Kinase 3, Leukemia, Myeloid, Acute, Hematology, Rare Diseases, Pediatric, Childhood Leukemia, Cancer, Pediatric Cancer, Clinical Research, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeThe FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but seldom reduces FLT3mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3mut AML.MethodsThis phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with FLT3 wild-type and FLT3mut (escalation) or FLT3mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria.ResultsSixty-one patients were enrolled (n = 56 FLT3mut); 64% (n = 36 of 56) of FLT3mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10-2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3mut patients was 10.0 months.ConclusionThe combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

Published
2022

8. Beat-AML 2024 ELN–refined risk stratification for older adults with newly diagnosed AML given lower-intensity therapy

Author

Hoff, Fieke W., Blum, William G., Huang, Ying, Welkie, Rina Li, Swords, Ronan T., Traer, Elie, Stein, Eytan M., Lin, Tara L., Archer, Kellie J., Patel, Prapti A., Collins, Robert H., Baer, Maria R., Duong, Vu H., Arellano, Martha L., Stock, Wendy, Odenike, Olatoyosi, Redner, Robert L., Kovacsovics, Tibor, Deininger, Michael W., Zeidner, Joshua F., Olin, Rebecca L., Smith, Catherine C., Foran, James M., Schiller, Gary J., Curran, Emily K., Koenig, Kristin L., Heerema, Nyla A., Chen, Timothy, Martycz, Molly, Stefanos, Mona, Marcus, Sonja G., Rosenberg, Leonard, Druker, Brian J., Levine, Ross L., Burd, Amy, Yocum, Ashley O., Borate, Uma M., Mims, Alice S., Byrd, John C., and Madanat, Yazan F.

Published
2024
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9. Patterns and Predictors of Functional Decline after Allogeneic Hematopoietic Cell Transplantation in Older Adults.

Author

Huang, Li-Wen, Sheng, Ying, Andreadis, Charalambos, Logan, Aaron C, Mannis, Gabriel N, Smith, Catherine C, Gaensler, Karin ML, Martin, Thomas G, Damon, Lloyd E, Huang, Chiung-Yu, and Olin, Rebecca L

Subjects
Humans, Neoplasms, Activities of Daily Living, Hematopoietic Stem Cell Transplantation, Prospective Studies, Quality of Life, Aged, Middle Aged, Allogeneic transplant, Functional status, Geriatric assessment, Older adults, Rehabilitation, Aging, Physical Rehabilitation, Regenerative Medicine, Clinical Research, Transplantation, 7.1 Individual care needs, Management of diseases and conditions, Mental health, Good Health and Well Being
Abstract

As allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, geriatric assessment (GA) has been identified as a useful tool for predicting outcomes, particularly functional status. However, very few studies have examined the longitudinal change in GA measures in the post-alloHCT period. The objectives of this study were to describe the longitudinal change in GA and quality of life (QoL) measures after alloHCT and to identify predictors of greater functional decline post-transplantation. In this single-center prospective cohort study, patients age ≥50 years scheduled for alloHCT completed a cancer-specific GA and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) survey at baseline prior to alloHCT and then at 3, 6, and 12 months post-transplantation. Changes in GA and QoL measures at each post-transplantation time point (3, 6, and 12 months) compared to baseline were analyzed using paired t-tests. Exploration of potential predictors of greater post-transplantation functional decline, as measured by instrumental activities of daily living (IADL) and the Medical Outcomes Study Physical Health scale (MOS-PH), were examined using linear regression and the chi-square 2-sample test of proportions. Mean functional status generally exhibited a pattern of decline at 3 to 6 months post-alloHCT, with recovery to near baseline by 12 months. Mean mental health and emotional QoL were lowest at baseline and improved at all post-transplantation time points. Differences in baseline clinical characteristics were not associated with any differences in functional trajectories. Differences in baseline GA measures-patient-rated Karnofsky Performance Status, IADL, MOS-PH, Timed-Up-and-Go, Blessed Orientation-Memory-Concentration test, and Mental Health Inventory 5-also did not predict greater functional decline at 3 months. Patients whose IADL was improved or maintained at 3 months generally maintained their functional status at 6 and 12 months. Similarly, most patients who had an IADL decline at 3 months still had a functional decline at 6 months, although a proportion did have functional recovery by 12 months. Compared with patients who had improved/maintained IADL at 3 months, those with a decline in IADL at 3 months were significantly more likely to have persistent functional decline at 6 months (P < .0001) and 12 months (P = .02). In older alloHCT recipients, mean functional status declines short term after alloHCT with the possibility of recovery by 6 to 12 months, whereas mean mental and emotional health improve post-alloHCT. Functional decline at 3 months post-alloHCT is associated with persistent functional decline at 12 months.

Published
2022

10. The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance MechanismsFF-10101 Overcomes FLT3 TKI Resistance Mechanisms

Author

Ferng, Timothy T, Terada, Daisuke, Ando, Makoto, Tarver, Theodore C, Chaudhary, Fihr, Lin, Kimberly C, Logan, Aaron C, and Smith, Catherine C

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Hematology, Orphan Drug, Rare Diseases, Pediatric, Childhood Leukemia, Pediatric Cancer, 5.1 Pharmaceuticals, Amides, Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, Leukemia, Myeloid, Acute, Mutation, Protein Kinase Inhibitors, Pyrimidines, Tumor Microenvironment, fms-Like Tyrosine Kinase 3, Pharmacology and Pharmaceutical Sciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance-causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.

Published
2022

11. Molecular profile of FLT3-mutated relapsed/refractory AML patients in the phase 3 ADMIRAL study of gilteritinib

Author

Smith, Catherine C, Levis, Mark J, Perl, Alexander E, Hill, Jason E, Rosales, Matt, and Bahceci, Erkut

Subjects
Genetics, Pediatric Cancer, Hematology, Clinical Research, Rare Diseases, Cancer, Childhood Leukemia, Pediatric, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aniline Compounds, Humans, Leukemia, Myeloid, Acute, Protein Kinase Inhibitors, Pyrazines, fms-Like Tyrosine Kinase 3
Abstract

The phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML. Baseline comutations, FLT3-internal tandem duplication (ITD) allelic ratio and length, and treatment-emergent mutations were analyzed in patients in the ADMIRAL trial. Baseline comutations were grouped according to gene subgroups (DNA methylation/hydroxymethylation, transcription, chromatin-spliceosome, receptor tyrosine kinase-Ras signaling, TP53-aneuploidy, NPM1, DNMT3A, DNMT3A/NPM1, WT-1, and IDH1/IDH2). Across all but 1 gene subgroup (TP53-aneuploidy), higher pretransplant response rates and a trend toward longer overall survival were observed with gilteritinib vs SC. Patients with DNMT3A/NPM1 comutations who received gilteritinib had the most favorable outcomes of any molecular subgroup analyzed. Survival outcomes with gilteritinib were not adversely affected by FLT3-ITD allelic ratio, FLT3-ITD length, or multiple FLT3-ITD mutations. Among patients who relapsed on gilteritinib, Ras/mitogen-activated protein kinase (MAPK) pathway and FLT3 F691L gene mutations were the most common mutational events associated with treatment resistance. However, the occurrence of Ras/MAPK pathway gene mutations at baseline did not preclude a clinical benefit from gilteritinib. Acquisition of multiple Ras/MAPK pathway gene mutations at relapse suggests a high level of pathway reactivation is needed to overcome the gilteritinib treatment effect. These findings provide insight into the R/R AML molecular profile and the impact of FLT3 inhibitors on mutational evolution associated with treatment resistance and benefit of gilteritinib across a wide spectrum of molecular and genetic subgroups in FLT3-mutated R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

Published
2022

12. Recurrent Mutations in Cyclin D3 Confer Clinical Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia

Author

Smith, Catherine C, Viny, Aaron D, Massi, Evan, Kandoth, Cyriac, Socci, Nicholas D, Rapaport, Franck, Najm, Matthieu, Medina-Martinez, Juan S, Papaemmanuil, Elli, Tarver, Theodore C, Hsu, Henry H, Le, Mai H, West, Brian, Bollag, Gideon, Taylor, Barry S, Levine, Ross L, and Shah, Neil P

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Pediatric Cancer, Hematology, Pediatric, Clinical Trials and Supportive Activities, Rare Diseases, Childhood Leukemia, Genetics, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Aminopyridines, Cell Line, Tumor, Cyclin D3, Drug Resistance, Neoplasm, Humans, Leukemia, Myeloid, Acute, Mutation, Protein Kinase Inhibitors, Pyrroles, fms-Like Tyrosine Kinase 3, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeBiomarkers of response and resistance to FLT3 tyrosine kinase inhibitors (TKI) are still emerging, and optimal clinical combinations remain unclear. The purpose of this study is to identify co-occurring mutations that influence clinical response to the novel FLT3 inhibitor pexidartinib (PLX3397).Experimental designWe performed targeted sequencing of pretreatment blasts from 29 patients with FLT3 internal tandem duplication (ITD) mutations treated on the phase I/II trial of pexidartinib in relapsed/refractory FLT3-ITD+ acute myeloid leukemia (AML). We sequenced 37 samples from 29 patients with available material, including 8 responders and 21 non-responders treated at or above the recommended phase II dose of 3,000 mg.ResultsConsistent with other studies, we identified mutations in NRAS, TP53, IDH2, and a variety of epigenetic and transcriptional regulators only in non-responders. Among the most frequently mutated genes in non-responders was Cyclin D3 (CCND3). A total of 3 individual mutations in CCND3 (Q276*, S264R, and T283A) were identified in 2 of 21 non-responders (one patient had both Q276* and S264R). No CCND3 mutations were found in pexidartinib responders. Expression of the Q276* and T283A mutations in FLT3-ITD MV4;11 cells conferred resistance to apoptosis, decreased cell-cycle arrest, and increased proliferation in the presence of pexidartinib and other FLT3 inhibitors. Inhibition of CDK4/6 activity in CCND3 mutant MV4;11 cells restored pexidartinib-induced cell-cycle arrest but not apoptosis.ConclusionsMutations in CCND3, a gene not commonly mutated in AML, are a novel cause of clinical primary resistance to FLT3 inhibitors in AML and may have sensitivity to CDK4/6 inhibition.

Published
2021

13. Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia.

Author

Demaree, Benjamin, Delley, Cyrille L, Vasudevan, Harish N, Peretz, Cheryl AC, Ruff, David, Smith, Catherine C, and Abate, Adam R

Subjects
Cell Line, Tumor, Jurkat Cells, Humans, DNA, Sequence Analysis, DNA, Immunophenotyping, Base Sequence, fms-Like Tyrosine Kinase 3, Leukemia, Myeloid, Acute, Genetic Association Studies, Single-Cell Analysis, Genotyping Techniques, Cancer, Childhood Leukemia, Human Genome, Pediatric Cancer, Bioengineering, Rare Diseases, Biotechnology, Hematology, Pediatric, Genetics, 2.1 Biological and endogenous factors
Abstract

Studies of acute myeloid leukemia rely on DNA sequencing and immunophenotyping by flow cytometry as primary tools for disease characterization. However, leukemia tumor heterogeneity complicates integration of DNA variants and immunophenotypes from separate measurements. Here we introduce DAb-seq, a technology for simultaneous capture of DNA genotype and cell surface phenotype from single cells at high throughput, enabling direct profiling of proteogenomic states in tens of thousands of cells. To demonstrate the approach, we analyze the disease of three patients with leukemia over multiple treatment timepoints and disease recurrences. We observe complex genotype-phenotype dynamics that illustrate the subtlety of the disease process and the degree of incongruity between blast cell genotype and phenotype in different clinical scenarios. Our results highlight the importance of combined single-cell DNA and protein measurements to fully characterize the heterogeneity of leukemia.

Published
2021

14. Single-cell DNA sequencing reveals complex mechanisms of resistance to quizartinib

Author

Peretz, Cheryl AC, McGary, Lisa HF, Kumar, Tanya, Jackson, Hunter, Jacob, Jose, Durruthy-Durruthy, Robert, Levis, Mark J, Perl, Alexander, Huang, Benjamin J, and Smith, Catherine C

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Human Genome, Biotechnology, Benzothiazoles, Phenylurea Compounds, Sequence Analysis, DNA, Cardiovascular medicine and haematology
Abstract

Single-cell sequencing exposes previously unmeasurable complexity of tumor heterogeneity and clonal evolution on quizartinib. Single-cell sequencing reveals on- and off-target mechanisms of resistance to quizartinib, which can preexist therapy.

Published
2021

16. Clinical Outcomes in Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated with Gilteritinib Who Received Prior Midostaurin or Sorafenib

Author

Perl, Alexander E, Altman, Jessica K, Hosono, Naoko, Montesinos, Pau, Podoltsev, Nikolai, Martinelli, Giovanni, Smith, Catherine C, Levis, Mark J, Roellig, Christoph, Gross-Langenhoff, Marco, Hasabou, Nahla, Lu, Qiaoyang, and Tiu, Ramon V

Subjects
AML, acute myeloid leukemia, FLT3 mutation, tyrosine kinase inhibitor, Clinical Sciences, Oncology and Carcinogenesis, Cardiovascular medicine and haematology, Oncology and carcinogenesis
Abstract

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin.

Published
2021

17. Standardising acute myeloid leukaemia classification systems: a perspective from a panel of international experts

Author

Shallis, Rory M, Daver, Naval, Altman, Jessica K, Komrokji, Rami S, Pollyea, Daniel A, Badar, Talha, Bewersdorf, Jan P, Bhatt, Vijaya R, de Botton, Stéphane, de la Fuente Burguera, Adolfo, Carraway, Hetty E, Desai, Pinkal, Dillon, Richard, Duployez, Nicolas, El Chaer, Firas, Fathi, Amir T, Freeman, Sylvie D, Gojo, Ivana, Grunwald, Michael R, Jonas, Brian A, Konopleva, Marina, Lin, Tara L, Mannis, Gabriel N, Mascarenhas, John, Michaelis, Laura C, Mims, Alice S, Montesinos, Pau, Pozdnyakova, Olga, Pratz, Keith W, Schuh, Andre C, Sekeres, Mikkael A, Smith, Catherine C, Stahl, Maximilian, Subklewe, Marion, Uy, Geoffrey L, Voso, Maria Teresa, Walter, Roland B, Wang, Eunice S, Zeidner, Joshua F, Žučenka, Andrius, and Zeidan, Amer M

Published
2023
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18. Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor

Author

James, Angela Joubert, Smith, Catherine C, Litzow, Mark, Perl, Alexander E, Altman, Jessica K, Shepard, Dale, Kadokura, Takeshi, Souda, Kinya, Patton, Melanie, Lu, Zheng, Liu, Chaofeng, Moy, Selina, Levis, Mark J, and Bahceci, Erkut

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Hematology, Clinical Research, 5.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aniline Compounds, Drug Interactions, Female, Humans, Male, Protein Kinase Inhibitors, Pyrazines, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

Background and objectiveGilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib.MethodsThe pharmacokinetic profile of gilteritinib was assessed from five clinical studies.ResultsDose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20-450 mg). Median maximum concentration was reached 2-6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function.ConclusionsGilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment.Clinical trial registrationNCT02014558, NCT02456883, NCT02571816.

Published
2020

19. A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD–mutant acute myeloid leukemia

Author

Smith, Catherine C, Levis, Mark J, Frankfurt, Olga, Pagel, John M, Roboz, Gail J, Stone, Richard M, Wang, Eunice S, Severson, Paul L, West, Brian L, Le, Mai H, Kayser, Sabine, Lam, Bao, Hsu, Henry H, Zhang, Chao, Bollag, Gideon, and Perl, Alexander E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Childhood Leukemia, Pediatric, Cancer, Pediatric Cancer, Hematology, Pediatric Research Initiative, Rare Diseases, 6.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 6.2 Cellular and gene therapies, Evaluation of treatments and therapeutic interventions, Aminopyridines, Humans, Leukemia, Myeloid, Acute, Phenylurea Compounds, Protein Kinase Inhibitors, Pyrroles, fms-Like Tyrosine Kinase 3, Cardiovascular medicine and haematology
Abstract

FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have activity in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (ITD) mutations, but efficacy is limited by resistance-conferring kinase domain mutations. This phase 1/2 study evaluated the safety, tolerability, and efficacy of the oral FLT3 inhibitor PLX3397 (pexidartinib), which has activity against the FLT3 TKI-resistant F691L gatekeeper mutation in relapsed/refractory FLT3-ITD-mutant AML. Ninety patients were treated: 34 in dose escalation (part 1) and 56 in dose expansion (part 2). Doses of 800 to 5000 mg per day in divided doses were tested. No maximally tolerated dose was reached. Plasma inhibitory assay demonstrated that patients dosed with ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line. Based on a plateau in drug exposure, the 3000-mg dose was chosen as the recommended phase 2 dose. The most frequently reported treatment-emergent adverse events were diarrhea (50%), fatigue (47%), and nausea (46%). Based on modified response criteria, the overall response rate to pexidartinib among all patients was 21%. Twenty-three percent of patients treated at ≥2000 mg responded. The overall composite complete response rate for the study was 11%. Six patients were successfully bridged to transplantation. Median overall survival (OS) of patients treated in dose expansion was 112 days (90% confidence interval [CI], 77-150 days), and median OS of responders with complete remission with or without recovery of blood counts was 265 days (90% CI, 170-422 days). This trial was registered at www.clinicaltrials.gov as #NCT01349049.

Published
2020

20. Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

Author

Tarver, Theodore C, Hill, Jason E, Rahmat, Leena, Perl, Alexander E, Bahceci, Erkut, Mori, Kenichi, and Smith, Catherine C

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Hematology, Clinical Research, Cancer, Aniline Compounds, Humans, Mutation, Protein Kinase Inhibitors, Pyrazines, fms-Like Tyrosine Kinase 3, Cardiovascular medicine and haematology
Abstract

Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at

Published
2020

21. Functional Status as Measured by Geriatric Assessment Predicts Inferior Survival in Older Allogeneic Hematopoietic Cell Transplantation Recipients.

Author

Huang, Li-Wen, Sheng, Ying, Andreadis, Charalambos, Logan, Aaron C, Mannis, Gabriel N, Smith, Catherine C, Gaensler, Karin ML, Martin, Thomas G, Damon, Lloyd E, Steinman, Michael A, Huang, Chiung-Yu, and Olin, Rebecca L

Subjects
Humans, Disease-Free Survival, Activities of Daily Living, Hematopoietic Stem Cell Transplantation, Geriatric Assessment, Survival Rate, Prospective Studies, Aged, Middle Aged, Female, Male, Leukemia, Myeloid, Acute, Allografts, Allogeneic transplantation, Functional status, Geriatric assessment, Cancer, Aging, Prevention, Clinical Research, Rehabilitation, Transplantation, Good Health and Well Being, Clinical Sciences, Immunology
Abstract

Allogeneic hematopoietic cell transplantation (alloHCT) has been increasingly offered to older adults with hematologic malignancies. However, optimal methods to determine fitness for alloHCT have yet to be defined. We evaluated the ability of a comprehensive geriatric assessment (CGA) to predict post-alloHCT outcomes in a single-center prospective cohort study of patients age 50 years and older. Outcomes included overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM). A total of 148 patients were included, with a median age of 62 years (range, 50 to 76 years). In multivariate regression analysis, several CGA measures of functional status were predictive of post-alloHCT outcomes, after adjusting for traditional prognostic factors. Any deficit in instrumental activities of daily living (IADL) was associated with inferior OS (hazard ratio [HR], 1.81, 95% confidence interval [CI], 1.07 to 3.08; P = .03) and PFS (HR, 1.85; 95% CI, 1.15 to 2.99; P = .01). A Medical Outcomes Study Physical Health scale (MOS-PH) score

Published
2020

22. FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

Author

Kennedy, Vanessa E and Smith, Catherine C

Subjects
Pediatric, Pediatric Cancer, Childhood Leukemia, Rare Diseases, Cancer, Clinical Research, Orphan Drug, Hematology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Acute Myeloid Leukemia, FLT3 inhibitor, FLT3 resistance, FLT3 inhibitor maintenance, non-canonical FLT3 mutation, Oncology and Carcinogenesis
Abstract

The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

Published
2020

24. Roman warfare: targeting of support cells in AML

Author

Smith, Catherine C

Subjects
Humans, Leukemia, Myeloid, Acute, Paracrine Communication, Receptors, Colony-Stimulating Factor, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology
Published
2019

25. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial

Author

Cortes, Jorge, Perl, Alexander E, Döhner, Hartmut, Kantarjian, Hagop, Martinelli, Giovanni, Kovacsovics, Tibor, Rousselot, Philippe, Steffen, Björn, Dombret, Hervé, Estey, Elihu, Strickland, Stephen, Altman, Jessica K, Baldus, Claudia D, Burnett, Alan, Krämer, Alwin, Russell, Nigel, Shah, Neil P, Smith, Catherine C, Wang, Eunice S, Ifrah, Norbert, Gammon, Guy, Trone, Denise, Lazzaretto, Deborah, and Levis, Mark

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Hematology, Clinical Trials and Supportive Activities, Cancer, Clinical Research, 6.1 Pharmaceuticals, 6.2 Cellular and gene therapies, Administration, Oral, Adult, Aged, Benzothiazoles, Canada, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Europe, Female, Humans, Internationality, Leukemia, Myeloid, Acute, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local, Phenylurea Compounds, Prognosis, Survival Rate, Treatment Outcome, United States, Young Adult, fms-Like Tyrosine Kinase 3, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundOld age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsWe did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed.FindingsBetween Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [

Published
2018

26. Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002)

Author

Adlou, Syed, Aley, Robert, Ali, Aabidah, Anslow, Rachel, Baker, Megan, Baker, Phillip, Barrett, Jordan R., Bates, Louise, Beadon, Kirsten, Beckley, Rebecca, Bell, Jonathan, Bellamy, Duncan, Beveridge, Amy, Bissett, Cameron, Blackwell, Luke, Bletchly, Heather, Boyd, Amy, Bridges-Webb, Alice, Brown, Charlie, Byard, Nicholas, Camara, Susana, Cifuentes Gutierrez, Liliana, Collins, Andrea M., Cooper, Rachel, Crocker, Wendy E.M., Darton, Thomas C., Davies, Hannah, Davies, Judith, Demissie, Tesfaye, Di Maso, Claudio, Dinesh, Tanya, Donnellan, Francesca R., Douglas, Alexander D., Drake-Brockman, Rachael, Duncan, Christopher J.A., Elias, Sean C., Emary, Katherine R.W., Ghulam Farooq, Mutjaba, Faust, Saul N., Felle, Sally, Ferreira, Daniela, Ferreira Da Silva, Carla, Finn, Adam, Ford, Karen J., Francis, Emma, Furze, Julie, Fuskova, Michelle, Galiza, Eva, Gibertoni Cruz, Ana, Godfrey, Leila, Goodman, Anna L., Green, Catherine, Green, Christopher A., Greenwood, Nicola, Harrison, Daisy, Hart, Thomas C., Hawkins, Sophia, Heath, Paul T., Hill, Helen, Hillson, Kushalinii, Horsington, Bryn, Hou, Mimi M., Howe, Elizabeth, Howell, Nicola, Joe, Carina, Jones, Elizabeth, Kasanyinga, Mwila, Keen, Jade, Kelly, Sarah, Kerr, David, Khan, Liaquat, Khozoee, Baktash, Kinch, Jasmin, Kinch, Patrick, Koleva, Stanislava, Kwok, Jonathan, Larkworthy, Colin W., Lawrie, Alison M., Lazarus, Rajeka, Lees, Emily A., Li, Grace, Libri, Vincenzo, Lillie, Patrick J., Linder, Aline, Long, Fei, Lopez Ramon, Raquel, Mabbett, Reece, Makinson, Rebecca, Marinou, Spyridoula, Marlow, Emma, Marshall, Julia L., Mazur, Olga, McEwan, Joanne, McGregor, Alastair C., Mokaya, Jolynne, Morey, Ella, Morshead, Gertraud, Morter, Richard, Muller, Jilly, Mweu, Philomena, Noristani, Rabiullah, Owino, Nelly, Polo Peralta Alvarez, Marco, Platt, Abigail, Pollock, Katrina M., Poulton, Ian, Provstgaard-Morys, Samuel, Pulido-Gomez, David, Rajan, Matthew, Ramos Lopez, Fernando, Ritchie, Adam, Roberts, Hannah, Rollier, Christine, Rudiansyah, Indra, Sanders, Katherine, Saunders, Jack E., Seddiqi, Samiullah, Sharpe, Hannah R., Shaw, Robert, Silva-Reyes, Laura, Singh, Nisha, Smith, David J., Smith, Catherine C., Smith, Andrew, Spencer, Alexandra J., Stuart, Arabella S.V., Sutherland, Rebecca, Szigeti, Anna, Tang, Karly, Thomas, Merin, Thomas, Tonia M., Thompson, Amber, Thomson, Emma C., Török, Estée M., Toshner, Mark, Tran, Nguyen, Trivett, Rose, Turnbull, Iain, Turner, Cheryl, Turner, David P.J., Ulaszewska, Marta, Vichos, Iason, Walker, Laura, Watson, Marion E., Whelan, Conor, White, Rachel, Williams, Sarah J., Williams, Christopher J.A., Wright, Daniel, Yao, Andy, Flaxman, Amy, Marchevsky, Natalie G, Jenkin, Daniel, Aboagye, Jeremy, Aley, Parvinder K, Angus, Brian, Belij-Rammerstorfer, Sandra, Bibi, Sagida, Bittaye, Mustapha, Cappuccini, Federica, Cicconi, Paola, Clutterbuck, Elizabeth A, Davies, Sophie, Dejnirattisai, Wanwisa, Dold, Christina, Ewer, Katie J, Folegatti, Pedro M, Fowler, Jamie, Hill, Adrian V S, Kerridge, Simon, Minassian, Angela M, Mongkolsapaya, Juthathip, Mujadidi, Yama F, Plested, Emma, Ramasamy, Maheshi N, Robinson, Hannah, Sanders, Helen, Sheehan, Emma, Smith, Holly, Snape, Matthew D, Song, Rinn, Woods, Danielle, Screaton, Gavin, Gilbert, Sarah C, Voysey, Merryn, Pollard, Andrew J, and Lambe, Teresa

Published
2021
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27. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials

Author

Aban, Marites, Abeyskera, Kushala W.M., Aboagye, Jeremy, Adam, Matthew, Adams, Kirsty, Adamson, James P., Adewatan, Gbadebo, Adlou, Syed, Ahmed, Khatija, Akhalwaya, Yasmeen, Akhalwaya, Saajida, Alcock, Andrew, Ali, Aabidah, Allen, Elizabeth R., Allen, Lauren, Alvernaz, Felipe B., Amorim, Fabio Santos, Andrade, Claudia Sala, Andritsou, Foteini, Anslow, Rachel, Arbe-Barnes, Edward H., Ariaans, Mark P., Arns, Beatriz, Arruda, Laiana, Assad, Luiza, Azi, Paula De Almeida, Azi, Lorena De Almeida, Babbage, Gavin, Bailey, Catherine, Baker, Kenneth F., Baker, Megan, Baker, Natalie, Baker, Philip, Baleanu, Ioana, Bandeira, Danieli, Bara, Anna, Barbosa, Marcella A.S., Barker, Debbie, Barlow, Gavin D., Barnes, Eleanor, Barr, Andrew S., Barrett, Jordan R., Barrett, Jessica, Barrett, Kelly, Bates, Louise, Batten, Alexander, Beadon, Kirsten, Beales, Emily, Beckley, Rebecca, Belij-Rammerstorfer, Sandra, Bell, Jonathan, Bellamy, Duncan, Belton, Sue, Berg, Adam, Bermejo, Laura, Berrie, Eleanor, Berry, Lisa, Berzenyi, Daniella, Beveridge, Amy, Bewley, Kevin R., Bharaj, Inderjeet, Bhikha, Sutika, Bhorat, Asad E., Bhorat, Zaheda E., Bijker, Else Margreet, Birch, Sarah, Birch, Gurpreet, Birchall, Kathryn, Bird, Adam, Bird, Olivia, Bisnauthsing, Karen, Bittaye, Mustapha, Blackwell, Luke, Blacow, Rachel, Bletchly, Heather, Blundell, Caitlin L., Blundell, Susannah R., Bodalia, Pritesh, Bolam, Emma, Boland, Elena, Bormans, Daan, Borthwick, Nicola, Bowring, Francesca, Boyd, Amy, Bradley, Penny, Brenner, Tanja, Bridges-Webb, Alice, Brown, Phillip, Brown, Claire, Brown-O'Sullivan, Charlie, Bruce, Scott, Brunt, Emily, Budd, William, Bulbulia, Yusuf A., Bull, Melanie, Burbage, Jamie, Burn, Aileen, Buttigieg, Karen R., Byard, Nicholas, Cabrera Puig, Ingrid, Calvert, Anna, Camara, Susana, Cao, Michelangelo, Cappuccini, Federica, Cardona, Rita, Cardoso, João R., Carr, Melanie, Carroll, Miles W., Carson-Stevens, Andrew, Carvalho, Yasmin de M., Casey, Helen R., Cashen, Paul, Castro, Thais R.Y., Castro, Lucia Carratala, Cathie, Katrina, Cavey, Ana, Cerbino-Neto, José, Cezar, Luiz Fernando F., Chadwick, Jim, Chanice, Chanice, Chapman, David, Charlton, Sue, Cheliotis, Katerina S., Chelysheva, Irina, Chester, Oliver, Chiplin, Emily, Chita, Sunder, Cho, Jee-Sun, Cifuentes, Liliana, Clark, Elizabeth, Clark, Matthew, Colin-Jones, Rachel, Collins, Sarah L.K., Colton, Hayley, Conlon, Christopher P., Connarty, Sean, Coombes, Naomi, Cooper, Cushla, Cooper, Rachel, Cornelissen, Lynne, Corrah, Tumena, Cosgrove, Catherine A., Costa, Fernanda Barroso, Cox, Tony, Crocker, Wendy E.M., Crosbie, Sarah, Cullen, Dan, Cunha, Debora R.M.F., Cunningham, Christina J., Cuthbertson, Fiona C., da Costa, Daniel Marinho, Da Guarda, Suzete N. Farias, da Silva, Larissa P., da Silva Moraes, Antonio Carlos, Damratoski, Brad E., Danos, Zsofia, Dantas, Maria T.D.C., Datoo, Mehreen S., Datta, Chandrabali, Davids, Malika, Davies, Sarah L., Davies, Kelly, Davies, Hannah, Davies, Sophie, Davies, Judith, Davis, Elizabeth J., Davis, John, de Carvalho, José A.M., De Jager, Jeanne, de Jesus Jnr, Sergio, De Oliveira Kalid, Lis Moreno, Dearlove, David, Demissie, Tesfaye, Desai, Amisha, Di Marco, Stefania, Di Maso, Claudio, Dinesh, Tanya, Docksey, Claire, Dong, Tao, Donnellan, Francesca R., Dos Santos, Tannyth Gomes, Dos Santos, Thainá G., Dos Santos, Erika Pachecho, Douglas, Naomi, Downing, Charlotte, Drake, Jonathan, Drake-Brockman, Rachael, Drury, Ruth, Du Plessis, Joan, Dunachie, Susanna J., Duncan, Andrew, Easom, Nicholas J.W., Edwards, Mandy, Edwards, Nick J., Edwards, Frances, El Muhanna, Omar M., Elias, Sean C., Ellison-Handley, Branwen, Elmore, Michael J., English, Marcus Rex, Esmail, Alisgair, Essack, Yakub Moosa, Farooq, Mutjaba, Fedosyuk, Sofiya, Felle, Sally, Ferguson, Susie, Ferreira Da Silva, Carla, Field, Samantha, Fisher, Richard, Fletcher, James, Fofie, Hazel, Fok, Henry, Ford, Karen J., Fothergill, Ross, Fowler, Jamie, Fraiman, Pedro H.A., Francis, Emma, Franco, Marilia M., Frater, John, Freire, Marilúcia S.M., Fry, Samantha H., Fudge, Sabrina, Furlan Filho, Renato, Furze, Julie, Fuskova, Michelle, Galian-Rubio, Pablo, Garlant, Harriet, Gavrila, Madita, Gibbons, Karyna A., Gilbride, Ciaran, Gill, Hardeep, Godwin, Kerry, Gokani, Karishma, Gonçalves, Maria Luisa Freire, Gonzalez, Isabela G.S., Goodall, Jack, Goodwin, Jayne, Goondiwala, Amina, Gordon-Quayle, Katherine, Gorini, Giacomo, Goyanna, Alvaro, Grab, Janet, Gracie, Lara, Green, Justin, Greenwood, Nicola, Greffrath, Johann, Groenewald, Marisa M., Gunawardene, Anishka, Gupta, Gaurav, Hackett, Mark, Hallis, Bassam, Hamaluba, Mainga, Hamilton, Elizabeth, Hamlyn, Joseph, Hammersley, Daniel, Hanrath, Aidan T., Hanumunthadu, Brama, Harris, Stephanie A., Harris, Clair, Harrison, Thomas D., Harrison, Daisy, Harris-Wright, Tara A., Hart, Thomas C., Hartnell, Birgit, Haughney, John, Hawkins, Sophia, Hayano, Laís Y.M., Head, Ian, Heath, Paul T., Henry, John Aaron, Hermosin Herrera, Macarena, Hettle, David B., Higa, Cristhiane, Hill, Jennifer, Hodges, Gina, Hodgson, Susanne, Horne, Elizea, Hou, Mimi M., Houlihan, Catherine F., Howe, Elizabeth, Howell, Nicola, Humphreys, Jonathan, Humphries, Holly E., Hurley, Katrina, Huson, Claire, Hyams, Catherine, Hyder-Wright, Angela, Ikram, Sabina, Ishwarbhai, Alka, Iveson, Poppy, Iyer, Vidyashankara, Jackson, Frederic, Jackson, Susan, Jaumdally, Shameem, Jeffers, Helen, Jesudason, Natasha, Jones, Carina, Jones, Christopher, Jones, Kathryn, Jones, Elizabeth, Jorge, Marianna Rocha, Joshi, Amar, Júnior, Eduardo A.M.S., Kailath, Reshma, Kana, Faeeza, Kar, Arnab, Karampatsas, Konstantinos, Kasanyinga, Mwila, Kay, Linda, Keen, Jade, Kellett Wright, Johanna, Kelly, Elizabeth J., Kelly, Debbie, Kelly, Dearbhla M., Kelly, Sarah, Kerr, David, Khan, Liaquat, Khozoee, Baktash, Khurana, Ankush, Kidd, Sarah, Killen, Annabel, Kinch, Jasmin, Kinch, Patrick, King, Lloyd D.W., King, Thomas B., Kingham, Lucy, Klenerman, Paul, Kluczna, Diana M., Knapper, Francesca, Knight, Julian C., Knott, Daniel, Koleva, Stanislava, Lages, Pedro M., Lang, Matilda, Lang, Gail, Larkworthy, Colin W., Larwood, Jessica P.J., Law, Rebecca, Lawrie, Alison M., Lazarus, Erica M., Leach, Amanda, Lees, Emily A., Lelliott, Alice, Lemm, Nana-Marie, Lessa, Alvaro Edson Ramos, Leung, Stephanie, Li, Yuanyuan, Lias, Amelia M., Liatsikos, Konstantinos, Linder, Aline, Lipworth, Samuel, Liu, Shuchang, Liu, Xinxue, Lloyd, Adam, Lloyd, Stephanie, Loew, Lisa, Lopez Ramon, Raquel, Lora, Leandro Bonecker, Luz, Kleber Giovanni, MacDonald, Jonathan C., MacGregor, Gordon, Madhavan, Meera, Mainwaring, David O., Makambwa, Edson, Makinson, Rebecca, Malahleha, Mookho, Malamatsho, Ross, Mallett, Garry, Manning, Nicola, Mansatta, Kushal, Maoko, Takalani, Marinou, Spyridoula, Marlow, Emma, Marques, Gabriela N., Marriott, Paula, Marshall, Richard P., Marshall, Julia L., Masenya, Masebole, Masilela, Mduduzi, Masters, Shauna K., Mathew, Moncy, Matlebjane, Hosea, Matshidiso, Kedidimetse, Mazur, Olga, Mazzella, Andrea, McCaughan, Hugh, McEwan, Joanne, McGlashan, Joanna, McInroy, Lorna, McRobert, Nicky, McSwiggan, Steve, Megson, Clare, Mehdipour, Savviz, Meijs, Wilma, Mendonça, Renata N.Õ., Mentzer, Alexander J., Mesquita, Ana Carolina F., Miralhes, Patricia, Mirtorabi, Neginsadat, Mitton, Celia, Mnyakeni, Sibusiso, Moghaddas, Fiona, Molapo, Kgaogelo, Moloi, Mapule, Moore, Maria, Moran, Marni, Morey, Ella, Morgans, Róisín, Morris, Susan J., Morris, Sheila, Morrison, Hazel, Morselli, Franca, Morshead, Gertraud, Morter, Richard, Mottay, Lynelle, Moultrie, Andrew, Moyo, Nathifa, Mpelembue, Mushiya, Msomi, Sibekezelo, Mugodi, Yvonne, Mukhopadhyay, Ekta, Muller, Jilly, Munro, Alasdair, Murphy, Sarah, Mweu, Philomena, Myerscough, Christopher, Naik, Gurudutt, Naker, Kush, Nastouli, Eleni, Ndlovu, Bongani, Nikolaou, Elissavet, Njenga, Cecilia, Noal, Helena C., Noé, Andrés, Novaes, Gabrielle, Nugent, Fay L., Nunes, Géssika Lanzillo A., O'Brien, Katie, O'Connor, Daniel, Oelofse, Suzette, Oguti, Blanche, Olchawski, Victoria, Oldfield, Neil J., Oliveira, Marianne G., Oliveira, Catarina, Oliveira, Isabelle Silva Queiroz, Oommen-Jose, Aylin, Oosthuizen, Angela, O'Reilly, Paula, O'Reilly, Peter J., Osborne, Piper, Owen, David R.J., Owen, Lydia, Owens, Daniel, Owino, Nelly, Pacurar, Mihaela, Paiva, Brenda V.B., Palhares, Edna M.F., Palmer, Susan, Parracho, Helena M. R.T., Parsons, Karen, Patel, Dipak, Patel, Bhumika, Patel, Faeezah, Patrick-Smith, Maia, Payne, Ruth O., Peng, Yanchun, Penn, Elizabeth J., Pennington, Anna, Peralta Alvarez, Marco Polo, Pereira Stuchi, Bruno Pereira, Perez, Ana Luiza, Perinpanathan, Tanaraj, Perring, James, Perumal, Rubeshan, Petkar, Sahir Yusuf, Philip, Tricia, Phillips, Jennifer, Phohu, Mary Kgomotso, Pickup, Lorinda, Pieterse, Sonja, Pinheiro, Jessica Morgana, Piper, Jo, Pipini, Dimitra, Plank, Mary, Plant, Sinéad, Pollard, Samuel, Pooley, Jennifer, Pooran, Anil, Poulton, Ian, Powers, Claire, Presa, Fernando B., Price, David A., Price, Vivien, Primeira, Marcelo R., Proud, Pamela C., Provstgaard-Morys, Samuel, Pueschel, Sophie, Pulido, David, Quaid, Sheena, Rabara, Ria, Radia, Kajal, Rajapaska, Durga, Rajeswaran, Thurkka, Ramos, Leonardo, Ramos, Alberto San Francisco, Ramos Lopez, Fernando, Rampling, Tommy, Rand, Jade, Ratcliffe, Helen, Rawlinson, Tom, Rea, David, Rees, Byron, Resuello-Dauti, Mila, Reyes Pabon, Emilia, Rhead, Sarah, Riaz, Tawassal, Ricamara, Marivic, Richards, Alexander, Richter, Alex, Ritchie, Neil, Ritchie, Adam J., Robbins, Alexander J., Roberts, Hannah, Robinson, Ryan E., Roche, Sophie, Rollier, Christine, Rose, Louisa, Ross Russell, Amy L., Rossouw, Lindie, Royal, Simon, Rudiansyah, Indra, Ryalls, Kim, Sabine, Charlotte, Saich, Stephen, Sale, Jessica C., Salman, Ahmed M., Salvador, Natalia, Salvador, Stephannie, Sampaio, Milla Dias, Samson, Annette D., Sanchez-Gonzalez, Amada, Sanders, Helen, Sanders, Katherine, Santos, Erika, Santos Guerra, Mayara F.S., Satti, Iman, Saunders, Jack E., Saunders, Caroline, Sayed, Aakifah Bibi Arif, Schim van der Loeff, Ina, Schmid, Annina B., Schofield, Ella, Screaton, Gavin R., Seddiqi, Samiullah, Segireddy, Rameswara R., Senger, Roberta, Serrano, Sonia, Shaik, Imam, Sharpe, Hannah R., Sharrocks, Katherine, Shaw, Robert, Shea, Adam, Sheehan, Emma, Shepherd, Amy, Shiham, Farah, Silk, Sarah E., Silva-Reyes, Laura, Silveira, Lidiana B. T.D., Silveira, Mariana B.V., Singh, Nisha, Sinha, Jaisi, Skelly, Donal T., Smith, Daniel C., Smith, Nick, Smith, Holly E., Smith, David J., Smith, Catherine C., Soares, Airanuédida S., Solórzano, Carla, Sorio, Guilherme L., Sorley, Kim, Sosa-Rodriguez, Tiffany, Souza, Cinthia M.C.D.L., Souza, Bruno S.D.F., Souza, Alessandra R., Souza Lopez, Thamyres, Sowole, Luciana, Spencer, Alexandra J., Spoors, Louise, Stafford, Lizzie, Stamford, Imogen, Stein, Ricardo, Stockdale, Lisa, Stockwell, Lisa V., Strickland, Louise H., Stuart, Arabella, Sturdy, Ann, Sutton, Natalina, Szigeti, Anna, Tahiri-Alaoui, Abdessamad, Tanner, Rachel, Taoushanis, Carol, Tarr, Alexander W., Tarrant, Richard, Taylor, Keja, Taylor, Ursula, Taylor, Iona Jennifer, Taylor, Justin, te Water Naude, Rebecca, Templeton, Kate, Themistocleous, Yrene, Themistocleous, Andreas, Thomas, Merin, Thomas, Kelly, Thomas, Tonia M., Thombrayil, Asha, Thompson, Julia, Thompson, Fawziyah, Thompson, Ameeka, Thompson, Amber, Thompson, Kevin, Thornton-Jones, Viv, Thotusi, Larissa H.S., Tighe, Patrick J., Tinoco, Lygia Accioly, Tiongson, Gerlynn Ferreras, Tladinyane, Bonolo, Tomasicchio, Michele, Tomic, Adriana, Tonks, Susan, Towner, James, Tran, Nguyen, Tree, Julia A., Trillana, Gerry, Trinham, Charlotte, Trivett, Rose, Truby, Adam, Tsheko, Betty Lebogang, Tubb, Philippa, Turabi, Aadil, Turner, Richard, Turner, Cheryl, Turner, Nicola, Tyagi, Bhavya, Ulaszewska, Marta, Underwood, Benjamin R., van Eck, Samual, Varughese, Rachel, Verbart, Dennis, Verheul, Marije K., Vichos, Iason, Vieira, Taiane A., Walker, Gemma, Walker, Laura, Wand, Matthew E., Wardell, Theresa, Warimwe, George M., Warren, Sarah C., Watkins, Bridget, Watson, Marion E.E., Watson, Ekaterina, Webb, Stewart, Webster, Angela, Welch, Jessica, Wellbelove, Zoe, Wells, Jeanette H., West, Alison J., White, Beth, White, Caroline, White, Rachel, Williams, Paul, Williams, Rachel L., Willingham, Silvia, Winslow, Rebecca, Woods, Danielle, Woodyer, Mark, Worth, Andrew T., Wright, Danny, Wroblewska, Marzena, Yao, Andy, Yim, Yee Ting Nicole, Zambrano, Marina Bauer, Zimmer, Rafael Leal, Zizi, Dalila, Zuidewind, Peter, Voysey, Merryn, Costa Clemens, Sue Ann, Madhi, Shabir A, Weckx, Lily Y, Folegatti, Pedro M, Aley, Parvinder K, Angus, Brian, Baillie, Vicky L, Barnabas, Shaun L, Bhorat, Qasim E, Bibi, Sagida, Briner, Carmen, Cicconi, Paola, Clutterbuck, Elizabeth A, Collins, Andrea M, Cutland, Clare L, Darton, Thomas C, Dheda, Keertan, Dold, Christina, Duncan, Christopher J A, Emary, Katherine R W, Ewer, Katie J, Flaxman, Amy, Fairlie, Lee, Faust, Saul N, Feng, Shuo, Ferreira, Daniela M, Finn, Adam, Galiza, Eva, Goodman, Anna L, Green, Catherine M, Green, Christopher A, Greenland, Melanie, Hill, Catherine, Hill, Helen C, Hirsch, Ian, Izu, Alane, Jenkin, Daniel, Joe, Carina C D, Kerridge, Simon, Koen, Anthonet, Kwatra, Gaurav, Lazarus, Rajeka, Libri, Vincenzo, Lillie, Patrick J, Marchevsky, Natalie G, Marshall, Richard P, Mendes, Ana V A, Milan, Eveline P, Minassian, Angela M, McGregor, Alastair, Mujadidi, Yama F, Nana, Anusha, Padayachee, Sherman D, Phillips, Daniel J, Pittella, Ana, Plested, Emma, Pollock, Katrina M, Ramasamy, Maheshi N, Ritchie, Adam J, Robinson, Hannah, Schwarzbold, Alexandre V, Smith, Andrew, Song, Rinn, Snape, Matthew D, Sprinz, Eduardo, Sutherland, Rebecca K, Thomson, Emma C, Török, M Estée, Toshner, Mark, Turner, David P J, Vekemans, Johan, Villafana, Tonya L, White, Thomas, Williams, Christopher J, Douglas, Alexander D, Hill, Adrian V S, Lambe, Teresa, Gilbert, Sarah C, and Pollard, Andrew J

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2021
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28. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Author

Aban, Marites, Abayomi, Fatola, Abeyskera, Kushala, Aboagye, Jeremy, Adam, Matthew, Adams, Kirsty, Adamson, James, Adelaja, Yemi A., Adewetan, Gbadebo, Adlou, Syed, Ahmed, Khatija, Akhalwaya, Yasmeen, Akhalwaya, Saajida, Alcock, Andrew, Ali, Aabidah, Allen, Elizabeth R., Allen, Lauren, Almeida, Thamires C. D. S. C, Alves, Mariana P.S., Amorim, Fabio, Andritsou, Foteini, Anslow, Rachel, Appleby, Matthew, Arbe-Barnes, Edward H., Ariaans, Mark P., Arns, Beatriz, Arruda, Laiana, Azi, Paula, Azi, Lorena, Babbage, Gavin, Bailey, Catherine, Baker, Kenneth F., Baker, Megan, Baker, Natalie, Baker, Philip, Baldwin, Lisa, Baleanu, Ioana, Bandeira, Danieli, Bara, Anna, Barbosa, Marcella A.S., Barker, Debbie, Barlow, Gavin D., Barnes, Eleanor, Barr, Andrew S., Barrett, Jordan R., Barrett, Jessica, Bates, Louise, Batten, Alexander, Beadon, Kirsten, Beales, Emily, Beckley, Rebecca, Belij-Rammerstorfer, Sandra, Bell, Jonathan, Bellamy, Duncan, Bellei, Nancy, Belton, Sue, Berg, Adam, Bermejo, Laura, Berrie, Eleanor, Berry, Lisa, Berzenyi, Daniella, Beveridge, Amy, Bewley, Kevin R., Bexhell, Helen, Bhikha, Sutika, Bhorat, Asad E., Bhorat, Zaheda E., Bijker, Else, Birch, Geeta, Birch, Sarah, Bird, Adam, Bird, Olivia, Bisnauthsing, Karen, Bittaye, Mustapha, Blackstone, Katherine, Blackwell, Luke, Bletchly, Heather, Blundell, Caitlin L., Blundell, Susannah R., Bodalia, Pritesh, Boettger, Bruno C., Bolam, Emma, Boland, Elena, Bormans, Daan, Borthwick, Nicola, Bowring, Francesca, Boyd, Amy, Bradley, Penny, Brenner, Tanja, Brown, Phillip, Brown, Claire, Brown-O'Sullivan, Charlie, Bruce, Scott, Brunt, Emily, Buchan, Ruaridh, Budd, William, Bulbulia, Yusuf A., Bull, Melanie, Burbage, Jamie, Burhan, Hassan, Burn, Aileen, Buttigieg, Karen R., Byard, Nicholas, Cabera Puig, Ingrid, Calderon, Gloria, Calvert, Anna, Camara, Susana, Cao, Michelangelo, Cappuccini, Federica, Cardoso, João R., Carr, Melanie, Carroll, Miles W., Carson-Stevens, Andrew, Carvalho, Yasmin de M., Carvalho, José A.M., Casey, Helen R., Cashen, Paul, Castro, Thais, Castro, Lucia Carratala, Cathie, Katrina, Cavey, Ana, Cerbino-Neto, José, Chadwick, Jim, Chapman, David, Charlton, Sue, Chelysheva, Irina, Chester, Oliver, Chita, Sunder, Cho, Jee-Sun, Cifuentes, Liliana, Clark, Elizabeth, Clark, Matthew, Clarke, Andrea, Clutterbuck, Elizabeth A., Collins, Sarah L.K., Conlon, Christopher P., Connarty, Sean, Coombes, Naomi, Cooper, Cushla, Cooper, Rachel, Cornelissen, Lynne, Corrah, Tumena, Cosgrove, Catherine, Cox, Tony, Crocker, Wendy E.M., Crosbie, Sarah, Cullen, Lorraine, Cullen, Dan, Cunha, Debora R.M.F., Cunningham, Christina, Cuthbertson, Fiona C., Da Guarda, Suzete N. Farias, da Silva, Larissa P., Damratoski, Brad E., Danos, Zsofia, Dantas, Maria T.D.C., Darroch, Paula, Datoo, Mehreen S., Datta, Chandrabali, Davids, Malika, Davies, Sarah L., Davies, Hannah, Davis, Elizabeth, Davis, Judith, Davis, John, De Nobrega, Maristela M.D., De Oliveira Kalid, Lis Moreno, Dearlove, David, Demissie, Tesfaye, Desai, Amisha, Di Marco, Stefania, Di Maso, Claudio, Dinelli, Maria I.S., Dinesh, Tanya, Docksey, Claire, Dold, Christina, Dong, Tao, Donnellan, Francesca R., Dos Santos, Tannyth, dos Santos, Thainá G., Dos Santos, Erika Pachecho, Douglas, Naomi, Downing, Charlotte, Drake, Jonathan, Drake-Brockman, Rachael, Driver, Kimberley, Drury, Ruth, Dunachie, Susanna J., Durham, Benjamin S., Dutra, Lidiana, Easom, Nicholas J.W., van Eck, Samual, Edwards, Mandy, Edwards, Nick J., El Muhanna, Omar M., Elias, Sean C., Elmore, Mike, English, Marcus, Esmail, Alisgair, Essack, Yakub Moosa, Farmer, Eoghan, Farooq, Mutjaba, Farrar, Madi, Farrugia, Leonard, Faulkner, Beverley, Fedosyuk, Sofiya, Felle, Sally, Feng, Shuo, Ferreira Da Silva, Carla, Field, Samantha, Fisher, Richard, Flaxman, Amy, Fletcher, James, Fofie, Hazel, Fok, Henry, Ford, Karen J., Fowler, Jamie, Fraiman, Pedro H.A., Francis, Emma, Franco, Marilia M., Frater, John, Freire, Marilúcia S.M., Fry, Samantha H., Fudge, Sabrina, Furze, Julie, Fuskova, Michelle, Galian-Rubio, Pablo, Galiza, Eva, Garlant, Harriet, Gavrila, Madita, Geddes, Ailsa, Gibbons, Karyna A., Gilbride, Ciaran, Gill, Hardeep, Glynn, Sharon, Godwin, Kerry, Gokani, Karishma, Goldoni, Ursula Carvalho, Goncalves, Maria, Gonzalez, Isabela G.S., Goodwin, Jayne, Goondiwala, Amina, Gordon-Quayle, Katherine, Gorini, Giacomo, Grab, Janet, Gracie, Lara, Greenland, Melanie, Greenwood, Nicola, Greffrath, Johann, Groenewald, Marisa M., Grossi, Leonardo, Gupta, Gaurav, Hackett, Mark, Hallis, Bassam, Hamaluba, Mainga, Hamilton, Elizabeth, Hamlyn, Joseph, Hammersley, Daniel, Hanrath, Aidan T., Hanumunthadu, Brama, Harris, Stephanie A., Harris, Clair, Harris, Tara, Harrison, Thomas D., Harrison, Daisy, Hart, Thomas C., Hartnell, Birgit, Hassan, Shadin, Haughney, John, Hawkins, Sophia, Hay, Jodie, Head, Ian, Henry, John, Hermosin Herrera, Macarena, Hettle, David B., Hill, Jennifer, Hodges, Gina, Horne, Elizea, Hou, Mimi M., Houlihan, Catherine, Howe, Elizabeth, Howell, Nicola, Humphreys, Jonathan, Humphries, Holly E., Hurley, Katrina, Huson, Claire, Hyder-Wright, Angela, Hyams, Catherine, Ikram, Sabina, Ishwarbhai, Alka, Ivan, Monica, Iveson, Poppy, Iyer, Vidyashankara, Jackson, Frederic, De Jager, Jeanne, Jaumdally, Shameem, Jeffers, Helen, Jesudason, Natasha, Jones, Bryony, Jones, Kathryn, Jones, Elizabeth, Jones, Christopher, Jorge, Marianna Rocha, Jose, Aylin, Joshi, Amar, Júnior, Eduardo A.M.S., Kadziola, Joanne, Kailath, Reshma, Kana, Faeeza, Karampatsas, Konstantinos, Kasanyinga, Mwila, Keen, Jade, Kelly, Elizabeth J., Kelly, Dearbhla M., Kelly, Debbie, Kelly, Sarah, Kerr, David, Kfouri, Renato de Ávila, Khan, Liaquat, Khozoee, Baktash, Kidd, Sarah, Killen, Annabel, Kinch, Jasmin, Kinch, Patrick, King, Lloyd D.W., King, Thomas B., Kingham, Lucy, Klenerman, Paul, Knapper, Francesca, Knight, Julian C., Knott, Daniel, Koleva, Stanislava, Lang, Matilda, Lang, Gail, Larkworthy, Colin W., Larwood, Jessica P.J., Law, Rebecca, Lazarus, Erica M., Leach, Amanda, Lees, Emily A., Lemm, Nana-Marie, Lessa, Alvaro, Leung, Stephanie, Li, Yuanyuan, Lias, Amelia M., Liatsikos, Kostas, Linder, Aline, Lipworth, Samuel, Liu, Shuchang, Liu, Xinxue, Lloyd, Adam, Lloyd, Stephanie, Loew, Lisa, Lopez Ramon, Raquel, Lora, Leandro, Lowthorpe, Vicki, Luz, Kleber, MacDonald, Jonathan C., MacGregor, Gordon, Madhavan, Meera, Mainwaring, David O., Makambwa, Edson, Makinson, Rebecca, Malahleha, Mookho, Malamatsho, Ross, Mallett, Garry, Mansatta, Kushal, Maoko, Takalani, Mapetla, Katlego, Marchevsky, Natalie G., Marinou, Spyridoula, Marlow, Emma, Marques, Gabriela N., Marriott, Paula, Marshall, Richard P., Marshall, Julia L., Martins, Flávia J., Masenya, Masebole, Masilela, Mduduzi, Masters, Shauna K., Mathew, Moncy, Matlebjane, Hosea, Matshidiso, Kedidimetse, Mazur, Olga, Mazzella, Andrea, McCaughan, Hugh, McEwan, Joanne, McGlashan, Joanna, McInroy, Lorna, McIntyre, Zoe, McLenaghan, Daniela, McRobert, Nicky, McSwiggan, Steve, Megson, Clare, Mehdipour, Savviz, Meijs, Wilma, Mendonça, Renata N.Á., Mentzer, Alexander J., Mirtorabi, Neginsadat, Mitton, Celia, Mnyakeni, Sibusiso, Moghaddas, Fiona, Molapo, Kgaogelo, Moloi, Mapule, Moore, Maria, Moraes-Pinto, M. Isabel, Moran, Marni, Morey, Ella, Morgans, Róisín, Morris, Susan, Morris, Sheila, Morris, Helen C., Morselli, Franca, Morshead, Gertraud, Morter, Richard, Mottal, Lynelle, Moultrie, Andrew, Moya, Nathifa, Mpelembue, Mushiya, Msomi, Sibekezelo, Mugodi, Yvonne, Mukhopadhyay, Ekta, Muller, Jilly, Munro, Alasdair, Munro, Claire, Murphy, Sarah, Mweu, Philomena, Myasaki, Celia Hatsuko, Naik, Gurudutt, Naker, Kush, Nastouli, Eleni, Nazir, Abida, Ndlovu, Bongani, Neffa, Fabio, Njenga, Cecilia, Noal, Helena, Noé, Andrés, Novaes, Gabrielle, Nugent, Fay L., Nunes, Géssika, O'Brien, Katie, O'Connor, Daniel, Odam, Miranda, Oelofse, Suzette, Oguti, Blanche, Olchawski, Victoria, Oldfield, Neil J., Oliveira, Marianne G., Oliveira, Catarina, Oosthuizen, Angela, O'Reilly, Paula, Osborne, Piper, Owen, David R.J., Owen, Lydia, Owens, Daniel, Owino, Nelly, Pacurar, Mihaela, Paiva, Brenda V.B., Palhares, Edna M.F., Palmer, Susan, Parkinson, Sivapriyai, Parracho, Helena M.R.T., Parsons, Karen, Patel, Dipak, Patel, Bhumika, Patel, Faeezah, Patel, Kelly, Patrick-Smith, Maia, Payne, Ruth O., Peng, Yanchun, Penn, Elizabeth J., Pennington, Anna, Peralta Alvarez, Marco Polo, Perring, James, Perry, Nicola, Perumal, Rubeshan, Petkar, Sahir, Philip, Tricia, Phillips, Daniel J., Phillips, Jennifer, Phohu, Mary Kgomotso, Pickup, Lorinda, Pieterse, Sonja, Piper, Jo, Pipini, Dimitra, Plank, Mary, Du Plessis, Joan, Pollard, Samuel, Pooley, Jennifer, Pooran, Anil, Poulton, Ian, Powers, Claire, Presa, Fernando B., Price, David A., Price, Vivien, Primeira, Marcelo, Proud, Pamela C., Provstgaard-Morys, Samuel, Pueschel, Sophie, Pulido, David, Quaid, Sheena, Rabara, Ria, Radford, Alexandra, Radia, Kajal, Rajapaska, Durga, Rajeswaran, Thurkka, Ramos, Alberto San Francisco, Ramos Lopez, Fernando, Rampling, Tommy, Rand, Jade, Ratcliffe, Helen, Rawlinson, Tom, Rea, David, Rees, Byron, Reiné, Jesús, Resuello-Dauti, Mila, Reyes Pabon, Emilia, Ribiero, Carla M., Ricamara, Marivic, Richter, Alex, Ritchie, Neil, Ritchie, Adam J., Robbins, Alexander J., Roberts, Hannah, Robinson, Ryan E., Robinson, Hannah, Rocchetti, Talita T., Rocha, Beatriz Pinho, Roche, Sophie, Rollier, Christine, Rose, Louisa, Ross Russell, Amy L., Rossouw, Lindie, Royal, Simon, Rudiansyah, Indra, Ruiz, Sarah, Saich, Stephen, Sala, Claudia, Sale, Jessica, Salman, Ahmed M., Salvador, Natalia, Salvador, Stephannie, Sampaio, Milla, Samson, Annette D., Sanchez-Gonzalez, Amada, Sanders, Helen, Sanders, Katherine, Santos, Erika, Santos Guerra, Mayara F.S., Satti, Iman, Saunders, Jack E., Saunders, Caroline, Sayed, Aakifah, Schim van der Loeff, Ina, Schmid, Annina B., Schofield, Ella, Screaton, Gavin, Seddiqi, Samiullah, Segireddy, Rameswara R., Senger, Roberta, Serrano, Sonia, Shah, Rajiv, Shaik, Imam, Sharpe, Hannah E., Sharrocks, Katherine, Shaw, Robert, Shea, Adam, Shepherd, Amy, Shepherd, James G., Shiham, Farah, Sidhom, Emad, Silk, Sarah E., da Silva Moraes, Antonio Carlos, Silva-Junior, Gilberto, Silva-Reyes, Laura, Silveira, Anderson D., Silveira, Mariana B.V., Sinha, Jaisi, Skelly, Donal T., Smith, Daniel C., Smith, Nick, Smith, Holly E., Smith, David J., Smith, Catherine C., Soares, Airanuédida, Soares, Tiago, Solórzano, Carla, Sorio, Guilherme L., Sorley, Kim, Sosa-Rodriguez, Tiffany, Souza, Cinthia M.C.D.L., Souza, Bruno S.D.F., Souza, Alessandra R., Spencer, Alexandra J., Spina, Fernanda, Spoors, Louise, Stafford, Lizzie, Stamford, Imogen, Starinskij, Igor, Stein, Ricardo, Steven, Jill, Stockdale, Lisa, Stockwell, Lisa V., Strickland, Louise H., Stuart, Arabella C., Sturdy, Ann, Sutton, Natalina, Szigeti, Anna, Tahiri-Alaoui, Abdessamad, Tanner, Rachel, Taoushanis, Carol, Tarr, Alexander W., Taylor, Keja, Taylor, Ursula, Taylor, Iona Jennifer, Taylor, Justin, te Water Naude, Rebecca, Themistocleous, Yrene, Themistocleous, Andreas, Thomas, Merin, Thomas, Kelly, Thomas, Tonia M., Thombrayil, Asha, Thompson, Fawziyah, Thompson, Amber, Thompson, Kevin, Thompson, Ameeka, Thomson, Julia, Thornton-Jones, Viv, Tighe, Patrick J., Tinoco, Lygia Accioly, Tiongson, Gerlynn, Tladinyane, Bonolo, Tomasicchio, Michele, Tomic, Adriana, Tonks, Susan, Towner, James, Tran, Nguyen, Tree, Julia, Trillana, Gerry, Trinham, Charlotte, Trivett, Rose, Truby, Adam, Tsheko, Betty Lebogang, Turabi, Aadil, Turner, Richard, Turner, Cheryl, Ulaszewska, Marta, Underwood, Benjamin R., Varughese, Rachel, Verbart, Dennis, Verheul, Marije, Vichos, Iason, Vieira, Taiane, Waddington, Claire S., Walker, Laura, Wallis, Erica, Wand, Matthew, Warbick, Deborah, Wardell, Theresa, Warimwe, George, Warren, Sarah C., Watkins, Bridget, Watson, Ekaterina, Webb, Stewart, Webb-Bridges, Alice, Webster, Angela, Welch, Jessica, Wells, Jeanette, West, Alison, White, Caroline, White, Rachel, Williams, Paul, Williams, Rachel L., Winslow, Rebecca, Woodyer, Mark, Worth, Andrew T., Wright, Danny, Wroblewska, Marzena, Yao, Andy, Zimmer, Rafael, Zizi, Dalila, Zuidewind, Peter, Voysey, Merryn, Clemens, Sue Ann Costa, Madhi, Shabir A, Weckx, Lily Y, Folegatti, Pedro M, Aley, Parvinder K, Angus, Brian, Baillie, Vicky L, Barnabas, Shaun L, Bhorat, Qasim E, Bibi, Sagida, Briner, Carmen, Cicconi, Paola, Collins, Andrea M, Colin-Jones, Rachel, Cutland, Clare L, Darton, Thomas C, Dheda, Keertan, Duncan, Christopher J A, Emary, Katherine R W, Ewer, Katie J, Fairlie, Lee, Faust, Saul N, Ferreira, Daniela M, Finn, Adam, Goodman, Anna L, Green, Catherine M, Green, Christopher A, Heath, Paul T, Hill, Catherine, Hill, Helen, Hirsch, Ian, Hodgson, Susanne H C, Izu, Alane, Jackson, Susan, Jenkin, Daniel, Joe, Carina C D, Kerridge, Simon, Koen, Anthonet, Kwatra, Gaurav, Lazarus, Rajeka, Lawrie, Alison M, Lelliott, Alice, Libri, Vincenzo, Lillie, Patrick J, Mallory, Raburn, Mendes, Ana V A, Milan, Eveline P, Minassian, Angela M, McGregor, Alastair, Morrison, Hazel, Mujadidi, Yama F, Nana, Anusha, O’Reilly, Peter J, Padayachee, Sherman D, Pittella, Ana, Plested, Emma, Pollock, Katrina M, Ramasamy, Maheshi N, Rhead, Sarah, Schwarzbold, Alexandre V, Singh, Nisha, Smith, Andrew, Song, Rinn, Snape, Matthew D, Sprinz, Eduardo, Sutherland, Rebecca K, Tarrant, Richard, Thomson, Emma C, Török, M Estée, Toshner, Mark, Turner, David P J, Vekemans, Johan, Villafana, Tonya L, Watson, Marion E E, Williams, Christopher J, Douglas, Alexander D, Hill, Adrian V S, Lambe, Teresa, Gilbert, Sarah C, and Pollard, Andrew J

Published
2021
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29. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial

Author

Aboagye, Jeremy, Adams, Kelly, Ali, Aabidah, Allen, Elizabeth R., Allen, Lauren, Allison, Jennifer L., Andritsou, Foteini, Anslow, Rachel, Arbe-Barnes, Edward H., Baker, Megan, Baker, Natalie, Baker, Philip, Baleanu, Ioana, Barker, Debbie, Barnes, Eleanor, Barrett, Jordan R., Barrett, Kelly, Bates, Louise, Batten, Alexander, Beadon, Kirsten, Beckley, Rebecca, Bellamy, Duncan, Berg, Adam, Bermejo, Laura, Berrie, Eleanor, Beveridge, Amy, Bewley, Kevin, Bijker, Else M., Birch, Geeta, Blackwell, Luke, Bletchly, Heather, Blundell, Caitlin L., Blundell, Susannah R., Bolam, Emma, Boland, Elena, Bormans, Daan, Borthwick, Nicola, Boukas, Konstantinos, Bower, Thomas, Bowring, Francesca, Boyd, Amy, Brenner, Tanja, Brown, Phillip, Brown-O'Sullivan, Charlie, Bruce, Scott, Brunt, Emily, Burbage, Jamie, Burgoyne, Joshua, Buttigieg, Karen R., Byard, Nicholas, Cabera Puig, Ingrid, Camara, Susana, Cao, Michelangelo, Cappuccini, Federica, Carr, Melanie, Carroll, Miles W., Cashen, Paul, Cavey, Ana, Chadwick, Jim, Challis, Ruth, Chapman, David, Charles, David, Chelysheva, Irina, Cho, Jee-Sun, Cifuentes, Liliana, Clark, Elizabeth, Collins, Sarah, Conlon, Christopher P., Coombes, Naomi S., Cooper, Rachel, Cooper, Cushla, Crocker, Wendy E.M., Crosbie, Sarah, Cullen, Dan, Cunningham, Christina, Cuthbertson, Fiona, Datoo, Brad E., Dando, Lynne, Datoo, Mehreen S., Datta, Chandrabali, Davies, Hannah, Davies, Sarah, Davis, Elizabeth J., Davis, Judith, Dearlove, David, Demissie, Tesfaye, Di Marco, Stefania, Di Maso, Claudio, DiTirro, Danielle, Docksey, Claire, Dong, Tao, Donnellan, Francesca R., Douglas, Naomi, Downing, Charlotte, Drake, Jonathan, Drake-Brockman, Rachael, Drury, Ruth E., Dunachie, Susanna J., Edwards, Christopher J., Edwards, Nick J., El Muhanna, Omar, Elias, Sean C., Elliott, Ryan S., Elmore, Michael J., English, Marcus Rex, Felle, Sally, Feng, Shuo, Ferreira Da Silva, Carla, Field, Samantha, Fisher, Richard, Fixmer, Carine, Ford, Karen J., Fowler, Jamie, Francis, Emma, Frater, John, Furze, Julie, Galian-Rubio, Pablo, Galloway, Celine, Garlant, Harriet, Gavrila, Madita, Gibbons, Felicity, Gibbons, Karyna, Gilbride, Ciaran, Gill, Hardeep, Godwin, Kerry, Gordon-Quayle, Katherine, Gorini, Giacomo, Goulston, Lyndsey, Grabau, Caroline, Gracie, Lara, Graham, Nichola, Greenwood, Nicola, Griffiths, Oliver, Gupta, Gaurav, Hamilton, Elizabeth, Hanumunthadu, Brama, Harris, Stephanie A., Harris, Tara, Harrison, Daisy, Hart, Thomas C., Hartnell, Birgit, Haskell, Louise, Hawkins, Sophia, Henry, John Aaron, Hermosin Herrera, Macarena, Hill, David, Hill, Jennifer, Hodges, Gina, Hodgson, Susanne H.C., Horton, Katie L., Howe, Elizabeth, Howell, Nicola, Howes, Jessica, Huang, Ben, Humphreys, Jonathan, Humphries, Holly E., Iveson, Poppy, Jackson, Frederic, Jackson, Susan, Jauregui, Sam, Jeffers, Helen, Jones, Bryony, Jones, Christine E., Jones, Elizabeth, Jones, Kathryn, Joshi, Amar, Kailath, Reshma, Keen, Jade, Kelly, Dearbhla M., Kelly, Sarah, Kelly, Debbie, Kerr, David, Khan, Liaquat, Khozoee, Baktash, Killen, Annabel, Kinch, Jasmin, King, Lloyd D.W., King, Thomas B., Kingham, Lucy, Klenerman, Paul, Knight, Julian C., Knott, Daniel, Koleva, Stanislava, Lang, Gail, Larkworthy, Colin W., Larwood, Jessica P.J., Law, Rebecca, Lee, Arlene, Lee, Kim Y.N., Lees, Emily A., Leung, Stephanie, Li, Yuanyuan, Lias, Amelia M., Linder, Aline, Lipworth, Samuel, Liu, Shuchang, Liu, Xinxue, Lloyd, Stephanie, Loew, Lisa, Lopez Ramon, Raquel, Madhavan, Meera, Mainwaring, David O., Mallett, Garry, Mansatta, Kushal, Marinou, Spyridoula, Marius, Phedra, Marlow, Emma, Marriott, Paula, Marshall, Julia L., Martin, Jane, Masters, Shauna, McEwan, Joanne, McGlashan, Joanna L., McInroy, Lorna, McRobert, Nicky, Megson, Clare, Mentzer, Alexander J., Mirtorabi, Neginsadat, Mitton, Celia, Moore, Maria, Moran, Marni, Morey, Ella, Morgans, Róisín, Morris, Susan J., Morrison, Hazel Morrison, Morshead, Gertraud, Morter, Richard, Moya, Nathifa A., Mukhopadhyay, Ekta, Muller, Jilly, Munro, Claire, Murphy, Sarah, Mweu, Philomena, Noé, Andrés, Nugent, Fay L., O'Brien, Katie, O'Connor, Daniel, Oguti, Blanché, Olchawski, Victoria, Oliveira, Catarina, O'Reilly, Peter John, Osborne, Piper, Owen, Lydia, Owino, Nelly, Papageorgiou, Panagiotis, Parracho, Helena, Parsons, Karen, Patel, Bhumika, Patrick-Smith, Maia, Peng, Yanchun, Penn, Elizabeth J., Peralta-Alvarez, Marco Polo, Perring, James, Petropoulos, Christos, Phillips, Daniel J., Pipini, Dimitra, Pollard, Samuel, Poulton, Ian, Pratt, Danny, Presland, Laura, Proud, Pamela C., Provstgaard-Morys, Samuel, Pueschel, Sophie, Pulido, David, Rabara, Ria, Radia, Kajal, Rajapaska, Durga, Ramos Lopez, Fernando, Ratcliffe, Helen, Rayhan, Sara, Rees, Byron, Reyes Pabon, Emilia, Roberts, Hannah, Robertson, Isla, Roche, Sophie, Rollier, Christine S., Romani, Rossana, Rose, Zoe, Rudiansyah, Indra, Sabheha, Sabeha, Salvador, Stephannie, Sanders, Helen, Sanders, Katherine, Satti, Iman, Sayce, Chloe, Schmid, Annina B., Schofield, Ella, Screaton, Gavin, Sedik, Cynthia, Seddiqi, Samiullah, Segireddy, Rameswara R., Selby, Beatrice, Shaik, Imam, Sharpe, Hannah R., Shaw, Robert, Shea, Adam, Silk, Sarah, Silva-Reyes, Laura, Skelly, Donal T., Smith, David J., Smith, Daniel C., Smith, Nicholas, Spencer, Alexandra J., Spoors, Louise, Stafford, Elizabeth, Stamford, Imogen, Stockdale, Lisa, Stockley, David, Stockwell, Lisa V., Stokes, Matthew, Strickland, Louise H., Stuart, Arabella, Sulaiman, Sulaiman, Summerton, Eloise, Swash, Zoe, Szigeti, Anna, Tahiri-Alaoui, Abdessamad, Tanner, Rachel, Taylor, Iona, Taylor, Keja, Taylor, Ursula, te Water Naude, Rebecca, Themistocleous, Andreas, Thomas, Merin, Thomas, Tonia M., Thompson, Amber, Thompson, Kevin, Thornton-Jones, Viv, Tinh, Lan, Tomic, Adriana, Tonks, Susan, Towner, James, Tran, Nguyen, Tree, Julian A., Truby, Adam, Turner, Cheryl, Turner, Richard, Ulaszewska, Marta, Varughese, Rachel, Verbart, Dennis, Verheul, Marije K., Vichos, Iason, Walker, Laura, Wand, Matthew E., Watkins, Bridget, Welch, Jessica, West, Alison J., White, Caroline, White, Rachel, Williams, Paul, Woodyer, Mark, Worth, Andrew T., Wright, Daniel, Wrin, Terri, Yao, Xin Li, Zbarcea, Diana-Andreea, Zizi, Dalila, Ramasamy, Maheshi N, Minassian, Angela M, Ewer, Katie J, Flaxman, Amy L, Folegatti, Pedro M, Owens, Daniel R, Voysey, Merryn, Aley, Parvinder K, Angus, Brian, Babbage, Gavin, Belij-Rammerstorfer, Sandra, Berry, Lisa, Bibi, Sagida, Bittaye, Mustapha, Cathie, Katrina, Chappell, Harry, Charlton, Sue, Cicconi, Paola, Clutterbuck, Elizabeth A, Colin-Jones, Rachel, Dold, Christina, Emary, Katherine R W, Fedosyuk, Sofiya, Fuskova, Michelle, Gbesemete, Diane, Green, Catherine, Hallis, Bassam, Hou, Mimi M, Jenkin, Daniel, Joe, Carina C D, Kelly, Elizabeth J, Kerridge, Simon, Lawrie, Alison M, Lelliott, Alice, Lwin, May N, Makinson, Rebecca, Marchevsky, Natalie G, Mujadidi, Yama, Munro, Alasdair P S, Pacurar, Mihaela, Plested, Emma, Rand, Jade, Rawlinson, Thomas, Rhead, Sarah, Robinson, Hannah, Ritchie, Adam J, Ross-Russell, Amy L, Saich, Stephen, Singh, Nisha, Smith, Catherine C, Snape, Matthew D, Song, Rinn, Tarrant, Richard, Themistocleous, Yrene, Thomas, Kelly M, Villafana, Tonya L, Warren, Sarah C, Watson, Marion E E, Douglas, Alexander D, Hill, Adrian V S, Lambe, Teresa, Gilbert, Sarah C, Faust, Saul N, and Pollard, Andrew J

Published
2020
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30. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

Author

Aboagye, Jeremy, Adams, Kelly, Ali, Aabidah, Allen, Elizabeth, Allison, Jennifer L., Anslow, Rachel, Arbe-Barnes, Edward H., Babbage, Gavin, Baillie, Kenneth, Baker, Megan, Baker, Natalie, Baker, Philip, Baleanu, Ioana, Ballaminut, Juliana, Barnes, Eleanor, Barrett, Jordan, Bates, Louise, Batten, Alexander, Beadon, Kirsten, Beckley, Rebecca, Berrie, Eleanor, Berry, Lisa, Beveridge, Amy, Bewley, Kevin R., Bijker, Else Margreet, Bingham, Tracey, Blackwell, Luke, Blundell, Caitlin L., Bolam, Emma, Boland, Elena, Borthwick, Nicola, Bower, Thomas, Boyd, Amy, Brenner, Tanja, Bright, Philip D., Brown-O'Sullivan, Charlie, Brunt, Emily, Burbage, Jamie, Burge, Sharon, Buttigieg, Karen R., Byard, Nicholas, Cabera Puig, Ingrid, Calvert, Anna, Camara, Susana, Cao, Michelangelo, Cappuccini, Federica, Carr, Melanie, Carroll, Miles W., Carter, Victoria, Cathie, Katrina, Challis, Ruth J., Charlton, Sue, Chelysheva, Irina, Cho, Jee-Sun, Cicconi, Paola, Cifuentes, Liliana, Clark, Helen, Clark, Elizabeth, Cole, Tom, Colin-Jones, Rachel, Conlon, Christopher P., Cook, Aislinn, Coombes, Naomi S., Cooper, Rachel, Cosgrove, Catherine A., Coy, Karen, Crocker, Wendy E.M., Cunningham, Christina J., Damratoski, Brad E., Dando, Lynne, Datoo, Mehreen S., Davies, Hannah, De Graaf, Hans, Demissie, Tesfaye, Di Maso, Claudio, Dietrich, Isabelle, Dong, Tao, Donnellan, Francesca R., Douglas, Naomi, Downing, Charlotte, Drake, Jonathan, Drake-Brockman, Rachael, Drury, Ruth Elizabeth, Dunachie, Susanna Jane, Edwards, Nick J., Edwards, Frances D.L., Edwards, Chris J., Elias, Sean C., Elmore, Michael J., Emary, Katherine R.W., English, Marcus Rex, Fagerbrink, Susanne, Felle, Sally, Feng, Shuo, Field, Samantha, Fixmer, Carine, Fletcher, Clare, Ford, Karen J., Fowler, Jamie, Fox, Polly, Francis, Emma, Frater, John, Furze, Julie, Fuskova, Michelle, Galiza, Eva, Gbesemete, Diane, Gilbride, Ciaran, Godwin, Kerry, Gorini, Giacomo, Goulston, Lyndsey, Grabau, Caroline, Gracie, Lara, Gray, Zoe, Guthrie, Lucy Belle, Hackett, Mark, Halwe, Sandro, Hamilton, Elizabeth, Hamlyn, Joseph, Hanumunthadu, Brama, Harding, Irasha, Harris, Stephanie A., Harris, Andrew, Harrison, Daisy, Harrison, Clare, Hart, Thomas C., Haskell, Louise, Hawkins, Sophia, Head, Ian, Henry, John Aaron, Hill, Jennifer, Hodgson, Susanne H.C., Hou, Mimi M., Howe, Elizabeth, Howell, Nicola, Hutlin, Cecilia, Ikram, Sabina, Isitt, Catherine, Iveson, Poppy, Jackson, Susan, Jackson, Frederic, James, Sir William, Jenkins, Megan, Jones, Elizabeth, Jones, Kathryn, Jones, Christine E., Jones, Bryony, Kailath, Reshma, Karampatsas, Konstantinos, Keen, Jade, Kelly, Sarah, Kelly, Dearbhla, Kerr, David, Kerridge, Simon, Khan, Liaquat, Khan, Uzma, Killen, Annabel, Kinch, Jasmin, King, Thomas B., King, Lloyd, King, Jade, Kingham-Page, Lucy, Klenerman, Paul, Knapper, Francesca, Knight, Julian C., Knott, Daniel, Koleva, Stanislava, Kupke, Alexandra, Larkworthy, Colin W., Larwood, Jessica P.J., Laskey, Anna, Lawrie, Alison M., Lee, Arlene, Ngan Lee, Kim Yee, Lees, Emily A, Legge, Helen, Lelliott, Alice, Lemm, Nana-Marie, Lias, Amelia M., Linder, Aline, Lipworth, Samuel, Liu, Xinxue, Liu, Shuchang, Lopez Ramon, Raquel, Lwin, May, Mabesa, Francesca, Madhavan, Meera, Mallett, Garry, Mansatta, Kushal, Marcal, Ines, Marinou, Spyridoula, Marlow, Emma, Marshall, Julia L., Martin, Jane, McEwan, Joanne, McInroy, Lorna, Meddaugh, Gretchen, Mentzer, Alexander J., Mirtorabi, Neginsadat, Moore, Maria, Moran, Edward, Morey, Ella, Morgan, Victoria, Morris, Susan Jane, Morrison, Hazel, Morshead, Gertraud, Morter, Richard, Mujadidi, Yama F., Muller, Jilly, Munera-Huertas, Tatiana, Munro, Claire, Munro, Alasdair, Murphy, Sarah, Munster, Vincent J., Mweu, Philomena, Noé, Andrés, Nugent, Fay L., Nuthall, Elizabeth, O'Brien, Katie, O'Connor, Daniel, Oguti, Blanché, Oliver, Jennifer L., Oliveira, Catarina, O'Reilly, Peter John, Osborn, Mairead, Osborne, Piper, Owen, Cathy, Owens, Daniel, Owino, Nelly, Pacurar, Mihaela, Parker, Kaye, Parracho, Helena, Patrick-Smith, Maia, Payne, Victoria, Pearce, Jennifer, Peng, Yanchun, Peralta Alvarez, Marco Polo, Perring, James, Pfafferott, Katja, Pipini, Dimitra, Plested, Emma, Pluess-Hall, Helen, Pollock, Katrina, Poulton, Ian, Presland, Laura, Provstgaard-Morys, Samuel, Pulido, David, Radia, Kajal, Ramos Lopez, Fernando, Rand, Jade, Ratcliffe, Helen, Rawlinson, Thomas, Rhead, Sarah, Riddell, Amy, Ritchie, Adam John, Roberts, Hannah, Robson, Joanna, Roche, Sophie, Rohde, Cornelius, Rollier, Christine S., Romani, Rossana, Rudiansyah, Indra, Saich, Stephen, Sajjad, Sara, Salvador, Stephannie, Sanchez Riera, Lidia, Sanders, Helen, Sanders, Katherine, Sapaun, Shari, Sayce, Chloe, Schofield, Ella, Screaton, Gavin, Selby, Beatrice, Semple, Calum, Sharpe, Hannah R., Shaik, Imam, Shea, Adam, Shelton, Holly, Silk, Sarah, Silva-Reyes, Laura, Skelly, Donal T., Smee, Heather, Smith, Catherine C., Smith, David J., Song, Rinn, Spencer, Alexandra J., Stafford, Elizabeth, Steele, Amy, Stefanova, Elena, Stockdale, Lisa, Szigeti, Anna, Tahiri-Alaoui, Abdessamad, Tait, Moira, Talbot, Helen, Tanner, Rachel, Taylor, Iona Jennifer, Taylor, Victoria, Te Water Naude, Rebecca, Thakur, Nazia, Themistocleous, Yrene, Themistocleous, Andreas, Thomas, Merin, Thomas, Tonia M., Thompson, Amber, Thomson-Hill, Samantha, Tomlins, Jennifer, Tonks, Susan, Towner, James, Tran, Nguyen, Tree, Julia A., Truby, Adam, Turkentine, Kate, Turner, Cheryl, Turner, Nicola, Turner, Sally, Tuthill, Toby, Ulaszewska, Marta, Varughese, Rachel, Van Doremalen, Neeltje, Veighey, Kristin, Verheul, Marije K., Vichos, Iason, Vitale, Elia, Walker, Laura, Watson, Marion E.E., Welham, Benjamin, Wheat, Julie, White, Caroline, White, Rachel, Worth, Andrew T., Wright, Danny, Wright, Suzie, Yao, Xin Li, Yau, Yasmine, Folegatti, Pedro M, Ewer, Katie J, Aley, Parvinder K, Angus, Brian, Becker, Stephan, Belij-Rammerstorfer, Sandra, Bellamy, Duncan, Bibi, Sagida, Bittaye, Mustapha, Clutterbuck, Elizabeth A, Dold, Christina, Faust, Saul N, Finn, Adam, Flaxman, Amy L, Hallis, Bassam, Heath, Paul, Jenkin, Daniel, Lazarus, Rajeka, Makinson, Rebecca, Minassian, Angela M, Pollock, Katrina M, Ramasamy, Maheshi, Robinson, Hannah, Snape, Matthew, Tarrant, Richard, Voysey, Merryn, Green, Catherine, Douglas, Alexander D, Hill, Adrian V S, Lambe, Teresa, Gilbert, Sarah C, and Pollard, Andrew J

Published
2020
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31. A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia

Author

Levis, Mark J., primary, Perl, Alexander E., additional, Schiller, Gary J., additional, Fathi, Amir T., additional, Roboz, Gail J., additional, Wang, Eunice S., additional, Altman, Jessica K., additional, Rajkhowa, Trivikram, additional, Ando, Makoto, additional, Suzuki, Takeaki, additional, Subach, Ruth Ann, additional, Maier, Gary, additional, Madden, Timothy, additional, Johansen, Mary, additional, Cheung, Kin, additional, Kurman, Michael, additional, and Smith, Catherine C., additional

Published
2024
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32. The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia

Author

Minson, Katherine A, Smith, Catherine C, DeRyckere, Deborah, Libbrecht, Clara, Lee-Sherick, Alisa B, Huey, Madeline G, Lasater, Elisabeth A, Kirkpatrick, Gregory D, Stashko, Michael A, Zhang, Weihe, Jordan, Craig T, Kireev, Dmitri, Wang, Xiaodong, Frye, Stephen V, Earp, H Shelton, Shah, Neil P, and Graham, Douglas K

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Hematology, Orphan Drug, Childhood Leukemia, Pediatric Cancer, Rare Diseases, Pediatric, Cancer, 5.1 Pharmaceuticals, Biomedical and clinical sciences, Health sciences
Abstract

FMS-like tyrosine kinase 3-targeted (FLT3-targeted) therapies have shown initial promise for the treatment of acute myeloid leukemia (AML) expressing FLT3-activating mutations; however, resistance emerges rapidly. Furthermore, limited options exist for the treatment of FLT3-independent AML, demonstrating the need for novel therapies that reduce toxicity and improve survival. MERTK receptor tyrosine kinase is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis. Here, we describe MRX-2843, a type 1 small-molecule tyrosine kinase inhibitor that abrogates activation of both MERTK and FLT3 and their downstream effectors. MRX-2843 treatment induces apoptosis and inhibits colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD, with a wide therapeutic window compared with that of normal human cord blood cells. In murine orthotopic xenograft models, once-daily oral therapy prolonged survival 2- to 3-fold over that of vehicle-treated controls. Additionally, MRX-2843 retained activity against quizartinib-resistant FLT3-ITD-mutant proteins with clinically relevant alterations at the D835 or F691 loci and prolonged survival in xenograft models of quizartinib-resistant AML. Together, these observations validate MRX-2843 as a translational agent and support its clinical development for the treatment of AML.

Published
2016

33. Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib

Author

Perl, Alexander E., Hosono, Naoko, Montesinos, Pau, Podoltsev, Nikolai, Martinelli, Giovanni, Panoskaltsis, Nicki, Recher, Christian, Smith, Catherine C., Levis, Mark J., Strickland, Stephen, Röllig, Christoph, Groß-Langenhoff, Marco, Chou, Wen-Chien, Lee, Je-Hwan, Yokoyama, Hisayuki, Hasabou, Nahla, Lu, Qiaoyang, Tiu, Ramon V., and Altman, Jessica K.

Published
2022
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34. Ebola virus antibody decay–stimulation in a high proportion of survivors

Author

Adaken, Charlene, Scott, Janet T., Sharma, Raman, Gopal, Robin, Dicks, Steven, Niazi, Saidia, Ijaz, Samreen, Edwards, Tansy, Smith, Catherine C., Cole, Christine P., Kamara, Philip, Kargbo, Osman, Doughty, Heidi A., van Griensven, Johan, Horby, Peter W., Gevao, Sahr M., Sahr, Foday, Dimelow, Richard J., Tedder, Richard S., Semple, Malcolm G., Paxton, William A., and Pollakis, Georgios

Published
2021
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35. Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 “Gatekeeper” F691L Mutation with PLX3397

Author

Smith, Catherine C, Zhang, Chao, Lin, Kimberly C, Lasater, Elisabeth A, Zhang, Ying, Massi, Evan, Damon, Lauren E, Pendleton, Matthew, Bashir, Ali, Sebra, Robert, Perl, Alexander, Kasarskis, Andrew, Shellooe, Rafe, Tsang, Garson, Carias, Heidi, Powell, Ben, Burton, Elizabeth A, Matusow, Bernice, Zhang, Jiazhong, Spevak, Wayne, Ibrahim, Prabha N, Le, Mai H, Hsu, Henry H, Habets, Gaston, West, Brian L, Bollag, Gideon, and Shah, Neil P

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Cancer, 5.1 Pharmaceuticals, Aminopyridines, Animals, Antineoplastic Agents, Benzothiazoles, Cell Line, Tumor, Drug Resistance, Neoplasm, Enzyme Activation, Heterografts, Humans, Leukemia, Myeloid, Acute, Mice, Models, Molecular, Molecular Conformation, Mutation, Phenylurea Compounds, Protein Binding, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors, Pyrroles, Recurrence, Structure-Activity Relationship, fms-Like Tyrosine Kinase 3, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledTyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKI) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase "gatekeeper" residues, which control access to an allosteric pocket adjacent to the ATP-binding site, has been frequently implicated in TKI resistance. The molecular underpinnings of gatekeeper mutation-mediated resistance are incompletely understood. We report the first cocrystal structure of FLT3 with the TKI quizartinib, which demonstrates that quizartinib binding relies on essential edge-to-face aromatic interactions with the gatekeeper F691 residue, and F830 within the highly conserved Asp-Phe-Gly motif in the activation loop. This reliance makes quizartinib critically vulnerable to gatekeeper and activation loop substitutions while minimizing the impact of mutations elsewhere. Moreover, we identify PLX3397, a novel FLT3 inhibitor that retains activity against the F691L mutant due to a binding mode that depends less vitally on specific interactions with the gatekeeper position.SignificanceWe report the first cocrystal structure of FLT3 with a kinase inhibitor, elucidating the structural mechanism of resistance due to the gatekeeper F691L mutation. PLX3397 is a novel FLT3 inhibitor with in vitro activity against this mutation but is vulnerable to kinase domain mutations in the FLT3 activation loop.

Published
2015

36. Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors

Author

Frett, Brendan, McConnell, Nick, Smith, Catherine C, Wang, Yuanxiang, Shah, Neil P, and Li, Hong-yu

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Rare Diseases, Orphan Drug, 5.1 Pharmaceuticals, Cancer, Animals, Cell Line, Chemistry Techniques, Synthetic, Computer-Aided Design, Drug Discovery, Drug Evaluation, Preclinical, Libraries, Digital, Ligands, Mice, Molecular Weight, Protein Kinase Inhibitors, Pyridines, Small Molecule Libraries, fms-Like Tyrosine Kinase 3, FLT3, Kinase inhibitor, AML, Ligand efficiency, Computer aided drug discovery, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, Pharmacology and pharmaceutical sciences, Medicinal and biomolecular chemistry, Organic chemistry
Abstract

The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates.

Published
2015

38. Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy.

Author

Warkentin, Alexander A, Lopez, Michael S, Lasater, Elisabeth A, Lin, Kimberly, He, Bai-Liang, Leung, Anskar Yh, Smith, Catherine C, Shah, Neil P, and Shokat, Kevan M

Subjects
Cell Line, Tumor, Animals, Zebrafish, Humans, Bone Marrow Diseases, Antineoplastic Agents, Structure-Activity Relationship, Mutation, Models, Biological, fms-Like Tyrosine Kinase 3, Leukemia, Myeloid, Acute, FLT3, KIT, biochemistry, chemical synthesis, human biology, leukemia, medicine, protein kinase, staurosporine, zebrafish, Orphan Drug, Hematology, Pediatric, Pediatric Cancer, Rare Diseases, Cancer, Clinical Research, Childhood Leukemia, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Biochemistry and Cell Biology
Abstract

Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a 'synthetic lethal toxicity' arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity.

Published
2014

39. Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

Author

Chatterjee, Anindya, Ghosh, Joydeep, Ramdas, Baskar, Mali, Raghuveer Singh, Martin, Holly, Kobayashi, Michihiro, Vemula, Sasidhar, Canela, Victor H, Waskow, Emily R, Visconte, Valeria, Tiu, Ramon V, Smith, Catherine C, Shah, Neil, Bunting, Kevin D, Boswell, H Scott, Liu, Yan, Chan, Rebecca J, and Kapur, Reuben

Subjects
Childhood Leukemia, Hematology, Cancer, Pediatric Cancer, Rare Diseases, Pediatric, Genetics, Aetiology, 2.1 Biological and endogenous factors, Animals, Benzothiazoles, Carcinogenesis, Cell Nucleus, Cell Proliferation, Focal Adhesion Protein-Tyrosine Kinases, Guanine Nucleotide Exchange Factors, Humans, Leukemia, Myeloid, Acute, Mastocytosis, Systemic, Mice, Inbred C57BL, Mutant Proteins, Mutation, Phenylurea Compounds, Phosphorylation, Protein Kinase Inhibitors, Protein Transport, Proto-Oncogene Proteins c-kit, STAT5 Transcription Factor, Signal Transduction, Survival Analysis, T-Lymphoma Invasion and Metastasis-inducing Protein 1, fms-Like Tyrosine Kinase 3, p21-Activated Kinases, rac1 GTP-Binding Protein, Biochemistry and Cell Biology, Medical Physiology
Abstract

Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

Published
2014

40. Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor

Author

Verstovsek, Srdan, Tam, Constantine S, Wadleigh, Martha, Sokol, Lubomir, Smith, Catherine C, Bui, Lynne A, Song, Chunyan, Clary, Douglas O, Olszynski, Patrycja, Cortes, Jorge, Kantarjian, Hagop, and Shah, Neil P

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Hematology, Rare Diseases, Clinical Research, Peripheral Neuropathy, Neurodegenerative, Neurosciences, Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Administration, Oral, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Drug Administration Schedule, Drug Monitoring, Early Termination of Clinical Trials, Female, Humans, Janus Kinase 2, Male, Middle Aged, Neurotoxicity Syndromes, Primary Myelofibrosis, Proline, Protein Kinase Inhibitors, Pyrimidines, Myelofibrosis, JAK2, XL019, Mutation, Inhibitor, Immunology, Cardiovascular medicine and haematology
Abstract

This phase I study evaluated selective JAK2 inhibitor XL019 in 30 patients with myelofibrosis. The initial dose cohorts were 100, 200, and 300 mg orally on days 1-21 of a 28-day cycle. Central and/or peripheral neurotoxicity developed in all patients. Subsequently, patients were treated on lower doses; neurotoxicity was again observed, leading to study termination. Peripheral neuropathy resolved in 50%, and central neurotoxicity in all patients within months after therapy cessation. Myelosuppression was minimal. The terminal half-life of XL019 was approximately 21 h, with steady state reached by Day 8. International Working Group defined responses were seen in three (10%) patients.

Published
2014

46. List of Contributors

Author

Acosta, Anna M., primary, Acuin, Jose M., additional, Adam, Rodney D., additional, Afroze, Farzana, additional, Ahmed, Nadia, additional, Ahmed, Sabeena, additional, Ahmed, Tahmeed, additional, Ahmed, A.M. Shamsir, additional, Ali, S. Asad, additional, Ali, Ibne K., additional, Alroy, Karen A., additional, Ananthakrishnan, Ashwin N., additional, Ansong, Daniel, additional, Anstead, Gregory M., additional, Appleby, Laura J., additional, Armah, George E., additional, Aronson, Naomi E., additional, Aston, Stephen J., additional, Barnett, Elizabeth D., additional, Bartelt, Luther A., additional, Bates, Imelda, additional, Bausch, Daniel G., additional, Beadling, Charles W., additional, Beeching, Nicholas J., additional, Bennish, Michael L., additional, Bern, Caryn, additional, Bernstein, Wendy B., additional, Bird, Brian H., additional, Bloom, Allyson K., additional, Bodeker, Gerard, additional, Boyer Chammard, Timothée, additional, Bradsher, Robert W., additional, Brooker, Simon J., additional, Brooks, W. Abdullah, additional, Brouqui, Philippe, additional, Brown, Michael, additional, Brown, Michael R., additional, Broyles, Laura N., additional, Bruschi, Fabrizio, additional, Bundy, Donald A.P., additional, Burton, Matthew, additional, Cabrera-Sosa, Luis, additional, Callahan, Michael V., additional, Carapetis, Jonathan R., additional, Cardemil, Cristina V., additional, Carrol, Enitan D., additional, Caswell, Rachel, additional, Caumes, Eric, additional, Cavalheiro, Ana P., additional, Chan, Abner L., additional, Charunwatthana, Prakaykaew, additional, Checkley, Anna M., additional, Chen, Lin H., additional, Chher, Tepirou, additional, Chiong, Charlotte M., additional, Chisti, M. Jobayer, additional, Christiani, David C., additional, Clark, Taryn N., additional, Connor, Bradley A., additional, Conway, Devin J., additional, Cooper, Philip J., additional, Cope, Jennifer R., additional, Coughlin, R. Richard, additional, Coulibaly, Yaya I., additional, Coyle, Christina M., additional, Crozier, Ian, additional, Cunliffe, Nigel A., additional, Cupido, Blanche, additional, Curren, Emily J., additional, Danta, Mark, additional, Day, Nicholas P.J., additional, Debboun, Mustapha, additional, DeFraites, Robert F., additional, Dekumyoy, Paron, additional, del Castillo, Maria, additional, den Hoed, Caroline M., additional, de Silva, Nilanthi, additional, Deye, Gregory, additional, Dillingham, Rebecca A., additional, Drancourt, Michel, additional, Durward, Callum S., additional, Eddleston, Michael, additional, El-Kamary, Samer S., additional, Elshaboury, Ramy H., additional, Endtz, Hubert P., additional, Endy, Timothy P., additional, Fang, Shona C., additional, Fawzi, Wafaie, additional, Feasey, Nicholas A., additional, Field, Vanessa K., additional, Fischer, Marc, additional, Forsyth, Kevin, additional, Fournier, Pierre-Edouard, additional, Friedlander, Arthur M., additional, Furin, Jennifer J., additional, Gandhi, Ronak G., additional, Garcia, Hector H., additional, Garcia, Lynne S., additional, Geretti, Anna Maria, additional, Gikas, Achilleas, additional, Gilman, Robert H., additional, Giri, Sidhartha, additional, Gkika, Meropi, additional, Gordon, Melita A., additional, Gosselin, Richard A., additional, Gotuzzo, Eduardo, additional, Gould, Carolyn V., additional, Graeff-Teixeira, Carlos, additional, Graham, Stephen M., additional, Grant, Alison D., additional, Graybill, John R., additional, Graz, Bertrand, additional, Green, Stephen T., additional, Griffiths, Jeffrey K., additional, Griffiths, Michael J., additional, Gryseels, Bruno, additional, Gubler, Duane J., additional, Guhadasan, Rathi, additional, Hall, Aron J., additional, Hamer, Davidson H., additional, Hand, Robert M., additional, Harley, David, additional, Harris, Jason B., additional, Hassall, Oliver, additional, Hay, Roderick J., additional, Hickey, Patrick, additional, Hill, David R., additional, Hills, Susan L., additional, Hobdell, Martin H., additional, Hochberg, Natasha S., additional, Hopkins, Donald R., additional, Hossain, M. Iqbal, additional, Hotez, Peter J., additional, Howard, Cynthia R., additional, Hu, Victor, additional, Hung, Chien-Ching, additional, Islam, Munirul, additional, Iturriza-Gómara, Miren, additional, Joekes, Elizabeth, additional, Johnston, Victoria, additional, Jose, Jo-Ann, additional, Junghanss, Thomas, additional, Kamgno, Joseph, additional, Kampondeni, Sam, additional, Kang, Gagandeep, additional, Kazanjian, Powel, additional, Keshtkar-Jahromi, Maryam, additional, Keshtkar-Jahromi, Marzieh, additional, Keystone, Jay S., additional, Kim, Arthur Y., additional, Kim, Sung-Han, additional, King, Christopher L., additional, Kittitrakul, Chatporn, additional, Kleine, Christian, additional, Klion, Amy D., additional, Knight, Richard, additional, Koren, Michael, additional, Kottilil, Shyamasundaran, additional, Krause, Peter J., additional, Krishna, Sanjeev, additional, Kuhn, Jens H., additional, Kuipers, Ernst J., additional, LaBeaud, Angelle D., additional, Labra, Patrick John P., additional, Lalloo, David G., additional, Lambert, Saba, additional, Lanternier, Fanny, additional, LaRocque, Regina C., additional, Last, Anna, additional, Lawrenson, John, additional, Le, Thuy, additional, Lee, Keun Hwa, additional, Lewis, David A., additional, Libraty, Daniel H., additional, Lo, Nathan C., additional, Lockwood, Diana N.J., additional, Lockwood, Stephen J., additional, Lommerse, Kinke, additional, López-Vélez, Rogelio, additional, Lortholary, Olivier, additional, Mabey, David, additional, Magill, Alan J., additional, Maguiña, Ciro P., additional, Manji, Hadi, additional, Marks, Michael, additional, Maurin, Max, additional, Mayaud, Philippe, additional, Mayosi, Bongani M., additional, M'baya, Bridon, additional, McCarthy, Matthew W., additional, McCartney, Daniel, additional, McCormick, Joseph B., additional, McKew, Stephen, additional, McLellan, Susan L.F., additional, McMinn, Peter C., additional, Mertz, Gregory, additional, Milner, Danny A., additional, Molyneux, Elizabeth M., additional, Montgomery, Susan P., additional, Moonah, Shannon, additional, Moss, William J., additional, Murrell, K. Darwin, additional, Nanda, Neha, additional, Navarro, Eileen E., additional, Ndayizeye, Leonard, additional, Neafie, Ronald C., additional, Negroni, Ricardo, additional, Nelson, Ann M., additional, Newton, Paul N., additional, Nichol, Stuart T., additional, Norman, Francesca F., additional, Nunes, Marcio R.T., additional, Nutman, Thomas B., additional, Nyirenda, Tonney S., additional, Ochoa, Theresa J., additional, O'Farrell, Nigel, additional, Olayemi, Edeghonghon, additional, Oldfield, Edward C., additional, Omidian, Zahra, additional, Ordaya, Eloy E., additional, Paddock, Christopher D., additional, Paessler, Slobodan, additional, Papanikolaou, Ilias C., additional, Paris, Luc, additional, Parry, Christopher M., additional, Patel, Pragna, additional, Peacock, Sharon J., additional, Peeling, Rosanna W., additional, Persson, Hans, additional, Phillips, Jonathan J., additional, Phillips, Richard O., additional, Poovorawan, Kittiyod, additional, Powers, Ann M., additional, Qamar, Farah Naz, additional, Qureshi, Sonia, additional, Rabe, Ingrid B., additional, Rahman, Atif, additional, Rahmati, Elham, additional, Raizes, Elliot, additional, Ramalho-Ortigao, Marcelo, additional, Raoult, Didier, additional, Rein, Michael F., additional, Retik, Alan B., additional, Reynes, Jean-Marc, additional, Rhatigan, Joseph J., additional, Rickard, Jennifer, additional, Riddle, Mark S., additional, Rimoin, Anne W., additional, Riviello, Robert, additional, Robert, Leon L., additional, Rodrigues, Ema G., additional, Rodriguez, Rubens, additional, Ronald, Allan R., additional, Rosenthal, Benjamin M., additional, Rosmarin, David, additional, Ryan, Edward T., additional, Saavedra, Arturo, additional, Schiaffino, Francesca, additional, Schumacher, Sandra K., additional, Sejvar, James J., additional, Sethi, Aisha, additional, Seung, Kwonjune J., additional, Seydel, Karl B., additional, Shah, Melisa M., additional, Shakoor, Sadia, additional, Shankar, Anuraj H., additional, Sharp, Trueman W., additional, Shin, Sonya S., additional, Shirley, Debbie-Ann, additional, Silachamroon, Udomsak, additional, Smith, Catherine C., additional, Snelling, Thomas L., additional, Solomon, Tom, additional, Staat, Mary Allen, additional, Staples, J. Erin, additional, Steiger, Samantha N., additional, Stewart, Robert C., additional, Stich, August, additional, Strickman, Daniel, additional, Suh, Kathryn N., additional, Suhrbier, Andreas, additional, Sutcliffe, Catherine G., additional, Tappe, Dennis, additional, Taylor, Terrie E., additional, Thanh, Nguyen Tat, additional, Thanh, Nguyen Thi, additional, Thwaites, C. Louise, additional, Thwaites, Guy E., additional, Tiwari, Tejpratap S.P., additional, Tsenempi, Xenia A., additional, Turner, Angus W., additional, van den Broek, Nynke R., additional, van Doorn, H. Rogier, additional, Van Sickels, Nicholas J., additional, Vannier, Edouard, additional, Varda, Briony K., additional, Vasconcelos, Pedro F.C., additional, Vega-López, Francisco, additional, Vietri, Nicholas J., additional, Vinetz, Joseph M., additional, Visvesvara, Govinda S., additional, Vyas, Keyur S., additional, Walsh, Thomas J., additional, Wansbrough-Jones, Mark H., additional, Warraich, Haider J., additional, Warrell, David A., additional, Warrell, Mary J., additional, Watt, George, additional, Wattanagoon, Yupaporn, additional, Watthanakulpanich, Dorn, additional, Weaver, Scott C., additional, Weil, Ana A., additional, Weiss, Louis M., additional, White, Nicholas J., additional, Whitty, Christopher J.M., additional, Wilson, Mary E., additional, Xavier, Ramnik J., additional, Xiao, Lihua, additional, Yoon, In-Kyu, additional, Yu, Hongjie, additional, and Zaidi, Anita K.M., additional

Published
2020
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48. Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib.

Author

Smith, Catherine C, Smith, Catherine C, Levis, Mark J, Perl, Alexander E, Hill, Jason E, Rosales, Matt, Bahceci, Erkut, Smith, Catherine C, Smith, Catherine C, Levis, Mark J, Perl, Alexander E, Hill, Jason E, Rosales, Matt, and Bahceci, Erkut

Abstract

The phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML. Baseline comutations, FLT3-internal tandem duplication (ITD) allelic ratio and length, and treatment-emergent mutations were analyzed in patients in the ADMIRAL trial. Baseline comutations were grouped according to gene subgroups (DNA methylation/hydroxymethylation, transcription, chromatin-spliceosome, receptor tyrosine kinase-Ras signaling, TP53-aneuploidy, NPM1, DNMT3A, DNMT3A/NPM1, WT-1, and IDH1/IDH2). Across all but 1 gene subgroup (TP53-aneuploidy), higher pretransplant response rates and a trend toward longer overall survival were observed with gilteritinib vs SC. Patients with DNMT3A/NPM1 comutations who received gilteritinib had the most favorable outcomes of any molecular subgroup analyzed. Survival outcomes with gilteritinib were not adversely affected by FLT3-ITD allelic ratio, FLT3-ITD length, or multiple FLT3-ITD mutations. Among patients who relapsed on gilteritinib, Ras/mitogen-activated protein kinase (MAPK) pathway and FLT3 F691L gene mutations were the most common mutational events associated with treatment resistance. However, the occurrence of Ras/MAPK pathway gene mutations at baseline did not preclude a clinical benefit from gilteritinib. Acquisition of multiple Ras/MAPK pathway gene mutations at relapse suggests a high level of pathway reactivation is needed to overcome the gilteritinib treatment effect. These findings provide insight into the R/R AML molecular profile and the impact of FLT3 inhibitors on mutational evolution associated with treatment resistance and benefit of gilteritinib across a wide spectrum of molecular and genetic subgroups in FLT3-mutated R/R AML. This trial was registered at w

Published
2022

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