Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study
Abstract
Background Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia.Methods In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179.Findings Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators.Interpretation Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted.Funding Amgen.
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Cytokine storm can be observed with other T-cell-engaging immunotherapies such as blinatumomab.
“Cytokine storm can be observed with other T-cell–engaging immunotherapies as well, such as blinatumomab, a bispecific antibody that binds to CD19+ and CD3+ T cells.56”
From Cytokine storm (2020) · cites this paper as [56]
Cites
Optimal two-stage designs for phase II clinical trials.
Simon, R. (1989) · Controlled Clinical Trials · doi:10.1016/0197-2456(89)90015-9 · Cited by 3,636 · see citing works
Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia
Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., Teachey, D. T., Chew, A., Hauck, B., Wright, J. F., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1215134 · Cited by 3,509 · see citing works
Brentjens, R. J., Davila, M. L., Riviere, I., Park, J., Wang, X., Cowell, L. G., Bartido, S., Stefanski, J., Taylor, C., Olszewska, M., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005930 · Cited by 2,063 · see citing works
Basch, E., Reeve, B. B., Mitchell, S. A., Clauser, S. B., Minasian, L. M., Dueck, A. C., Mendoza, T. R., Hay, J. L., Atkinson, T. M., Abernethy, A. P., et al. (2014) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dju244 · Cited by 1,167 · see citing works
Analysis of survival by tumor response.
Anderson, J. R., Cain, K. C., & Gelber, R. (1983) · Journal of Clinical Oncology · doi:10.1200/jco.1983.1.11.710 · Cited by 1,125 · see citing works
Tumor Regression in Cancer Patients by Very Low Doses of a T Cell–Engaging Antibody
Bargou, R., Leo, E., Zugmaier, G., Klinger, M., Goebeler, M., Knop, S., Noppeney, R., Viardot, A., Hess, G., Schuler, M., et al. (2008) · Science · doi:10.1126/science.1158545 · Cited by 1,078 · see citing works
Self-citationAnalysis of survival by tumor response.
Anderson, J. R., & Davis, R. B. (1986) · Journal of Clinical Oncology · doi:10.1200/jco.1986.4.1.115 · Cited by 1,002 · see citing works
Topp, M., Kufer, P., Gokbuget, N., Goebeler, M., Klinger, M., Neumann, S., Horst, H., Raff, T., Viardot, A., Schmid, M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.32.7270 · Cited by 914 · see citing works
Self-citationFielding, A. K., Richards, S. M., Chopra, R., Lazarus, H. M., Litzow, M. R., Buck, G. A. N., Durrant, I. J., Luger, S. M., Marks, D. I., FRANKLIN, I. M., et al. (2006) · Blood · doi:10.1182/blood-2006-05-018192 · Cited by 841 · see citing works
Self-citationTopp, M. S., Gökbuget, N., Zugmaier, G., Klappers, P., Stelljes, M., Neumann, S., Viardot, A., Marks, R., Diedrich, H., Faul, C., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.56.3247 · Cited by 659 · see citing works
Self-citationGökbuget, N., Stanze, D., Beck, J., Diedrich, H., Horst, H., Hüttmann, A., Kobbe, G., Kreuzer, K., Leimer, L., Reichle, A., et al. (2012) · Blood · doi:10.1182/blood-2011-12-399287 · Cited by 470 · see citing works
Self-citationMantel, N., & Byar, D. P. (1974) · Journal of the American Statistical Association · doi:10.1080/01621459.1974.10480131 · Cited by 446 · see citing works
Kantarjian, H. M., Thomas, D. A., Jorgensen, J. L., Jabbour, E. J., Kebriaei, P., Rytting, M., York, S., Ravandi, F., Kwari, M. I., Faderl, S. H., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70386-2 · Cited by 411 · see citing works
Self-citationDreier, T., Lorenczewski, G., Brandl, C., Hoffmann, P., Syring, U., Hanakam, F., Kufer, P., Riethmüller, G., Bargou, R. C., & Baeuerle, P. A. (2002) · International Journal of Cancer · doi:10.1002/ijc.10557 · Cited by 348 · see citing works
Self-citationHoffmann, P., Hofmeister, R., Brischwein, K., Brandl, C., Crommer, S., Bargou, R., Itin, C., Prang, N., & Baeuerle, P. A. (2005) · International Journal of Cancer · doi:10.1002/ijc.20908 · Cited by 344 · see citing works
Self-citationBrüggemann, M., Schrauder, A., Raff, T., et al. (2009) · Leukemia · doi:10.1038/leu.2009.268 · Cited by 342 · see citing works
Self-citationKantarjian, H. M., Thomas, D. A., Jorgensen, J. L., Kebriaei, P., Jabbour, E. J., Rytting, M., York, S., Ravandi, F., Garris, R. E., Kwari, M. I., et al. (2013) · Cancer · doi:10.1002/cncr.28136 · Cited by 306 · see citing works
Self-citationOriol, A., Vives, S., Hernández‐Rivas, J. M., Tormo, M., Heras, I., Rivas, C., Bethencourt, C., Moscardó, F., Bueno, J., Grande, C., et al. (2010) · Haematologica · doi:10.3324/haematol.2009.014274 · Cited by 293 · see citing works
Self-citationTavernier, E., Boiron, J., Huguet, F., Bradstock, K. F., Vey, N., Kovacsovics, T. J., Delannoy, A., Fegueux, N., Fenaux, P., Stamatoullas, A., et al. (2007) · Leukemia · doi:10.1038/sj.leu.2404824 · Cited by 256 · see citing works
Self-citationRaff, T., Gökbuget, N., Lüschen, S., Reutzel, R., Ritgen, M., Irmer, S., Böttcher, S., Horst, H., Kneba, M., Hoelzer, D. F., et al. (2006) · Blood · doi:10.1182/blood-2006-07-037093 · Cited by 240 · see citing works
Self-citationRaponi, S., Propris, M. S. D., Intoppa, S., et al. (2011) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2011.559668 · Cited by 229 · see citing works
Campana, D., Janossy, G., Bofill, M., et al. (1985) · The Journal of Immunology · doi:10.4049/jimmunol.134.3.1524 · Cited by 184 · see citing works
Outcome of adults with acute lymphocytic leukemia after second salvage therapy
O'Brien, S. M., Thomas, D. M., Ravandi, F., Faderl, S. H., Cortes, J. E., Borthakur, G., Pierce, S. A., Garcia‐Manero, G., & Kantarjian, H. M. (2008) · Cancer · doi:10.1002/cncr.23919 · Cited by 150 · see citing works
Self-citationLöffler, A., Gruen, M., Wuchter, C., Schriever, F., Kufer, P., Dreier, T., Hanakam, F., Baeuerle, P. A., Bommert, K., Karawajew, L., et al. (2003) · Leukemia · doi:10.1038/sj.leu.2402890 · Cited by 150 · see citing works
Self-citationO'Brien, S. M., Thomas, D. A., Ravandi, F., et al. (2008) · Cancer · doi:10.1002/cncr.23819 · Cited by 132 · see citing works
Self-citationKantarjian, H. M., Thomas, D. A., Ravandi, F., Faderl, S. H., Jabbour, E. J., Garcia‐Manero, G., Pierce, S. A., Shan, J., Cortes, J. E., & O'Brien, S. M. (2010) · Cancer · doi:10.1002/cncr.25354 · Cited by 124 · see citing works
Self-citationBillips, L. G., Lassoued, K., Núnêz, C., Wang, J. O., Kubagawa, H., Gartland, G. L., Burrows, P. D., & Cooper, M. D. (1995) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1995.tb55798.x · Cited by 72 · see citing works
Topp, M. S., Goekbuget, N., Zugmaier, G., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.30.15_suppl.6500 · Cited by 18 · see citing works
Self-citationDavila, M. L., Rivière, I., Wang, X., et al. (2013) · Blood · doi:10.1182/blood.v122.21.69.69 · Cited by 9 · see citing works
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Cited by
Sorted by citations
Fajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196 · see citing works
Top 10 Challenges in Cancer Immunotherapy
Hegde, P. S., & Chen, D. S. (2020) · Immunity · doi:10.1016/j.immuni.2019.12.011 · Cited by 2,238 · see citing works
Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma
Locke, F. L., Miklos, D. B., Jacobson, C. A., Perales, M.-A., Kersten, M.-J., Oluwole, O. O., Ghobadi, A., Rapoport, A. P., McGuirk, J., Pagel, J. M., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2116133 · Cited by 1,607 · see citing works
Norelli, M., Camisa, B., Barbiera, G., Falcone, L., Purevdorj, A., Genua, M., Sanvito, F., Ponzoni, M., Doglioni, C., Cristofori, P., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0036-4 · Cited by 1,406 · see citing works
Gust, J., Hay, K. A., Hanafi, L.-A., Li, D., Myerson, D., Gonzalez-Cuyar, L. F., Yeung, C., Liles, W. C., Wurfel, M., Lopez, J. A., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0698 · Cited by 1,400 · see citing works
Bispecific antibodies: a mechanistic review of the pipeline
Labrijn, A. F., Janmaat, M. L., Reichert, J. M., & Parren, P. W. H. I. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0028-1 · Cited by 1,303 · see citing works
Targeting neoantigens to augment antitumour immunity
Yarchoan, M., Johnson, B. A., Lutz, E. R., Laheru, D. A., & Jaffee, E. M. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2016.154 · Cited by 997 · see citing works
The immune system and cancer evasion strategies: therapeutic concepts
Muenst, S., Läubli, H., Soysal, S. D., Zippelius, A., Tzankov, A., & Hoeller, S. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12470 · Cited by 304 · see citing works
Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia
Frey, N. V., & Porter, D. L. (2016) · Hematology · doi:10.1182/asheducation-2016.1.567 · Cited by 222 · see citing works
Mandikian, D., Takahashi, N., Lo, A. A., Li, J., Eastham-Anderson, J., Slaga, D., Ho, J., Hristopoulos, M., Clark, R., Totpal, K., et al. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0657 · Cited by 155 · see citing works
Cytokine and Chemokine Signals of T‐Cell Exclusion in Tumors
Zhang, Y., Guan, X.-Y., & Jiang, P. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.594609 · Cited by 133 · see citing works
Treatment options for triple-class refractory multiple myeloma.
Mikhael, J. (2020) · Clinical Lymphoma Myeloma and Leukemia · doi:10.1016/j.clml.2019.09.621 · Cited by 126 · see citing works
Neurological sequelae of cancer immunotherapies and targeted therapies
Wick, W., Hertenstein, A., & Platten, M. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30571-x · Cited by 87 · see citing works
Haematological malignancies: at the forefront of immunotherapeutic innovation
Bachireddy, P., Burkhardt, U. E., Rajasagi, M., & Wu, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3907 · Cited by 85 · see citing works
Global survey of the immunomodulatory potential of common drugs
Vladimer, G. I., Snijder, B., Krall, N., Bigenzahn, J. W., Huber, K. V. M., Lardeau, C.-H., Sanjiv, K., Ringler, A., Berglund, U. W., Sabler, M., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2360 · Cited by 87 · see citing works
Clinical Pharmacology and Translational Aspects of Bispecific Antibodies
Trivedi, A., Stienen, S., Zhu, M., Li, H., Yuraszeck, T., Gibbs, J., Heath, T., Loberg, R., & Kasichayanula, S. (2017) · Clinical and Translational Science · doi:10.1111/cts.12459 · Cited by 76 · see citing works
- Authors
- Topp, M. S., Gökbuget, N., Stein, A. S., Zugmaier, G., O'Brien, S., Bargou, R. C., Dombret, H., Fielding, A. K., Heffner, L., Larson, R. A., Neumann, S., Foà, R., Litzow, M., Ribera, J.-M., Rambaldi, A., Schiller, G., Brüggemann, M., Horst, H. A., Holland, C., Jia, C., Maniar, T., Huber, B., Nagorsen, D., Forman, S. J., & Kantarjian, H. M.
- Affiliations
- University of Würzburg (DE)
- Goethe University Frankfurt (DE)
- City Of Hope National Medical Center (US)
- Amgen (Germany) (DE)
- The University of Texas MD Anderson Cancer Center (US)
- Comprehensive Cancer Center Mainfranken (DE)
- Hôpital Saint-Louis (FR)
- University College London (GB)
- Emory University (US)
- University of Chicago (US)
- Sapienza University of Rome (IT)
- Mayo Clinic (US)
- Ospedale Papa Giovanni XXIII (IT)
- University of California, Los Angeles (US)
- University Hospital Schleswig-Holstein (DE)
- Amgen (United States) (US)
- Corresponding author
- Topp, Max S
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 16
- Issue
- 1
- Pages
- 57-66
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2107925822
- Cited by
- 1,269
- References
- 29
- Citations by year
- 2026: 53 · 2025: 75 · 2024: 93 · 2023: 106 · 2022: 93 · 2021: 115 · 2020: 117 · 2019: 120 · 2018: 96 · 2017: 163 · 2016: 143 · 2015: 88 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 129.35
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-04-01)
- Open access
- closed
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Amgen
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- blinatumomab, CD19, bispecific T-cell engagers, complete remission, allogeneic hematopoietic stem cell transplantation, febrile neutropenia, cytokine release syndrome, neurotoxicity
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Antineoplastic Agents, Drug Administration Schedule, Europe, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Recurrence, Remission Induction, Time Factors, United States, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Salvage Therapy, Treatment Outcome, Antibodies, Bispecific, Hematopoietic Stem Cell Transplantation, Disease-Free Survival, Drug Resistance, Neoplasm, Kaplan-Meier Estimate, Young Adult, Intention to Treat Analysis
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