The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index.
Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity
Open accessAbstract
Background Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles.Methods In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809.Findings 55 patients were enrolled (median age 59 years, IQR 51-67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40-218).Interpretation Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study.Funding Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“Drugs with single or limited targets, such as Nutlin3a (an MDM2 inhibitor) or navitoclax (a BCL-2 inhibitor), can have off-target apoptotic effects on multiple non-Snc types, such as neutrophils and platelets in the case of navitoclax (75), making them panolytic.”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [75]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“N can cause thrombocytopenia and neutropenia, even after brief exposures57,88–91”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [89]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“these agents exhibited notable drawbacks, such as dose-dependent thrombocytopenia, variable therapeutic efficacy, and the emergence of resistance mechanisms.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [33]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Trials assessing navitoclax as an anticancer agent report neutropenia and thrombocytopenia (Wilson et al. 2010).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Wilson et al. 2010
In the citing paper
“However, chronic administration of at least some senolytics in humans can be associated with toxic side effects (Kaefer et al., 2014; Wilson et al., 2010) which may be due to off-target killing of non-senescent cells.”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Wilson et al., 2010
In the citing paper
“In oncology trials, 44–50% of patients experienced grade 3 or 4 thrombocytopenia33,34.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [33]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1992) · Springer series in statistics · doi:10.1007/978-1-4612-4380-9_25 · Cited by 45,239
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1958) · Journal of the American Statistical Association · doi:10.1080/01621459.1958.10501452 · Cited by 39,158
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues
Swerdlow, S. H. (2017) · Medical Entomology and Zoology · Cited by 12,933
Danial, N. N., & Korsmeyer, S. J. (2004) · Cell · doi:10.1016/s0092-8674(04)00046-7 · Cited by 4,651
Hallek, M. J., Cheson, B. D., Catovsky, D., Caligaris‐Cappio, F., Dighiero, G., Döhner, H., Hillmen, P., Keating, M. J., Montserrat, E., Rai, K. R., et al. (2008) · Blood · doi:10.1182/blood-2007-06-093906 · Cited by 3,782
Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death
Hockenbery, D., Nuñez, G., Milliman, C., Schreiber, R. D., & Korsmeyer, S. J. (1990) · Nature · doi:10.1038/348334a0 · Cited by 3,720
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Oltersdorf, T., Elmore, S. W., Shoemaker, A. R., Armstrong, R. C., Augeri, D. J., Belli, B., Bruncko, M., Deckwerth, T. L., Dinges, J., Hajduk, P. J., et al. (2005) · Nature · doi:10.1038/nature03579 · Cited by 3,407
Self-citationCheson, B. D., Horning, S., Coiffier, B., Shipp, M., Fisher, R. I., Connors, J. M., Lister, T., Vose, J., Grillo-López, A., Hagenbeek, A., et al. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.4.1244 · Cited by 3,210
A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic Leukemia
Calin, G. A., Ferracin, M., Cimmino, A., Leva, G. D., Shimizu, M., Wojcik, S. E., Iorio, M. V., Visone, R., Sever, N. İ., Fabbri, M., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050995 · Cited by 2,415
ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
Tse, C., Shoemaker, A. R., Adickes, J., Anderson, M. G., Chen, J., Jin, S., Johnson, E. F., Marsh, K. C., Mitten, M. J., Nimmer, P., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5836 · Cited by 1,992
Self-citationTsujimoto, Y., Finger, L. R., Yunis, J. J., Nowell̀, P. C., & Croce, C. M. (1984) · Science · doi:10.1126/science.6093263 · Cited by 1,769
Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma
Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., Kohlhammer, H., Lamy, L., Zhao, H., Yang, Y., et al. (2010) · Nature · doi:10.1038/nature08638 · Cited by 1,651
Self-citationApoptosis: Mechanisms and Roles in Pathology
Arends, M. J., & Wyllie, A. H. (1991) · International review of experimental pathology · doi:10.1016/b978-0-12-364932-4.50010-1 · Cited by 1,334
Reed, J. C. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64779-7 · Cited by 1,307
McDonnell, T. J., Deane, N., Platt, F. M., Nunez, G., Jaeger, U., McKearn, J. P., & Korsmeyer, S. J. (1989) · Cell · doi:10.1016/0092-8674(89)90174-8 · Cited by 1,213
Programmed Anuclear Cell Death Delimits Platelet Life Span
Mason, K. D., Carpinelli, M. R., Fletcher, J. I., Collinge, J. E., Hilton, A. A., Ellis, S., Kelly, P. N., Ekert, P. G., Metcalf, D., Roberts, A. W., et al. (2007) · Cell · doi:10.1016/j.cell.2007.01.037 · Cited by 1,031
Tsujimoto, Y., Gorham, J. D., Cossman, J., Jaffe, E. S., & Croce, C. M. (1985) · Science · doi:10.1126/science.3929382 · Cited by 990
Nguyen, M., Marcellus, R. C., Roulston, A., Watson, M., Serfass, L., Madiraju, S. R. M., Goulet, D., Viallet, J., Bélec, L., Billot, X., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709443104 · Cited by 671
miR-15a and miR-16-1 in cancer: discovery, function and future perspectives
Aqeilan, R. I., Calin, G. A., & Croce, C. M. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.69 · Cited by 657
Moore, V. D. G., Brown, J. R., Certo, M. V., Love, T. M., Novina, C. D., & Letai, A. G. (2007) · Journal of Clinical Investigation · doi:10.1172/jci28281 · Cited by 617
Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL
Degterev, A., Lugovskoy, A. A., Cardone, M. H., Mulley, B., Wagner, G., Mitchison, T. J., & Yuan, J. (2001) · Nature Cell Biology · doi:10.1038/35055085 · Cited by 550
Deng, J., Carlson, N. E., Takeyama, K., Cin, P. D., Shipp, M. A., & Letai, A. G. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.07.001 · Cited by 528
Gascoyne, R. D., Adomat, S. A., Krajewski, S., Krajewska, M., Horsman, D. E., Tolcher, A. W., O’Reilly, S. E., Hoskins, P. J., Coldman, A. J., Reed, J. C., et al. (1997) · Blood · doi:10.1182/blood.v90.1.244 · Cited by 508
Waters, J. S., Webb, A., Cunningham, D., Clarke, P. A., Raynaud, F. I., Stefano, F. D., & Cotter, F. E. (2000) · Journal of Clinical Oncology · doi:10.1200/jco.2000.18.9.1812 · Cited by 454
Bcl-2 family proteins are essential for platelet survival
Zhang, H., Nimmer, P. M., Tahir, S. K., Chen, J., Fryer, R. M., Hahn, K. R., Iciek, L. A., Morgan, S. J., Nasarre, M. C., Nelson, R., et al. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402081 · Cited by 427
Self-citationKitada, S., Leone, M., Sareth, S., Zhai, D., Reed, J. C., & Pellecchia, M. (2003) · Journal of Medicinal Chemistry · doi:10.1021/jm030190z · Cited by 382
Mitochondria--the Death Signal Integrators
Brenner, C., & Kroemer, G. (2000) · Science · doi:10.1126/science.289.5482.1150 · Cited by 361
Akbar, A. N., Borthwick, N., Salmon, M., Gombert, W. M., Bofill, M., Shamsadeen, N., Pilling, D., Pett, S. L., Grundy, J. E., & Janossy, G. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.178.2.427 · Cited by 336
Vogler, M., Butterworth, M., Majid, A., Walewska, R. J., Sun, X.-M., Dyer, M. J. S., & Cohen, G. M. (2008) · Blood · doi:10.1182/blood-2008-08-173310 · Cited by 324
Developmental regulation of the Bcl‐2 protein and susceptibility to cell death in B lymphocytes.
Merino, R., Ding, L.-Y., Novack, D. V., Korsmeyer, S. J., & Núñez, G. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06307.x · Cited by 302
Iqbal, J., Sanger, W. G., Horsman, D. E., Rosenwald, A., Pickering, D. L., Davé, B. J., Davé, S. S., Li, X., Cao, K., Zhu, Q., et al. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63284-1 · Cited by 279
O'Brien, S. M., Claxton, D. F., Crump, M., Faderl, S. H., Kipps, T. J., Keating, M. J., Viallet, J., & Cheson, B. D. (2008) · Blood · doi:10.1182/blood-2008-02-137943 · Cited by 274
Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins
Chipuk, J. E., Fisher, J. C., Dillon, C. P., Kriwacki, R. W., Kuwana, T., & Green, D. R. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808036105 · Cited by 245
Wilson, W. H., Teruya‐Feldstein, J., Fest, T., Harris, C. A., Steinberg, S. M., Jaffe, E. S., & Raffeld, M. A. (1997) · Blood · doi:10.1182/blood.v89.2.601 · Cited by 221
Self-citationDifferent forms of cell death induced by putative BCL2 inhibitors
Vogler, M., Weber, K., Dinsdale, D. D., Schmitz, I., Schulze‐Osthoff, K., Dyer, M. J. S., & Cohen, G. M. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.48 · Cited by 203
Liu, G., Kelly, W. K., Wilding, G., Leopold, L. H., Brill, K. J., & Somer, B. G. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2985 · Cited by 181
Villunger, A., Scott, C. L., Bouillet, P., & Strasser, A. (2003) · Blood · doi:10.1182/blood-2002-07-2132 · Cited by 158
Hwang, J. J., Kuruvilla, J., Mendelson, D., Pishvaian, M. J., Deeken, J. F., Siu, L. L., Berger, M. S., Viallet, J., & Marshall, J. L. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-0822 · Cited by 109
Klasa, R. J., Bally, M. B., Ng, R. A., Goldie, J. H., Gascoyne, R. D., & Wong, F. M. (2000) · PubMed · Cited by 107
Kondo, E., Nakamura, S., Onoue, H., Matsuo, Y., Yoshino, T., Aoki, H., Hayashi, K., Takahashi, K., Minowada, J., & Nomura, S. (1992) · Blood · doi:10.1182/blood.v80.8.2044.2044 · Cited by 98
Apoptosis mechanisms: implications for cancer drug discovery.
Reed, J. C. (2004) · PubMed · Cited by 76
Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR
Petros, A. M., Huth, J. R., Oost, T. K., Park, C., Ding, H., Wang, X., Zhang, H., Nimmer, P. M., Mendoza, R. R., Sun, C. C., et al. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.09.033 · Cited by 73
Self-citationFragment-Based Design of Small Molecule X-Linked Inhibitor of Apoptosis Protein Inhibitors
Huang, J., Zhang, Z., Wu, B., Cellitti, J. F., Zhang, X., Dahl, R. S., Shiau, C., Welsh, K., Emdadi, A., Stebbins, J. L., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm8006992 · Cited by 56
Saikumar, P., & Venkatachalam, M. A. (2009) · Molecular pathology library · doi:10.1007/978-0-387-89626-7_4 · Cited by 17
Reed, J. C. (2008) · Oncogene · doi:10.1038/onc.2008.296 · Cited by 4
Cited by
Sorted by citations
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Souers, A. J., Leverson, J. D., Boghaert, E. R., Ackler, S. L., Catron, N. D., Chen, J., Dayton, B. D., Ding, H., Enschede, S. H., Fairbrother, W. J., et al. (2013) · Nature Medicine · doi:10.1038/nm.3048 · Cited by 3,058
Self-citationTargeting apoptosis in cancer therapy
Carneiro, B. A., & El‐Deiry, W. S. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0341-y · Cited by 2,676
Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia
Roberts, A. W., Davids, M. S., Pagel, J. M., Kahl, B. S., Puvvada, S. D., Gerecitano, J. F., Kipps, T. J., Anderson, M. A., Brown, J. R., Gressick, L. A., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1513257 · Cited by 1,930
“No chromosome 17p or 11q deletion 16/49 (33) 27/53 (51) 43/102 (42)”
Self-citationCellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270
Senolytic drugs: from discovery to translation
Kirkland, J. L., & Tchkonia, T. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13141 · Cited by 1,227
Metadata
- Authors
- Wilson, W. H., O'Connor, O. A., Czuczman, M. S., LaCasce, A. S., Gerecitano, J. F., Leonard, J. P., Tulpule, A., Dunleavy, K., Xiong, H., Chiu, Y.-L., Cui, Y., Busman, T., Elmore, S. W., Rosenberg, S. H., Krivoshik, A. P., Enschede, S. H., & Humerickhouse, R. A.
- Affiliations
- National Institutes of Health (US)
- Roswell Park Comprehensive Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- University of Southern California (US)
- Abbott (United States) (US)
- Corresponding author
- Wilson, Wyndham H
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 11
- Issue
- 12
- Pages
- 1149-1159
- ISSN
- 1470-2045 (ISSN-L)
- PMC
- PMC3025495
- OpenAlex
- W2150680216
- Cited by
- 876
- References
- 47
- Citations by year
- 2026: 44 · 2025: 58 · 2024: 66 · 2023: 49 · 2022: 66 · 2021: 69 · 2020: 70 · 2019: 43 · 2018: 42 · 2017: 53 · 2016: 52 · 2015: 63 · 2014: 60 · 2013: 55 · 2012: 50
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Abbott Fund
- Abbott Laboratories
- National Institutes of Health
- National Cancer Institute (ZIABC010716)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Keywords
- navitoclax, BCL-2 inhibitor, Bcl-xL, lymphoid malignancies, relapsed/refractory lymphoma, dose-limiting toxicity, thrombocytopenia, neutropenia, anemia, pharmacokinetics, pharmacodynamics, T cell proliferation, platelet function, antitumour activity, intermittent dosing
- MeSH terms
- Aged, Aniline Compounds, Antineoplastic Agents, Blood Platelets, Dosage Forms, Humans, Lymphoma, Middle Aged, Sulfonamides, T-Lymphocytes, Survival Analysis, Drug Delivery Systems, Proto-Oncogene Proteins c-bcl-2, Maximum Tolerated Dose
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
