Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia
Open accessAbstract
Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome–positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL–mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).
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
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?
Prior oncology research shows dasatinib can exhibit CNS efficacy at low or subnanomolar concentrations.
“prior research in oncology has shown that the medication can exhibit CNS efficacy at low or even subnanomolar concentrations36,39.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [36]
The Discussion links dasatinib’s low or subnanomolar activity to its potential CNS antitumor effect, and Experiment 3 reports an in-vitro proliferation IC50 of 0.5 nM. But the paper does not demonstrate CNS efficacy at subnanomolar concentrations: it reports patient CSF concentrations of 1.4–20.1 nM and mouse brain concentrations of 10–100 nM in the cited experiments. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn patients with CML or ALL treated with dasatinib, HPLC/MS studies of CSF have reported low concentrations and high inter-individual variability.
“However, HPLC/MS studies conducted in CSF taken from D-treated individuals with CML or ALL have reported low CSF concentrations and high variability across individuals36,37.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [36]
Experimental — accuracy not yet measuredIn preclinical studies, dasatinib prevented intracranial tumor growth, stabilized and regressed CNS disease, indicating CNS action.
“In preclinical studies, D prevented intracranial tumor growth, stabilized and regressed CNS disease indicating its action in the CNS36, suggesting a CNS treatment effect.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [36]
In mice, oral dasatinib reaches brain homogenate concentrations 12- to 31-fold lower than plasma.
“Following oral ingestion of D in mice, a prior study reported D in brain homogenates using HPLC/MS at concentrations that were 12- to 31-fold lower than in plasma36.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [36]
Dasatinib reaches peak plasma concentrations within two hours after administration in humans.
“In plasma, D has been shown to reach peak concentrations within 2 h of administration36”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [36]
The ‘Dasatinib concentrations in CSF’ section describes patient samples collected about three hours after dosing, but does not establish when plasma concentrations peaked. The plasma pharmacokinetic measurements described elsewhere are from mice. A search for human peak plasma concentration or time to peak found no supporting passage in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Both dasatinib and quercetin penetrate the blood-brain barrier in rodent models, with some supportive data from cancer patients.
“Both D and Q have demonstrated blood-brain barrier penetrance in rodent models with some supportive data in clinical studies of individuals undergoing cancer treatment (41, 42).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [41]
In preclinical studies and clinical trials of other age-related conditions, D+Q showed an encouraging safety profile and modest but promising therapeutic outcomes.
“Our pilot study evaluating a novel therapeutic agent for AD is a direct follow-up to the preclinical studies and clinical trials utilizing D+Q for other age-related conditions, which demonstrated an encouraging safety profile coupled with modest but promising therapeutic outcomes (18, 34, 40–42).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [41]
Dasatinib and/or quercetin can cross the blood-brain barrier in rodent models and in cancer patients.
“While it has been shown that D and/or Q can cross the blood barrier in rodent models and individuals undergoing cancer treatment, the central nervous system drug penetrance in individuals with AD remains unknown (41, 42).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [41]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
Shah, N. P., Tran, C., Lee, F. Y., Chen, P., Norris, D. J., & Sawyers, C. L. (2004) · Science · doi:10.1126/science.1099480 · Cited by 1,785 · see citing works
Self-citationMellor, D. H. (1981) · Cited by 1,699 · see citing works
Gabert, J. A., Beillard, E. J., van der Velden, V. H. J., Bi, W., Grimwade, D. J., Pallisgaard, N., Barbany, G., Cazzaniga, G., Cayuela, J., Cavé, H., et al. (2003) · Leukemia · doi:10.1038/sj.leu.2403135 · Cited by 1,515 · see citing works
Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML
Jamieson, C. H. M., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., Gotlib, J., Li, K., Manz, M. G., Keating, A., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040258 · Cited by 1,485 · see citing works
Lombardo, L. J., Lee, F. Y., Chen, P., Norris, D. J., Barrish, J. C., Behnia, K., Castaneda, S., Cornelius, L. A. M., Das, J., Doweyko, A. M., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm049486a · Cited by 1,303 · see citing works
Self-citationO'Hare, T., Walters, D. K., Stoffregen, E. P., Jia, T., Manley, P. W., Mestan, J., Cowan-Jacob, S. W., Lee, F. Y., Heinrich, M. C., Deininger, M. W. N., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0259 · Cited by 1,036 · see citing works
Self-citationDonato, N. J., Wu, J. Y., Stapley, J., Gallick, G. E., Lin, H., Arlinghaus, R. B., & Talpaz, M. (2002) · Blood · doi:10.1182/blood.v101.2.690 · Cited by 663 · see citing works
Branford, S., Rudzki, Z., Walsh, S., Grigg, A., Arthur, C., Taylor, K. M., Herrmann, R., Lynch, K., & Hughes, T. P. (2002) · Blood · doi:10.1182/blood.v99.9.3472 · Cited by 649 · see citing works
Hochhaus, A., Kantarjian, H. M., Baccarani, M., Lipton, J. H., Apperley, J. F., Druker, B. J., Facon, T. T. F., Goldberg, S. L., Cervantes, F., Niederwieser, D. W., et al. (2006) · Blood · doi:10.1182/blood-2006-09-047266 · Cited by 601 · see citing works
Requirement for CD44 in homing and engraftment of BCR-ABL–expressing leukemic stem cells
Krause, D. S., Lazarides, K., von Andrian, U. H., & Etten, R. A. V. (2006) · Nature Medicine · doi:10.1038/nm1489 · Cited by 415 · see citing works
Cortes, J. E., Rousselot, P. H., Kim, D., Ritchie, E. K., Hamerschlak, N., Coutre, S. E., Hochhaus, A., Guilhot, F., Saglio, G. N., Apperley, J. F., et al. (2006) · Blood · doi:10.1182/blood-2006-09-046888 · Cited by 409 · see citing works
Kantarjian, H. M., Pasqüini, R., Hamerschlak, N., Rousselot, P. H., Hołowiecki, J., Jootar, S., Robak, T., Khoroshko, N. D., Masszi, T., Skotnicki, A. B., et al. (2007) · Blood · doi:10.1182/blood-2006-11-056028 · Cited by 376 · see citing works
Guilhot, F., Apperley, J. F., Kim, D., Bullorsky, E. O., Baccarani, M., Roboz, G. J., Amadori, S., Souza, C. A. D., Lipton, J. H., Hochhaus, A., et al. (2007) · Blood · doi:10.1182/blood-2006-09-046839 · Cited by 365 · see citing works
Ottmann, O. G., Dombret, H., Martinelli, G., Simonsson, B., Guilhot, F., Larson, R. A., Rege‐Cambrin, G., Radich, J. P., Hochhaus, A., Apanovitch, A. M., et al. (2007) · Blood · doi:10.1182/blood-2007-02-073528 · Cited by 365 · see citing works
Self-citationDistinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia
Castor, A., Nilsson, L., Åstrand‐Grundström, I., Buitenhuis, M., Ramirez, C., Anderson, K., Strömbeck, B., Garwicz, S., Békássy, A. N., Schmiegelow, K., et al. (2005) · Nature Medicine · doi:10.1038/nm1253 · Cited by 334 · see citing works
Porkka, K., Laakkonen, P. M., Hoffman, J. A., Bernasconi, M., & Ruoslahti, E. I. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.062189599 · Cited by 292 · see citing works
Self-citationDistribution of STI-571 to the Brain Is Limited by P-Glycoprotein-Mediated Efflux
Dai, H. I., Marbach, P., Lemaire, M., Hayes, M., & Elmquist, W. F. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.045260 · Cited by 274 · see citing works
Dai, Y., Rahmani, M., Corey, S. J., Dent, P., & Grant, S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402290200 · Cited by 237 · see citing works
Ptasznik, A., Nakata, Y., Kalota, A., Emerson, S. G., & Gewirtz, A. M. (2004) · Nature Medicine · doi:10.1038/nm1127 · Cited by 229 · see citing works
Burger, J. A., & Bürkle, A. (2007) · British Journal of Haematology · doi:10.1111/j.1365-2141.2007.06590.x · Cited by 161 · see citing works
Takayama, N., Sato, N., O’Brien, S. G., Ikeda, Y., & Okamoto, S. (2002) · British Journal of Haematology · doi:10.1046/j.1365-2141.2002.03881.x · Cited by 152 · see citing works
Winkler, K., Bielack, S., Delling, G., Salzer-Kuntschik, M., Kotz, R. I., Greenshaw, C., Jürgens, H., Ritter, J., Kusnierz-Glaz, C. R., Erttmann, R., et al. (1990) · Cancer · doi:10.1002/1097-0142(19901015)66:8 · Cited by 145 · see citing works
Soverini, S., Martinelli, G., Amabile, M., et al. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2004.031112 · Cited by 121 · see citing works
Leis, J. F., Stepan, D. E., Curtin, P. T., et al. (2003) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190310001625728 · Cited by 117 · see citing works
Wolff, N. C., Richardson, J. A., Egorin, M. J., & Ilaria, R. L. (2003) · Blood · doi:10.1182/blood-2002-10-3059 · Cited by 111 · see citing works
Pfeifer, H., Waßmann, B., Hofmann, W., et al. (2003) · PubMed · Cited by 107 · see citing works
Slevin, M. L., Piall, E. M., Aherne, G. W., et al. (1982) · Medical and Pediatric Oncology · doi:10.1002/mpo.2950100715 · Cited by 68 · see citing works
Central Nervous System Involvement in Adult Acute Lymphocytic Leukemia
Cortes, J. E. (2001) · Hematology/Oncology Clinics of North America · doi:10.1016/s0889-8588(05)70203-3 · Cited by 62 · see citing works
Bujassoum, S. M., Rifkind, J., & Lipton, J. H. (2003) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190310001593184 · Cited by 54 · see citing works
Bornhäuser, M., Jenke, A., Freiberg‐Richter, J., et al. (2004) · Annals of Hematology · doi:10.1007/s00277-003-0829-4 · Cited by 53 · see citing works
Matsuda, M., Morita, Y., Shimada, T., et al. (2005) · International Journal of Hematology · doi:10.1532/ijh97.04188 · Cited by 38 · see citing works
Gleevec does not cross blood–brain barrier
Senior, K. (2003) · The Lancet Oncology · doi:10.1016/s1470-2045(03)01050-7 · Cited by 36 · see citing works
Abdelhalim, A., Barcos, M. P., Block, A. W., et al. (2007) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190701258370 · Cited by 22 · see citing works
Lee, F. Y., Wen, M.-L., Bhide, R. S., et al. (2005) · Blood · doi:10.1182/blood.v106.11.1994.1994 · Cited by 18 · see citing works
Self-citationMeningeal carcinomatosis in small cell carcinoma of the lung
Oster, M. W., & Fetell, M. R. (1982) · Medical and Pediatric Oncology · doi:10.1002/mpo.2950100207 · Cited by 15 · see citing works
p53 gene mutations and 17p allelic deletions in hepatocellular carcinoma from Japan
Nose, H., Imazeki, F., Ohto, M., & Omata, M. (1993) · Cancer · doi:10.1002/1097-0142(19930715)72:2
Flagged first, then by citations
Research works printed but not linked: 2
- [19]19. Odom LF, Wilson H, Cullen J, Bank J, Blake M, Jamieson B. Significance of blasts in low-cell- count cerebrospinal fluid specimens from children with acute lymphoblastic leukemia. Cancer. 1990; 66:1748-1754.
- [29]29. Morra E, Lazzarino M, Brusamolino E, et al. The role of systemic high-dose cytarabine in the treat- ment of central nervous system leukemia: clinical results in 46 patients. Cancer. 1993;72:439-445.
Cited by
Sorted by citations
Ogrodnik, M., Evans, S. A., Fielder, E., Victorelli, S., Kruger, P., Salmonowicz, H., Weigand, B. M., Patel, A. D., Pirtskhalava, T., Inman, C. L., et al. (2021) · Aging Cell · doi:10.1111/acel.13296 · Cited by 405 · see citing works
The Role of Src in Solid Tumors
Wheeler, D. L., Iida, M., & Dunn, E. F. (2009) · The Oncologist · doi:10.1634/theoncologist.2009-0009 · Cited by 346 · see citing works
Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial
Gonzales, M. M., Garbarino, V. R., Kautz, T. F., Palavicini, J. P., Lopez-Cruzan, M., Dehkordi, S. K., Mathews, J. J., Zare, H., Xu, P., Zhang, B., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02543-w · Cited by 310 · see citing works
Gonzales, M. M., Garbarino, V. R., Marques Zilli, E., Petersen, R. C., Kirkland, J. L., Tchkonia, T., Musi, N., Seshadri, S., Craft, S., & Orr, M. E. (2022) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2021.62 · Cited by 203 · see citing works
CCL2 disrupts the adherens junction: implications for neuroinflammation
Roberts, T. K., Eugenin, E. A., Lopez, L., Romero, I. A., Weksler, B. B., Couraud, P.-O., & Berman, J. W. (2012) · Laboratory Investigation · doi:10.1038/labinvest.2012.80 · Cited by 115 · see citing works
De Simone, A., Tumiatti, V., Andrisano, V., & Milelli, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00931 · Cited by 110 · see citing works
Chiaretti, S., Vitale, A., Vignetti, M., Piciocchi, A., Fazi, P., Elia, L., Falini, B., Ronco, F., Ferrara, F., De Fabritiis, P., et al. (2016) · Haematologica · doi:10.3324/haematol.2016.144535 · Cited by 98 · see citing works
Clinical Pharmacokinetics and Pharmacodynamics of Dasatinib
Levêque, D., Becker, G., Bilger, K., & Natarajan-Amé, S. (2020) · Clinical Pharmacokinetics · doi:10.1007/s40262-020-00872-4 · Cited by 90 · see citing works
Lindauer, M., & Hochhaus, A. (2010) · Recent Results in Cancer Research · doi:10.1007/978-3-642-01222-8_7 · Cited by 57 · see citing works
Gong, X., Li, L., Wei, H., Liu, B., Zhou, C., Zhang, G., Liu, K., Lin, D., Gong, B., Wei, S., et al. (2021) · Clinical Therapeutics · doi:10.1016/j.clinthera.2021.05.009 · Cited by 28 · see citing works
- Authors
- Porkka, K., Koskenvesa, P., Lundán, T., Rimpiläinen, J., Mustjoki, S., Smykla, R., Wild, R., Luo, R., Arnan, M., Brethon, B., Eccersley, L., Hjorth-Hansen, H., Höglund, M., Klamova, H., Knutsen, H., Parikh, S., Raffoux, E., Gruber, F., Brito-Babapulle, F., Dombret, H., Duarte, R. F., Elonen, E., Paquette, R., Zwaan, C. M., & Lee, F. Y. F.
- Affiliations
- Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland;
- Helsinki University Hospital (FI)
- North Karelia Central Hospital (FI)
- Bristol-Myers Squibb (United States) (US)
- OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, CO;
- ICO-Hospital Duran i Reynals, Barcelona, Spain;
- Hôpital Saint-Louis, Pediatric Hematology, Paris, France;
- Ealing Hospital (GB)
- Department of Hematology, St Olavs Hospital and Department of Molecular Medicine and Cancer Research, Norwegian University of Science and Technology, Trondheim, Norway;
- Uppsala University Hospital (SE)
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic;
- Akershus University Hospital (NO)
- Duke Medical Center (US)
- Hôpital Saint-Louis (FR)
- UiT The Arctic University of Norway (NO)
- Ealing Hospital, Southall, United Kingdom;
- Duran i Reynals Hospital (ES)
- Departments of Clinical Chemistry and Medicine/Hematology, and
- University of California, Los Angeles (US)
- Erasmus MC (NL)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-08-15
- Volume
- 112
- Issue
- 4
- Pages
- 1005-1012
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2064831267
- Cited by
- 445
- References
- 36
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 27 · 2023: 26 · 2022: 27 · 2021: 28 · 2020: 22 · 2019: 23 · 2018: 17 · 2017: 26 · 2016: 22 · 2015: 22 · 2014: 19 · 2013: 21 · 2012: 24
- FWCI
- 21.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Funders
- Bristol-Myers Squibb
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- dasatinib, blood-brain barrier penetration, central nervous system leukemia, Philadelphia chromosome-positive leukemia, BCR-ABL tyrosine kinase inhibitors, imatinib, intracranial relapse, dasatinib resistance, Src kinase inhibition, pediatric leukemia
- MeSH terms
- Dasatinib, Adolescent, Adult, Aged, Animals, Blood-Brain Barrier, Child, Disease Models, Animal, Drug Evaluation, Preclinical, Female, Humans, Male, Middle Aged, Pyrimidines, Remission Induction, Spinal Puncture, Thiazoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Survival Rate, Central Nervous System Neoplasms, Treatment Outcome, Drug Monitoring, Cytogenetic Analysis, Tumor Burden, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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
