Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies
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Purpose: Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and Methods: Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results: Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion: Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.
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Ibrutinib's rapid clearance could enable kinase selectivity by maintaining BTK engagement while minimizing reversible off-target inhibition.
“The rapid clearance of ibrutinib (which has a half-life of 2–3 h) could also enable kinase selectivity; ibrutinib should maintain activity against BTK owing to prolonged covalent engagement, while the reversible inhibition of off-targets is minimized65.”
From Advances in covalent drug discovery (2022) · cites this paper as [65]
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BackgroundIbrutinib‐associated bleeding: pathogenesis, management and risk reduction strategies
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Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology
Verheijen, R. B., Yu, H., Schellens, J. H. M., Beijnen, J. H., Steeghs, N., & Huitema, A. D. R. (2017) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.787 · Cited by 279 · see citing works
Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer
Varughese, T., Taur, Y., Cohen, N., Palomba, M. L., Seo, S. K., Hohl, T. M., & Redelman-Sidi, G. (2018) · Clinical Infectious Diseases · doi:10.1093/cid/ciy175 · Cited by 271 · see citing works
“Ibrutinib was approved by the US Food and Drug Administration for the treatment of patients with CLL, previously treated mantle cell lymphoma (MCL) or marginal zone lymphoma, WM, or refractory chronic graft-versus-host disease, and by the European Medicines Agency for the treatment of patients with CLL, WM, or previou…”
MethodCheah, C. Y., Seymour, J. F., & Wang, M. L. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.63.5904 · Cited by 269 · see citing works
Walter, H. S., Rule, S. A., Dyer, M. J. S., Karlin, L., Jones, C. H., Cazin, B., Quittet, P., Shah, N., Hutchinson, C. V., Honda, H., et al. (2015) · Blood · doi:10.1182/blood-2015-08-664086 · Cited by 270 · see citing works
“Anemia 4 (14) 13 (21) 3 (11) 9 (15) 29 (32)”
InfluentialComparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects
Estupiñan, H. Y., Berglöf, A., Zain, R., & Smith, C. I. E. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.630942 · Cited by 272 · see citing works
“Ibrutinib (Imbruvica R (cid:13) ), the first-in-class BTK inhibitor (BTKi), is an irreversible binder, which has revolutionized the therapeutic landscape for B-cell malignancies (Honigberg et al., 2010; Advani et al., 2013).”
BackgroundInhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances
Wen, T., Wang, J., Shi, Y., Qian, H., & Liu, P. (2020) · Leukemia · doi:10.1038/s41375-020-01072-6 · Cited by 272 · see citing works
“The PCYC-1103 study established 420 mg as the RP2D, and the randomized phase III RESONATE trial (PCYC-1112) proved that ibrutinib is superior to anti-CD20 ofatumumab, even in patients with unfavourable risks, such as del 17p, del 11q, and unmutated IGVH [53–55].”
BackgroundInfluentialCrawford, J. J., Johnson, A. R., Misner, D., Belmont, L. D., Castanedo, G. M., Choy, R., Coraggio, M., Dong, L., Eigenbrot, C. W., Erickson, R., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01712 · Cited by 263 · see citing works
Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment
Hallek, M. J. (2015) · American Journal of Hematology · doi:10.1002/ajh.23979 · Cited by 264 · see citing works
Covalent Inhibition in Drug Discovery
Ghosh, A. K., Samanta, I., Mondal, A., & Liu, W. R. (2019) · ChemMedChem · doi:10.1002/cmdc.201900107 · Cited by 265 · see citing works
Younes, A., Thiéblemont, C., Morschhauser, F., Flinn, I. W., Friedberg, J. W., Amorim, S., Hivert, B., Westin, J. R., VERMEULEN, J. T., Bandyopadhyay, N., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70311-0 · Cited by 254 · see citing works
Hunter, J. C., Gurbani, D., Ficarro, S. B., Carrasco, M. A., Lim, S. M., Choi, H. G., Xie, T., Marto, J. A., Chen, Z., Gray, N. S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1404639111 · Cited by 242 · see citing works
“The recent emergence of several FDA-approved covalent kinase inhibitors, including Ibrutinib and Afatinib, suggests that the methods and technology for rationally designing covalent inhibitors have matured to the point that they may be broadly applicable (50, 51).”
BackgroundDetermining target engagement in living systems
Simon, G. M., Niphakis, M. J., & Cravatt, B. F. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1211 · Cited by 246 · see citing works
Herman, S. E. M., Mustafa, R. Z., Gyamfi, J., Pittaluga, S., Chang, S., Chang, B. Y., Farooqui, M. Z. H., & Wiestner, A. U. (2014) · Blood · doi:10.1182/blood-2014-02-548610 · Cited by 246 · see citing works
“Ibrutinib has been shown to be well tolerated and active across a spectrum of mature B-cell malignancies, with the highest response rates in CLL and mantle cell lymphoma.(17,27,28) In recently completed studies inCLL, the response rates with single agent were 71% in both relapsed/refractory and treatment-naı̈ve elderl…”
BackgroundMethodInfluentialSelf-citationThe Expanding Field of Secondary Antibody Deficiency: Causes, Diagnosis, and Management
Patel, S. Y., Carbone, J., & Jolles, S. R. A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00033 · Cited by 242 · see citing works
Ibrutinib and novel BTK inhibitors in clinical development
Akinleye, A., Chen, Y., Mukhi, N., Song, Y., & Liu, D. (2013) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-6-59 · Cited by 233 · see citing works
“MCL, MZL, DLBCL, and WM who had failed at least one previous therapy [57].”
BackgroundIbrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation
Kamel, S. I., Horton, L., Ysebaert, L., Levade, M., Burbury, K., Tan, S., Cole‐Sinclair, M. F., Reynolds, J., Filshie, R., Schischka, S., et al. (2014) · Leukemia · doi:10.1038/leu.2014.247 · Cited by 232 · see citing works
The influence of subclonal resistance mutations on targeted cancer therapy
Schmitt, M. W., Loeb, L. A., & Salk, J. J. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.175 · Cited by 224 · see citing works
Sun, C., Tian, X., Lee, Y. S., Gunti, S., Lipsky, A. H., Herman, S. E. M., Salem, D., Stetler‐Stevenson, M., Yuan, C. M., Kardava, L., et al. (2015) · Blood · doi:10.1182/blood-2015-04-639203 · Cited by 224 · see citing works
“12 months Patients n = 55 n = 30 n = 29 Median (Min-Max) 45 (5-90) 68 (17-97) 0.”
Evans, E. K., Tester, R. W., Aslanian, S., Karp, R., Sheets, M. P., Labenski, M., Witowski, S. R., Lounsbury, H. A., Chaturvedi, P., Mazdiyasni, H., et al. (2013) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.203489 · Cited by 223 · see citing works
Cervantes-Gomez, F., Lamothe, B., Woyach, J. A., Wierda, W. G., Keating, M. J., Balakrishnan, K., & Gandhi, V. V. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2809 · Cited by 222 · see citing works
Second-generation inhibitors of Bruton tyrosine kinase
Wu, J., Liu, C., Tsui, S. T., & Liu, D. (2016) · Journal of Hematology & Oncology · doi:10.1186/s13045-016-0313-y · Cited by 216 · see citing works
Gardner, H. L., Fenger, J. M., & London, C. A. (2016) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-022114-110911 · Cited by 215 · see citing works
PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1
Ebi, H., Costa, C., Faber, A. C., Nishtala, M. V., Kotani, H., Juric, D., Pelle, P. D., Song, Y., Yano, S., Mino-Kenudson, M. A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1314124110 · Cited by 209 · see citing works
“In early clinical trials, BTK inhibitors are yielding promising activity in lymphoid malignancies (34, 35).”
BackgroundFlinn, I. W., Kahl, B. S., Leonard, J. P., Furman, R. R., Brown, J. R., Byrd, J. C., Wagner‐Johnston, N. D., Coutre, S. E., Benson, D. M., Peterman, S., et al. (2014) · Blood · doi:10.1182/blood-2013-11-538546 · Cited by 211 · see citing works
“Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (‡1 lymph nodes ‡5 cm), and 37 (58%) had refractory disease.”
BackgroundSelf-citationIbrutinib-Associated Atrial Fibrillation
Ganatra, S., Sharma, A. K., Shah, S. P., Chaudhry, G. M., Martin, D. T., Neilan, T. G., Mahmood, S. S., Barac, A., Groarke, J. D., Hayek, S. S., et al. (2018) · JACC. Clinical electrophysiology · doi:10.1016/j.jacep.2018.06.004 · Cited by 211 · see citing works
“BTK, a member of the Tec kinase family, is a signaling molecule positioned early within the B-cell antigen receptor signaling cascade (14).”
BackgroundB-cell receptor signaling as a driver of lymphoma development and evolution
Niemann, C. U., & Wiestner, A. U. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.09.001 · Cited by 206 · see citing works
“In the first clinical trial reported with ibrutinib, an OR of 54% across different B-cell malignancies was reported, 7/9 for MCL, 11/16 for CLL, 6/16 for FL (later updated with response in 11/16 patients), 2/7 for DLBCL (no data on subtype), and 3/4 for WM [14,161].”
BackgroundChang, B. Y., Francesco, M. R., de Rooij, M. F. M., Magadala, P., Steggerda, S. M., Huang, M. M., Kuil, A., Herman, S. E. M., Chang, S., Pals, S. T., et al. (2013) · Blood · doi:10.1182/blood-2013-02-482125 · Cited by 203 · see citing works
“Dramatic early increases of PB lymphocytes occur consistently among CLL patients treated with small-molecule antagonists of the BCR signaling pathway (Syk, PI3Kd, and BTK inhibitors).(26,43,44) Here we report and characterize similar early transient elevations of lymphocytes among MCL patients treated with the irrever…”
BackgroundMethodSelf-citationNon-Hodgkin Lymphoma: Diagnosis and Treatment
Ansell, S. M. (2015) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2015.04.025 · Cited by 198 · see citing works
Bruton Tyrosine Kinase Inhibitors
Burger, J. A. (2019) · The Cancer Journal · doi:10.1097/ppo.0000000000000412 · Cited by 197 · see citing works
Herman, S. E. M., Niemann, C. U., Farooqui, M., Jones, J. A., Mustafa, R. Z., Lipsky, A. H., Saba, N. S., Martyr, S. E., Soto, S., Valdez, J. M., et al. (2014) · Leukemia · doi:10.1038/leu.2014.122 · Cited by 196 · see citing works
Inhibition of ER stress–associated IRE-1/XBP-1 pathway reduces leukemic cell survival
Tang, C.-H. A., Ranatunga, S., Kriss, C. L., Cubitt, C. L., Tao, J., Pinilla-Ibarz, J. A., Valle, J. R. D., & Hu, C. A. (2014) · Journal of Clinical Investigation · doi:10.1172/jci73448 · Cited by 193 · see citing works
Younes, A., Brody, J., Carpio, C. D. C., López‐Guillermo, A., Ben‐Yehuda, D., Ferhanoğlu, B., Nagler, A., Özcan, M., Avivi, I. M., Bosch, F., et al. (2019) · The Lancet Haematology · doi:10.1016/s2352-3026(18)30217-5 · Cited by 195 · see citing works
Ibrutinib: A First in Class Covalent Inhibitor of Bruton's Tyrosine Kinase
Davids, M. S., & Brown, J. R. (2014) · Future Oncology · doi:10.2217/fon.14.51 · Cited by 195 · see citing works
Bulian, P., Shanafelt, T. D., Fegan, C., Zucchetto, A., Cro, L., Nückel, H., Baldini, L., Kurtova, A. V., Ferrajoli, A., Burger, J. A., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.50.8515 · Cited by 191 · see citing works
Small molecule inhibitors targeting the cancers
Liu, G., Chen, T., Zhang, X., Ma, X., & Shi, H. (2022) · MedComm · doi:10.1002/mco2.181 · Cited by 198 · see citing works
Ruella, M., Kenderian, S. S., Shestova, O. E., Fraietta, J. A., Qayyum, S., Zhang, Q., Maus, M. V., Liu, X., Nuñez-Cruz, S., Klichinsky, M., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1527 · Cited by 188 · see citing works
“31 (6-8) However, up to one third of MCL patients do not respond to ibrutinib and among 32 the responders only a third achieve complete remission (CR).”
BackgroundCheng, S.-H., Ma, J., Guo, A., Lu, P., Leonard, J., Coleman, M., Liu, M., Buggy, J., Furman, R., & Wang, Y.-L. (2014) · Leukemia · doi:10.1038/leu.2013.358 · Cited by 179 · see citing works
Self-citationPrognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era
Vaidya, R., & Witzig, T. E. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu109 · Cited by 187 · see citing works
Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Sharman, J. P., Wierda, W. G., Zhao, W., Heerema, N. A., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2856 · Cited by 185 · see citing works
Self-citationThe development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review
Liang, C., Tian, D., Ren, X., Ding, S., Jia, M., Xin, M., & Thareja, S. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.03.062 · Cited by 178 · see citing works
Mantle cell lymphoma: evolving management strategies
Campo, E., & Rule, S. A. (2014) · Blood · doi:10.1182/blood-2014-05-521898 · Cited by 174 · see citing works
de Claro, R. A., McGinn, K. M., Verdun, N. C., Lee, S., Chiu, H.-J., Saber, H., Brower, M. E., Chang, C., Fletcher, E. P., Habtemariam, B. A., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2225 · Cited by 174 · see citing works
“Ibrutinib is an inhibitor of BTK, a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways that activate pathways necessary for B-cell trafficking, chemotaxis, and adhesion (8, 9).”
Camicia, R., Winkler, H. C., & Hassa, P. O. (2015) · Molecular Cancer · doi:10.1186/s12943-015-0474-2 · Cited by 169 · see citing works
Splenic marginal zone lymphoma: from genetics to management
Arcaini, L., Rossi, D., & Paulli, M. (2016) · Blood · doi:10.1182/blood-2015-11-624312 · Cited by 166 · see citing works
Non-Hodgkin’s Lymphomas, Version 4.2014
Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N. L., Byrd, J. C., Czuczman, M. S., Fayad, L., et al. (2014) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2014.0125 · Cited by 165 · see citing works
Self-citationThe BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
Reiff, S. D., Mantel, R., Smith, L. L., Greene, J. T., Muhowski, E. M., Fabian, C. A., Goettl, V. M., Tran, M., Harrington, B. K., Rogers, K. A., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1409 · Cited by 165 · see citing works
Ibrutinib: First Global Approval
Cameron, F., & Sanford, M. (2014) · Drugs · doi:10.1007/s40265-014-0178-8 · Cited by 162 · see citing works
“The BCR pathway is an important regulator of B cell differentiation, migration, proliferation and apoptosis and is thought to be important in the development of B cell malignancies [7, 9].”
BackgroundResultInfluentialPathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma
Saba, N. S., Liu, D., Herman, S. E. M., Underbayev, C., Tian, X., Behrend, D., Weniger, M. A., Skarzynski, M., Gyamfi, J., Fontán, L., et al. (2016) · Blood · doi:10.1182/blood-2015-11-681460 · Cited by 164 · see citing works
“A phase I trial of ibrutinib in patients with relapsed NHL demonstrated a high response rate in MCL, an unexpected finding that was confirmed in a disease-specific phase II trial demonstrating objective responses in 68% of patients, including 21% with complete response, and an overall survival (OS) rate of 58% at 18 m…”
ResultAlu, A., Lei, H., Han, X., Wei, Y., & Wei, X. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01353-w · Cited by 157 · see citing works
Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial
Bartlett, N. L., Costello, B. A., LaPlant, B. R., Ansell, S. M., Kuruvilla, J. G., Reeder, C. B., Thye, L. S., Anderson, D. M., Krysiak, K., Ramirez, C. A., et al. (2017) · Blood · doi:10.1182/blood-2017-09-804641 · Cited by 158 · see citing works
Cheng, S.-H., Guo, A., Lu, P., Ma, J., Coleman, M., & Wang, Y.-L. (2014) · Leukemia · doi:10.1038/leu.2014.263 · Cited by 155 · see citing works
Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765)
Burger, J. A., & Buggy, J. J. (2013) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2013.777837 · Cited by 156 · see citing works
Self-citationKrenske, E. H., Petter, R. C., & Houk, K. N. (2016) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.6b02188 · Cited by 152 · see citing works
Herman, S. E. M., Montraveta, A., Niemann, C. U., Mora-Jensen, H. I., Gulrajani, M., Krantz, F., Mantel, R., Smith, L. L., McClanahan, F., Harrington, B. K., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0463 · Cited by 156 · see citing works
“Notably, in patients, acalabrutinib can be dosed twice daily and may result inmore sustained inhibition of BTK than once daily administration of ibrutinib (28, 37).”
BackgroundSelf-citationChronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment
Hallek, M. J. (2013) · American Journal of Hematology · doi:10.1002/ajh.23491 · Cited by 154 · see citing works
- Authors
- Advani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., Kolibaba, K. S., Furman, R. R., Rodriguez, S., Chang, B. Y., Sukbuntherng, J., Izumi, R., Hamdy, A., Hedrick, E., & Fowler, N. H.
- Affiliations
- University of Vermont (US)
- Corresponding author
- Advani, Ranjana H.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2013-01-01
- Volume
- 31
- Issue
- 1
- Pages
- 88-94
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC5505166
- OpenAlex
- W2171771895
- Cited by
- 1,128
- References
- 32
- Citations by year
- 2026: 17 · 2025: 38 · 2024: 47 · 2023: 44 · 2022: 46 · 2021: 90 · 2020: 79 · 2019: 92 · 2018: 73 · 2017: 117 · 2016: 94 · 2015: 135 · 2014: 134 · 2013: 110 · 2012: 6
- FWCI
- 58.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Abbott Laboratories
- GlaxoSmithKline
- Gilead Sciences
- Celgene
- Genentech
- Takeda Oncology
- Pharmacyclics
- National Cancer Institute (P30CA016672)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Dermatology › Cutaneous lymphoproliferative disorders research
- Keywords
- ibrutinib, BTK inhibitors, relapsed/refractory B-cell malignancies, B-cell lymphoma, chronic lymphocytic leukemia, B cell receptor signaling, irreversible kinase inhibitors, BTK occupancy, dose-limiting toxicity, pharmacokinetics, progression-free survival
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Administration, Oral, Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Piperidines, Prognosis, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell, Salvage Therapy, Drug Resistance, Neoplasm, Maximum Tolerated Dose, Protein Kinase Inhibitors
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