Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disease that is characterized by the proliferation of monoclonal B-cells. It accounts for 25 to 30% of leukemia cases in the United States and is the most prevalent adult leukemia in the western countries. It has a clinically diverse effect that primarily affects elderly people around a median onset age of 70 years. Even though the disease can progress slowly, most individuals experience symptoms of their underlying condition and need treatment.
In the past, patients were given chemo-immunotherapy regimens based on fludarabine/cyclophosphamide/rituximab (FCR), bendamustine/rituximab (BR), or chlorambucil. But these regimens may cause relapse or recurrence in CLL patients. To overcome this limitation, there is a continuous research for the development of newer drugs. This led to the constant development of targeted drugs that inhibit the crucial elements of the B-cell receptor (BCR) pathway (a pathway that plays an important role in the pathogenesis of CLL) .
What are BCR inhibitors?
The B-cell receptor (BCR) expressed on the malignant cells in CLL, contributes to disease pathogenesis, by sending signals required for cell survival and proliferation.
In the BCR pathway, the BTK (Bruton's tyrosine kinase) inhibitor is essential because when it is activated, it phosphorylates and activates PLC γ 2(an enzyme involved in the pathogenesis of CLL), releasing intracellular calcium stores and increasing the activity of transcription factors that are required for leukemic cell growth.
The signal transduction pathway started by the interaction of this receptor is now the focus of various treatment approaches in CLL.
The invention of various targeted BCR inhibitors, that suppress this BTK has revolutionized the way CLL is treated.
Their judicious use was made possible by understanding of the B-cell receptor (BCR) pathway and its role in the pathogenesis of CLL.
What is the rationale behind using zanubrutinib?
Among the BTK inhibitors, ibrutinib, a first-in-class oral Bruton's tyrosine kinase (BTK) inhibitor, has been shown to be superior to conventional chemo-immunotherapy in terms of progression-free survival (PFS) and overall survival (OS) in both treatment-naive(previously untreated) and relapsed/refractory CLL cases.
Despite being clinically efficient, it was not used by majority of the patients, because of its side effects, which are considered to be caused by off-target kinase inhibition.
To overcome this, zanubrutinib, a second-generation non-covalent BTK inhibitor with greater efficacy, was introduced.
What is the clinical efficacy of zanubrutinib in CLL?
The Food and Drug Administration (FDA) approved zanubrutinib available under the trade name Brukinsa® for the treatment of chronic lymphoid leukemia and small cell lymphomas. The following are the clinical trials that are being conducted for this drug:
In a phase III controlled randomized trial, zanubrutinib demonstrated more efficacy when compared to the combination of bendamustine and rituximab(ClinicalTrials.gov identifier - NCT03336333) in terms of progression-free survival in treatment-naive CLL patients.
Another phase III trial called ALPINE was conducted to determine the efficacy of zanubrutinib when compared to ibrutinib in treating recurrent cases of CLL (ClinicalTrials.gov identifier - NCT03734016). The study results indicated that when compared with ibrutinib, zanubrutinib is more efficient in terms of progression free survival in recurrent cases of CLL and small cell lymphomas.
Apart from CLL, this drug is also used to treat mantle cell lymphoma. As zanubrutinib allows for more effective BTK inhibition and is associated with fewer cardiac adverse effects when compared to ibrutinib, it is considered as an alternative to the latter .
Clinical trials in the early stages have shown outstanding efficacy and a well-tolerated safety profile for zanubrutinib. Although more research is required, zanubrutinib shows promising effects as a CLL treatment with acceptable side effects and will be an intriguing addition to our paradigm for care.
1. J. M. Rhodes and A. R. Mato, “Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia,” Drug Des Devel Ther, vol. 15, pp. 919–926, 2021, doi: 10.2147/DDDT.S250823.
2. J. C. Byrd and W. Rothbaum, “Zanubrutinib in Chronic Lymphocytic Leukemia,”N Engl J Med, vol. 388, no. 18, pp. 1719–1720, May 2023, doi: 10.1056/NEJMc2302350.
3. P. R. Geethakumari and F. Awan, “An evaluation of zanubrutinib, a BTK inhibitor, for the treatment of chronic lymphocytic leukemia,”Expert Rev Hematol, vol. 13, no. 10, pp. 1039–1046, Oct. 2020, doi: 10.1080/17474086.2020.1817735.
4. D. Killock, “Zanubrutinib succeeds in head-to-head with ibrutinib in R/R CLL,”Nat Rev Clin Oncol, vol. 20, no. 2, p. 64, Feb. 2023, doi: 10.1038/s41571-022-00724-z.