Biologic Targets in Chronic Lymphocytic Leukemia: BCL2, BTK, and PI3K

For many years, the standard first-line treatment for patients with chronic lymphocytic leukemia (CLL) was chemotherapy plus a monoclonal antibody (a type of immunotherapy), typically with the drug rituximab (Rituxan).¹ Oncologists and researchers call this regimen “chemoimmunotherapy.” Today, advances in technology have helped researchers to develop the next generation of CLL treatments. These drugs, known as targeted therapies or biologic drugs, have proved to be effective, and have manageable side effects.¹

Researchers now know more about the biology of CLL, including how these cancer blood cells grow. A recent discovery has focused on the role of B-cell receptor signaling, which tells cancer cells to grow and divide. Understanding how this signaling pathway works helps researchers to design drugs that block the growth of cancer cells.¹ These targeted therapies include oral drugs that block (or inhibit the growth of) specific cancer-cell proteins. For example, ibrutinib (Imbruvica) and acalabrutinib (Calquence) are drugs that block Bruton tyrosine kinase (BTK). Idelalisib (Zydelig) is an example of a drug that blocks phosphoinositide 3-kinase (PI3K) delta.

For patients with CLL receiving treatment in doctors’ offices or cancer clinics, the availability of these targeted drugs can result in better outcomes. This is especially important for patients with high-risk CLL based on genetic features. Examples of high-risk CLL features include the immunoglobulin heavy-chain (IGHV) gene that is not mutated (rather than IGHV mutation), and chromosome 17p deletion. Recent clinical trial results have shown that BTK inhibitors (such as ibrutinib and acalabrutinib) used with or without other new drugs, are very effective as first-line treatment for most patients with CLL.^1-5

Additional progress in CLL has been achieved with the introduction of venetoclax (Venclexta), a drug that blocks the protein called BCL2. When CLL cells make too much BCL2 protein, they are readied to self-destruct; that is, the BCL2 inhibitors push these CLL cells to their death. “Dead” cancer cells lead to a positive outcome for a person with cancer. Data from clinical trials show that the use of venetoclax has long-term benefits for patients with CLL.^1,6-10 Venetoclax-based regimens may become the new gold standard in CLL treatment, based on these findings.¹

Beginning with the initial FDA approval of fludarabine in 1992, there have been several notable new drug approvals in CLL, particularly in recent years. These approvals have been paralleled by improvements in survival among patients with CLL.^1,11 As exciting developments in CLL treatments continue, the use of conventional chemotherapy drugs is no longer common, and a cure for CLL is becoming a reality.¹

References

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2. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912). Blood. 2018;132:LBA-4.
3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. New England Journal of Medicine. 2018;379:2517-2528.
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5. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(supplement_1):31.
6. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncology. 2016;17:768-778.
7. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. Journal of Clinical Oncology. 2018;36:1973-1980.
8. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncology. 2018;19:65-75.
9. Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131:1704-1711.
10. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. New England Journal of Medicine. 2018;378:1107-1120.
11. da Cunha-Bang C, Simonsen J, Rostgaard K, et al. Improved survival for patients diagnosed with chronic lymphocytic leukemia in the era of chemo-immunotherapy: a Danish population-based study of 10455 patients. Blood Cancer Journal. 2016;6:e499.