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Supplements The Emerging Role of Targeted Therapies for the Treatment of Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia: An Overview of Diagnosis, Prognosis, and Treatment

Ibrutinib is an inhibitor of BTK, a signaling molecule of the B-cell receptor (BCR) and cytokine receptor pathway that is involved in B-cell trafficking, chemotaxis, and adhesion. It inhibits malignant B-cell proliferation and survival. Ibrutinib is indicated for the treatment of CLL and SLL with or without del(17p) and is taken as an oral capsule or tablet once daily.23

Acalabrutinib is a second-generation BTK inhibitor and is effective in patients with relapsed or refractory CLL. It is administered as an oral capsule twice a day.5,24 Acalabrutinib should not be used in patients with BTK C481S mutations who are refractory to ibrutinib.5

B-Cell Lymphoma 2 Inhibitor

Venetoclax is a selective, small molecule inhibitor of B-cell lymphoma 2 (BCL-2), an antiapoptotic protein that may be overexpressed in CLL cells. It allows for the apoptosis of tumor cells that overexpress BCL-2. Venetoclax is indicated as a once-daily oral dose for the treatment of CLL and SLL with or without del(17p) in patients who have received at least 1 prior therapy.25

PI3K Inhibitors

Idelalisib is an inhibitor of phosphoinositide 3-kinase (PI3K), which is included in several B-cell signaling pathways (including BCR, CXCR4, and CXCR5) involved in the trafficking and homing of B cells to the lymph nodes and bone marrow. It inhibits and reduces chemotaxis, adhesion, and cell viability. Idelalisib is indicated for relapsed CLL in combination with rituximab in patients in whom rituximab alone would not be considered appropriate therapy due to comorbidities. It is also recommended for patients who have received at least 2 prior systemic therapies. Idelalisib is taken orally, twice daily.26

Duvelisib is a dual inhibitor of PI3K-δ and PI3K-γ isoforms in different B-cell signaling pathways (BCR and CXCR12-mediated chemotaxis of malignant B cells) and has demonstrated the induction of growth inhibition and reduction of viability of malignant B cells and primary CLL tumor cells. Duvelisib is indicated for relapsed/refractory CLL/SLL after 2 prior therapies as a twice-daily oral dose.27

Hematopoietic Cell Transplantation

The role of hematopoietic cell transplantation (HCT) is changing with the emergence of novel pharmacologic treatments. Allogeneic HCT has been shown to provide long-term benefits for patients with del(17p) and TP53 mutations. With the availability of small molecule inhibitors (eg, ibrutinib and venetoclax) that have favorable outcomes in patients with del(17p) and TP53 mutations who are refractory to or have relapsed on first-line therapies, allogeneic HCT may be reserved for patients who have first used small molecule inhibitors.5


Investigators continue research to identify reliable, reproducible, and readily accessible prognostic factors to aid in treatment decisions and improve the overall course of CLL. Many patients undergoing therapy will eventually relapse or progress, resulting in the need for multiple lines of therapy and novel therapeutic options. Because there is no standard of care for CLL, many challenges and questions exist. Research is needed to determine the best treatment regimen for patients who are contemplating the diversity of genetic mutations and factors when initiating treatment.

The potential development of further mutations and the changing factors that can occur during the course of the disease must be considered when treatment decisions are made. As response rates and durations increase and the understanding of CLL of improves, patients may face longer treatment durations, greater exposure to therapies, and longer contact with the toxicities associated with therapies. Research is needed to optimize treatment strategies to limit toxicities and increase overall quality of life. As patients continue to live for many years with CLL, additional treatment options are needed—those that will simplify regimens with fewer adverse effects and toxicities and those that will target aggressive, relapsed, or refractory disease. Continued research to find a pharmacologic cure, as well as to learn more about cause and prevention, is needed as well.

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  23. Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics LLC; 2018. Accessed November 7, 2018.
  24. Calquence [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. Accessed November 7, 2018.
  25. Venclexta [prescribing information]. North Chicago, IL: AbbVie Inc; 2018. Accessed November 7, 2018.
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