Chronic Lymphocytic Leukemia (CLL) Medication

Updated: Dec 07, 2023
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
  • Print

Medication Summary

Targeted agents are increasingly used in the treatment of chronic lymphocytic leukemia (CLL). 

Examples of targeted biologics include: 

  • Bruton tyrosine kinase (BTK) inhibitors  
  • B-Cell lymphoma inhibitors 
  • Monoclonal antibodies (eg, anti-CD20, anti-CD52) 

Fludarabine (a purine nucleoside analogue that acts as an antimetabolite) and the alkylating agents bendamustine and chlorambucil are chemotherapy agents that were previously used very commonly in the treatment of CLL. Purine analogues, fludarabine in particular, are very active against CLL. However, recent evidence suggests that the targeted therapies and biologic agents may have less adverse effects and have a significantly higher complete response rate relative to chemotherapy agents, making them more favorable as first-line therapies. 


Antineoplastic Agents

Class Summary

Antineoplastic agents act by inhibiting the key factors responsible for neoplastic transformation of cells.

Pentostatin (Nipent)

Pentostatin inhibits adenosine deaminase, resulting in deoxyadenosine and deoxyadenosine 5+-triphosphate accumulation that may inhibit DNA or RNA synthesis, causing cell death.

Chlorambucil (Leukeran)

Chlorambucil is a nitrogen mustard derivative with bifunctional alkylating activity. It forms intrastrand crosslinks, interfering with DNA replication and RNA transcription and translation.

Fludarabine (Fludara)

A nucleotide analogue of vidarabine, fludarabine is converted to 2-fluoro-ara-A, which enters the cell and is phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. Inhibits DNA polymerase and ribonucleotide reductase as well as DNA primase and DNA ligase I.

Bendamustine (Belrapzo, Bendeka, Treanda)

Alkylating agent that cross-links single or double DNA strands resulting in DNA breakdown; cell cycle-nonspecific


Bruton Tyrosine Kinase Inhibitors

Class Summary

In B-cells, Bruton tyrosine kinase (BTK) signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. 

Acalabrutinib (Calquence)

Bruton tyrosine kinase (BTK) inhibitor; acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity

Ibrutinib (Imbruvica)

Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor that forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. It is indicated for CLL including patients who are treatment-naïve or have been previously treated. It is also indicated for patients who carry a deletion in chromosome 17 (del 17p CLL), which is associated with poor responses to standard treatment.

Pirtobrutinib (Jaypirca)

BTK inhibitor that is indicated for chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) in adults who have received at ≥2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. 

Zanubrutinib (Brukinsa)

Small-molecule inhibitor of Bruton tyrosine kinase (BTK), with significant specificity for BTK. It forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity, preventing cell proliferation. FDA granted accelerated approval granted accelerated approval for zanubrutinib to treat patients with CLL or SLL.


Monoclonal Antibodies

Class Summary

Monoclonal antibodies are antibody proteins that are produced from a particular lineage and function to target a particular epitope, or marker, that is usually present on the leukemic cells.

Ofatumumab (Arzerra)

Ofatumumab is an anti-CD20 human monoclonal antibody that inhibits B-cell activation in early stages. It is indicated for CLL refractory to fludarabine and alemtuzumab, for previously untreated CLL in combination with chlorambucil, as extended treatment (as a single agent) for patients who are in complete or partial response after at least 2 lines of therapy for recurrent or progressive CLL, and for refractory CLL in combination with fludarabine and cyclophosphamide.

Obinutuzumab (Gazyva)

Obinutuzumab is a CD20-directed cytolytic antibody, which, upon binding to CD20, mediates B-cell lysis. Mediation may be through engagement of immune effector cells, by directly activating intracellular death-signaling pathways, and/or by activation of the complement cascade. The CD20 antigen is expressed on the surface of pre–B cells and mature B lymphocytes. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. It is indicated for previously untreated CLL in combination with chlorambucil.


Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on B-cells, T-cells, and almost all CLL cells. It binds to the CD52 receptor of the lymphocytes, which slows the proliferation of leukocytes. Indicated as a single agent for treatment of B-cell chronic lymphocytic leukemia (B-CLL).

Rituximab (Rituxan, Truxima)

Rituximab is a humanized murine monoclonal antibody against CD20, an antigen found on B-cells. This agent binds CD20 on lymphocytes and induces apoptosis as well as initiating complement-mediated killing of bound cells. Because CLL B-cells have low levels of CD20 expression, increased doses of rituximab may be necessary. It is available as an IV formulation.

Rituximab-hyaluronidase (Rituxan Hycela)

The SC product is combined with hyaluronidase human, which increases subcutaneous tissue permeability. It is indicated, in combination with fludarabine and cyclophosphamide (FC), for treatment of adults with previously untreated and previously treated CLL.


B-Cell Lymphoma Inhibitors

Class Summary

Overexpression of B-cell lymphoma 2 (Bcl-2) has been demonstrated in CLL cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutic agents. 

Venetoclax (Venclexta)

Venetoclax is a selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, an antiapoptotic protein. Overexpression of Bcl-2 has been demonstrated in CLL cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutic agents. It is indicated for patients with CLL as monotherapy or in combination with obinutuzumab and/or rituximab.


Antineoplastics, PI3K Inhibitors

Class Summary

Phosphoinositide 3-kinase (PI3K) delta inhibitors induce apoptosis and inhibit proliferation in cell lines derived from malignant B cells. PI3K delta kinase is expressed in normal and malignant B cells. 

Duvelisib (Copiktra)

Selective oral small molecule inhibitor of PI3K-delta and PI3K-gamma. Inhibiting PI3K induces growth inhibition and reduces viability in cell lines derived from malignant B cells and in primary CLL tumor cells. It is indicated for adults with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least 2 prior therapies.

Idelalisib (Zydelig)

Idelalisib is a phosphoinositide 3-kinase (PI3K) delta inhibitor. Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B cells and in primary tumor cells; also inhibits several cell- signaling pathways, including B cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B cells to the lymph nodes and bone marrow. It is indicated relapsed chronic lymphocytic leukemia (CLL).