Immunotherapy combinations for chronic lymphocytic leukemia: advantages and disadvantages

ABSTRACT

In the last few years, BTK inhibitors, PI3K inhibitors, and venetoclax have been approved for clinical use against chronic lymphocytic leukemia (CLL), both as single agents, and in combination. This article summarizes recent achievements in the treatment of patients with CLL, and pays special attention to novel targeted drugs and monoclonal antibodies (Mabs). A literature search was conducted of the PubMed and Google Scholar databases. Rituximab and obinutuzumab have been combined with chemotherapy, and more recently, with BTK inhibitors, PI3K inhibitors, and venetoclax. These agents have demonstrated high activity in treatment naïve (TN) and relapsed or refractory (RR) CLL. Immunochemotherapy regimens are currently considered in TN younger patients with IGHV-mutated disease and should not be given in patients without IGHV mutation. BTK inhibitors are more commonly used as monotherapy in TN and RR patients. PI3K inhibitors can be combined with CD20 Mabs, but their use in CLL is limited due to safety concerns. Venetoclax is typically combined with anti-CD20 Mabs in CLL. Generally, the optimal sequencing of therapies remains to be established, and the selection of upfront therapy needs to be tailored to the individual patient.

KEYWORDS:

• Acalabrutinib
• BTK inhibitors
• chronic lymphocytic leukemia
• ibrutinib
• immunochemotherapy
• monoclonal antibodies
• obinutuzumab
• PI3K inhibitors
• rituximab
• venetoclax

Article highlights

• For several years, the standard first-line treatment in most CLL patients has been combined chemotherapy with anti-CD20 monoclonal antibodies (Mabs).

• At present, immunochemotherapy remains an option only for treatment-naïve patients with IGHV-mutated disease

• Recently, significant progress has been made with the introduction of targeted drugs, Bruton’s tyrosine kinase (BTK) inhibitors and the BCL-2 inhibitor venetoclax

• Targeted drugs are being increasingly used in both previously untreated and relapsed/refractory patients.

• Targeted drugs demonstrate even higher clinical activity when used in combination than as single agents.

• Clinical trials with novel agents, including covalent and noncovalent BTK inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, BCL-2 inhibitors, Mabs, and cellular immunotherapies, are ongoing, and the results will change treatment approaches in the near future.

This box summarizes key points contained in the article.

Acknowledgments

We thank Edward Lowczowski from the Medical University of Lodz, Poland for editorial assistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

P Robak and T Robak wrote and reviewed the manuscript. Both authors have read and agreed to the published version of the manuscript.

Additional information

Funding

This work was supported in part by the grants from the Medical University of Lodz, Poland (No. 503/1-093-01/503-11-004 and 503/1093-1/503-11-003).