Is there a role for anti-CD20 antibodies in CLL?

Abstract

Anti-CD20 monoclonal antibodies (mAbs) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) by improving survival of patients with CLL in conjunction with chemotherapy. However, the novel targeted agents such as Bruton tyrosine kinase inhibitors (BTKis) and venetoclax have now mostly replaced chemotherapy in frontline treatment of CLL. Several clinical trials have been conducted to examine the role of anti-CD20 mAbs in combination with BTK inhibitors and venetoclax. Addition of rituximab to ibrutinib does not improve progression-free survival (PFS) of treatment-naive patients with CLL, possibly related to ibrutinib's antagonistic effect on anti-CD20 antibodies. Alternatively, addition of a glycoengineered anti-CD20 mAb obinutuzumab to a more selective BTKi acalabrutinib may improve PFS but does not improve overall survival of patients with CLL in the frontline setting, pending long-term follow-up. Thus, we suggest that the addition of an anti-CD20 mAb to a BTKi is of most benefit to patients with autoimmune cytopenia or rapidly progressive disease. In contrast to BTKis, combination of fixed-duration venetoclax and anti-CD20 mAb can induce deep remission with high rates of undetectable minimal residual disease, correlating with improved survival of patients with CLL in both frontline and relapsed/refractory settings. In this review, we discuss clinical trials of BTKis and venetoclax that have investigated the role of anti-CD20 mAbs in frontline and relapsed settings of CLL treatment. We also provide an algorithm suggesting how anti-CD20 mAbs may be incorporated in the treatment of patients with CLL, including specific scenarios.

Graphical abstract

Figure 1.

Mechanism of action of select anti-CD20 monoclonal antibodies used to treat CLL. More “+” sign indicates stronger mechanism of action. ADCP, antibody-dependent cellular phagocytosis; CDC, complement dependent cytotoxicity; MAC, membrane attack complex.

Figure 2.

How to incorporate anti-CD20 monoclonal antibody into frontline treatment for patients with CLL. *All eligible patients should be considered for participation in clinical trials if available. **Anti-C20 monoclonal antibody. ⁺Pending Food and Drug Administration approval for marketing for CLL at time of submission. GERD, gastroesophageal reflux disease; IGHV, immunoglobulin variable heavy chain; TLS, tumor lysis syndrome.

Figure 3.

How to incorporate anti-CD20 monoclonal antibody into subsequent lines of treatment for patients with CLL. *All eligible patients should be considered for participation in clinical trials if available. **Anti-C20 monoclonal antibody. ⁺Pending Food and Drug Administration approval for marketing for CLL at time of submission. GERD, gastroesophageal reflux disease; IGHV, immunoglobulin variable heavy chain; TLS, tumor lysis syndrome.