The fading star of obinutuzumab-chlorambucil regimen in patients with comorbidities with chronic lymphocytic leukemia – are we ready for chemo-free immunotherapy approach?

ABSTRACT

Introduction

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries occurring typically in elderly patients. These patients often present with comorbidities limiting treatment options. During the last decade, the treatment paradigm has rapidly changed with the introduction of novel oral targeted agents and monoclonal antibodies.

Areas covered

The review focuses on the combination of type II antiCD20 antibody obinutuzumab in combination with chemotherapy or oral targeted agents in patients not suited for fludarabine-based therapy because of comorbidities or age. The main focus of the review is whether classical immunochemotherapy with obinutuzumab-chlorambucil is still a valid therapeutic option or whether the combination of obinutuzumab and ibrutinib or venetoclax presents novel standard of care.

Expert opinion

Both pivotal and registrational studies iLLLUMINATE study testing the combination of ibrutinib and obinutuzumab and CLL14 study testing the fixed combination of venetoclax and obinutuzumab have shown major benefit over chemoimmunotherapy approach in this population. Furthermore, they have excellent activity in high-risk subgroups of CLL paving the road toward a chemo-free immunotherapy approach in this setting. However, there are some pitfalls in these strategies warranting further research.

KEYWORDS:

• Chronic lymphocytic leukemia
• venetoclax
• ibrutinib
• acalabrutinib
• obinutuzumab

Article highlights

• Until recently, treatment options in CLL were limited to chemoimmunotherapy and presented a great unmet need in this area. Furthermore, chemoimmunotherapy approach cannot overcome high-risk features of CLL.

• An introduction of single oral targeted therapy has revolutionized the area and has become a standard of care in chronic lymphocytic leukemia in elderly patients with comorbidities. However, accessibility, side effects, and financial toxicity limit its use in every day practice.

• Chemoimmunotherapy with obinutuzumab plus chlorambucil should only be used in patients with good risk genetic features.

• The combination of type II antiCD20 antibody obinutuzumab with ibrutinib has shown a major progression-free survival benefit in patients with CLL including high-risk patients defined by genomic aberrations.

• The combination of obinutuzumab and venetoclax is an alternative approach offering a fixed duration of therapy. However, it should not be used in patients harboring del17p aberration.

• Acalabrutinib plus obinutuzumab may present another approach to these patients although the pivotal trial was not powered enough to establish the superiority of combination regimen over single-agent monotherapy.

• Yet, due to short follow-up, no OS advantage has been shown in iLLUMINATE and CLL14 RCTs.

• None of these approaches have been tested against ibrutinib monotherapy as a standard of care raising questions about the true values of these combinations in CLL.

• More data from randomized controlled trials and real-world and registry data are needed to support these combinations as the standard of care in this setting.

Acknowledgments

The authors would like to acknowledge Domagoj Ćorić for text editing.

Declaration of interest

V Milunović has received speaker bureau from Roche; S Ostojic Kolonic has received speaker bureau from Roche, Abbvie and Janssen; I Mandac Rogulj has received speaker bureau from Roche, Abbvie and Janssen; M Martinović has received speaker bureau from Roche, Abbvie and Janssen; D Radić-Krišto has received speaker bureau from Roche, Abbvie and Janssen. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.