Investigational treatments for chronic lymphocytic leukemia: a focus on phase 1 and 2 clinical trials

ABSTRACT

Introduction: During recent years, the introduction of novel drugs, particularly small molecule inhibitors, has led to remarkable progress in both previously untreated and relapsed/refractory (RR) patients in chronic lymphocytic leukemia (CLL). However, further research is necessary to find an optimal cure that responds to the individual needs of the patient.

Areas covered: This review discusses new agents in phase 1 and 2 clinical trials currently underway in CLL patients. A literature review of the MEDLINE database for articles in English concerning novel drugs, clinical trials, phase 1, phase 2 and CLL was conducted via PubMed. Publications from 2000 through January 2020 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association and American Society of Clinical Oncology were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. The search also included clinical trials registered in clinicaltrials.gov.

Expert opinion: The use of BTK and PI3Kδ inhibitors and BCL-2 antagonist have changed the treatment strategy of CLL. Several clinical trials with novel, unapproved agents are currently ongoing. Their findings should define the role of these novel drugs in the treatment of patients with previously untreated and RR CLL.

KEYWORDS:

• Acalabrutinib
• BTK inhibitors
• chronic lymphocytic leukemia
• cirmtuzumab phase1
• phase 2
• umbralisib
• vecabrutinib
• voruciclib

Article highlights

• Novel agents, especially BTK and PI3K inhibitors, BCL-2 inhibitors and monoclonal antibodies have improved the prognosis of CLL patients.

• More specific BTK inhibitors, including acalabrutinib and zanubrutinib, demonstrate greater selectivity than ibrutinib, with minimal off-target activity and a better expected safety profile

• Second generation PI3K inhibitors in development including duvelisib and umbralisib have shown preliminary activity and an acceptable safety profile in CLL

• Several small-molecule inhibitors of Bcl-2, especially venetoclax, are highly active in CLL and have a promising therapeutic potential

• New promising therapies, such as the new monoclonal antibodies, CDK-selective inhibitor, immunomodulatory monoclonal antibodies and bispecific antibodies are under investigation.

• Recent studies indicate that CAR-T demonstrates less efficacy against CLL than B-ALL and DLBCL due to the T cells being less effective in CLL. Previous therapy with ibrutinib can improve the safety and efficacy of autologous CD19-directed CAR T cells.

• The limitations of CAR T cells, i.e. substantial toxic effect and complexity of production, can be overcome by using natural killer (NK) cells modified to express an anti-CD19 CAR.

• The combination of novel targeted agents can increase efficacy, decrease the risk of resistance and reduce toxicity.

• There is a need for a rational design of new clinical trials on non-chemotherapy-based combinations, which include well-tolerated and effective drugs.

This box summarizes key points contained in the article.

Declaration of interest

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 relationships or otherwise to disclose.

Additional information

Funding

The authors are funded by a grant from the Medical University of Lodz, Poland (No. 503/1-093-01/503-11-004).