Future Landscapes of Bispecific Antibodies in Chronic Lymphocytic Leukemia (CLL). Systematic Review of Ongoing Trials
Authors: Shahzad Moazzam , Basharat Ahmad , Irfan Sohib , Sadiq Muhammad Hamza , Amin Muhammad Kashif , Jaglal Michael V. 
Published: December 2024

Introduction
Bispecific antibodies are emerging as a promising therapeutic strategy for hematological malignancies, particularly in relapsed or refractory cases. This Systematic review focuses on their potential in treating Chronic Lymphocytic Leukemia (CLL), analyzing ongoing clinical trials to explore future applications. These trials could herald a new era in CLL management, potentially offering more effective treatment options for patients who have exhausted other therapies.
Methods
We comprehensively searched Clinicaltrials.gov and the European trial network using the keywords “Chronic Lymphocytic Leukemia OR CLL” and “Bispecific Antibodies.” This search included all recruiting, yet-to-recruit, and terminated trials as of April 30, 2024. Data were extracted on the location, bispecific antibody type, targets, recruitment status, therapy line, and drug combinations. Ten ongoing trials met the inclusion criteria for this review.
Results
We identified 10 ongoing trials investigating bispecific antibodies targeting CLL. Among these, 6 (60%) are industry-sponsored. 6 (60%) are actively recruiting, 3 (30%) are active but not yet recruiting, and 1 (10%) initiated in 2020 has been terminated. The trials are distributed as follows: 2(20%) are Phase 1, 6(60%) are Phase 1/2, and 2(20%) are Phase 2 with a total enrollment of 1,506 patients. Notably, 8(80%) trials were updated in 2024, and 2(20%) were updated in 2023, although only one trial has preliminary results available.
The 3(30%) trials are exclusively dedicated to CLL, while the others also include different other diseases of which Diffuse Large B-cell lymphoma (DLBCL) being the most common, present in 5(50%) of the trials. The bispecific antibodies under investigation include Epcoritamab (4 trials), Mosunetuzumab (3 trials), and Plamotumab, Glofitamab, and GEN3009 (one trial each). All trials (100%) target CD3/CD20. The trials primarily explore bispecific antibodies as third-line therapy in 5(50%) of the trials and as second-line therapy in 4(40%) of the trials, with Venetoclax being the most common combination therapy used. None of the patients in these trials have prior exposure to CAR-T therapy.
Safety and tolerability are the primary outcomes in 7 (70%) trials. The terminated trial was halted due to strategic evaluation and technical issues, and not because of any safety or regulatory concerns. Geographically, 2(20%) of the trials are solely based in the United States (US), while 8(80%) have locations both in US and Europe. Additionally, Australia, Asia, and the Middle East (Israel) are part with the US in 5(50%), 3(30%), and 1(10%) trial, respectively.
Discussion
The ongoing bispecific antibody trials in CLL have the potential to revolutionize treatment, offering more effective options for relapsed and refractory cases. These trials are expected to enhance CLL management's precision and efficacy significantly. The diverse geographic distribution and variety of bispecific antibodies under investigation underscore the global effort to advance CLL treatment. The focus on safety and tolerability ensures that these new therapies will be effective and manageable for patients, paving the way for improved outcomes in this challenging disease.