New Options for First-Line Treatment of Chronic Lymphocytic Leukemia

Most patients with chronic lymphocytic leukemia (CLL) now have several options for first-line therapy, thanks to new clinical trial results and novel targeted agents. Many patients with CLL, a slowly progressive blood cancer in which the bone marrow makes too many white blood cells, don’t need immediate treatment but can be observed — sometimes for many years — until they develop symptoms or the disease begins to progress rapidly. 

As recently as five years ago, the standard initial therapy for the disease was a combination of the chemotherapy agents fludarabine and cyclophosphamide plus the antibody drug rituximab, a regimen known as FCR. (Patients over age 65 also received the chemotherapy agent bendamustine.) Advances in the understanding of the biology of the disease have resulted in an array of drugs that target specific vulnerabilities in CLL cells. While some patients still choose FCR treatment, most prefer one of the new options. 

Today, the main first-line treatments for CLL are: 

• A combination of the drugs venetoclax and obinutuzumab.  Venetoclax targets the BCL-2 protein, which is critical to the survival of CLL cells. Obinutuzumab is a monoclonal antibody drug that targets the CD20 protein on CLL cells. 
• Acalabrutinib or zanubrutinib, drugs that target a protein called Bruton tyrosine kinase, or BTK, a lynchpin of CLL cell survival. 
• A combination of acalabrutinib and obinutuzumab. 

New treatment approaches 

The effectiveness of these therapies as initial treatment for CLL has prompted researchers to study regimens of BTK inhibitors plus BCL-2 inhibitors. At Dana-Farber, investigators are leading several trials of these combinations. They include: 

• A trial of acalabrutinib, venetoclax, and obinutuzumab in patients whose CLL cells have a 17p deletion – the loss of part of the short arm chromosome 17. Enrollment in the trial has completed, and researchers will present an update on the results at the December 2024 Annual Meeting of the American Society of Hematology. 
• A soon-to-launch trial of obinutuzumab and the “non-covalent” BTK inhibitor pirtobrutinib.  (Covalent inhibitors like ibrutinib, acalabrutinib, and zanubrutinib form strong, lasting bonds with their targets in cancer cells; non-covalent inhibitors form reversible bonds that are able to target the resistance mutations that occur on covalent inhibitors and potentially also result in result milder side effects.)  The trial follows the recent approval of pirtobrutinib for patients with relapsed, treatment-resistant CLL. 

“The research that we have done over the last 10-15 years has transformed CLL therapy and continues to transform CLL therapy, giving patients highly effective and well tolerated treatment options that are only continuing to improve with our new research,” says Jennifer Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber. “I encourage all patients to seek out novel clinical trials, which not only provide early access to these exciting treatment options but also allow us to continue to move the field forward.” 

About the Medical Reviewer

Jennifer R. Brown, MD, PhD is the Director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston, Massachusetts. Dr. Brown completed a B.S. and M.S. simultaneously in molecular biophysics and biochemistry (MB&B) at Yale, graduating summa cum laude with distinction. She proceeded to Harvard Medical School where she received her MD and PhD in molecular genetics in 1998 and was awarded the James Tolbert Shipley Prize. She then served as an intern and resident in Internal Medicine at Massachusetts General Hospital followed by fellowship in Hematology and Medical Oncology at DFCI. Dr. Brown joined the faculty of DFCI and Harvard Medical School in 2004, where she has an active clinical-translational research program in CLL.

Her interests include the development of novel targeted therapeutics for CLL, as well as CLL genomics. She has been instrumental in the clinical development of idelalisib and ibrutinib, leading to their regulatory approvals in CLL. Her genomics work has characterized the somatic mutation profile of CLL, and she is now particularly interested in the implementation of genomic technology in the clinic. She also has a longstanding research interest in the inherited predisposition to CLL. To date she has published about 250 papers in the scientific literature, predominantly in CLL. In 2014 she was the recipient of two awards from DFCI, the Clinical Innovation Award, as well as the George Canellos Award. She is a member of the International Workshop on CLL (iwCLL) and enjoys a worldwide reputation as a CLL expert having made the Highly Cited Researchers list by Clarivate, with multiple papers ranking in the top 1% by citations for their field and year of publication.