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In this video, Dr. Matthew Davids, M.D., an Associate Professor of Medicine at Harvard Medical School and the Director of Clinical Research for Lymphoma at Dana-Farber Cancer Institute in Boston, discusses his views on treatment strategies of patients with chronic lymphocytic leukemia (CLL). This video was recorded at the 62nd Annual Meeting of the American Society of Hematology, held virtually in December 2020. Dr. Davids specializes in CLL and serves on the CLL Society’s Medical Advisory Board.
- The 2014 FDA approval of ibrutinib (Imbruvica®) for relapsed or refractory CLL treatment changed the treatment landscape in CLL treatment dramatically. Other agents have gained government approval in the seven years that have followed, giving CLL physicians and patients more options. We know that ibrutinib is a drug that a patient needs to take continuously until either their disease progresses or they cannot tolerate the side effects. Ibrutinib, when given alone, is an example of a single drug strategy. Dr. Davids opines that single drug therapies such as ibrutinib, acalabrutinib (Calquence®), or venetoclax (Venclexta®) alone may still be a good option for CLL patients who require treatment but have favorable prognostic genetic markers.
- A sequential drug strategy is a way to address the need to find a new treatment for CLL patients after their disease progresses. One common reason for a patient to relapse while on a specific CLL drug is that their cancer cells mutate and essentially “block” the drug from attacking the malignant cells. Since the advent of targeted therapies just seven years ago, a typical sequence has been to move a patient to single-agent venetoclax if their disease progressed on ibrutinib.
- Recently, there has been a lot of interest in combination therapy strategies. In the past, when chemotherapy was the only available option for treating CLL, practitioners learned over time that combinations were more effective than single agents in eradicating cancer cells. For example, fludarabine (F) was initially used as a single agent; later, doctors added cyclophosphamide (C) to fludarabine, and this two-drug combination was more effective than either agent alone. The addition of rituximab, a monoclonal antibody to FC, was even more effective. The triple combination of FCR remains an option for treating younger (<65) patients with favorable markers and mutated IGHV.
- The April 2021 National Comprehensive Cancer Network (NCCN) guidelines list several combinations as “Preferred” treatments for treatment naïve and relapsed/refractory patients, including:
- venetoclax + obinutuzumab,
- venetoclax + rituximab,
- acalabrutinib + obinutuzumab, and
- idelalisib (Zydelig®) + rituximab.
- Ibrutinib was approved in April 2020 with rituximab and several other combinations are in trials or can be used “off label” such as venetoclax with ibrutinib or acalabrutib or duvelisib; or ibrutinib with obinutuzumab or with FCR; and many other trials with two and even three drugs
- Researchers are currently studying many combinations. Dr. Davids believes that patients with unfavorable prognostic indicators such as deletion (17p) or a TP53 mutation may benefit the most from combinations.
The treatment landscape for chronic lymphocytic leukemia is changing quickly, and there are currently more than 1800 clinical trials for CLL worldwide. Researchers hope to answer questions on optimal treatment strategies for the future and which patients would benefit from single-agent, sequential, or combination approaches. CLL is not a homogenous disease, and there are many variables in the disease. Researchers and clinicians hope to develop patient-tailored strategies that maximize efficacy and minimize side effects.
On a personal note, I am the beneficiary of combination therapy. I am a complex karyotype patient with unmutated IGHV and deletion (17p) along with other mutations. I recently attained undetectable minimal residual disease (uMRD) when my doctor agreed to add venetoclax to the ibrutinib I was already taking. Reaching uMRD allowed me to stop the venetoclax after one year, and I remain on ibrutinib alone. Extensive data shows that patients who attain uMRD generally benefit with more prolonged progression-free survival (PFS) and overall survival (OS).
Thanks for reading this summary and viewing this short video.
Stay strong; we are all in this together!
Thomas. E. Henry III, MBA, RPh, CPh
Thomas E. Henry III is a Registered Pharmacist and CLL Patient. He is President and Senior Consultant for Burlington Consulting Associates, a company that provides consulting services to health systems nationwide. Tom is a CLL Society Medical Advisory Board member and strives to educate other CLL patients through his blog https://www.cllpharmacist.com. He has a forty-two-year career as a licensed pharmacist and has served as Chief Pharmacy Officer at two Top-15 Comprehensive Cancer Centers, Moffitt (Tampa, FL) and Roswell Park Cancer Institute (Buffalo, NY).