In this video, Dr. Richard R. Furman, M.D, The Morton Coleman, M.D Distinguished Professor of Medicine at Weill Cornell Medical College, Columbia University (NYC), and Director of the CLL Research Center at New York-Presbyterian Hospital is interviewed by CLL Society’s Board Chair, Mr. Steven Bloom. This interview occurred during the virtual 62nd Annual Meeting of the American Society of Hematology in 2020, held virtually due to the coronavirus pandemic. Steve is a fellow pharmacist who has been active in the pharmaceutical industry throughout his career.
Mr. Bloom asked Dr. Furman to offer an opinion on what presentations he was most looking forward to hearing during the ASH 2020 Annual Meeting. Dr. Furman stated that he was especially interested in two MRD-Driven studies, the Murano and Captivate trials. These two studies involve fixed-duration therapies for chronic lymphocytic leukemia.
Minimal Residual Disease (MRD) refers to the small number of cancer cells in the body after treatment. Many clinicians are pushing for a move to refer to this as Measurable Residual Disease. Until recently, the most common means of determining MRD has been the Flow Cytometry test, which can detect one malignant cell among 10,000 leukocytes. Next-generation sequencing testing on a platform such as clonoSEQ can find one malignant cell in a million leukocytes. The FDA approved clonoSEQ for testing MRD from peripheral blood or bone marrow samples in August 2020.
The Murano trial compared the combination of venetoclax plus rituximab to the chemoimmunotherapy combination of bendamustine plus rituximab. The venetoclax-based combination showed continued superiority in the five-year follow-up data presented at ASH 2020. In this study, relapsed/refractory (R/R) CLL patients received venetoclax for 24 months along with rituximab during the first six months.
In the Captivate study, patients received ibrutinib as monotherapy for three months and then started the ramp-up of venetoclax in the fourth month. The duration of this protocol was also 24-months. The subjects in this study were previously untreated CLL patients (treatment-naïve).
- Furman correctly states that the current primary role for evaluating a patient’s MRD status is to assess post-treatment response. In the case of clinical trials, there may be interim checks at different times within the study.
- As with any new technology, Dr. Furman believes that to more fully use MRD status, physicians will continue to learn from clinical trials, and new uses of MRD status may arise.
- Fixed-duration combination therapies that rely on MRD response at present utilize arbitrary durations. As mentioned, the Murano and Captivate trial were 24 months in duration. The CLL14 study of venetoclax and obinutuzumab was only twelve months. Dr. Furman believes that over time we will be able to determine what the optimal period should be.
- One fear that Dr. Furman has is that some patients remain MRD positive with these fixed duration clinical trials at the end of therapy. He wonders if these patients would benefit from a more extended period of treatment. He states, “It is important that we not leave efficacy on the table.”
- Some researchers believe that there is a plateau in attaining uMRD at approximately 18 months. A benefit of longer-term follow-up will be our ability to determine if this is correct or if some patients respond later than others.
- The advent of ibrutinib (Imbruvica®), the first Bruton’s Tyrosine Kinase inhibitor (BTKi), has dramatically changed the treatment of Chronic Lymphocytic Leukemia (CLL) in the last decade. Dr. Furman says in his practice, eighty (80) percent of patients do extraordinarily well on ibrutinib with a low rate of progression. The remaining twenty (20) percent experience adverse effects, including transformation to more aggressive lymphomas or resistance to ibrutinib. BTKi monotherapy may be the best choice for the eighty percent, but combinations may be the answer for the 20%.
- Furman believes that the combination of ibrutinib and venetoclax may be more potent than either the venetoclax plus obinutuzumab or venetoclax plus rituximab combinations. Those of you who follow me know that I was able to reach uMRD seven months after my physician agreed to add venetoclax to the ibrutinib I had been on for 3.5 years. I stopped the venetoclax one year after a bone marrow biopsy confirmed uMRD.
The treatment landscape for those of us with CLL/SLL has changed dramatically in the past decade or less. We see decreasing reliance on chemoimmunotherapies that were the only option in the past. We have seen a move from sequential use of targeted therapies to control our CLL to combinations of drugs that allow patients to attain undetectable MRD.
Evidence has shown that patients who get to uMRD have more prolonged progression-free survival and overall survival. Dr. Furman eloquently points out that we still have much to learn about MRD and its use in clinical practice.
To learn more about clinical trials, in general, go to https://cllsociety.org/clinical-trials
There is much to learn from Dr. Furman’s thoughtful perspectives during this interview on MRD and fixed duration therapies. Please note that there is only audio for Dr. Furman.
Thanks for reading this summary and viewing this interview.
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).