expert roundtables

Novel Therapeutic Combinations for Chronic Lymphocytic Leukemia

by Jennifer R. Brown, MD, PhD, Jan A. Burger, MD, PhD, Anthony Mato, MD, MSCE

Overview

There is growing interest in novel therapeutic combinations for the treatment of patients with chronic lymphocytic leukemia (CLL), especially in the context of high-risk disease. Excitement stems from the availability of newer agents to target the disease-specific biology of CLL and from the prospect of very durable responses with combination therapy. Clinical trials are under way to identify the most promising combinations and sequencing strategies. Our featured experts express optimism, but it is tempered by several anticipated challenges, including the perceived need for more nimble, actionable clinical trial designs and for increased patient access to and affordability of multiple novel therapies at once.

Q: What are your thoughts on the use of novel therapy combinations to achieve synergistic effects in the treatment of aggressive CLL?

Jan A. Burger, MD, PhD

Professor, Tenured, Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

“As we look to the future, there is excitement about the possibility of replacing chemotherapy-based treatments with these novel agents for many patients.”

Jan A. Burger, MD, PhD

The novel agents continue to generate excitement among clinicians and patients, and building on this excitement is the fact that these novel therapies were introduced when we began to learn much about disease biology, especially the role of B-cell receptor signaling. During the last decade, there has been a tremendous increase in knowledge regarding the biology of CLL, and, by blocking B-cell receptor signaling and by antagonizing BCL-2, the novel agents are geared toward targeting those critical elements of the disease. Thus, the excitement at this time comes from having agents available to address disease-specific biology. As we look to the future, there is excitement about the possibility of replacing chemotherapy-based treatments with these novel agents for many patients. It will be interesting to see what the role of chemotherapy will become once we are informed by randomized clinical trials comparing novel agents with chemoimmunotherapy in the front-line setting. I am also interested in more fully understanding the benefits of combination therapy vs long-term monotherapy, sequential therapy, or even intermittent therapy. There is enthusiasm about combination treatments because they may lead to minimal residual disease (MRD) negativity in patients, but it is unproven with the novel agents that MRD negativity will eventually translate into improved long remission and treatment-free survival.

Jennifer R. Brown, MD, PhD

Director, Center for Chronic Lymphocytic Leukemia
Dana-Farber Cancer Institute
Professor of Medicine
Harvard Medical School
Boston, MA

“I am also very excited about the potential of novel agent combinations—and the potential for very durable responses based on those combinations.”

Jennifer R. Brown, MD, PhD

I am also very excited about the potential of novel agent combinations—and the potential for very durable responses based on those combinations. We believe that giving high-risk patients 2 such drugs is likely to be of great benefit because of the likelihood of reducing the outgrowth of resistant clones from clonal evolution. That is, with combination therapy, the development of resistance may be forestalled or hindered. However, we cannot get such a regimen paid for currently, and, in the absence of registration trials designed to register those combinations, it is not clear that we will be able to get them paid for. That is something that is quite frustrating.

Anthony R. Mato, MD, MSCE

Director, Chronic Lymphocytic Leukemia Program
Associate Attending, Memorial Sloan Kettering Cancer Center
New York, NY

“While this may not be currently evident based on available data, we are certainly getting to the point where it is possible to imagine patients having deep, durable responses without the need for traditional cytotoxic chemotherapy or transplantation—and that is incredibly exciting to me.”

Anthony Mato, MD, MSCE

In the next generation of studies, control arms and/or next therapies after the censoring of patients should be considered in the trial designs to help shed light on certain areas. For example, if all combinations are on the table, how does one go about selecting the right combination, and/or is sequential monotherapy superior to combination therapy? That said, we are approaching a time that may be characterized by a sufficient understanding of CLL disease biology and a sufficient number of therapeutic tools available for clinical use. A time in which we might be inducing deep enough remissions with novel agents or with cellular therapies that cure without significant toxicity is not impossible to imagine for a larger subset of cases. While this may not be currently evident based on available data, we are certainly getting to the point where it is possible to imagine patients having deep, durable responses without the need for traditional cytotoxic chemotherapy or transplantation—and that is incredibly exciting to me.

References

Burger JA, Landau DA, Taylor-Weiner A, et al. Clonal evolution in patients with chronic lymphocytic leukemia developing resistance to BTK inhibition. Nat Commun. 2016;7:11589. 

Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3705-3715. 

Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 2017; 31(10): 2075-2084. 

Hamasy A, Wang Q, Blomberg KE, et al. Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant. Leukemia. 2017;31(1): 177-185. 

Itchaki G, Brown JR. Experience with ibrutinib for first-line use in patients with chronic lymphocytic leukemia. Ther Adv Hematol. 2018;9(1):3-19. 

Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050-1056. 

Pilot Trial Of Autologous T Cells Engineered To Express Anti-CD19 Chimeric Antigen Receptor (CART19) In Combination With Ibrutinib In Patients With Relapsed Or Refractory CD19+ Chronic Lymphocytic Leukemia (CLL)Or Small Lymphocytic Lymphoma (SLL). Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02640209. Accessed April 15, 2018. 

Shustik C, Bence-Bruckler I, Delage R, Owen CJ, Roze CL, Coutre S.. Advances in the treatment of relapsed/refractory chronic lymphocytic leukemia. Ann Hematol. 2017;96(7):1185-1196. 

Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with cd19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35(26):3010-3020. 

Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol. 2018;36 (suppl; abstr 7502).

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