expert roundtables

Unmet Needs in Chronic Lymphocytic Leukemia

by John C. Byrd, MD; Ian W. Flinn, MD, PhD; and Jeff Sharman, MD

Overview

Targeted agents have dramatically improved clinical outcomes in patients with chronic lymphocytic leukemia (CLL) over the last decade. Nonetheless, certain unmet needs remain, including aggressive CLL subsets, disease-related immune dysfunction, and Richter’s transformation (RT).

Q:

What are the unmet needs in CLL? 

Ian W. Flinn, MD, PhD

Director, Lymphoma Research
Sarah Cannon Research Institute
Tennessee Oncology
Nashville, TN

“One of the most important unmet needs in CLL is learning how to improve the patient's own immune system to decrease morbidity and mortality.”

Ian W. Flinn, MD, PhD

A significant challenge in CLL right now is the management of the infectious complications of the disease, and this has been highlighted by the current COVID-19 pandemic. Infection continues to be a leading cause of mortality in patients with CLL.

Further, we have not yet been able to separate some of the malignant B-cell depletion from normal B-cell depletion. This problem has improved with our current therapies, but it is still an issue. 

One of the most important unmet needs in CLL is learning how to improve the patient's own immune system to decrease morbidity and mortality. Other than ceasing treatment with a current therapy, I do not know with certainty how this could be achieved; however, I think that addressing this issue might go a long way toward decreasing the patient's risk of developing some of the infectious complications of CLL.

Jeff Sharman, MD

Medical Director of Hematology Research
The US Oncology Network
Attending Physician
Willamette Valley Cancer Institute and Research Center
Eugene, OR

“The younger the patient and the more aggressive the disease, the more likely we are to exhaust the existing therapies and strategies. This is an area where we need novel strategies.”

Jeff Sharman, MD

The unmet medical needs in CLL are truly diminishing. For instance, for the typical patient with CLL who presents at, say, age 72 years, undergoes a couple of years of watch and wait, and then begins therapy, there is a very good chance that they will not succumb to the disease and that we will be able to control the CLL with existing agents for the remainder of their lifetime. 

The younger the patient and the more aggressive the disease, the more likely we are to exhaust the existing therapies and strategies. This is an area where we need novel strategies. At this point, we do not have good answers, and the problem of RT has not been solved with our current treatment strategies.

John C. Byrd, MD

The Gordon and Helen Hughes Taylor Professor and Chair
Department of Internal Medicine
University of Cincinnati College of Medicine
Cincinnati, OH

“Managing CLL in patients who relapse after treatment with targeted therapies is another area in which there is a lot of opportunity for improvement.”

John C. Byrd, MD

Managing RT is one of the greatest unmet needs in CLL. Current treatment strategies are not very effective. In my own practice, we have moved toward early chimeric antigen receptor T-cell therapy for patients with RT. There appears to be a subset of patients who benefit from this approach, but treatment with chimeric antigen receptor T cells is quite complicated, and we need to improve our understanding of RT and develop better strategies for this population.

I also agree with Dr Flinn and Dr Sharman that addressing the immune suppression of the disease is very important. The immune suppression of CLL leads to secondary cancers, and increased rates of infections and other complications can occur, even in those who undergo the watch-and-wait approach. It would be advantageous if there were avenues that we could pursue to effectively prevent these complications, even in asymptomatic patients with early stage disease.

Managing CLL in patients who relapse after treatment with targeted therapies is another area in which there is a lot of opportunity for improvement. We still lose patients with CLL to the disease or its complications, and this occurs in those who have disease progression with first- and second-line therapies.

References

Bose P, Gandhi V. Managing chronic lymphocytic leukemia in 2020: an update on recent clinical advances with a focus on BTK and BCL-2 inhibitors. Fac Rev. 2021;10:22. doi:10.12703/r/10-22

Ding W. The ongoing unmet needs in chronic lymphocytic leukemia: TP53 disruption, Richter, and beyond. Hematol Oncol Clin North Am. 2021;35(4):739-759. doi:10.1016/j.hoc.2021.04.001

Fakhri B, Andreadis C. The role of acalabrutinib in adults with chronic lymphocytic leukemia. Ther Adv Hematol. 2021;12:2040620721990553. doi:10.1177/2040620721990553

Mato AR, Davids MS, Sharman J, et al. Recognizing unmet need in the era of targeted therapy for CLL/SLL: “what’s past is prologue” (Shakespeare). Clin Cancer Res. 2022;28(4):603-608. doi:10.1158/1078-0432.CCR-21-1237

Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5

Morawska M. Reasons and consequences of COVID-19 vaccine failure in patients with chronic lymphocytic leukemia. Eur J Haematol. 2022;108(2):91-98. doi:10.1111/ejh.13722

Ortiz-Maldonado V, Frigola G, Español-Rego M, et al. Results of ARI-0001 CART19 cells in patients with chronic lymphocytic leukemia and Richter's transformation. Front Oncol. 2022;12:828471. doi:10.3389/fonc.2022.828471

Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia. J Hematol Oncol. 2021;14(1):69. doi:10.1186/s13045-021-01054-w

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