expert roundtables

Optimal Duration and Dose of Novel Agents for Chronic Lymphocytic Leukemia

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

Overview

Novel agents such as ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, and idelalisib, a phosphatidylinositol 3-kinase (PI3K) inhibitor, achieve survival benefits without inducing complete remissions in patients with chronic lymphocytic leukemia (CLL). These therapies are generally maintained at their approved doses until patients show substantial side effects or until disease progression occurs. Dose modifications do occur in practice, in accordance with labeling information. Additionally, the theoretical possibility of novel agent discontinuation after a fixed duration is of interest to researchers and patients; however, no data exist to support the practice. Our featured experts in the field discuss the optimal dose and duration of novel agents for CLL.

Q: In our physician survey, the optimal dose and duration of novel agents for CLL was a topic of great interest. What might account for this interest, and what are the unanswered questions in this area?

Anthony Mato, MD, MSCE

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

“Novel agents work very well, and, after 6 months to 1 year on therapy, patients often feel that they are doing fine and wonder whether they may stop, or at least question reasons for continued therapy.”

Anthony Mato, MD, MSCE

The question of duration of therapy with the novel agents is somewhat patient-driven. Novel agents work very well, and, after 6 months to 1 year on therapy, patients often feel that they are doing fine and wonder whether they may stop, or at least question reasons for continued therapy. So, that is an issue being raised more and more by patients. However, at this time, there is no approved drug labeling that involves discontinuation of a novel agent after a fixed duration. The question is being asked, but there are no data yet to support that practice.

Jan A. Burger, MD, PhD

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

“The question regarding the optimal duration of therapy with the novel agents, particularly ibrutinib and idelalisib, is unanswered.”

Jan A. Burger, MD, PhD

The question regarding the optimal duration of therapy with the novel agents, particularly ibrutinib and idelalisib, is unanswered. The current practice is to treat patients until they are intolerant and develop side effects (ie, side effects that warrant treatment discontinuation or change in treatment) or until they develop resistance. And whether that is the right strategy has not really been tested in studies—at least not for the BTK and PI3K inhibitors. It is different if you are considering venetoclax, which, conceptually, is a limited-time treatment and often is terminated after 1 or 1.5 years. The standard with ibrutinib, the most widely used novel agent in CLL, is long-term treatment to avoid relapse. Now, with acalabrutinib, there is another BTK inhibitor that may come into use at some point in the future. I am critical of the concept of long-term treatment to avoid relapse, as there is no proof that this is the best way to use these agents. I believe that other alternatives should be explored, based on the concept of clonal evolution (ie, that long-term treatment with 1 agent or 1 mechanism may lead to the emergence of cells that find a way around this particular pathway).

We know that patients with 17p deletion (del[17p]) tend to have a higher rate of eventually losing response due to emerging clones that are resistant, and that is thought to be a clonal evolution process whereby resistant subclones (which are very rare at the beginning of treatment) over time and with continuous therapeutic pressure begin to grow and demonstrate a growth advantage. This finding is reminiscent of what was found earlier with fludarabine, cyclophosphamide, and rituximab (FCR) that applies therapeutic pressure on the CLL clone as well, and allows the outgrowth of high-risk subclones. And with the novel agents, we are seeing something that seems somewhat similar. So, how can we avoid that possibility of clonal evolution during treatment with these novel agents? This key question is particularly relevant for patients with del(17p). For these high-risk individuals, new treatments may need to be designed that apply either intermittent rather than continuous treatment or alternatively sequenced treatment, whereby patients would be treated with a BTK inhibitor for a certain period of time (not indefinitely), and then treatment would need to be stopped and later switched to avoid the emergence of selected resistant subclones. Hopefully, clinical trials will eventually address these types of questions.

Jennifer R. Brown, MD, PhD

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

“The other question is whether getting patients into deep remission and stopping treatment is preferred to keeping patients on therapy and relapsing on therapy. We do not really have any current data to address that or studies planned to address it in a comparative fashion.”

Jennifer R. Brown, MD, PhD

The other question is whether getting patients into deep remission and stopping treatment is preferred to keeping patients on therapy and relapsing on therapy. We do not really have any current data to address that or studies planned to address it in a comparative fashion.

Anthony Mato, MD, MSCE

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

Regarding the optimal dose, we follow the US Food and Drug Administration (FDA)–approved doses per the drug labeling information. However, dose modification (eg, for toxicities or adverse events) may occasionally be required in accordance with drug labeling recommendations. And, in that regard, we have been interested in learning more about the potential impact of modified dosing on outcomes. Barr and colleagues found an association between higher dosing intensity of ibrutinib (defined as the proportion of actually administered vs planned doses of 420 mg) and improved progression-free survival, with patients who missed more than 1 week of treatment experiencing more progression-free survival events. We conducted a multicenter, retrospective analysis of patients with CLL who had been treated with ibrutinib using doses below the FDA-recommended starting dose. Ibrutinib is approved at a daily dose of 420 mg. Reduced-dose ibrutinib was defined in our study as a sustained (≥2 months) dosing at less than 420 mg per day, either at treatment initiation or within 3 months of starting therapy. The overall response rate, including partial response with lymphocytosis, in the standard-dose cohort was 85% vs 84% in the reduced-dose group; the median overall survival for the standard-dose and reduced-dose cohorts were not reached. Further, in Cox regression univariate analyses, ibrutinib dose (standard dose vs reduced dose) did not impact progression-free survival. So, while this was a retrospective analysis and follow-up is limited, it may provide some reassurance to oncologists and patients if and when a dose reduction is indicated clinically.

References

Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.

Barr PM, Brown JR, Hillmen P, et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129(19):2612-2615.

Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.

Mato AR, Timlin C, Ujjani C, et al. Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced-dose ibrutinib: results from a multi-centre study. Br J Haematol. 2018;181(2):259-261.

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