clinical topic updates

Fixed-Duration Combination Therapy vs Indefinite Therapy for Chronic Lymphocytic Leukemia

by Susan O’Brien, MD

Overview

Continuous therapy with Bruton tyrosine kinase (BTK) inhibitors and fixed-duration regimens (eg, venetoclax/obinutuzumab) are effective as first-line treatment of chronic lymphocytic leukemia (CLL). There are several disease- and patient-related factors that can help to guide selection between these options.

Expert Commentary

Susan O’Brien, MD

Associate Director for Clinical Science
Chao Family Comprehensive Cancer Center
Medical Director
Sue and Ralph Stern Center for Cancer Clinical Trials and Research
University of California, Irvine Health
Irvine, CA

There are factors related to the different durations of therapy, the different side effects, and the different clinical trials in terms of the efficacy shown in distinct CLL populations.”

Susan O’Brien, MD

Every time I start a patient on therapy now, it is, frankly, a much longer discussion than it might have been 5 or 10 years ago. And you have to put in that time to really find out what is important to the patient. When I discuss fixed-duration regimens vs continuous or indefinite therapy with BTK inhibitors, I think that it is important to put indefinite therapy into context. It should be noted that individuals who are taking blood pressure medicine, for instance, are already on an indefinite therapy. When you state it that way, it seems like a simpler concept to patients and it helps them understand. I also tell my patients that indefinite therapy does not have to mean forever, and that we can consider discontinuation if, after at least a couple of years of treatment, they achieve a nice deep response. While I typically do not have such complicated discussions with patients, I am comfortable telling them that if they want to stop the drug after a certain amount of time, then we can discuss that. 

Another consideration of continuous therapy is cost. I had a patient who initially opted to take a BTK inhibitor but, when they found out about the co-payment, they became more interested in finite therapy because the associated expenses would cease following completion of the treatment. And, obviously, side effects, which are somewhat different from the BTK inhibitors to venetoclax, are considered in view of the individual patient and their comorbidities. Bleeding risk and atrial fibrillation are concerns with the BTK inhibitors, especially in older patients; acalabrutinib is a newer BTK inhibitor that has US Food and Drug Administration approval for CLL and appears to have a lower risk of atrial fibrillation. With venetoclax, some of the concerns relate to renal dysfunction and the potential for tumor lysis syndrome, as well as neutropenia. So, if I have a patient who has frequent infections, that might be a less attractive option if there are concerns related to the onset of neutropenia.

Thus, there are factors related to the different durations of therapy, the different side effects, and the different clinical trials in terms of the efficacy shown in distinct CLL populations. A limitation of time-limited venetoclax-based regimens is the decreased efficacy seen in patients with 17p deletion or TP53 mutation. Updated data from the CLL14 trial suggest that these patients have a poorer response to venetoclax/obinutuzumab compared with those without these aberrations. In contrast, a recent analysis presented at the 62nd American Society of Hematology Annual Meeting and Exposition included combined long-term efficacy data for patients with 17p deletion or TP53 mutation from 4 different clinical trials. After 4 years of follow-up, progression-free survival was 79% and overall survival was 88% among 89 patients with TP53 aberrations receiving first-line ibrutinib. Thus, at this point, available data suggest that, from the perspective of duration of response, BTK therapy may be preferable over fixed-duration venetoclax in patients with 17p deletion or TP53 mutation.

References

Allan JN. Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukemia (CLL) with 4 years of follow-up in patients with TP53 aberrations (del[17p] or TP53 mutation): a pooled analysis from 4 clinical trials [abstract 2219]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020. 

Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol2020;21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5

Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. Blood. 2020;135(15):1204-1213. doi:10.1182/blood.2018884940

Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1915281

Shanafelt TD, Wang V, Kay NE, et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCT in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. Blood. 2019;134(suppl 1):33. doi:10.1182/blood-2019-126824

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