Chronic Lymphocytic Leukemia
Novel Agents for Chronic Lymphocytic Leukemia: Implications of a Skipped Dose vs Intermittent Dosing
Based on the available data, patients with chronic lymphocytic leukemia (CLL) being treated with novel agents such as ibrutinib or venetoclax can be assured that appropriate dose reductions or interruptions need not sacrifice their outcomes.
Director, Chronic Lymphocytic Leukemia Program
“It is important to reassure patients who may require a dose reduction or may need to have their treatment withheld for a few days (ie, in accordance with the labeling) that they can still expect good outcomes.”
One topic that has arisen with the novel agents, particularly with ibrutinib but also with venetoclax, is whether patients must be treated at the standard dose per the US Food and Drug Administration labels. The answer is yes, but it is also important to reassure patients who may require a dose reduction or may need to have their treatment withheld for a few days (ie, in accordance with the labeling) that they can still expect good outcomes with respect to the CLL.
We have published data suggesting that indicated dose reductions for these agents do not appear to significantly impact progression-free or overall survival. This is an important point to make when offering reassurance to patients. Reassuring data have also been reported by Roeker et al on the impact of dose interruptions with venetoclax due to tumor lysis syndrome and other adverse events. Further, we talk to patients in terms of risks and benefits, so we might say, for instance, that the risk of bleeding after a hip replacement or other procedure outweighs any small impact on outcomes that might result from holding ibrutinib for a few days. Some of the literature specific to the duration of dose interruption has been confusing. For example, retrospective analyses conducted by Barr et al found that withholding ibrutinib for 8 or more days was associated with a reduced median progression-free survival as compared with shorter treatment breaks. Other data later emerged suggesting that dose interruptions exceeding 8 days do not significantly impact clinical outcomes. We were interested in this research question ourselves, and we conducted several multicenter, retrospective, real-world analyses in this area. We were not able to reproduce the findings reported by Barr et al. Our data were reassuring and consistent with the ibrutinib clinical trial experience and the label.
Now, intermittent dosing of the novel agents is a separate concept where, for instance, a treatment might be given for 2 out of 4 weeks, or per some similarly modified dosing schedule. From a clinical practice perspective, I would strongly discourage those types of strategies. I have not seen any compelling data to support them. Intermittent dosing of phosphoinositide 3-kinase inhibitors is being studied because they tend to be quite toxic and there is interest in potentially minimizing adverse events through intermittent dosing. For instance, intermittently dosed duvelisib is being investigated, but results have not been published.
Ahn IE, Basumallik N, Tian X, Soto S, Wiestner A. Clinically indicated ibrutinib dose interruptions and reductions do not compromise long-term outcomes in CLL. Blood. 2019;133(22):2452-2455.
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.
Clinicaltrials.gov. Intermittent duvelisib dosing in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. https://clinicaltrials.gov/ct2/show/NCT03961672. Accessed October 24, 2019.
Mato AR, Thompson M, Allan JN, et al. Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Haematologica. 2018;103(9):1511-1517.
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.
Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019 Sep 11. doi: 10.1002/ajh.25638. [Epub ahead of print]
Roeker LE, Fox CP, Eyre TA, et al. Tumor lysis, adverse events, and dose adjustments in 297 venetoclax-treated CLL patients in routine clinical practice. Clin Cancer Res. 2019;25(14):4264-4270.