Initial Ibrutinib Dose and Its Modification Do Not Affect Survival in Patients with CLL

In a study published in Cancer Medicine, researchers found that in a large cohort of patients with chronic lymphocytic leukemia (CLL) receiving commercial ibrutinib (Imbruvica), initial ibrutinib dose and dose modification during therapy did not appear to impact event-free survival (EFS) or overall survival (OS).

These findings highlighted the challenges associated with continuous oral therapy with ibrutinib in patients with CLL. The results also confirmed observations from other “real-world” analyses that more patients stop ibrutinib due to toxicity rather than due to progression of disease. 

“This latter finding has major implications for clinical trial design where combination therapies with fixed duration of treatment that achieve deep remission may be more desirable than chronic long-term treatment,” the authors wrote. 

Conducting a retrospective study of patients with CLL treated with ibrutinib outside the context of a clinical trial at Mayo Clinic from November 2013 to December 2017, researchers identified 209 individuals. Overall, 131 (74%) of the patients had unmutated IGHV, 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. 

A total of 87 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician reference; n = 33, concomitant medications; and n = 11, other). Over 281 person-years of treatment, 91 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7% other). 

After a median follow-up of 24 months, the estimated median EFS was 36 months, and median OS was not reached. Using multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR], 2.37, P = 0.006) and TP53 disruption at ibrutinib initiation (HR, 1.81, P = 0.048) were found to be associated with shorter EFS, whereas only TP53 disruption (HR, 2.38, P = 0.015) was associated with shorter OS. 

“These findings should be interpreted with caution since patients who are able to adhere to therapy are generally those who are able to tolerate treatment better, and have no major comorbidities,” the authors wrote. “In this regard, patients who held ibrutinib for surgical procedures had better EFS and OS compared to those patients who held ibrutinib for toxicity.”

According to the researchers, whether lower doses of ibrutinib may be equally effective and less toxic needs to be investigated in a clinical trial, and such strategy is already being planned. Moreover, longer term follow-up in larger cohorts of patients is necessary before a lower starting dose can be considered as standard practice.

Given the need for more data, it was recommended that all patients receive therapy with ibrutinib according to the manufacturer’s prescribing information at this time. 

Notably, during the study interval, the understanding of ibrutinib-related toxicities, such as whether or not it was safe to combine with anticoagulation, and other aspects of management in this patient population evolved. Further, other agents such as idelalisib (Zydelig) and venetoclax (Venclexta) were approved by the FDA during the conduct of this study, which may have altered practice patterns, particularly in regard to stopping treatment with ibrutinib for toxicity due to availability of an alternate effective therapy.

Reference:

Parikh SA, Achenback SJ, Call TG, et al. The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice. Cancer Medicine. doi:10.1002/cam4.2998.