What Is The Optimal Sequencing of Novel Agents for CLL?

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Current guidelines do not define the optimal sequence of ibrutinib, idelalisib, or venetoclax for CLL treatment.
Current guidelines do not define the optimal sequence of ibrutinib, idelalisib, or venetoclax for CLL treatment.

Ibrutinib appears to be superior to idelalisib as first kinase inhibitor for patients with chronic lymphocytic leukemia (CLL), with an alternate kinase inhibitor or venetoclax appearing superior to chemoimmunotherapeutic options in the setting of kinase inhibitor failure, according to a retrospective real-world study published in Annals of Oncology.1

Ibrutinib, idelalisib, and venetoclax are approved by the U.S. Food and Drug Administration for the treatment of patients with CLL; however, current guidelines do not define the optimal sequence of these novel agents. 

To evaluate the optimal sequencing of these agents, researchers retrospectively analyzed data from 683 patients with CLL who received kinase inhibitors or venetoclax. Baseline characteristics were similar in the ibrutinib and idelalisib groups.

With a median follow-up of 17 months, results showed that median progression-free survival and overall survival for the entire cohort was 35 months and not reached, respectively.

Among those receiving a first kinase inhibitor, 69% of patients treated with ibrutinib achieved an overall response vs 81% of those who received idelalisib.

Median progression-free survival was significantly better with ibrutinib than idelalisib in the frontline setting (hazard ratio [HR], 2.8; 95% CI, 1.3-6.3; P = .01), the relapsed/refractory setting (HR, 2.8; 95% CI, 1.9-4.1; P < .001), in patients harboring a 17p deletion (HR, 2.0; 95% CI, 1.2-3.4; P = .008), and in those with a complex karyotype (HR, 2.5; 95% CI, 1.2-5.2; P = .02).

Investigators also found that an alternate kinase inhibitor or venetoclax was superior with respect to progression-free survival as compared with chemoimmunotherapy in patients who failed the initial kinase inhibitor.

In addition, patients who discontinued ibrutinib therapy due to disease progression or unacceptable toxicity had a nonsignificant 40% reduced risk of progression or death if they received venetoclax as opposed to idelalisib (HR, 0.6; 95% CI, 0.3-1.0; P = .06).

These findings ultimately support the need for prospective trials evaluating sequencing strategies of novel agents to optimize treatment algorithms for patients with CLL.


1. Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multi-center study of 683 patients. Ann Oncol. 2017 Jan 25. [Epub ahead of print]
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