Ibrutinib (Ibr), idelalisib (Ide), and venetoclax (Ven) are all now approved for treating chronic lymphocytic leukemia (CLL) patients in the United States. However, in the absence of head-to-head comparator trials, there is a lack of understanding on the optimal sequence of these agents and the best management choice upon failure of the first selected agent. To address these practice gaps, 9 large US cancer centers and the Connect CLL Registry collaborated to capture the experience of 683 CLL patients treated with kinase inhibitors (KIs), focusing on optimal sequencing and patterns of failure. Mato and colleagues now report on the results from a multicenter, retrospective analysis of CLL patients treated with Ibr-, Ide-, or Ven-based therapy. They examined demographics, discontinuation rates, reasons for discontinuation, overall response rates (ORRs), survival, and post-KI salvage strategies. The primary end point was progression-free survival (PFS) (time from KI treatment to progression, death, or last follow-up). Secondary end points included overall survival (OS), ORRs, and reasons for discontinuation of the agent.
A total of 683 patients treated with KI therapy (Ibr as first KI = 621/Ide as first KI = 62) were identified. ORR to Ibr as first KI was 69% [complete response (CR) 11%, partial response (PR) 45%, and PR with lymphocytosis [PR-L] 13%) and Ide was 81% (CR 5%, PR 71%, PR-L 5%). With a median follow-up from start of first KI of 17 months, median PFS and OS for the entire cohort from first KI was 35 months (216 events) and not reached, respectively (107 events). Interestingly, patients treated with Ibr (vs Ide) as first KI had a significantly better PFS in all settings; frontline (hazard ratio [HR], 2.8; confidence interval [CI], 1.3-6.3; P=0.01), relapsed-refractory (HR, 2.8; CI, 1.9-4.1; P<0.001), clinical trials (HR, 3.3; CI, 1.8-5.9; P<0.001), commercial use (HR, 2.5; CI, 1.5-4.0; P<0.001), del17p (HR, 2.0; CI, 1.2-3.4; P=0.008), or complex karyotype (HR, 2.5; CI, 1.2-5.2; P=0.02). Moreover, at the time of initial KI failure, the use of either an alternate KI or Ven was associated with superior PFS compared with chemoimmunotherapy (CIT) combinations. When treated with an alternate KI (Ibr followed by Ide or Ide followed by Ibr), patients intolerant of KI therapy due to toxicity had a superior PFS compared with those taken off KI therapy due to CLL progression (P=0.03). Furthermore, patients who had failed therapy with Ibr had a marginally better PFS if treated with Ven (ORR, 79%) versus Ide (ORR, 46%) (HR, 0.6; CI, 3-1.0; P=0.06). Reasons for discontinuation of ibr included toxicity (52%), progression of disease (20.5%), and other causes (eg, death, patient’s preference, Richter transformation, stem-cell transplant, secondary malignancy, and cost). Similarly, reasons for Ide discontinuation included toxicity (45%), progression of disease (27%), and the other causes listed above. ORR was 46% in the Ibr→Ide switch group, 75% in the Ide→Ibr switch group, and 74% in the KI→Ven switch group.
This was the largest multicenter experience of real-world outcomes of CLL patients treated with these novel agents. The authors concluded that Ibr appears superior to Ide in all settings as first choice KI. Furthermore, in the setting of KI failure, an alternate KI or Ven therapy appears superior to CIT combinations. An alternate KI appears particularly effective in the setting of intolerance to a prior KI. However, the use of Ven upon Ibr failure may be superior to the use of Ide. These data provide guidance for sequencing of novel agents, and support the need for trials directly comparing novel agents and sequencing strategies in CLL to achieve value-based medicine.
Mato AR, et al. ASH 2016. Abstract 4400.