Ibrutinib was approved by the FDA in February 2014 for the treatment of patients with CLL whose disease did not respond to at least one prior therapy.

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Ibrutinib is an irreversible Bruton tyrosine kinase (BTK) inhibitor, leading to the decreased activity of downstream signaling events and, ultimately, the proliferation of leukemic cells.4,5

Furthermore, ibrutinib has been shown to suppress the expression adhesion proteins in the bone marrow microenvironment, impairing B-cell homing.6

The efficacy of ibrutinib in relapsed and heavily pretreated patients with CLL was demonstrated in a multicenter, nonrandomized, open-label, phase 1b/2 trial.7

In this trial, the overall response rate was 71% in both the 420-mg and 840-mg arms. Importantly, the response rate among patients with a 17p deletion was similar at 68%; however, patients with a mutated immunoglobulin variable-region heavy-chain (IGHV) gene had a significantly lower response rate (P=0.005).

The PFS and OS rates were 75% and 83%, respectively, at 26 months. In addition, among patients with the 17p deletion, the 26-month PFS rate was 57% and OS rate was 70%.

The most common AEs included diarrhea, upper respiratory tract infection, and fatigue. Pneumonia, dehydration, and neutropenia were the most common grade 3 or higher AEs.

The phase 2 RESONATE-17 trial further demonstrated ibrutinib’s efficacy in patients with a 17p deletion.8 In this nonrandomized trial, patients with relapsed CLL or small lymphocytic leukemia (SLL) with a 17p deletion received ibrutinib monotherapy for a median follow-up of 13 months. The 12-month PFS rate was 79.3%, and the median duration of response had not yet been reached.


In July 2015, the FDA approved the use of idelalisib in combination with rituximab in patients with relapsed CLL in whom rituximab monotherapy is considered appropriate due to the presence of comorbidities. Idelalisib specifically and reversibly binds to the p110δ isoform of PI3 kinase (PI3K), reducing the phosphorylation of downstream signaling factors such as Akt. As a result, the tumor microenvironment within the bone marrow and chemokine signaling is disrupted, thereby promoting apoptosis of leukemic cells.9,10

A randomized, double-blind, phase 3 trial demonstrated that idelalisib plus rituximab improved overall response rates compared with placebo plus rituximab.11 Median PFS was not reached in the idelalisib arm, but was 5.5 months in the placebo arm (HR, 0.15; P<0.001). In addition, the 12-month OS rate was 92% in the idelalisib arm compared with 80% in the placebo arm (HR, 0.21; P=0.02).

A second interim analysis of the trial demonstrated that the addition of idelalisib improved PFS for patients with unfavorable cytogenetics, including a 17p deletion, TP53 mutation, or ZAP70 positivity.12

Furthermore, a nonrandomized, open-label, phase 2 extension of study 101-08 of front-line idelalisib monotherapy resulted in a 90% response rate.13

Serious AEs were more common in the idelalisib arm, and the most common AEs included diarrhea, nausea, pyrexia, fatigue, and chills. Anemia, neutropenia, thrombocytopenia, and liver enzyme elevation were more common in the idelalisib arm compared with the placebo arm.