Frail patients with relapsed CLL, especially those characterized by adverse prognostic factors such as the presence of del17p and/or TP53 mutation, present a significant therapeutic challenge. Idelalisib is a first-in-class, oral inhibitor of PI3Kd that was recently approved for the treatment of relapsed CLL in combination with rituximab. At ASH 2014, Sharman and colleagues presented a second interim analysis of a phase 3 study evaluating idelalisib in combination with rituximab in relapsed CLL with a focus on high-risk subgroups (Blood. 2014;124. Abstract 330). A total of 220 patients with relapsed CLL were randomized to idelalisib plus rituximab versus placebo plus rituximab; the patients in this study were high risk, and 42% to 45% had del17p and/or TP53 mutation, 30% to 34% had del11q, 83% to 85% had unmutated IGVH, 85% to 92% were ZAP70-positive, and 78% to 85% had ?2-microglobulin of >4 mg/L.
At the time of this analysis, the median exposure was 5 months with idelalisib-rituximab and 4 months with placebo-rituximab. The median PFS was not reached in the idelalisib-rituximab group, and was 5.5 months in the placebo-rituximab group, with 12-month PFS rates of 66% for idelalisib-rituximab and 13% for placebo-rituximab. The PFS strongly favored idelalisib-rituximab in all high-risk subgroups, including patients with del17p, TP53 mutation, del11q, or unmutated IGVH, as well as those with disease-related risk factors, such as advanced Rai stage or high levels of ?2-microglobulin. Similarly, the median OS was not reached in the idelalisib-rituximab group, but was 14.8 months in the placebo-rituximab group. The most common AEs in patients receiving idelalisib-rituximab included pyrexia, fatigue, nausea, chills, and diarrhea/colitis.
In frail patients with relapsed CLL, idelalisib-rituximab demonstrated significant improvement over placebo plus rituximab in PFS, ORR, and OS, with an acceptable safety profile. Most important, these benefits were observed across all high-risk subgroups, including those with high-risk genomic markers and disease severity markers.
