Our highest-risk patients continue to be those with del(17p) or TP53 mutation, and this is probably true even with newer therapies. Thus, it is important to identify these patients up front, to triage away from chemoimmunotherapy and toward novel agent therapies. Other important factors include immunoglobulin heavy chain variable region (IGHV ) gene mutation status and certain patient-specific factors (eg, age, comorbidities, stage of disease). And these things were codified, to some extent, in the CLL International Prognostic Index, although that was developed based on data from the chemoimmunotherapy era.

We recently published on the extended follow-up data and the impact of high-risk prognostic factors from the phase 3 RESONATE (NCT01578707) study in patients with previously treated CLL/small lymphocytic lymphoma. In our analysis, we found that efficacy with ibrutinib remains high at the 2-year follow-up point of the RESONATE study, with 74% of patients alive and progression-free. The marked benefit of ibrutinib continues and was preserved in all evaluable genetic subgroups.

RESONATE was a randomized comparison of ibrutinib to ofatumumab in previously treated patients with CLL; many patients had high-risk prognostic factors. The first report of this trial demonstrated that ibrutinib significantly improved progression-free survival (PFS), overall survival, and overall response rates (ORR) compared with ofatumumab, and was acceptably tolerated, leading to the full approval of ibrutinib for previously treated CLL and del(17p) CLL.

Consistent with a relapsed, higher-risk population, the frequencies of TP53, NOTCH1, SF3B1, and BIRC3 mutations were high among participants in the RESONATE trial. Ibrutinib markedly improved PFS and ORR in all genetic subgroups over ofatumumab; in particular, with an additional year of follow-up, patients on ibrutinib with either del(17p) or TP53 mutation did not show markedly worse PFS than those without these genetic abnormalities. Of note, similar to prior reports, more than half of patients with TP53 mutations did not have del(17p)—such patients experience poor outcomes to chemotherapy regimens, yet TP53 mutational testing is not standardly performed in the United States. Furthermore, those patients with both del(17p) and TP53 did show reduced PFS compared with patients with neither, even at this 2-year follow-up report.