IGHV Mutation Status Does Not Affect CLL Survival Among Ibrutinib-Treated Patients

Unmutated immunoglobulin heavy chain variable region gene (IGHV) status does not adversely impact survival among ibrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), according to an integrated analysis of data from three phase III clinical studies (RESONATE, RESONATE-2, and HELIOS), presented (abstract CT158/24) at the American Association for Cancer Research (AACR) Annual Meeting 2017, held April 1–5 in Washington, DC.

Unmutated-IGHV disease was “an adverse predictor of outcome” for patients who received standard treatment, but not for ibrutinib-treated patients, the authors explained. The findings suggest that ibrutinib does an end-run around IGHV’s role in CLL/SLL.

Patients with unmutated IGHV are already known to fare more poorly under standard-of-care chemotherapy than those harboring IGHV-mutated disease. The authors sought to determine the prognostic implications of unmutated IGHV status for patients who are treated with ibrutinib, which targets Bruton’s tyrosine kinase signaling on B cells.

The authors studied the associations between survival outcomes following ibrutinib administration and IGHV mutation status in 985 CLL/SLL participants in the three studies. They pooled data for analysis from 491 control-group patients (366 with IGHV-unmutated CLL and 125 with IGHV mutations) who did not receive ibrutinib, and 494 patients who received ibrutinib (420 mg/d; 351 with IGHV-unmutated disease and 143 with mutated IGHV).

Control-group patients had received ofatumumab, chlorambucil, and/or bendamustine/rituximab. At baseline, patients with IGHV-unmutated disease were less likely to be treatment-naïve (17% vs 31% of patients) and more likely to have bulky disease (60% vs 37%) or to have del(11q) mutations (32% vs 16%), the authors cautioned. Patient characteristics at baseline were otherwise similar.

At a median follow-up of 21.4 months for ibrutinib-administered patients and 20.6 months for control-group patients, progression-free survival (PFS) and overall survival (OS) were similar among ibrutinib-treated patients (P = .93 for ibrutinib vs control), regardless of IGHV mutation status (2-year OS: 88% vs 89% for IGHV-unmutated and mutated disease, respectively; P = .86).

However, as expected, in control-group patients, IGHV-unmutated disease was associated with poorer survival than IGHV-mutation-harboring disease, even in multivariate analyses that adjusted for age, sex, baseline ECOG, del(11q) and del(17p) status, prior lines of therapy, and other prognostic variables (2-year OS: 78% vs 87%; adjusted P = .01).

Adverse event (AE) rates and rates of AEs leading to treatment discontinuation were similar among patients who received ibrutinib and standard treatment, regardless of IGHV status.