INTEGRATED ANALYSIS: OUTCOMES OF IBRUTINIB‐TREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LEUKEMIA (CLL/SLL) WITH HIGH‐RISK PROGNOSTIC FACTORS

Abstract

Introduction: In phase 3 studies, ibrutinib (ibr) was superior to ofatumumab in relapsed/refractory (R/R) CLL/SLL or chlorambucil in treatment (tx)-naïve (TN) CLL/SLL. Ibr + bendamustine/rituximab (BR) was superior to BR in R/R CLL/SLL. Clinical outcomes of pts in these 3 studies were examined to determine the impact of certain prognostic risk factors other than del17p. Methods: RESONATE: R/R CLL/SLL, ibr 420 mg/d until progressive disease (PD) or ofatumumab (≤24 wk). RESONATE-2: TN CLL/SLL (no del17p) ≥65 y, ibr 420 mg/d until PD or chlorambucil (≤12 cycles). HELIOS: R/R CLL/SLL (no del17p), BR (≤6 cycles) ± ibr 420 mg/d followed by ibr or placebo until PD. Data from 3 studies (N = 1238) were pooled to analyze outcomes with/without genomic risk factors IGHV, del11q, trisomy 12, or complex karyotype (CK). Covariates for a multivariate analysis (MVA) for progression-free and overall survival (PFS, OS): the 4 genomic risk factors, age, sex, ECOG PS, cytopenias, LDH, bulky disease, and number of prior therapies. Results: Median follow-up was 21 mo for both ibr- and comparator-tx pts. In each subgroup, PFS, OS, and response rates were higher in ibr- than comparator-tx pts, regardless of these genomic risk factors. By univariate analysis (UVA, Table) in ibr-tx pts, genomic risk factors were not associated with shorter PFS or OS, and del11q was associated with a trend of longer PFS and OS. In comparator-tx pts, unmutated (U)-IGHV, del11q, and CK were associated with shorter PFS, and U-IGHV and CK with shorter OS. By MVA for PFS/OS, in ibr-tx pts (without del17p), only ≥1 prior tx was associated with shorter PFS and OS. Age ≥ 65 and elevated LDH were associated with shorter OS, and del11q with a trend of longer OS. In comparator-tx pts, ≥1 prior tx, U-IGHV, del11q, CK, male sex, and bulky disease ≥5 cm were associated with shorter PFS; CK, male sex, bulky disease ≥5 cm, ECOG PS ≥1 and elevated LDH were associated with shorter OS. Cumulative rates of adverse events were similar in pts with/without genomic factors and reflect a median exposure of 19-20 mo for ibr-tx pts and 5-10 mo for comparator-tx pts. Conclusions: In UVA and MVA for ibr-tx pts, no clear associations were found for U-IGHV, del11q, trisomy 12, and CK with poor outcomes; del11q associated with trends of longer PFS and OS in UVA, and longer OS in MVA. In comparator-tx pts, U-IGHV, del11q, and CK associated with shorter PFS, OS, and/or lower response rate. Results suggest that risk factors associated with poor outcomes with chemotherapy have less relevance with ibr. CRR, complete response rate; HR, hazard ratio; NE, not evaluable; OR, odds ratio; ORR, overall response rate. *For IGHV, indicates mutated IGHV. **18 mo PFS rate was 8%. Keywords: chronic lymphocytic leukemia (CLL); ibrutinib; small lymphocytic lymphoma (SLL).