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Clinical Trial
. 2018 Jan;32(1):83-91.
doi: 10.1038/leu.2017.175. Epub 2017 Jun 8.

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL

J R Brown  1 , P Hillmen  2 , S O'Brien  3 , J C Barrientos  4 , N M Reddy  5 , S E Coutre  6 , C S Tam  7 , S P Mulligan  8 , U Jaeger  9 , P M Barr  10 , R R Furman  11 , T J Kipps  12 , F Cymbalista  13 , P Thornton  14 , F Caligaris-Cappio  15 , J Delgado  16 , M Montillo  17 , S DeVos  18 , C Moreno  19 , J M Pagel  20 , T Munir  2 , J A Burger  3 , D Chung  21 , J Lin  21 , L Gau  21 , B Chang  21 , G Cole  21 , E Hsu  21 , D F James  21 , J C Byrd  22
Affiliations
Clinical Trial

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL

J R Brown et al. Leukemia. 2018 Jan.

Abstract

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

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Conflict of interest statement

JRB has received honoraria from Celgene, Gilead, Infinity, Genentech/Roche, Janssen, Pharmacyclics, Pfizer and Sub BioPharma, has served in an advisory role for Celgene, Gilead, Infinity, Genentech, Janssen, Pfizer and Pharmacyclics, and has been reimbursed for expenses by Gilead, Sun BioPharma, Pfizer and Janssen. PH has served as a consultant for Roche, Glaxo Smith Kline, Janssen, Gilead, and AbbVie, received honoraria from AbbVie, Gilead, Glaxo Smith Kline, Roche, Novartis, Pharmacyclics and Janssen, and research funding from Roche, Novartis, Glaxo Smith Kline, Janssen, Gilead, AbbVie, Celgene, Pharmacyclics. SOB has served as a consultant and received honoraria from Pharmacyclics and Janssen, and received research funding from Pharmacyclics. JCBarrientos has served as a consultant to Gilead, AbbVie, and Janssen, and received research funding from AbbVie and Gilead. NMR has served as a consultant for Celgene, Infinity, Gilead, and AbbVie. SEC has served in an advisory role for Janssen and Pharmacyclics, and has received research funding from AbbVie and Pharmacyclics. CT has received honoraria from Janssen, research funding from Janssen, and has served in an advisory role for Janssen. SPM has served as a consultant for and received honoraria from AbbVie, Gilead, Glaxo Smith Kline, Janssen, Roche, received research funding from AbbVie, Janssen, Roche, participated in speakers’ bureau for AbbVie, Gilead, Janssen, Roche. UJ has served as a consultant, and received honoraria and reimbursements from Janssen and Roche. PMB has served as a consultant for Pharmacyclics, AbbVie and received research funding from Pharmacyclics. RRF has received honoraria from Pharmacyclics, and has served in an advisory role and on Speakers’ Bureaus for Pharmacyclics. TJK has served as a consultant for AbbVie, Genentech, Gilead, and received research funding from AbbVie, Genentech, Pharmacyclics. FC has received research funding from Janssen, honoraria from Gilead, Janssen, Mundipharma and AbbVie, has consulted for Gilead, Janssen and AbbVie, and been reimbursed by Janssen, and Roche. PT has served as a consultant for Janssen. FCC has received honoraria and served as a consultant for Celgene, Janssen, Pharmacyclics. JD has received honoraria from and served as a consultant for Gilead, Novartis, Glaxo Smith Kline, Janssen, Roche, and received research funding from Infinity, Roche. MM has received honoraria from and served in a consultancy role for Roche, Gilead, and Janssen, and received honoraria from Novartis. SDV and CM have no relevant conflicts of interest to disclose. JMP has served as a consultant for Gilead and Pharmacyclics, and received research funding from Pharmacyclics, AbbVie, and TG Therapeutics. TM has received honoraria from Pharmacyclics, Gilead, and Alexion and has served as a consultant for Morphosys. JAB has served as a consultant for Janssen, Portola, has received research funding from Gilead, Pharmacyclics, and reimbursement from Janssen, Roche. DC is employed by Pharmacyclics and has stock/ownership in Gilead and AbbVie. JL, LG, BC, GC, EH, DFJ are employed by Pharmacyclics and have stock/ownership in AbbVie. JCByrd has no relevant conflict of interest to disclose.

Figures

Figure 1
Figure 1
PFS in patient subgroups. (a) Overall PFS; P<0.0001 for the comparison of ibrutinib vs ofatumumab. (b) PFS in patients with del17p CLL; P=0.2575 for ibrutinib-treated patients with and without del17p and P=0.0582 for ofatumumab-treated patients with and without del17p. (c) PFS in patients with 1 vs >1 prior therapy; P=0.0348 for ibrutinib-treated patients with 1 prior line vs >1 prior line of therapy and P=0.2761 for ofatumumab-treated patients with 1 prior line vs >1 prior line of therapy. (d) PFS in patients who did or did not develop lymphocytosis; P=0.0259 for ibrutinib-treated patients with and without lymphocytosis at baseline and P=0.0095 for ofatumumab-treated patients with and without lymphocytosis.
Figure 2
Figure 2
PFS with ibrutinib by cytogenetics (FISH)/mutational association. (a) PFS in patients by del17p/del11q CLL subgroups; the del17p subgroup contains patients with del17p with or without del11q (P=0.2160 comparing all three groups). (b) PFS in patients by del17p/TP53 CLL subgroups (P=0.1737 for both del17p and TP53 mutation vs either del17p or TP53 mutation; P=0.0381 for both del17p and TP53 mutation vs neither; P=0.5022 for either del17p or TP53 mutation vs no del17p or TP53 mutation).
Figure 3
Figure 3
PFS with ibrutinib by del17p/TP53 status and complex karyotype. (a) PFS with ibrutinib in patients by any del17p/TP53 alteration vs none. (b) PFS with ibrutinib in all patients with or without complex karyotype.
Figure 4
Figure 4
Overall survival with ibrutinib by del17p/TP53 status and complex karyotype. (a) Overall survival with ibrutinib in patients by any del17p/TP53 alteration vs none. (b) Overall survival with ibrutinib in all patients with or without complex karyotype.
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