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Two-year follow-up of the phase III RESONATE trial of ibrutinib versus ofatumumab in R/R CLL

Jul 31, 2017

In Leukemia on 8th June 2017, Jennifer R. Brown from the Dana-Farber Cancer Institute, Boston, MA, USA, and colleagues published extended 19-month follow-up data and the impact of high-risk prognostic factors in patients with R/R CLL/SLL in the phase III RESONATE trial (NCT01578707).

RESONATE was a randomized, multicenter, open-label study comparing ibrutinib with ofatumumab. At the time of this updated analysis, 123 patients originally randomized to ofatumumab crossed-over to ibrutinib. PFS, OS, and other updated efficacy measures were evaluated by investigator assessment.

Key Highlights:

Patient characteristics and disposition

  • Ibrutinib pts (n=195):
    • Median number of 3 previous therapies, 18% of pts had only received 1 prior treatment
    • 53% received ibrutinib as their fourth-line of therapy or higher
    • del(17p) = 32%; del(11q) = 32%; TP53 mutation = 51%
  • Ofatumumab pts (n=196):
    • Median number of 2 previous therapies, 27% of pts had only received 1 prior treatment; 46% received ofatumumab as their fourth-line of therapy or higher
    • TP53 mutation = 46%
  • Median follow-up = 19 months (maximum 26 months on study)
  • 145 (74%) pts on the ibrutinib arm continue ibrutinib on study
  • Ibrutinib has been discontinued in 26% (n=50) pts due to PD (10%; n=19), AEs (7%; n=13), and death (5%; n=10)


  • At time of analysis, 86% of ibrutinib and 77% of ofatumumab pts were alive
  • Ibrutinib significantly prolonged PFS (median Not Reached [NR]) vs ofatumumab (8.1 months); HR = 0.106; benefit of ibrutinib observed in all clinical and genetic subgroups
  • In multivariate analysis, del(17p), del(11q), and β2M were found to be significant prognostic factors for PFS in all pts
  • ORR was higher in the ibrutinib arm in all evaluable subgroups versus ofatumumab (P < 0.0001)
  • Ibrutinib arm:
    • 24-month PFS rate with ibrutinib = 74%; 18-month PFS was similar regardless of baseline genetic factors but pts with SF3B1 mutation trended toward poorer 18-month PFS rate (P = 0.1424)
    • Pts with both del(17p) and TP53 mutation (n=38) versus pts with neither abnormality (n=68) had worse PFS (P = 0.0381)
    • 18-month OS for whole group = 86%; for del(17p) subgroup = 83%; for del(11q) subgroup = 89%; for neither deletion = 85%; for CK = 79%
    • PFS outcomes with ibrutinib were significantly longer (P = 0.0348), and OS outcomes were non-significantly longer (HR, 2.874; P = 0.1324), with second-line therapy vs those achieved in later lines of therapy
    • Lymphocytosis reported in 69% of pts, resolved with continued therapy in 87% of cases; median duration = 14.1 weeks
    • Best ORR increased with 90% of pts now achieving PR with Lymphocytosis (PR-L) compared to 83% vs 23% (ibrutinib vs ofatumumab; P < 0.0001) at interim analysis
    • CR/CRi rate improved to 7% of pts versus 2% at interim analysis
    • Twenty-eight pts progressed; 8 had Richter Transformation (RT), of which 6 developed Large Cell Lymphoma and 2 Hodgkin Lymphoma
  • Ofatumumab arm:
    • Pts with unmutated IGHV (P = 0.0436) and presence of del(11q) (P = 0.0654) had lower 18-month PFS rates
    • NOTCH1 mutation associated with worse overall PFS (P = 0.0064)
    • Pts with del(11q) and Complex Karyotype (CK) had significantly lower ORR versus those without del(11q) and CK (P = 0.0038 and P = 0.0015, respectively)
    • Five pts had RT, including one after crossover to ibrutinib

Safety with ibrutinib

  • The most common cumulative AE of any grade remains diarrhea, increased to 54% from 48% compared to interim analysis, followed by fatigue (34% vs 28%), nausea (31% vs 26%), and fever (30% vs 24%)
  • The most common grade ≥3 infections included upper respiratory tract infections (0.5%, sinusitis (0.5%), urinary tract infections (4%), and pneumonia (12%)
  • Grade 5 infections included pneumonia (n=4), sepsis (n=2), and neutropenic sepsis (n=1); none were considered related to study treatment
  • New onset of diarrhea, Atrial Fibrillation (AF), arthralgia, and grade ≥3 infection decreased over time
  • Grade ≥3 bleeding events were infrequent with three additional events over approximately 1-year follow-up since interim analysis: grade 3 epistaxis and spontaneous psoas hematoma (in same patient) and grade 4 subdural hematoma
  • Any grade AF was reported in 7% of pts (n=13) with a median time to onset of first event being 5.1 months; AF event resolved in 8 pts (62%)

During this 2-year follow-up of the RESONATE study, it was observed that the efficacy of ibrutinib still remained high, with nearly three-quarters (74%) of patients remaining alive and progression-free. Furthermore, tolerability was well maintained. The authors concluded that, due to a lack of PFS events, the follow-up is too short to determine if different subgroups of patients characterized by high-risk mutations have poorer PFS. It was noted that PFS seemed better in patients who developed lymphocytosis compared to those who did not. Overall, most patients “continue to do extremely well, underscoring the significant impact of ibrutinib in altering the course of relapsed CLL.”

During iwCLL 2017, Thomas J. Kipps, MD, PhD, from the University of California, San Diego, Moores Cancer Center, California, USA, gave an abstract presentation on pooled data from RESONATE, RESONATE-2, and HELIOS trials assessing the outcomes of ibrutinib-treated CLL patients with high-risk characteristics; read more here.


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.

  1. Brown J.R. et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2017 Jun 8. DOI: 10.1038/leu.2017.175. [Epub ahead of print].