Oncology
Chronic Lymphocytic Leukemia
RESONATE at 2 Years: Continued Efficacy in Relapsed, High-risk Chronic Lymphocytic Leukemia
Overview
Clinical Study Title:
Extended Follow-up and Impact of High-risk Prognostic Factors From the Phase 3 RESONATE Study in Patients With Previously Treated CLL/SLL
Clinical Study 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.
Reference:
Brown JR, Hillmen P, O’Brien S, 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. 2018;32(1):83-91.
Expert Commentary
Jennifer R. Brown, MD, PhD
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RESONATE (NCT01578707) was a randomized comparison of ibrutinib to ofatumumab in previously treated patients with chronic lymphocytic leukemia (CLL), with many individuals having high-risk prognostic factors. The first report of this trial demonstrated that ibrutinib significantly improved PFS, OS, and ORR compared with ofatumumab and was acceptably tolerated, leading to the approval of ibrutinib for previously treated CLL and 17p deletion (del[17p]) CLL. In the present report, we find that efficacy with ibrutinib remains high at this 2-year follow-up 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. |
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“In the present report, we find that efficacy with ibrutinib remains high at this 2-year follow-up 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.”
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. Furthermore, those patients with both del(17p) and TP53 did show reduced PFS compared with patients with neither abnormality, even at this 2-year follow-up report. 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.
“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.”
Tolerability to ibrutinib was well maintained in this relapsed patient population with extended treatment. The most common side effects were similar to those at interim analysis, with only a slight increase in the cumulative event rate despite the additional year of therapy. Ongoing monitoring of toxicity, particularly in patients who may remain on ibrutinib for many years, remains important.
References
A phase 3 study of ibrutinib (PCI-32765) versus ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (RESONATE™). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01578707. Accessed May 17, 2018.
Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):3247-3254.
Rossi D, Khiabanian H, Spina V, et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood. 2014;123(14):2139-2147.
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