Chronic Lymphocytic Leukemia patients with high-risk genetics respond well with minimal toxicity to ONO/GS-4059 therapy – 3-year follow-up results of a phase I extension study

In a letter to the editor of Blood, published on 4th April 2017, Harriet S. Walter from the Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK, et al. report updated, 3-year follow-up results of a phase I extension study of ONO/GS-4059 in patients with R/R CLL.1

The safety and tolerability of ONO/GS-4059, a selective BTK inhibitor, in patients with R/R B-cell malignancies was assessed in the POE001 phase I trial (NCT01659255). In total, 90 patients were enrolled and those who continued to respond or who achieved stable disease were eligible to enroll in the long-term ONO/GS-US-1787 extension study (NCT02457559).

Key Highlights:
  • All 28 pts in the CLL cohort of the extension study were evaluable for efficacy and safety
  • At the time of updated analysis, 11 pts (39.3%) had discontinued ONO/GS-4059
  • Reasons for discontinuation included death (n=3), PD (n=4), AEs (n=3), and sponsor decision due to extended drug interruption (n=1)
  • Subjects remaining on study were receiving doses ranging from 40mg–600mg once daily or 300mg twice-daily; no MTD was determined in patients with CLL
  • Median duration on study at censoring = 32.5 months
  • Estimated median PFS = 38.5 months; median OS = 44.9 months
  • In the initial phase I trial, responses (CR or PR) were reported in 96% (24/25) evaluable pts and 23 pts (82%) demonstrated lymphocytosis with a mean fold increase above baseline of 4.52
  • At day 8, serum levels of CCL3, CCL4, TNF-α, IL10, IL6, and IL8 had significantly decreased
  • Immunoglobulin levels did not change significantly with long-term ONO/GS-4059 therapy
  • DNA was extracted from peripheral blood from 27/28 patients before initiation of trial therapy
  • At study entry, 21/25 pts had unmutated IGHV, 7 of these pts have discontinued treatment
  • Of pts with TP53 mutation, 7/10 remain on therapy; of the 3 that discontinued therapy, 1 progressed, 1 withdrew due to an AE, and 1 died from septicemia
  • Of pts with ATM mutation, 1/3 has progressed on study (930 days)
  • Of pts with SF3B1 mutations, 5/8 have discontinued treatment (1 due to progression)
  • Of pts with NOTCH1 mutations, 3/7 have come off study (1 due to progression)
  • No mutations appeared to predict shorter PFS with ONO/GS-4059
  • Previously unreported mutations in CLL included a mutation in MEK1 (E203K) in 1 patient with early progression and a POT1 mutation (E67K)
  • The majority of TEAEs were grade 1–2
  • The most reported all grade AEs = bruising (35.7%) and neutropenia (35.7% each), and anemia (32.1%)
  • Only 1 grade 3 bleeding event (3.6%; hematoma) reported during the study
  • ≥Grade 3 infections reported in 12 pts (42.9%); grade 1–3 weight gain reported in 14 pts (50%)
  • No cases of Richter’s transformation reported

The authors concluded that patients with high-risk CLL genetics responded well to ONO/GS-4059 therapy with minimal toxicity. They went on to say that the tolerability of ONO/GS-4059 is beneficial especially “in the context of combination therapies and in ibrutinib intolerant patients.”




  1. Walter H.S. et al. Long-term follow-up of patients with CLL treated with the selective Bruton's tyrosine kinase inhibitor ONO/GS-4059. Blood. 2017 Apr 4. pii: blood-2017-02-765115. DOI: 10.1182/blood-2017-02-765115. [Epub ahead of print].
  2. Walter H.S. et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016 Jan 28;127(4):411-9. DOI: 10.1182/blood-2015-08-664086. Epub 2015 Nov 5.