Updated results from the phase III HELIOS trial for relapsed or refractory CLL/SLL

On 12 October 2018, Graeme Fraser from Juravinski Cancer Center, ON, Canada, and colleagues, published in Leukemia updated results from the phase III HELIOS clinical trial (NCT01611090). This study evaluated the efficacy of ibrutinib in combination with bendamustine (B) and rituximab (R) for the treatment of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

The primary analysis of the randomized, placebo-controlled phase III trial HELIOS enabled the licensing of ibrutinib + BR for R/R CLL/SLL patients in the US and Europe. This was due to the fact that ibrutinib + BR significantly prolonged progression-free survival (PFS) in R/R CLL/SLL patients, as compared to placebo during HELIOS. In this analysis, the investigators report updated results of the HELIOS study after a three-year follow-up. The primary endpoint of the study was PFS, as assessed by an independent review committee (IRC). Key secondary endpoints included: investigator-assessed PFS, overall survival (OS), response rates, and safety.

Study design
  • Eligible patients had R/R CLL/SLL following ≥ 1 systemic therapy lines, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, computed tomography (CT) measurable lymph node disease (> 1.5 cm), and lack of the 17p deletion
  • N = 240 out of 578 patients from the original trial were included in this updated analysis
  • Patients were randomly assigned 1:1 to ibrutinib + BR or placebo + BR. Ibrutinib was administered daily at a 420-mg dose. Bendamustine was administered intravenously at 70 mg/m2 on Days 2–3 in cycle 1 and Days 1–2 in cycles 2–6. Rituximab was administered at 375 mg/m2 on Day 1 of cycle 1 and 500 mg/m2 on Day 1 of cycles 2–6). BR was administered for up to six cycles for 6 months with ibrutinib or placebo, then patients continued ibrutinib treatment or placebo alone.
  • Sixty-six percent of ibrutinib-treated patients stayed on the treatment for ≥ 24 months
  • Median follow-up (range) = 34.8 (0.1−45.8) months
  • Ibrutinib + BR: median treatment duration (range) = 34.7 (0.2−43.3) months
  • Placebo + BR: median treatment duration (range) = 14.3 (0.2−30.6) months
Key findings
  • PFS for ibrutinib +BR was not reached, while placebo + BR PFS was 14.3 months (HR = 0.206; [95% CI, 0.159–0.265]; P < 0.0001)
  • PFS rate at 36 months was 68% for ibrutinib +BR versus 9% for placebo + BR
  • Median OS was not reached in either arm but was significantly longer for the ibrutinib + BR arm (HR = 0.652; [95% CI, 0.454–0.935]; P = 0.019)
  • OS rate at 36 months was 81.6% for ibrutinib +BR versus 9% for placebo + BR
  • In patients with one prior line, PFS at 36 months was 70.2% in the ibrutinib + BR arm versus5% in the placebo + BR (P < 0.0001)
  • In patients with more than one previous line, PFS at 36 months was 65.9% in the ibrutinib + BR arm versus2% in the placebo + BR (P < 0.0001)
  • Investigator-assessed overall response rate (ORR) was 82.7% for ibrutinib + BR and 66.4% for placebo + BR (P < 0.0001).
    • Complete response (CR/CRi) rate was 38.1% for ibrutinib + BR versus0% for placebo + BR


  • Follow-up safety data included in this analysis are exclusively from the ibrutinib + BR arm, thus no updated comparisons to the placebo arm could be assessed
  • The occurrence of treatment-emergent adverse events (TEAEs) decreased over time after the first year, with the exceptions of muscle spasms and hypertension (stable)
  • Grade 3−4 AEs were reported in 78.7% patients (ibrutinib + BR)
  • Most common ≥ Grade 3 AEs were consistent with the initial analysis and included:
    • Neutropenia (53.7%)
    • Thrombocytopenia (15.0%)
    • Pneumonia (14.3%)
    • Febrile neutropenia (12.5%)
  • Serious TEAEs occurred in 61.3% patients with the most common being pneumonia (13.6%) and febrile neutropenia (10.1%)
  • Serious atrial fibrillation or flutter was reported in 4.9% patients (compared to 2.8% in the initial analysis)
  • No new major hemorrhagic events or deaths were reported

The three-year follow-up data from the phase III clinical trial HELIOS are suggestive of the prolonged survival benefit of ibrutinib-based therapy for R/R CLL/SLL patients. Superior PFS and OS in ibrutinib-treated patients versus placebo, were maintained in the long-term follow-up, while ORR and OS further improved. According to the authors, the extended results provide further validation to the manageable toxicity and the safety of ibrutinib-based regimens for R/R CLL/SLL patients.

  1. Fraser G., et al. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2018 Oct 12. DOI: 10.1038/s41375-018-0276-9. [Epub ahead of print]
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