Ibrutinib/Venetoclax vs Chlorambucil/Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia: GLOW Trial 4-Year Follow-up

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As reported in The Lancet Oncology by Niemann et al, the 4-year follow-up of the phase III GLOW trial has shown a continued progression-free survival benefit with fixed-duration ibrutinib/venetoclax vs chlorambucil/obinutuzumab in the first-line treatment of chronic lymphocytic leukemia in patients aged ≥ 65 or with comorbidities. The trial supported the August 2022 European Union approval of ibrutinib plus venetoclax in this setting on the basis of superior progression-free survival after a median follow-up of 27.7 months.

Study Details

In the open-label trial, 211 patients from sites in 14 countries aged ≥ 65 or 18 to 64 with a cumulative illness rating scale score greater than 6 or creatinine clearance less than 70 mL/min were randomly assigned between May 2018 and April  2019 to receive ibrutinib/venetoclax (n = 106) or chlorambucil/obinutuzumab (n = 105).

Ibrutinib/venetoclax was given as 3 cycles of ibrutinib lead-in at 420 mg/d, followed by 12 cycles of ibrutinib plus venetoclax at 400 mg/d (including a 5-week dose ramp-up). Chlorambucil/obinutuzumab was given as 6 cycles of chlorambucil at 0.5 mg/kg on days 1 and 15 of each cycle and obinutuzumab at 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2 through 6. Cycles were 28 days. The primary endpoint was progression-free survival in the intention-to-treat population on independent review committee assessment.

Key Findings

Median follow-up was 46 months (interquartile range = 43–47 months). Median progression-free survival was not reached in the ibrutinib/venetoclax group vs 21.7 months (95% confidence interval [CI] = 16.7–26.1 months) in the chlorambucil/obinutuzumab group (hazard ratio [HR] = 0.21, 95% CI =  0.14–0.33, P < .0001). The rate at 42 months was 74.6% (95% CI = 65.0%–82.0%) vs 24.8% (95% CI = 16.5%–34.1%).

According to IGHV mutation status in the ibrutinib/venetoclax group, 42-month progression-free survival rates were 69.8% among 67 patients with unmutated IGHV vs 90.0% among 32 patients with mutated IGHV (HR = 3.77, 95% CI = 1.13–12·58, P = .031). In the chlorambucil/obinutuzumab group, the 42-month progression-free survival rate was 15.0% among 57 patients with unmutated IGHV vs 43.1% among 35 patients with mutated IGHV (HR = 2.17, 95% CI = 1.29–3.66, P = .0036).

At 46-month follow-up, an overall survival advantage was observed for the ibrutinib/venetoclax group vs the chlorambucil/obinutuzumab group (HR = 0.49, 95% CI = 0.26–0.91, P = .021). The rate at 42 months was 87.5% (95% CI = 79.4%–92.5%) vs 77.6% (95% CI = 68.2%–84.5%).

Since primary analysis, one patient in the chlorambucil/obinutuzumab group developed myelodysplastic syndrome. Treatment-related deaths were reported in one patient receiving ibrutinib/venetoclax (from cardiac failure, pneumonia, and sinus node dysfunction) and in one patient receiving chlorambucil/obinutuzumab (pneumonia).

The investigators concluded: “After 4 years of follow-up, ibrutinib/venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukemia, supporting its use as a first-line option.”

Carsten U. Niemann, MD, PhD, of Rigshospitalet, Copenhagen University Hospital, is the corresponding author of The Lancet Oncology article.

Disclosure: The study was funded by Janssen Research & Development and Pharmacyclics. For full disclosures of the study authors, visit

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