Abstract
The oral BCL2 inhibitor navitoclax has moderate single-agent efficacy in chronic lymphocytic leukaemia (CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B-cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200-325 mg) daily and four standard weekly doses of rituximab. Twenty-nine patients were enrolled across three dose-escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19+ counts were severely reduced, while CD3+ cells (∼ 20%) and serum immunoglobulin M levels (∼ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low-grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials.
Original language | English (US) |
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Pages (from-to) | 669-678 |
Number of pages | 10 |
Journal | British Journal of Haematology |
Volume | 170 |
Issue number | 5 |
DOIs | |
State | Published - Sep 1 2015 |
Externally published | Yes |
Keywords
- B-cell malignancy
- BCL2
- Navitoclax
- Rituximab
ASJC Scopus subject areas
- Hematology