Obinutuzumab plus Ibrutinib as Induction and Maintenance Therapy After Bendamustine Debulking in Patients with CLL: Interim Results of a Phase 2 CLL2-BIG Trial
Obinutuzumab is a glycoengineered anti-CD20 monoclonal antibody that showed superior survival outcomes in combination chlorambucil compared with chlorambucil alone in patients with chronic lymphocytic leukemia (CLL).1 Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton’s tyrosine kinase that is approved for the treatment of patients with previously treated CLL in patients who have received at least 1 prior therapy and in patients with the high-risk deletion 17p cytogenetic feature.2 The CLL2-BIG trial of the German CLL Study Group evaluated the novel combination regimen of obinutuzumab and ibrutinib for induction and maintenance treatment; this was preceded by debulking with bendamustine to reduce the risk of severe infusion-related reactions (IRRs) in patients with high tumor burden. Von Tresckow and colleagues reported the interim results of this trial at the 2015 ASH meeting.3
In this trial, 6 cycles of induction treatment were followed by maintenance therapy every 3 months until achievement of minimal residual disease (MRD)-negative complete remission or up to 24 months. The primary end point is overall response rate (ORR) at the end of induction; secondary end points included ORR after debulking and maintenance, MRD evaluations, safety, and survival parameters. Of the 66 patients enrolled, 31 patients were treatment-naïve, 35 had relapsed/refractory disease, 10 patients had del (17p) cytogenetic abnormality, and 46 patients had unmutated IgHV status.
Overall, 46 patients underwent bendamustine debulking, of which, 27 patients were previously untreated and 19 had relapsed/refractory disease. In the debulking phase, 13 serious adverse events (SAEs) were reported, including infections (n = 6), eye disorders (n = 2), tumor lysis syndrome, and 1 incidence each of pyrexia, systemic inflammatory response syndrome, worsening of renal insufficiency, and diarrhea. Obinutuzumab induction therapy was administered to 62 patients, of whom 42 underwent debulking. Thisresulted in 19 IRRs, which occurred after debulking, and the rest (n = 11) were in patients without prior debulking. No grade 4 IRRs were reported. During the induction cycle, 2 SAEs of IRR and thrombocytopenia were reported in the first cycle and 2 SAEs of upper abdominal pain and lymph node abscess during subsequent induction cycles. Based on these preliminary results of the CLL2-BIG trial, obinutuzumab plus ibrutinib following debulking with bendamustine in patients with high tumor burden might reduce the occurrence of severe IRRs, and warrants further investigation.
- Goede V, et al. N Engl J Med. 2014;370:1101-1110.
- Imbruvica (ibrutinib) [Prescribing information]. 2015.
- Von Tresckow J, et al. ASH 2015. Abstract 4151.