In chronic lymphocytic leukemia (CLL), combination therapy with anti-CD20 antibodies (rituximab and obinutuzumab) with chlorambucil has demonstrated efficacy and tolerability in previously untreated CLL patients with comorbidities.1 Moreover, the Bruton’s tyrosine kinase inhibitor ibrutinib has been approved for the treatment of previously untreated and relapsed/refractory CLL. With the CLL2-BIG trial, the German CLL Study Group designed a regimen composed of obinutuzumab and ibrutinib for induction and maintenance therapy following debulking with bendamustine. Patients with high tumor burden received bendamustine as debulking, resulting in the proposed “sequential triple-T” concept of a Tailored and Targeted treatment aiming at Total eradication of minimal residual disease (MRD).2 von Tresckow and colleagues now present the results of the primary endpoint analysis of the trial. This was a prospective, open-label, multicenter phase 2 trial to investigate the efficacy and safety of a novel regimen for physically fit and unfit CLL patients requiring treatment, irrespective of high-risk genetics. A total of 61 patients were recruited according to a predefined allocation to first-line (n = 30) and relapsed/refractory (n = 31) treatment. Two cycles of bendamustine 70 mg/m2 IV were followed by 6 cycles of induction treatment with obinutuzumab and ibrutinib, followed by maintenance therapy with continuous ibrutinib and obinutuzumab every 3 months until achievement of an MRD-negative complete remission or up to 24 months. The primary end point was overall response rate (ORR) 3 months after the start of the last induction cycle; secondary end points included ORR after debulking and at the end of maintenance therapy, MRD evaluations, progression-free survival, overall survival, and safety parameters. Of the 66 patients enrolled, 5 patients completed less than 2 cycles of induction and were, therefore, excluded from the full analysis set as defined by protocol. The current analysis included 61 patients. Of these, 42 (70%) had unmutated IGVH, 8 (13%) had del17p, and 14 (23%) had del11q.
Forty-four (72%) patients received bendamustine debulking, of these 27 (66%) responded; 4 (9%) patients achieved clinical complete remission (CR), 3 (7%) clinical CR with incomplete recovery of the bone marrow (Cri), and 22 (50%) achieved partial remission (PR). A total of 61 patients completed 6 cycles of induction treatment. The combination showed promising efficacy with an ORR of 100% by investigator assessment at the end of induction, with 41% clinical CR, 5% clinical Cri, and 54% PR. A total of 29 (48%) patients achieved MRD negativity in peripheral blood (pB) at the end of induction. An intermediate MRD status (≥10-4 and <10-2) was found in 15 (25%) patients, whereas 13 (21%) patients were MRD-positive (≥10-2). So far, 38 (65%) patients received at least 1 dose of maintenance treatment; 1 patient stopped treatment due to MRD-negativity as defined per protocol. Grade 3-4 adverse events occurred in 19 (33%) patients during induction therapy; the most common toxicities observed included diarrhea, fatigue, neutropenia, nasopharyngitis, thrombocytopenia, vertigo, rash, and nausea.
The authors concluded that with an ORR of 100% and an MRD-negativity rate of 47% in the pB, the BIG regimen has demonstrated excellent efficacy in a heterogeneous CLL study population, with acceptable toxicity. Further evaluation of the secondary end points of the study will be reported at a later time.
Von Tresckow J, et al. ASH 2016. Abstract 640.
- Goede V, et al. N Engl J Med. 2014;370:1101-1110.
- Hallek M. Blood. 2013;122:3723-3734.