Induction of Ibrutinib Regimen Achieves 100% Response Rate in CLL

Combination induction therapy with ibrutinib (Imbruvica) and obinutuzumab (Gazyva) after bendamustine debulking induced a 100% response rate in patients with chronic lymphocytic leukemia (CLL), according to findings from the phase II CLL2-BIG trial. 

Julia von Tresckow, MD

Combination induction therapy with ibrutinib (Imbruvica) and obinutuzumab (Gazyva) after bendamustine debulking induced a 100% response rate in patients with chronic lymphocytic leukemia (CLL), according to findings from the phase II CLL2-BIG trial. The minimal residual disease (MRD) negativity rate in the peripheral blood at final restaging was 47.5%.

“The BIG regimen showed very promising efficacy in a heterogeneous CLL population,” lead study author Julia von Tresckow, MD, department of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University of Cologne, Germany, said when presenting the data at the 2016 ASH Annual Meeting.

The prospective, open-label, multicenter phase II CLL2-BIG trial, had an all-comer study population, including patients with CLL regardless of fitness, treatment line, or cytogenetic risk classification.

Between January and August 2015, 66 patients with CLL were recruited to the trial. The data reported at ASH were for only 61 patients, as 5 patients were excluded because they completed fewer than 2 cycles of induction therapy (1 death, 2 due to adverse events [AEs], and 2 patient self-withdrawals).

Among the 61-patient analysis set, the median age was 66 years (range, 36-83), with 50.8% (n = 31) of patients aged >65 years and 34.4% (n = 21) of patients aged >70 years.

Males comprised 57.4% (n = 35) of the patient population. The Binet stage breakdown for stages A, B, and C was 26.2% (n = 16), 37.7% (n = 23), and 36.1% (n = 22), respectively. The median from initial diagnosis was 56.5 months (range, 2.1-222.8). Patients had an ECOG performance status of 0 or 1.

The median CIRS score was 3 (range, 0-11). The median creatine clearance was 76.5 ml/min (range, 33.1-154.7). The median number of prior treatment lines was 1 (range 1-5). Thirty patients were receiving frontline therapy and 31 patients were relapsed/refractory.

Identified cytogenetic risk factors included unmated IGHV mutational status (70%), del(17p) [13.1%], del(11q) [23%], trisomy 12 (19.7%), del(13q) [50.8%], TP53 deletion (19.7%), NOTCH1 (18%), and SF3B1 (19.7%).

Patients with an absolute lymphocyte count ≥25.000/µl and/or lymph nodes ≥ 5 cm (72.1%; n = 44) received 2 cycles of bendamustine (70 mg/m2 IV on days 1 and 2 of each cycle) as a debulking regimen before induction. Induction therapy involved 6 cycles of the anti-CD20 antibody obinutuzumab and the BTK inhibitor ibrutinib.

In cycle 1, obinutuzumab was administered at 100 mg on day 1, another 900 mg on day 1 or 2, 1000 mg on day 8, and 1000 mg on day 15, all intravenously. In cycles 2 through 6, patients received 1000 mg on day 1. Ibrutinib was not administered in cycle 1. In cycles 2 through 6, patients received ibrutinib at 420 mg orally once daily on days 1 through 28.

Following induction, maintenance treatment consisted of single-agent therapy until MRD-negative complete remission (CR) was reached or a maximum of 24 months. The maintenance regimen of obinutuzumab was 1000 mg intravenously on day 1 of cycles 1 through 8. Maintenance ibrutinib consisted of 420 mg orally once daily on days 1 through 72 of cycles 1 through 8.

The primary endpoint was overall response rate (ORR) at final restaging. Secondary endpoints include ORR after debulking and end of maintenance, MRD levels in peripheral blood or bone marrow, overall survival, progression-free survival, and safety.

The ORR with bendamustine debulking was 65.9%, including an unconfirmed CR rate of 9.1% (n = 4), an unconfirmed CR rate with incomplete recovery of the bone marrow (CRi) of 6.8% (n = 3), and a partial remission (PR) rate of 50% (n = 22). The stable disease rate was 25% (n = 11) and the progressive disease rate was 4.5% (n = 2).

The 100% ORR after induction ibrutinib/obinutuzumab (P<.001) included an unconfirmed CR rate of 41% (n = 25), an unconfirmed CRi rate of 4.9% (n = 3), and a PR rate of 54.1% (n = 33).

Among patients receiving first-line induction, the unconfirmed CR, unconfirmed CRi and PR rates were 40%, 3.3%, and 56.7%, respectively. In relapsed/refractory patients, the rates were 41.9%, 6.5%, and 51.6%, respectively.

No unexpected toxicities emerged in the trial. The most commonly reported grade 3/4 toxicities included neutropenia (14.8%), thrombocytopenia (13.1%), infusion related reaction (4.8%), and pneumonia (3.3%). Grade 3/4 acute vestibular syndrome, anemia, bursitis, cholestasis, cluster headache, febrile infection, headache, inguinal hernia, lymph node abscess, nodule, pancreas infection, serum, tumor lysis syndrome all occurred in 1.6% of patients.


von Tresckow J, Cramer P, Bahlo J, et al. CLL2-BIG - a novel treatment regimen of bendamustine followed by GA101 and ibrutinib followed by ibrutinib and GA101 maintenance in patients with chronic lymphocytic leukemia (CLL): results of a phase II-trial. Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 640.