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): Interim Results of a Phase II-Trial

Introduction:

In chronic lymphocytic leukemia (CLL) treatment with anti-CD20 antibodies including obinutuzumab (GA101) and targeted drugs, such as ibrutinib, show promising efficacy and tolerability compared to standard chemoimmunotherapy.

With the CLL2-BIG trial, the German CLL Study Group (GCLLSG) designed a novel combination regimen composed of obinutuzumab and ibrutinib for induction and maintenance treatment. To reduce the risk of severe infusion related reactions (IRR) during the first infusion of obinutuzumab, patients with high tumor burden receive bendamustine as debulking resulting in the proposed "sequential triple-T" concept [Hallek M., ASH 2013] of a t ailored and t argeted treatment aiming at t otal eradication of minimal residual disease (MRD).

Methods:

The phase-II CLL2-BIG trial investigates the safety and efficacy of a novel regimen for physically fit and unfit CLL patients, irrespective of high-risk genetics. 62 patients had to be recruited according to a predefined allocation for the two strata of first-line and relapse treatment.

Six cycles of induction treatment with obinutuzumab and ibrutinib are administered followed by maintenance therapy with ibrutinib and obinutuzumab every three months until achievement of MRD-negative complete remission or up to 24 months. Patients with initial high tumor burden (absolute lymphocyte count > 25.000/µl and/or lymph nodes > 5cm) receive two cycles of debulking with bendamustine before start of induction. Primary endpoint is overall response rate (ORR) at the end of induction; secondary endpoints include ORR after debulking and maintenance, MRD evaluations as well as safety and survival parameters.

Results:

As of July 2015, 62 patients were included. Of these, 29 were treatment-naïve and 33 relapsed/refractory. The median age was 65.5 (36-86) years, the median time from initial diagnosis 4.8 (0.2 - 18.6) years and the median cumulative illness rating scale (CIRS) score 2 (0-11). Among 55 pts with cytogenetic analyses, 10 patients had a del(17p) and 40 patients an unmutated IGHV status.

44 patients (71%; 26 first-line and 18 relapsed/refractory) received bendamustine debulking. Four patients stopped treatment after the first course of debulking, one due to physicians' decision, two patients withdrew their consent and one patient died.

During debulking 11 serious adverse events (SAE) occurred in 7 patients: four infections (including three pneumonias and one fatal sepsis) in four patients, two surgical interventions for a known cataract in one patient and one tumor lysis syndrome (TLS), one pyrexia, one systemic inflammatory response syndrome, one worsening of renal insufficiency and one diarrhea.

Thus far, obinutuzumab was administered to 41 patients of whom 22 received prior debulking. In 19 patients debulking was omitted due to contraindications or low tumor burden. 14 IRRs (CTC AE v4.0 grade I-III) were reported in connection with infusions of obinutuzumab in 13 patients. Only 4 IRRs occurred after two cycles of debulking (18%). In contrast, 10 IRRs were observed without prior debulking (48%). 2 IRRs were reported as SAEs, one after prior debulking and one without. No grade IV IRRs occured so far. IRRs were reported during the first infusion in 9 patients, during the second infusion in three patients and during the first and second infusion in one patient. There were no IRRs after the first two infusions of obinutuzumab.

In addition, after prior debulking two SAEs were reported during the first induction cycle: IRR and thrombocytopenia. Without prior debulking two SAEs (IRR and pneumonia) occurred during the first and two SAEs (upper abdominal pain and lymph node abscess) during subsequent induction cycles.

Occurrence of IRRs and baseline characteristics of all patients as well as first efficacy data will be available for presentation at the meeting.

Conclusion:

In the CLL2-BIG trial, a combination regimen consisting of obinutuzumab and ibrutinib after prior debulking with bendamustine for patients with high CLL tumor load is investigated. So far, the data suggest that debulking prior to obinutuzumab might reduce the occurrence of severe IRRs compared to historical data [Goede V., NEJM 2014] and to patients who did not receive debulking. The rate of infections seen with bendamustine in this trial seems comparable to previous reports for bendamustine monotherapy in CLL [Bergmann M., Haematologica 2005 and Knauf W., JCO 2010].