Low Incidence of Tumor Lysis Syndromes (TLS) and Infusion Related Reactions (IRR) in the CLL2-Bag Trial Evaluating a Sequential Treatment of Bendamustine (B), Obinutuzumab (GA101, G) and Venetoclax (ABT-199, A) in Patients with Chronic Lymphocytic Leukemia (CLL): Interim Safety Results of a Phase-II-Trial of the German CLL Study Group (GCLLSG)

Introduction:

Several targeted agents have been introduced for CLL, including the CD20-antibody obinutuzumab (GA101, G) and the Bcl-2 antagonist venetoclax (ABT-199, A). Both agents show exciting efficacy which comes at the cost of an increased risk of TLS and IRRs and mandate several safety precautions especially during the first treatment cycles and in patients (pts) with a higher tumor load and/or renal insufficiency.

Based on the theoretical "sequential triple-T" concept [Hallek M., Blood 2013; 122(23): 3723-34] of a tailored and targeted treatment aiming for total eradication of minimal residual disease (MRD), the GCLLSG designed the CLL2-BAG trial combining G and A in an induction and maintenance treatment. To reduce the risk of TLS and IRRs, G and A were started sequentially during the induction phase and patients with high tumor burden received bendamustine (B) as a debulking step before the induction treatment.

Methods:

This prospective, open-label, multicenter phase-II trial investigates the safety and efficacy of a sequential treatment with B, G and A in an all-comer population of physically fit and unfit, treatment-naïve and relapsed/refractory CLL pts requiring treatment, irrespective of high-risk genetics.

Pts with an absolute lymphocyte count (ALC) ≥ 25.000/µl and/or lymph nodes (LN) ≥ 5cm received 2 cycles of B as debulking treatment (70mg/m² d1&2 q28 days). In the induction G was administered 3 times in cycle 1 (days 1/2, 8 & 15) and every 4 weeks in cycles 2-6. Daily intake of A started in cycle 2 with a slow dose ramp-up over 5 weeks and several safety precautions including blood sampling, hydration, allopurinol and rasburicase (depending on patient's TLS risk category). In the maintenance phase, A was continued and G administered every 3 months until achievement of a MRD-negative complete response or for up to 24 months. The primary endpoint was the overall response rate (ORR) at the end of induction therapy; secondary endpoints include safety parameters, MRD evaluations and survival parameters.

Results:

Between May 2015 and January 2016, 66 pts were enrolled, among them 35 with treatment naïve and 31 with relapsed/refractory CLL (median number of prior therapies: 2, range: 1-8). Median age was 59 (28-77) years and the median CIRS score was 2 (0-14). 12 of 48 pts (25%) had an impaired renal function at baseline with a creatinine clearance of 30-70ml/min. 11 of 62 pts (18%) had a del(17p) and 48 of 64 (75%) had an unmutated IGHV status.

47 (71%) pts received B debulking and 19 (29%) pts immediately started with G due to a low tumor burden (6), contraindications for B [known hypersensitivity or refractoriness] (4) and/or physicians decision (13). Median ALC was 52.3 (0.6-423.5) at baseline and 0.9 (0.2-102.0) after first induction cycle. Risk categories for TLS at baseline were: low (LR: ALC <25.000/µl and LN <5cm): 9 pts (14%), intermediate (IR: ALC ≥ 25.000/µl or LN 5-10cm): 37 (59%) and high risk (HR: ALC ≥ 25.000/µl and LN 5-10cm or LN >10cm): 17 (27%), 3 missing. After debulking and/or 1st cycle with G risk categories were re-assessed in 19 pts and were LR in 13 (68%) and IR in 6 (32%) pts.

As of July 20th2016, 76 serious adverse events (SAEs) were reported in 36 of the 66 pts, among them 64 (84%) related to study drug. 57 SAEs (75%) were CTC°3-4 and 3 deaths (septicaemias in heavily pretreated pts). So far 13 (17%) SAEs occurred during B debulking, 62 (82%) in the induction and 1 (1%) in the maintenance phase. Most common SAEs were infections (26 in 15 pts; among them 12 CTC°3-5) and hematological disorders (18 in 11 pts; 10 CTC°3-4); especially pneumonias (8 in 3 pts), sepsis (3 in 3 pts; all CTC°5) and neutropenias with/without fever (5 and 7 each; in 7 pts). Six serious IRRs occurred in 6 pts (4 CTC°3-4), 5 occurred during the first infusion of G; 3 of the affected pts had not received prior B. Five SAEs were laboratory TLS, which all resolved quickly; 1 occurred during the debulking with B and 4 during the induction therapy (1 in induction cycle 1 with G, 2 in cycle 3 and 1 in cycle 4 with G and A), all in pts without prior B debulking.

Conclusion:

The administration of B as a debulking step, followed by G helps to effectively reduce the patient's tumor load providing the ability to prevent serious IRRs and TLS. With this concept and the established safety precautions no clinical TLS occurred so far. Aside from 3 septicaemias with fatal outcome in heavily pretreated pts, the toxicity profile of this regimen is acceptable.