Abstract
Introduction:
The prospective, open-label, multicenter phase-II CLL2-BIO trial is based on a concept proposed as a "sequential triple-T" therapy [Hallek M., Blood 2013; 122(23): 3723-34], consisting of tailored, targeted therapies and aiming for total eradication of minimal residual disease (MRD). It uses a sequential application of bendamustine debulking, followed by ofatumumab and ibrutinib as induction and maintenance therapy in an all-comer population of physically fit and unfit, treatment-naïve (TN) and relapsed/refractory (R/R) CLL patients (pts) irrespective of high-risk genetic markers.
Methods:
Pts with an absolute lymphocyte count ≥ 25.000/µl and/or lymph nodes ≥ 5cm were to receive 2 cycles of bendamustine as debulking (70 mg/m² d1&2 q28 days), unless contraindicated. In the induction phase ofatumumab was administered 3 times in cycle 1 (300 mg on day 1, 1000 mg on days 8 & 15) and every 4 weeks in cycles 2 to 6 (1000 mg on day 1); ibrutinib was added in cycle 2 (420 mg once daily). In the maintenance phase, daily dosing of ibrutinib was continued and ofatumumab was 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, which was tested versus the null hypothesis of 75% via binomial test. Secondary endpoints include MRD evaluations, safety and survival parameters.
Results:
Between February and October 2016, 66 pts were enrolled and constitute the safety population. However, 10 pts had incomplete documentation of the final restaging at end of induction treatment and 1 patient with less than 2 cycles of induction treatment (discontinuation due to adverse event generalized seizure in the 2nd cycle) was excluded from the efficacy analysis as predefined by protocol. Thus, this first primary endpoint analysis is based on 55 pts; an update including all 65 pts will be presented at the meeting.
Of the 55 pts, 32 pts were treatment-naïve and 23 had R/R CLL (median number of prior therapies: 1, range: 1-5). Median age was 60 (32-81) years, the median CIRS score was 3 (0-8). 20 pts (37%) were considered unfit due to a CIRS score >6 (7 pts) and an impaired renal function with a Creatinine Clearance <70ml/Min (17 pts). 12 pts (22%) had a del(17p) and 11 (20%) had a del(11q); 38 pts (69%) had an unmutated IGHV status.
Forty-two pts (76%) received bendamustine debulking, 13 (24%) pts immediately started with the induction. Fifty-two pts completed 6 induction cycles with ofatumumab and ibrutinib. Thirty-one of 32 TN (97%) and 20 of 23 R/R pts (87%) responded; with an ORR of 93% at the end of induction, the primary endpoint was met (CI: 85.9 - 99.6, p=0.0024). According to investigator assessment 46 pts achieved a partial response (PR), among them 17 pts were only lacking a bone marrow examination or CT scan for confirmation of a complete remission, 5 achieved a PR with lymphocytosis; 3 pts had a SD and 1 progressed (table 1). At the end of induction, the majority of pts (46 of 55 pts, 84%) were still MRD positive; MRD negativity (<10-4 by flow cytometry) in peripheral blood was achieved in 4 TN pts (7%) and 2 RR pts (4%) had an intermediate MRD level (≥10-4 and < 10-2).
As of July 3rd 2017, 76 serious adverse events (SAEs) were reported in 32 (49%) of the 66 pts, including 64 SAEs (84%) related to study treatment (table 2a). Fifty SAEs (67%) were CTC grade 3-4 and 1 had a fatal outcome (sepsis after the 6th induction cycle). Most SAEs occurred during the induction phase (58%) and the majority resolved without sequelae (91%). Most common SAEs were infusion related reactions (17 in 13 pts, including 9 of CTC°III-IV), lower respiratory tract and lung infections (6 in 5 pts), supraventricular arrhythmias (5 in 4 pts) followed by diarrhea (3 in 3 pts) and pyrexia (3 in 2 pts) (table 2b).
Summary/Conclusion:
This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an ORR of 93%. Ongoing maintenance treatment aims at deeper responses with MRD negativity.
Cramer: Novartis: Consultancy, Research Funding; GSK: Research Funding; Gilead: Other: travel support, Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy; F. Hoffmann-LaRoche: Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding. von Tresckow: F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel grants, Research Funding; Abbvie: Consultancy, Honoraria; Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; Celgene: Other: travel grants. Bahlo: F. Hoffmann-LaRoche: Honoraria, Other: travel grants. Al-Sawaf: Abbvie: Honoraria, Other: Travel fees; Roche: Honoraria, Other: Travel fees; Gilead: Other: Travel fees. Langerbeins: F. Hoffmann-LaRoche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Mundipharma: Other: Travel support; Abbvie: Honoraria. Heinz: Basilea: Honoraria, Other: travel support; Pfizer: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead Sciences: Consultancy, Honoraria, Other: travel support; Astellas: Honoraria; Alexion: Honoraria, Other: Travel support; MSD (Merck Shap & Dohme: Consultancy, Honoraria, Other: travel support, Research Funding. Vehling-Kaiser: Lilly: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Amgen: Consultancy; F. Hoffmann-LaRoche: Consultancy; MSD: Consultancy. Dürig: Lead Discovery Center: Research Funding. Tausch: AbbVie: Other: Travel support; Amgen: Other: travel support; Celgene: Other: travel support. Hensel: AbbVie: Other: travel grants; F. Hoffmann-LaRoche: Consultancy, Other: travel support. Fink: AbbVie: Honoraria, Other: travel support; Celgene: Other: Grant; Hoffmann La Roche: Other: Travel grant; Mindipharma: Other: Travel Grant. Fischer: Roche: Other: Travel Grants. Kreuzer: Mundipharma: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal Fees, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Böttcher: AbbVie: Honoraria, Research Funding; Celgene: Research Funding; F. Hoffmann-LaRoche: Honoraria, Research Funding. Ritgen: BMS: Consultancy, Other: travel support; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Other: travel support; Pfizer: Consultancy. Kneba: AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner: Novartis: Other: Personal Fees; Gilead: Other: Personal Fees; Servier: Other: Grant, Personal Fees; Morphosys: Other: Personal Fees; Abbvie: Other: Personal Fees; Celgene: Consultancy, Research Funding; Janssen-Cilag: Other: Personal Fees; Mundipharma: Other: Grant, Personal Fees; Hoffmann La Roche: Other: Grant, Personal Fees. Stilgenbauer: Mundipharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Eichhorst: Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Other: trav, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: tra, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding. Hallek: Celgene: Consultancy, Honoraria, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.
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