HOVON 140 CLL13 (FL)

A phase 3, multicenter, randomized, prospective, open-label trial of standard chemoimmunotherapy (FCR/BR) versus rituximab plus venetoclax (RVe) versus obinutuzumab (GA101) plus venetoclax (GVe) versus obinutuzumab plus ibrutinib plus venetoclax (GIVe) in fit patients with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation.

Study treatments

Arm 1	Rituximab 375 (500) mg/m² IV c1-6 (before chemo) Fludarabine 25 mg/m² IV c1-6 d1-3 Cyclophosphamide 250 mg/m² IV c1-6 d1-3 (or) Bendamustine 90 mg/m² c1-6 d1-2
Arm 2	Rituximab 375 (500) mg/m² IV (c1-6 day 1) Venetoclax c1 d22 - c 12 d28 400 mg PO daily (ramp-up)
Arm 3	Obinutuzumab 1000 mg IV (c1 d1 (2)/8/15, c2-6 d1) Venetoclax c1 d22 - c12 d28 400 mg PO daily (ramp-up)
Arm 4	Obinutuzumab 1000 mg IV (c1 d1(2)/8/15, c2-6 d1) Ibrutinib d1-MRD-/PD 420 mg po daily for up to 36 month or until MRD negativity is achieved, whatever occurs first Venetoclax c1 d22 - c12 d28 400 mg po daily (ramp-up)

Inclusion criteria

Documented CLL requiring treatment according to iwCLL criteria
Age at least 18 years
Life expectancy ≥ 6 months
Adequate bone marrow function indicated by a platelet count >30x10⁹/L
Creatinine clearance ≥ 70ml/min
Adequate liver function
ECOG score of 0-2

Exclusion criteria

Any prior CLL-specific therapies
Transformation of CLL
Decompensated hemolysis
Detected del(17p) or TP53 mutation
Patients with a history of PML
Any comorbidity or organ system impairment rated with a single CIRS score of 4 or a total CIRS score of more than 6
Anticoagulant therapy with warfarin or phenoprocoumon

Participating sites

Ziekenhuis Netwerk Antwerpen (ZNA) - Stuivenberg
AZ St-Jan Brugge - Oostende
Cliniques Universitaires UCL Saint-Luc
Jan Yperman Ziekenhuis Ieper