Abstract

Introduction

FCR improves PFS and OS in CLL.  Previous non-randomised Phase II trials suggest adding mitoxantrone to FCR (FCM-R) improves outcomes.  The rituximab dose in CLL was inferred from lymphoma but in CLL even low doses of rituximab lead to the loss of CD20 expression (“shaving”) suggesting that low dose rituximab with chemotherapy may be effective. 

Aims

The primary objective was to assess whether the CR rate to FCM-miniR was not inferior to FCR.  Secondary objectives were MRD eradication, overall response rates and safety.  Late endpoints (not reported) were PFS, OS and MRD relapse. 

Methods

ARCTIC was a phase IIB, randomised, controlled, parallel group trial in previously untreated CLL performed in 34 UK centres.  206 patients were to be randomised to FCR or FCM-miniR with an 80% power to show that FCM-miniR did not lead to 10% worse CR rates compared to FCR.  A formal interim analysis on the primary endpoint was planned after 103 patients.  The schedule for oral FCR was equivalent to iv FCR with iv rituximab given on Day 1 (375mg/m2 Cycle 1; 500mg/m2 Cycles 2-6), oral fludarabine (24mg/m2/day for 5 days; Days 1-5) and oral cyclophosphamide (150mg/m2/day for 5 days; Days 1-5).  FCM-miniR included intravenous mitoxantrone (6mg/m2/day) and 100mg rituximab on Day 1 of 6 cycles given 28 days apart.  Patients with neutropenia delaying therapy received G-CSF (lenograstim 263mcg/day; Days 7-13) on all remaining cycles.  Prophylaxis with co-trimoxazole and acyclovir was used. 

Results

200 patients were recruited, 100 to each arm.  The interim analysis after 103 patients indicated that although the CR rate to FCM-miniR was similar to predicted it was inferior to FCR.  The independent DMC advised that the trial would not show non-inferiority for FCM-miniR and recruitment was stopped.  A further 97 patients were recruited up to the interim analysis.  21 patients still receiving FCM-miniR were advised to cross-over to FCR.  100 patients received FCR, 79 FCM-miniR and 21 patients randomised to FCM-miniR crossed over to FCR. 

ARCTIC was stopped prematurely as it was clear that the arm containing mitoxantrone and low dose rituximab would not be non-inferior to FCR.  However both FCR and FCM-miniR performed well with CR rates of 78% and 60% respectively.  This compares favourably to CR rates of 38% for FC in LRF CLL4 Trial and 44% for FCR in the GCLLSG CLL8 Trial.  MRD was undetectable in 55% of patients receiving FCR and 46% for FCM-miniR. Oral FCR in front-line CLL results in extremely high CR rates and the eradication of detectable MRD in the majority.  Low dose rituximab (100mg per cycle; 600mg total dose compared to 2875mg/m2 for standard FCR) in combination with FCM appears to be effective although FCM-miniR is inferior to full dose FCR.  However there is more toxicity associated with the addition of mitoxantrone confounding the comparison of rituximab doses. 

Disclosures:

Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria.  Off Label Use: The use of ofatumumab in combination with chlorambucil in previously untreated CLL.  The reported trial will support the extension of the ofatumumab licence.  Schuh:GSK: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria.