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3428 An Open-Label Phase II Study to Investigate the Safety and Efficacy of Rituximab Plus Chlorambucil in Previously Untreated Patients with CD20-Positive B-Cell Chronic Lymphocytic Leukaemia (CLL)

Oral and Poster Abstracts
Poster Session: CLL - Therapy, excluding Transplantation Poster II
Monday, December 7, 2009, 6:00 PM-8:00 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board III-365

Peter Hillmen, MB, ChB, PhD1, John G. Gribben, MD, DSc2, George A Follows3*, Donald W. Milligan, MD, MBChB4, Hazem A. Sayala, MBChB, MRCP5*, Paul Moreton6*, David Oscier, MD7*, Claire E. Dearden, MD8, Daniel B. Kennedy9*, Andrew R. Pettitt, PhD, MRCPath10*, Amit Nathwani, MD, PhD11, Dena Cohen12*, Walter M Gregory12*, Andy C. Rawstron, PhD1, Colin R.W. Hayward, MBBS13* and Christopher Pocock14*

1Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
2Medical Oncology, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
3Addenbrookes Hospital, Cambridge, United Kingdom
4Dept. of Haematology, Birmingham Heartlands Hospital, Birmingham
5Castle Hill Hospital, Cottingham, England
6Pinderfields General Hospital, Wakefield, United Kingdom
7Dept. of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
8The Royal Marsden Hospital, London, United Kingdom
9Leicester Royal Infirmary, Leicester, United Kingdom
10Royal Liverpool University Hospital, Liverpool, United Kingdom
11Dept. of Haematology, University College London, London, England
12University of Leeds, Leeds, United Kingdom
13F.Hoffmann-La Roche Ltd, Basel, Switzerland
14East Kent Hospitals NHS Trust, Canterbury, United Kingdom

Introduction: Despite the increasing use of fludarabine (F) plus cyclophosphamide (C), and recently rituximab (R)-FC combinations in CLL, chlorambucil (Chl) remains a first-line treatment option, particularly for elderly patients and those with co-morbidities with chronic lymphocytic leukemia (CLL). However, rates of complete response (CR) are relatively low (up to 7%) as are overall responses (approximately 65%) with Chl. In this study we assessed the feasibility of adding R to Chl in order to improve outcomes. Methods: Previously untreated patients with CLL who required therapy according to IWCLL criteria received R (day 1; 375 mg/m2 i.v. cycle 1, 500 mg/m2 cycles 2–6) plus Chl (days 1-7; 10mg/m2/day p.o.) repeated every 28 days for 6 cycles. A further 6 cycles of Chl alone was permitted in patients with continuing clinical response at 6 cycles. The primary endpoint was the adverse event (AE) profile. Secondary endpoints included response rates, progression-free and overall survival and assessment of minimal residual disease. Efficacy results from this study were compared with historical data from patients in the UK LRF CLL4 study who received Chl at the same dose but as monotherapy between 1999 and 2004. Each of the 50 patients in the Chl-R trial were matched to 3 patients from the CLL4 trial by Binet Stage (B or C), VH Mutation (mutated or unmutated), 11q FISH (deleted or not) and age.

Results:This is a planned interim analysis (IA) based on the first 50 patients out of the total 100 patients from 12 centres. Of these 47 patients were evaluable (2 missing bone marrow at time of IA; 1 protocol violation received only 1 cycle). The median age of patients was 70.5 years (range 48–86), 62% were male and 52% had Binet stage C CLL. The most common AEs were gastrointestinal disorders. There were 25 serious AEs (SAEs) reported in 17 patients. The most common SAEs were infections (10 SAEs, in 6 patients). Additionally there were 3 SAEs (in 3 patients) of febrile neutropenia – grade 3 or 4 neutropenia was reported in 40% of patients. Overall response rate on an intent-to-treat analysis was 84%. When compared with the well matched subset of Chl patients from the UK LRF CLL4 study, the overall response rate was 17.3% higher (95% CI 4.7% - 30.0%), indicating that the Chl-R patients have improved responses. Conclusions: Based on this planned interim analysis, the addition of R to Chl is a feasible combination with no unexpected AEs. The combination of R and Chl was effective for untreated patients with CLL. It is important to note that the median age of patients in this study was considerably greater than the median age of patients in the UK LRF CLL4 and other large trials in CLL, and more representative of the typical age of patients presenting with CLL in the clinic. The combination of R and Chl was well-tolerated and effective for untreated patients with CLL who cannot tolerate a more intensive regimen, and suggest investigation in a Phase III study is warranted.

Table: Matched analysis of Chl-R and selected controls treated with Chl alone in LRF CLL4

Overall Response Rate and 95% Confidence Interval
Trial
Achieved at least PR
Did not achieve PR
Missing
95% CI for percentage
of patients achieving
at least a PR*
Total number
of patients
Chl-R
42 (84.0%)
5 (10.0%)
3 ( 6.0%)
[70.9, 92.8]
50
CLL4 (Chl)
100 (66.7%)
45 (30.0%)
5 ( 3.3%)
[58.5, 74.1]
150
* Confidence intervals are calculated using the Exact method

Disclosures: Hillmen: Alexion Pharmaceuticals: Consultancy; F.Hoffmann-La Roche Ltd: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Schering: Consultancy. Hayward: F.Hoffmann-La Roche Ltd: Former Employee.

*signifies non-member of ASH