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921 Final Analysis From the International Trial of Single-Agent Ofatumumab In Patients with Fludarabine-Refractory Chronic Lymphocytic LeukemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: CLL - Therapy, excluding Transplantation: Relapsed/Refractory Disease and Therapeutic Problems
Tuesday, December 7, 2010: 8:00 AM
Valencia A (Orange County Convention Center)

William G. Wierda, MD, PhD1, Thomas J. Kipps, M.D., Ph.D2, Jiri Mayer, MD3*, Tadeusz Robak, MD, PhD4, Martin JS Dyer, MA, DPhil, FRCP, FRCPath5*, Richard R. Furman, MD6, Peter Hillmen, MBChB, PhD7, Stephan Stilgenbauer, MD8, Catherine D. Williams, FRCPath9*, Marek Trneny10, Guillaume Cartron, MD, PhD11*, Francisco J. Hernandez-Ilizaliturri, MD12, Swaminathan Padmanabhan, MBBS, MS13*, Geoffrey W. Chan, MD14*, Ira V. Gupta, MD14*, Michele M. Gorczyca, MS14*, Randy L. Davis, DrPH15*, Nedjad Losic, MSc16*, Steen Lisby, MD, DMSc17 and Anders Österborg, MD, PhD18*

1Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, TX
2The University of California, San Diego, La Jolla, CA
3Department of Haematol-oncology, University Hospital Brno, Brno, Czech Republic
4Department of Haematology, Medical University of Lodz, Lodz, Poland
5MRC Toxicology Unit, Leicester University, Leicester, United Kingdom
6Weill Cornell Medical College, New York, NY
7Department of Haematology, St. James's University Hospital, Leeds, United Kingdom
8University of Ulm, Ulm, Germany
9Centre for Clinical Haematology, Nottingham University Hospital, Nottingham, United Kingdom
101st Dept Medicine, Charles University General Hospital, Prague, Czech Republic
11Service d'Hématologie-Oncologie Médicale, Hôpital Saint Eloi, Montpellier, France
12Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY
13Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX
14GlaxoSmithKline, Collegeville, PA
15GlaxoSmithKline, Research Triangle Park, NC
16Genmab A/S, Copenhagen K, Denmark
17Genmab, Copenhagen, Denmark
18Dept of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden

Background: Patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab (FA-ref) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (BF-ref) have poor prognosis with salvage regimens (Tam et al. Leuk Lymphoma 2007). Ofatumumab, a human CD20 monoclonal antibody, was recently approved by the US FDA and EMEA for treatment of CLL refractory to fludarabine and alemtuzumab based on the interim analysis of the pivotal international clinical trial, which included data from 138 patients with FA-ref and BF-ref CLL. At the interim analysis, the overall response rate (ORR; primary endpoint) with single-agent ofatumumab was 58% (99% CI: 40, 74) in the FA-ref group and 47% (99% CI: 32, 62) in the BF-ref group (Wierda et al. J Clin Oncol 2010). Here, we report the final result for the primary endpoint in 206 patients with FA-ref or BF-ref CLL enrolled in this study.

Methods: Patients with FA-ref or BF-ref CLL received 8 weekly doses of ofatumumab followed by 4 monthly doses (dose 1, 300 mg; doses 2–12, 2000 mg). Premedication included acetaminophen, antihistamine and glucocorticoid. The primary endpoint (ORR, 1996 NCI-WG criteria) was evaluated over the 24-week treatment period by an Independent Endpoint Review Committee (IRC). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS) and safety.

Results: Baseline characteristics are summarized in the Table; 89% and 50% of patients completed 8 and 12 ofatumumab doses, respectively. The ORR (95% CI) by IRC evaluation was 51% (40, 61) for the FA-ref group and 44% (35, 64) for the BF-ref group. Two patients in the BF-ref group achieved complete remission (Table). Results for time-to-event analyses are shown in the Table. Infusion-related AEs occurred in 63% of patients, which primarily occurred during doses 1 and 2, and diminished with subsequent doses. Infusion-related reactions were grade 1–2 events in 95% of patients; no fatal reactions were reported. The most common (≥5% of all patients) grade ≥3 adverse events (AEs) that occurred from start of treatment until 30 days after the last infusion were infections (24%), neutropenia (12%) and anemia (5%). The most common grade ≥3 infection was pneumonia (8% of patients). Fatal infections occurred in 8% of patients (13% in FA-ref; 5% in BF-ref groups). Grade 3–4 thrombocytopenia occurred in 8 patients (4%), febrile neutropenia in 4 patients (2%) and autoimmune hemolytic anemia in 2 patients (1%). Early death (within 8 weeks from start of treatment) occurred in 5 patients (5%) in the FA-ref group (infections, n=5) and 4 patients (4%) in the BF-ref group (infections, n=2; myocardial infarction, n=1; pulmonary edema, n=1).

Conclusions: These final results from the pivotal trial clearly demonstrate the efficacy and safety of ofatumumab monotherapy in this heavily pretreated patient population with FA-ref and BF-ref CLL. Additional data analyses are ongoing, and efficacy outcomes for patient subgroups will be presented.

Table. Pretreatment characteristics and response to therapy





Median (range)

Age, years

64 (41–86)

64 (43–87)

No. of prior therapies

5 (1–14)

4 (1–16)


% of patients




Rai Stage III–IV at screening



Binet Stage C at screening



Prior rituximab-containing regimen




% of patients

ORR (95% CI)

51 (40, 61)

44 (35, 64)

Complete response



Nodular partial response



Partial response



Stable disease



Progressive disease



Not evaluable



Time-to-event outcomes

Median (95% CI), months

Duration of response

5.7 (3.7, 7.2)

6.0 (4.2, 7.0)

Progression-free survival

5.5 (3.9, 6.3)

5.5 (4.9, 6.4)

Overall survival

14.2 (9.8, 20.4)

17.4 (15.0, 23.4)


Disclosures: Wierda: GlaxoSmithKline: Honoraria, Research Funding. Kipps: GlaxoSmithKline: Research Funding. Mayer: GlaxoSmithKline: Consultancy, Research Funding. Robak: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Furman: GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Stilgenbauer: Mundipharma: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Cartron: GlaxoSmithKline: Honoraria; Roche: Honoraria. Padmanabhan: GlaxoSmithKline: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Chan: GlaxoSmithKline: Employment. Gupta: GlaxoSmithKline: Employment. Gorczyca: GlaxoSmithKline: Employment. Davis: GlaxoSmithKline: Employment. Losic: Genmab A/S: Employment, Equity Ownership. Lisby: Genmab A/S: Employment. Österborg: Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Merck KGaA: Research Funding.

*signifies non-member of ASH