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Ofatumumab Combined With Fludarabine and Cyclophosphamide (O-FC) Shows High Activity in Patients With Previously Untreated Chronic Lymphocytic Leukemia: Results From a Randomized, Multicenter, International, Two-Dose, Parallel-Group Phase II Trial.
MedLine Citation:
PMID:  20511150     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Introduction: Chemoimmunotherapy regimens are the treatment standard for fit patients with chronic lymphocytic leukemia (CLL). Ofatumumab is a human monoclonal antibody that binds to a unique membrane-proximal epitope composed of both the large- and small-loop domains of CD20. Overall response rates (ORRs) of 47%-58% have been observed with single-agent ofatumumab in patients with fludarabine-refractory CLL. We evaluated the efficacy and tolerability of 2 doses of ofatumumab combined with fludarabine and cyclophosphamide (O-FC) in previously untreated patients with CLL in an international, randomized, parallel-group phase II trial. Patients and Methods: Patients with active CLL were randomized to ofatumumab 500 mg (group A) or 1000 mg (group B) day 1, with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 days 2-4, course 1; days 1-3, courses 2-6; administered every 4 weeks for 6 courses. For both groups, first dose of ofatumumab was 300 mg. The primary endpoint was complete response (CR) rate (1996 NCI-WG criteria) assessed by an Independent Review Committee (IRC), measured from the start of treatment up to 3 months after the last course. Results: There were 61 patients enrolled and randomized on this study (Table 1). Seventy-one percent and 57% of patients in groups A (n = 31) and B (n = 30), respectively, completed all 6 courses of O-FC treatment. The CR rate by IRC evaluation was 32% (95% CI, 17%-51%) for group A and 50% (95% CI, 31%-69%) for group B; the ORR was 77% (95% CI, 59%-90%) and 73% (95% CI, 54%-88%), respectively (Table 1). The CR rate and ORR for patients who received all 6 courses of O-FC were 56% and 92%, respectively. Follow-up is ongoing for progression-free and overall survival. No grade 3-4 infusion-related reactions on the day of ofatumumab infusion were reported. During treatment and up to 30 days following the last dose, the most common (> 10% of patients) grade 3-4 adverse events (AEs) reported by investigators were infections in 11 patients (group A, n = 4; group B, n = 7), including febrile neutropenia in 3 patients in each group, and hematologic AEs, including neutropenia in 29 patients (group A, n = 11; group B, n = 18), anemia in 8 patients (group A, n = 2; group B, n = 6), and thrombocytopenia in 9 patients (group A, n = 2; group B, n = 7). Grade 3-4 hemolytic anemia occurred in 2 patients in group A and 1 in group B. In group A, a patient died 50 days from last dose during follow-up (febrile neutropenia). In group B, a patient died 19 days from last dose during treatment (dyspnea; etiology unknown), and another patient died 186 days from last dose (neutropenia following alternative treatment for progressive CLL). Conclusions: The O-FC regimen is active in previously untreated patients with CLL at the ofatumumab doses investigated. AEs with the O-FC regimen were manageable with no unexpected toxicities. The 1000 mg dose of ofatumumab is currently being evaluated in combination with chemotherapy in other studies for patients with CLL.
Authors:
William G Wierda; Thomas J Kipps; Jan D?rig; Laimonas Griskevicius; Stephan Stilgenbauer; Jiri Mayer; Lukas Smolej; Georg Hess; Rasa Griniute; Francisco J Hernandez-Ilizaliturri; Swaminathan Padmanabhan; Michele Gorczyca; Ira Gupta; Tina G Nielsen; Charlotte A Russell
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Clinical lymphoma, myeloma & leukemia     Volume:  10     ISSN:  2152-2669     ISO Abbreviation:  Clin Lymphoma Myeloma Leuk     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-31     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101525386     Medline TA:  Clin Lymphoma Myeloma Leuk     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E33-4     Citation Subset:  IM    
Affiliation:
M. D. Anderson Cancer Center, The University of Texas, Houston, TX.
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