Chemoimmunotherapy with ofatumumab, fludarabine, and cyclophosphamide (O-FC) in previously untreated patients with chronic lymphocytic leukemia (CLL).

Abstract

6520^ Background: Ofatumumab, a human monoclonal antibody targeting a unique epitope encompassing both large- and small-loop of CD20, demonstrated high overall response rates (ORR) in a pivotal study in refractory CLL. We conducted an international, randomized, phase II trial to assess efficacy and safety of two dose levels of O-FC in previously untreated patients (pts) with CLL. Methods: Pts with active CLL were randomized to ofatumumab 500 mg (Group A) or 1,000 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; every 4 weeks for 6 courses. First ofatumumab dose was 300 mg. The primary endpoint was complete response (CR) rate (1996 NCI-WG criteria) evaluated by an Independent Review Committee during treatment until 3 months after last dose. Results: 61 pts were randomized (Group A, n=31; Group B, n=30). CR rate was 32% and 50% for Group A and B; ORR was 77% and 73%, respectively. Responses by baseline and treatment parameters are shown (Table). Short median follow-up (8 months) currently does not permit analyses of time-to-event endpoints. Ofatumumab Cmax (426 vs. 201 mg/L) and Cmin (60 vs. 20 mg/L) at 6th infusion were higher in Group B vs. Group A. Based on exploratory univariable regression analyses, lower β2-microglobulin (as continuous variable), completion of 6 courses of O-FC, and higher ofatumumab Cmin prior to last infusion were significantly correlated with increased likelihood for response including CR, and decreased risk for progression. Additional pharmacokinetic analyses are ongoing. Conclusions: O-FC is highly active in previously untreated pts with CLL. β2-microglobulin level, number of O-FC courses completed, and Cmin prior to last course correlated with outcomes with O-FC Parameters N % CR % ORR All pts 61 41 75 Age <65 50 44 76 ≥65 yrs 11 27 73 ALC <30 × 109/L 11 64 82 ≥30 × 109/L 50 36 74 Lymph nodes ≤5 cm 51 39 78 >5 cm 10 50 60 Rai stage 0-II 33 36 73 III- IV 28 46 79 β2-M <4 mg/L 32 53 84 ≥4 mg/L 28 29 68 CD38+ <30% 48 44 77 ≥30% 12 33 67 IGHV mutated 28 46 75 IGHV unmutated 25 36 84 17p del 8 13 63 11q del 10 40 70 Trisomy 12q 9 56 56 No FISH abn. 7 71 100 13q del (sole) 25 32 80 No. of O-FC courses received: 6 39 56 92 4–5 9 33 78 1–3 13 0 23 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Genomic Health, sanofi-aventis Amgen, Genomic Health, sanofi-aventis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.