Dual targeting fixed duration frontline monoclonal antibody therapy for chronic lymphocytic leukemia: A phase 2 study. (November 2022)

• Record Type: Journal Article
• Authors: Ma, Shuo; Rosen, Steven T.; Winqvist, Maria; Frankfurt, Olga; Winter, Jane N.; Gordon, Leo; Helenowski, Irene; Zhang, Hui; Kreutzer, Jennifer; Sönnert-Husa, Sonja; Österborg, Anders; Lundin, Jeanette
• Is Part Of: Leukemia research. Volume 122(2022)
• Publication Date: 2022-11
• Subjects: Alemtuzumab -- Ofatumumab -- CLL -- Immunotherapy -- Frontline treatment -- Fixed duration; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2022.106945
• Languages: English
• ISSNs: 0145-2126

Abstract

Abstract: This phase 2 study describes long-term clinical and immunological effects of fixed-duration ofatumumab (anti-CD20) and alemtuzumab (anti-CD52) combination immunotherapy in 52 patients with previously untreated CLL. The median age was 65 years (range 45–79), 60% had Rai stage 3–4, 40% were IgHV unmutated and 25% had del(17p)/ TP53 mutation. Alemtuzumab was given subcutaneously (30 mg tiw, 18 weeks) and ofatumumab intravenously (300–2000 mg) starting week 3 q2 weeks (8 doses). Overall response rate was 98% with 48% complete remissions including 60% bone marrow MRD-undetectable. After a median follow-up time of 68 months, the median PFS, TTNT, DOR and OS were 31, 62, 30 months and not reached, respectively. The estimated 5-year PFS, TTNT, DOR and OS were 35%, 51%, 35% and 87%, respectively. CD59 (complement-inhibitory molecule) was rapidly downregulated (p < 0.01) during the initial CD52 mAb run-in period. Our study demonstrated that dual targeting of CD20 and CD52 represents an early successful example of time-limited (4–5 months) chemotherapy-free precision therapy for previously untreated CLL. Highlights: Alem-Ofa is effective in untreated CLL with ORR 98%, CR 48% and 60% bone marrow uMRD. The median PFS, TTNT, DOR and OS were 31, 62, 30 months and not reached, respectively. Achieving deep responses (CR or uMRD) led to significantly prolonged DOR of 73 months. Advanced stage, TP53 del/mut, or unmutated IgVH didn't negatively impact PFS and TTNT. Early stopping of alem upon bone marrow clearance is essential to prevent cytopenias.