Combination Therapy with Ofatumumab and Lenalidomide in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): Results of a Phase II Trial
Authors: Ferrajoli Alessandra , O'Brien Susan , Wierda William G. , Faderl Stefan , Badoux Xavier , Estrov Zeev , Schlette Ellen , Smith Susan C. , Ayala Ana B. , Falchi Lorenzo , Calin Steliana , Kantarjian Hagop M. , Keating Michael J 
Published: October 2019

Abstract
Abstract 1788
Patients with relapsed CLL have limited effective treatment options, and new therapies are needed. We report the results of a phase II study which investigated the efficacy and tolerability of a combination regimen with ofatumumab and lenalidomide in patients (pts) with relapsed CLL. These agents were evaluated as a combination regimen for pts with relapsed CLL based on their documented single-agent efficacy, distinct and potentially complimentary mechanisms of action and non-overlapping toxicities. Furthermore, the combination of rituximab and lenalidomide was active in relapsed CLL (Badoux et al. 2010). Pts with symptomatic disease who met treatment indications were eligible. Other inclusion criteria required prior treatment with purine analogs, an ECOG PS score of 0–2, and adequate organ function (creatinine clearance > 30ml/min, total bilirubin < to 2 mg/dl, ALT < 2 × ULN). Pts with any neutrophil count were eligible. Pts were excluded for platelets < 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis. Pts received ofatumumab IV weekly for four weeks (300mg week 1; 1,000 mg weeks 2 to 4), monthly during months 2–6, and every other month during months 7–24. Lenalidomide 10 mg PO daily was started on day 9 and continued daily for a maximum of 24 months. Allopurinol 300mg PO daily was given during the first two weeks of cycle 1. No pts received antibiotic or DVT prophylaxis. The use of growth factors was according to standard guidelines. Responses were assessed after 3, 6, 12, 18 and 24 months. Between January 2010 and January 2011, 36 pts were enrolled and 34 pts are evaluable (one pt withdrew consent prior to treatment and one was excluded because of concomitant MDS). The median age of the pts was 62 yrs (34–82). Twenty pts (59%) had Rai III-IV disease. The median beta-2M level at start of therapy was 4.4 mg/dL (1.7-16.5). The median number of prior treatments was 2 (1–8). All pts had received prior chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR). Twelve pts (35%) were fludarabine-refractory. Twenty-two pts (65%) had unmutated IgHV genes, 9 (26%) del(17p) and 4 (12%) del(11q). Responses were evaluated according to the 2008 NCI-WG criteria: 5 pts (15%) achieved CR (including 1 CRi) and 17 pts (50%) PR, for an ORR of 65%. Of the 5 CR pts, 1 was MRD-negative by flow cytometry. Two of the PR pts achieved marrow CR and only had persistent lymphadenopathy. Of the 22 responders, 13 are continuing on therapy with ongoing response (median time on therapy 14 months, range 8–20 months). Despite ongoing response, 7 pts discontinued therapy due to: transition to HSCT (3 pts; after 3, 6 and 6 months, respectively), pulmonary embolism (1 pt; after 4 months), recurrent zoster infection (1 pt; after 17 months of therapy) and physician choice (2 pts; after 9 and 16 months of therapy). Two pts discontinued therapy because of loss of response after 12 and 18 months of treatment, respectively. Thirty-one pts (91%) are alive. There have been no deaths on therapy. Three deaths occurred after discontinuation of therapy due to refractory disease (1), following HSCT (1) and due to progressive disease and adenocarcinoma of the lung (1). The most common grade 3–4 treatment-related hematological adverse events included neutropenia (15 pts, 44%), thrombocytopenia (3 pts, 9%) and anemia (1 pt, 3%). Thrombotic events occurred in 2 pts (6%). One pt experienced grade 3 pulmonary embolism and another patient grade 2 superficial vein thrombosis. In both cases with thrombotic event, ESAs were concomitantly administered. One pt (3%) experience a grade 3 infusion reaction during the first ofatumumab administration. Eight grade 3 infectious episodes occurred: pneumonia (3), neutropenic fever (2), parotitis (1), LE cellulitis (1) and CNS toxoplasmosis based on radiological findings (1). Intermittent grade 1–2 diarrhea was reported by 8 pts (24%). Grade 1–2 lenalidomide-associated tumor flare reaction was seen in 8 pts (24%). The median tolerated daily dose of lenalidomide was 5 mg/day (2.5-10 mg). In conclusion, the combination of ofatumumab and lenalidomide is well tolerated. Neutropenia was the most common toxicity. This combination induced responses in 65% of pts with relapsed CLL, all of whom had received prior chemoimmunotherapy. Responses are durable and ongoing in some pts.

Disclosures:
Ferrajoli: GlaxoSmithKline: Research Funding; Celgene: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Celgene: Consultancy. Wierda:GlaxoSmithKline: Research Funding.