Front-Line Treatment with Ofatumumab for Older Unfit Patients with Chronic Lymphocytic Leukemia
Authors: Vitale Candida , Ciccone Maria , Hinojosa Christina , Keating Michael , Pemmaraju Naveen , O'Brien Susan , Wierda William , Thomas Deborah A , Borthakur Gautam , Ohanian Maro , Burger Jan A. , Ferrajoli Alessandra 
Published: October 2019

Abstract
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a disease of the elderly, and patients frequently present with multiple concomitant medical problems such as other cancers. These patients, although common in the real-world clinical practice, are usually not considered eligible for clinical trials. We therefore designed a phase II study to investigate the activity and toxicity of ofatumumab in older unfit patients with CLL/SLL. Patients were considered candidates for this trial if they had a diagnosis of treatment-naïve CLL/SLL, treatment indication according to 2008 IWCLL guidelines, age ≥65 years, and ECOG performance status of 2-3 and/or Charlson comorbidity index ≥2. Patients with the diagnosis of another malignancy, or the coexistence of other serious medical conditions were enrolled in this study. Ofatumumab was administered intravenously weekly for the first month (300 mg day 1 and 2,000 mg day 8, 15, 22), then monthly (2,000 mg day 1) for a total of 12 months. The first 8 patients received ofatumumab at 1,000 mg, however, starting from patient number 9 the trial was amended and the administered dose of ofatumumab was increased to 2,000 mg, based on reports of increased efficacy with this dose. Acetaminophen, prednisolone and diphenhydramine were administered prior to ofatumumab to ameliorate infusion reactions.
To date, twenty-seven of the thirty-four planned patients have been enrolled.
Patients' characteristics were as follows:
Table. Number of patients 27 Age, years, median (range) 73 (65-86) Male/Female 12/15 Rai stage 3-4 13 (48%) Absolute lymphocyte count, 106/µl, median (range) 35.4 (0.8-226.2) β2 microglobulin, mg/L, median (range) 3.7 (1.6-11.9) Months from diagnosis, median (range) 32 (0-251) FISH1 normal/del(13q)tris(12)del(11q)del(17p) 9 (33%)8 (30%)9 (33%)1 (4%) IGVH Unmutated2 13 (59%) ZAP70 positive3 16 (64%) CD38 positive3 14 (56%) 1Hierarchical classification. 2Data available for 22 patients. 3Data available for 25 patients.
Eight patients (30%) had another concomitant cancer diagnosis: melanoma, basal cell carcinoma, squamous cell carcinoma, papillary thyroid carcinoma, cervical cancer, colorectal cancer, meningioma, essential thrombocythemia, pancreatic neuroendocrine cancer.
Twenty-five patients are evaluable for response: one patient is too early for response evaluation and one patient discontinued treatment during the first month due to the development of hemophagocytic lymphohistiocytosis (HLH). Eighteen patients achieved a response for an overall response rate of 72%. We observed complete responses (CR) in 4 patients (16%), and partial responses in 6 patients (56%). One CR patient achieved minimal residual disease negativity. Of note, the higher ofatumumab dose seems to be associated with increased efficacy, with responses observed in 14/17 (82%) patients treated at the 2,000 mg dose, and in 4/8 (50%) patients treated at the 1,000 mg dose. At this time, 17 patients remain progression-free and 10 patients have progressed, with a median follow up of 13 months (range 2-39 months). The estimated median time to next treatment is 20 months. Twenty-five patients are alive. One patient died of infectious complications two years after receiving ofatumumab while on a subsequent treatment regimen, and one patient died of complications of HLH, less than 4 months after treatment initiation.
All 27 patients are evaluable for toxicity. Infusion-related reactions (IRR) were the most common treatment-related adverse events (AEs). We observed IRR grade (G)3 in one patient (4%) and G1-2 in 18 patients (67%). Fifteen patients (55%) experienced G1-2 infectious AEs, but no G3-4 infectious AEs were observed. Additional G3-4 AEs which were considered to be at least possibly related to the study drug were: diarrhea/nausea/vomiting G3 (1 patient), hyperglycemia G3 (2 patients), pulmonary embolism G3 (1 patient).
In conclusion, our experience indicates that single agent ofatumumab is a feasible and well tolerated therapeutic approach for treatment-naïve older unfit patients with CLL/SLL. This treatment is able to obtain clinical response in 72% of these patients. In this trial, ofatumumab could be safely administered to patients with severe comorbidities and other cancer diagnoses.

Disclosures
Keating: Celgene Corp.: Consultancy; Glaxo-Smith-Kline Inc.: Other: Advisory board. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding.