Early Results of a Phase II Study of Ofatumumab As Front-Line Treatment in Elderly, Unfit Patients with Chronic Lymphocytic Leukemia (CLL)
Authors: Ciccone Maria , Vitale Candida , Hinojosa Christina , Keating Michael J , Pemmaraju Naveen , O'Brien Susan , Burger Jan A. , Thomas Deborah A. , Kantarjian Hagop M. , Strati Paolo , Wierda William G. , Ferrajoli Alessandra 
Published: October 2019

Abstract
Background
Patients with chronic lymphocytic leukemia (CLL) that are elderly and have multiple comorbidities show poor tolerance to chemoimmunotherapy. This population is frequent in the real-world clinical practice, but is usually excluded from participating in clinical trials. We, therefore, decided to investigate the activity and toxicity of ofatumumab, a fully human anti-CD20 monoclonal antibody in elderly unfit patients.
Methods
Patients with untreated CLL requiring therapy (2008 NCI-WG guidelines), aged ≥65 years, who had an ECOG performance status of 2-3 or ECOG 0-1 and a Charlson comorbidity index ≥2 were considered eligible. Patients with another malignancy or with an ongoing serious medical condition were allowed to participate in this trial. Treatment consisted of ofatumumab given as intravenous infusions weekly for the first month (300 mg day 1 and 1,000 mg day 8, 15, 22), then monthly (1,000 mg day 1) for a total of 12 months. The trial was amended after the first 8 patients, and the dose of ofatumumab was increased from 1,000 to 2,000 mg in subsequent patients in view of reports of increased efficacy with the 2,000 mg dose. Acetaminophen, prednisolone and diphenhydramine were administered prior to ofatumumab infusion to ameliorate infusion reactions.
Results
From January 2012 to the present time, 18 patients have been enrolled in this trial. Patients’ characteristics at treatment initiation are summarized as follows:
Table 1 Number of patients 18 Age, years, median (range) 73 (67-85) Male/Female 8/10 Rai stage 3-4 7 (39%) Absolute lymphocyte count, 106/µl, median (range) 30.5 (6.1-149.7) β2 microglobulin, mg/L, median (range) 3.6 (1.6-11.9) Months from diagnosis, median (range) 14 (0-166) FISH1 normal/del(13q) tris(12) del(11q) del(17p) 7 (39%) 5 (28%) 5 (28%) 1 (5%) IGVH Unmutated2 5 (56%) ZAP70 positive2 3 (33%) CD38 positive 12 (67%)
1Hierarchical classification. 2Data available for 9 patients.
Six patients (33%) had other cancers (melanoma, basal cell carcinoma, squamous cell carcinoma, papillary thyroid carcinoma, cervical cancer, colorectal cancer, meningioma, essential thrombocythemia). At the time of study entry 6 patients had a positive direct antiglobulin test, and one patient had immune-mediated thrombocytopenia.
At the present time, 13 patients are evaluable for response and 5 patients are too early for response evaluation having not yet completed 6 months of therapy. Nine patients achieved a response for an overall response rate of 69%; complete responses were observed in 3 patients (23%), and partial responses in 6 patients (46%). None of the patients obtained minimal residual disease negativity. Of note, the increase in ofatumumab dose appears to be associated with a superior efficacy, with responses observed in all the 5 patients treated at the 2,000 mg dose, whereas only 4 of the 8 patients treated at the 1,000 mg dose achieved a response.
At a median follow up of 24 months, 6 patients remain progression-free, 7 patients have progressed and required subsequent treatment with a median time to next treatment of 15 months. None of the patients died on study; one patient died of infectious complications two years after receiving ofatumumab, while receiving subsequent therapies.
Eighteen patients are evaluable for toxicity. The most common treatment-related adverse events (AEs) were infusion-related reactions, grade (G)3 in one patient (5%) and G1-2 in 6 patients (33%). Additional G3 AEs, reported in 4 patients, were diarrhea (2 patients), hyperglycemia (1 patient) and neutropenia (1 patient). No G4 AEs were observed.
Conclusions
Based on our experience, therapy with ofatumumab as frontline single agent for elderly unfit CLL patients is feasible, well tolerated, and clinically effective, obtaining response in 69% of patients. This treatment was safely administered to patients with other cancer diagnoses.

Disclosures
O'Brien: MorphoSys, Acerta, TG Therapeutics: Research Funding; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, GSK: Consultancy.