Patients with chronic lymphocytic leukemia (CLL) are often older at the time of diagnosis (median age = 72 years), and typically receive treatment for coexisting medical conditions. In a Letter to the Editor published in Blood, Kirsten Fischer, MD, from the Center for Integrated Oncology Cologne-Bonn at the University Hospital Cologne in Germany, and co-authors reported results from the ongoing phase III CLL14 trial, which is comparing the safety and efficacy of obinutuzumab with either chlorambucil or venetoclax in older patients with CLL.
Dr. Fischer and colleagues shared results from the venetoclax-treated arm of the study, which enrolled 13 adult patients with previously untreated CLL (median age = 75 years; range = 59-88 years) from Australia, Canada, Germany, New Zealand, the United States, and Spain between December 2014 and April 2015. All patients responded to treatment with venetoclax and obinutuzumab, and more than half of the 12 patients who completed treatment (58%; n=7/12) had a complete response (per International Workshop on CLL guidelines).
Patients were included in the trial if they had a cumulative illness rating scale (CIRS) score of >6 (indicating the presence of multiple comorbidities) and, at baseline, patients had a median CIRS score of 8 (range = 6-14).
Patients received six cycles of intravenous obinutuzumab (cycle 1: either 100 mg on day 1 and 900 mg on day 2, or 1,000 mg on day 1 followed by 1,000 mg on days 8 and 15; cycles 2-6: obinutuzumab 1,000 mg on day 1). Venetoclax was administered orally on day 22 of cycle 1, at a starting dose of 20 mg; the dose was increased to 60 mg, 100 mg, 200 mg, and 400 mg through cycle 12.
At data cutoff, all but two patients received the full 12 months of therapy. One of these patients developed a grade 4 infusion-related reaction (IRR) and was withdrawn from the study, while the other chose to discontinue treatment at cycle 8.
The authors observed "a rapid reduction in the peripheral lymphocyte count in all patients within the first cycle of obinutuzumab." One patient had incomplete bone marrow (BM) recovery because of a hemoglobin value of 10.2 g/dL. Five patients reported a partial response; three of whom had blood count normalization and lymphadenopathy resolution.
At cycle 7, 10 of 11 patients with evaluable minimal residual disease (MRD) had peripheral blood (PB) samples that were MRD-negative, whereas the other patient was deemed to have "intermediate" MRD (â‰¥10-4 and <10-2). At cycles 9 and 12, all patients with available MRD data were MRD-negative. At the final staging (3 months after the end of treatment), 11 of 12 patients were MRD-negative; the other patient was MRD-intermediate.
At cycle 9, of the five patients who had BM aspirates available, three were MRD-negative, one was MRD-intermediate, and one was MRD-positive. At final staging, BM samples were available for seven patients, five of whom were MRD-negative and two of whom were MRD-intermediate. This represents "a 92 percent MRD-negativity rate," the authors noted. But they cautioned, "given the limited number of available BM samples and a few discordances observed between MRD levels assessed in PB and BM, further follow-up is needed to evaluate the depth of response."
At a median follow-up of 15 months, no progressive disease or deaths were reported.
All patients experienced at least one adverse event (AE), and 83.3 percent (n=10) had at least one grade 3/4 AE. The most common any-grade AEs (occurring in â‰¥50%) included IRRs (75%; n=9), neutropenia (66.7%; n=8), infections (66.7%; n=8), pruritus (58.3%; n=7), diarrhea (50%; n=6), and cough (50%; n=6). No fatal AEs were reported.
Two patients (16.7%) experienced tumor lysis syndrome (TLS); one event occurred during venetoclax dose increase to 200 mg in cycle 2, and the other occurred on the first day of cycle 1 after obinutuzumab 100 mg infusion. "Further treatment and observation [are] warranted in the main phase [of the study] to assess TLS frequency in this patient population," the authors wrote. However, they concluded that "venetoclax and obinutuzumab can be safely administered in previously untreated CLL patients of advanced age who have coexisting medical conditions."
The study is limited by its small patient population, single arm design, and short duration of follow-up. The randomized portion of the CLL14 study is ongoing.
Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017 March 21. [Epub ahead of print]