In the phase 3 CLL14 clinical trial, fixed-duration venetoclax plus obinutuzumab was superior to chlorambucil plus obinutuzumab as front-line therapy in older patients with chronic lymphocytic leukemia (CLL) and comorbidities. The fixed-duration regimen significantly improved progression-free survival (PFS), complete response (CR) rate, and minimal residual disease (MRD) negativity versus chlorambucil plus obinutuzumab, and was superior in patients with poor prognostic factors, such as unmutated IGHV and TP53 alterations.
Fixed-duration venetoclax plus obinutuzumab combination was hailed as a new standard of care by experts at the 2019 American Society of Clinical Oncology Annual Meeting, where study results were presented and published simultaneously in the New England Journal of Medicine (Fischer K, et al. N Engl J Med. 2019;380:2225-2236).
“This study is practice-changing in the front-line setting. For most patients, we should be considering venetoclax plus obinutuzumab for front-line therapy,” said formal discussant Matthew S. Davids, MD, MMSc, Associate Director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute, Boston, MA. He emphasized the fixed duration of treatment and high rates of MRD negativity achieved in the trial as distinguishing this regimen from others being studied in CLL, including front-line ibrutinib, which is given continuously.
“Fixed-duration targeted therapy combining venetoclax and obinutuzumab can be applied safely to elderly CLL patients with comorbidities. Our study showed it is superior to fixed-duration chlorambucil and obinutuzumab. Venetoclax plus obinutuzumab achieves the highest rates of MRD negative response so far observed in a randomized prospective trial [of patients with CLL],” stated lead investigator Kirsten Fischer, MD, Department of Internal Medicine, Center for Integrated Oncology Bonn, University Hospital Cologne, Germany.
Follow-up is a median of 28 months and thus far there is no survival difference between the 2 regimens. “It might be too early to see an effect on survival,” Dr Fischer said.
The open-label, randomized, phase 3 CLL14 clinical trial enrolled 432 previously untreated patients with CD20-positive CLL in need of therapy. Patients had to have clinically significant comorbidities, indicated by a score of >6 on the Cumulative Illness Rating Scale or a creatinine clearance of <70 mL per minute. Patients were randomized 1:1 to receive either venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab for 12 cycles lasting 28 days.
Treatment arms were well balanced for demographic and disease characteristics. Median age was 72 years, median Cumulative Illness Rating Scale score was 8, and median creatinine clearance was 66.4 mL per minute. In total, 13.8% of patients had TP53 deletion, mutation, or both, and 59.8% of patients had unmutated IGHV.
With a median follow-up of 28 months, median PFS was not reached in either group. Estimated 24-month PFS was 88.2% in the venetoclax plus obinutuzumab arm versus 64.1% in the chlorambucil plus obinutuzumab arm (P <.0001).
“MRD negativity was achieved early with venetoclax, and stayed that way over time,” Dr Fischer told listeners.
Three months after treatment ended, an intent-to-treat analysis showed that the rate of MRD negativity in peripheral blood was 75.5% for venetoclax plus obinutuzumab versus 35.2% for chlorambucil plus obinutuzumab (P <.001) and in bone marrow 56.9% versus 17.1%, respectively (P <.001).
Overall response rates were 84.7% versus 71.3%, respectively (P <.001); and CR rates were 49.5% versus 23.1%, respectively (P <.001). The rates of patients with CR and MRD negativity in peripheral blood were significantly higher in the venetoclax plus obinutuzumab group: 42.1% versus 14.4%, respectively (P <.001); and in bone marrow, 33.8% versus 10.6%, respectively (P <.001).
Safety and Tolerability
At least 1 adverse event of any grade was reported in 94.5% of the venetoclax plus obinutuzumab arm and 99.5% of those in the chlorambucil plus obinutuzumab arm (total safety population, 426 patients). Adverse events leading to treatment discontinuation occurred in 16% and 15.4% of patients, respectively. The most common grade 3 or 4 event was neutropenia. Grade 3 or 4 febrile neutropenia occurred in 5.2% and 3.7% of patients, respectively, and grade 3 or 4 infections occurred in 17.5% and 15%, respectively. No patient developed symptoms that met clinical criteria for tumor lysis syndrome. The rate of grade 3 and 4 infusion reactions was similar in both arms (9% and 10.3%, respectively). The rate of second cancers was not significantly different between the 2 treatment arms.