For patients with chronic lymphocytic leukemia (CLL) who are considered unfit for FCR chemotherapy (fludarabine, cyclophosphamide, rituximab), a fixed-duration regimen of venetoclax plus obinutuzumab followed by consolidation with venetoclax led to high rates of undetectable measurable residual disease (MRD), according to results from the HOVON 139/GIVE trial. Findings from this phase II randomized trial were shared by Mark-David Levin, MD, from Albert Schweitzer Hospital in the Netherlands, at EHA2021 Virtual.
Previous research has found that treatment with 12 cycles of the anti-CD20 antibody obinutuzumab led to longer progression-free survival and high rates of MRD negativity in patients with both treatment-naïve and relapsed/refractory CLL. However, studies have not investigated the effects of venetoclax consolidation in treatment-naïve patients, Dr. Levin explained.
The HOVON 139/GIVE trial enrolled patients with previously untreated CLL who were considered unfit to receive first-line FCR. All participants received induction with obinutuzumab plus venetoclax, then were randomized 1:1 to one of the following maintenance regimens:
- 12 cycles of venetoclax irrespective of MRD (arm A)
- MRD-guided venetoclax, with treatment limited to patients with detectable MRD after induction (arm B)
MRD was centrally assessed by flow cytometry in bone marrow after 12 and 24 cycles and in peripheral blood at screening, cycle 6, cycle 12, and every three months thereafter until month 27.
Of 67 evaluable patients, 53% of patients in arm A and 57% of patients in arm B achieved the primary endpoint, defined as undetectable MRD and no progression after a maximum of 24 venetoclax-containing cycles.
The authors also reported high overall response rates (ORRs) during the first phase of the trial, with an ORR of 43% after two cycles of obinutuzumab in induction that rose to 94% after the second induction phase with obinutuzumab plus venetoclax. Hematologic adverse events and infections were the most commonly reported toxicities during this phase, the researchers added. Hematologic toxicity caused four patients to stop obinutuzumab during the first induction phase, while another four patients stopped venetoclax.
Five patients were not randomized to receive maintenance therapy due to death, refusal to continue, and excessive toxicity, leaving 62 patients in the maintenance phase analysis. Thirty-two patients received fixed-duration venetoclax (arm A) and 30 received MRD-guided venetoclax (arm B). Dr. Levin noted that only two patients in arm B received venetoclax, as the remainder had undetectable MRD.
MRD negativity appeared to be related to improvements in survival, Dr. Levin and colleagues noted, with an estimated overall survival at 48 months of 94%. They also reported that MRD positivity was not associated with high-risk baseline characteristics, such as unmutated IGVH or del17p/TP53 mutation.
“Both fixed-duration venetoclax and MRD-guided venetoclax consolidation resulted in an undetectable MRD rate of more than 50% and no disease progression after a maximum of 24 cycles of venetoclax,” Dr. Levin concluded. He added that these findings warrant further study of consolidation in this treatment setting.
Study authors report no relevant conflicts of interest.
Levin MD, Dubois J, Nasserinejad K, et al. MRD-guided or fixed 12 cycles of venetoclax consolidation after venetoclax plus obinutuzumab treatment in first-line FCR unfit patients with CLL: primary endpoint analysis of the HOVON 139/GIVE trial. Abstract #S149. Presented at the EHA2021 Virtual Congress, June 9-17, 2021.