Only 1 Year of Tx: Venetoclax/Obinutuzumab Combo in CLL

Nancy A. Melville

June 18, 2019

AMSTERDAM — The combination of venetoclax (Venclexta, AbbVie/Genentech) and obinutuzumab (Gazyva/Gazyvaro, Genentech/Roche) offers a new chemotherapy-free regimen for patients with previously untreated chronic lymphocytic leukemia (CLL).

One of the practical benefits of this combination is that treatment is completed within 12 months, whereas other treatment options need to be continued for longer, or indefinitely.

The current standard options of CLL require ongoing treatment, making the 12-month regimen especially beneficial, commented Kirsten Fischer, MD, of the Department of Internal Medicine, the Center for Integrated Oncology Aachen–Bonn–Cologne–Duesseldorf, University Hospital Cologne and the University of Cologne, Germany.

She was presenting results from the CLL14 study here at the European Hematology Association (EHA) 2019 Annual Meeting. The full results were published online June 6 in the New England Journal of Medicine.

The venetoclax-obinutuzumab combination received FDA approval for previously untreated CLL and small lymphocytic lymphoma in March 2019 on the basis of this phase 3 study.

That study showed that the combination yielded improved progression-free survival (PFS) when compared with the standard of care (obinutuzumab combined with chlorambucil [Leukeran, Aspen Global]) for this tough-to-treat population, Fischer commented.

"We showed that fixed-duration venetoclax-obinutuzumab therapy can be safely administered to elderly patients with CLL and relevant comorbidities with no new toxicities and no increases in known toxicities," she commented.

"The current standard of care for these patients is either fixed-duration chemoimmunotherapy or, more recently, continuous indefinite targeted therapy, and that's why we decided to develop a new therapy that is fixed-duration and targeted therapy," she explained.

Important New Option

The new combination provides an important option for the treatment of CLL in the elderly, commented Anton Hagenbeek, MD, professor of hematology at the Academic Medical Center at the University of Amsterdam, the Netherlands.

"The thing is, many new drugs are given eternally, and there is a lot of money involved," Hagenbeek told Medscape Medical News.

"But the good thing of this regimen is it is limited, and clearly it works, because patients soon came into MRD [minimal residual disease] negativity, and they stayed there," he said.

He added, "It's not necessarily a surprise that response rates were higher compared to indefinite treatment. Venetoclax is one of the most active agents in CLL, and if you combine it with an active antibody like obinutuzumab, which is anti-CD20, you have two different modes of action.

"Venetoclax is going to be much more expensive, but these results show you gain significant success in terms of increased progression-free survival with a much shorter duration of treatment," he said.

Study Details

The CLL14 trial involved 432 previously untreated CLL patients who were randomly assigned to receive either the combination of the targeted agent venotoclax with obintuzumab or the chemotherapy chlorambucil with obintuzumab.

The median age of the patients was 72 years. The median cumulative illness rating scale score was 8, which is consistent with the general population of CLL patients. The median creatinine clearance for these patients was 66.4 mL/min.

The study met the primary outcome of PFS. At a median follow-up of 24 months, for the patients who received venetoclax plus obinutuzumab, the PFS rate was 88.2%, compared to 64.1% for the comparison group, which received chlorambucil plus obinutuzumab (hazard ratio [HR], 0.35; P < .0001).

Importantly, improvements in PFS were seen even in subgroups with unmutated immunoglobulin heavy chain variable (IGHV) status.

"This benefit in progression-free survival is also seen in all relevant subgroups, including patients with unmutated IGHV status, compared to chlorambucil group, indicating that this therapy was able to overcome the adverse risk of the unmutated IGHV state," Fischer said.

Of the patients in the venetoclax-obinutuzumab group, 76% had negative MRD, as determined on the basis of results of ASO-PCR (allele-specific oligonucleotide–polymerase chain reaction) assay, in peripheral blood 3 months after completion of treatment. For the patients in the comparison group, the rate of MRD in peripheral blood was 35% (P < .0001). For bone marrow, the MRD rate was 57% for the venetoclax-obinutuzumab group, vs 17% for the comparison group (P < .0001).

The correspondence between blood and bone marrow is known to be linked to improved outcomes. Overall, 75% of the patients who received venetoclax-obinutuzumab were MRD negative with respect to peripheral blood and were also MRD negative with respect to bone marrow. In the comparison group, 49% were MRD negative for both peripheral blood and bone marrow.

The rates of MRD negativity were sustained in 81% of the venetoclax-obinutuzumab group 12 months following completion of treatment, compared to 27% in the chlorambucil-plus-obinutuzumab group (HR for MRD conversion, 0.19).

"What is most important and remarkable to me is that these results are seen with just a 12-month fixed-duration therapy, and hence, it achieves the highest rate of MRD-negative responses observed in a randomized clinical study so far," Fischer said.

There were no new safety signals or higher incidences of toxic effects with either treatment combination. Contrary to findings from a previous trial, the venetoclax-obinutuzumab combination was not associated with an increased risk for tumor lysis syndrome.

The study was supported by Genentech and AbbVie. Fischer has received honoraria from Abbvie. Hagenbeek is a consultant for Takeda USA.

European Hematology Association (EHA) 2019 Annual Meeting: Abstract S147. Presented June 14, 2019.

N Engl J Med. Published online June 6, 2019. Abstract

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