Success of Venetoclax and Obinutuzumab Use in Patients with CLL

Research presented by Dr. Kirsten Fischer at the 24^th Congress of European Hematology Association (EHA) in Amsterdam on June 14 shows the efficacy of venetoclax (VENCLEXTA) and obinutuzumab (GAZYVA) in treating patients with chronic lymphocytic leukemia (CLL). This work supports the use of such treatment as a first-line therapy in patients with CLL and co-existing conditions.

Venetoclax is a selective inhibitor of BCL2, a protein responsible for regulating cell death that is overexpressed in CLL cells. By inhibiting this protein, venetoclax functions to rapidly induce apoptosis in these malignant cells. Obinutuzumab is an anti-CD20 monoclonal antibody that can bind and destroy CLL cells.

With pre-clinical data suggesting a maximal additive effect for venetoclax when used in concert with obinutuzumab, this study was conducted to test the efficacy of such treatment in elderly patients with previously untreated CLL. Current treatments for CLL patients are continuous and indefinite targeted therapy or fixed duration chemoimmunotherapy. Venetoclax-obinutuzumab treatment presents as a new fixed duration targeted treatment regimen that could potentially bolster CLL care.

This CLL14 study was created by the German CLL Study Group to evaluate a non-chemotherapeutic fixed-duration treatment consisting of venetoclax and obinutuzumab. The efficacy of this treatment was compared to that of a standard chemoimmunotherapy treatment with chlorambucil and obinutuzumab in untreated patients with CLL and other comorbidities.

When presenting these findings at the 24^th EHA Congress, Fischer emphasized data on minimal residual disease (MRD) from the CLL14 study. It was found that the use of venetoclax and obinutuzumab yielded better outcomes than chlorambucil and obinutuzumab did regarding progression free survival. 88% of the patients treated with venetoclax-obinutuzumab showed no disease progression two years after treatment, compared to only 64% of those treated with chlorambucil-obinutuzumab.

In addition, 76% of the patients treated with venetoclax-obinutuzumab showed no MRD in the blood three months after treatment, compared to 35% in the standard group.

The researchers concluded that venetoclax–obinutuzumab fixed-duration targeted therapy can safely be used in elderly CLL patients with co-existing conditions. Such treatment was superior to chlorambucil-obinutuzumab treatment in progression free survival, overall response rate, complete response rate, MRD negative responses, and in all relevant subgroups including IGVH unmutated, del(17p) or TP53 mutated patients. The team also noted that venetoclax–obinutuzumab treatment could present as an alternative to continuous indefinite BTK inhibitor treatment.

The presenters also noted that this approach yielded the highest rate of MRD negative results observed in a such a study thus far. This work helped venetoclax–obinutuzumab treatment receive Breakthrough Therapy Designation by the FDA, a review under the Real-Time Oncology Review Pilot Program, and approval for treatment of previously untreated CLL/small lymphocytic lymphoma patients this past May.

Penultimate presentation in the #CLL session argues that ibrutinib and venetoclax together has the potential to help people achieve MRD negativity, and patients only need continue ibrutinib if they do not respond. #EHA24 @LeukaemiaCareUK pic.twitter.com/FOZex0VmWX

— Charlotte Martin (@scicommchar) June 14, 2019