The current standard of care for patients with chronic lymphocytic leukaemia (CLL) and coexisting conditions is fixed duration chemoimmunotherapy or continuous and indefinite targeted therapy.
As an answer to an unmet clinical need we developed a new fixed duration targeted treatment regimen.
Venetoclax rapidly induces apoptosis of CLL by selective inhibition of BCL2, a protein that regulates cell death and is overexpressed in CLL cells.
Obinutuzumab is an anti-CD20 monoclonal antibody that is able to bind and destroy malignant CLL cells.
Pre-clinical data suggests a maximal additive effect for venetoclax when combined with obinutuzumab.
The CLL14 study was designed by the German CLL Study Group to investigate the effect of a chemotherapy-free fixed-duration treatment of venetoclax plus obinutuzumab versus a standard chemoimmunotherapy regimen of chlorambucil plus obinutuzumab in previously untreated patients with CLL and co-existing comorbidities.
The results of the CLL14 study, with particular emphasis on efficacy data including data on minimal residual disease (MRD), were presented at the 2019 European Hematology Association (EHA) Annual Meeting.
Venetoclax plus obinutuzumab was confirmed to be superior to chlorambucil plus obinutuzumab with regard to the primary endpoint of progression free survival (PFS) with 88% versus 64% of the patients being free of disease progression at 2 years after start of treatment (median PFS not reached in both arms).
Furthermore, three months after the completion of treatment, 76% of the patients in the venetoclax plus obinutuzumab group were confirmed negative for minimal residual disease in the blood; the MRD negative response rate was more than doubled when compared to a negativity rate of 35% of the patients in the standard arm.
Fixed-duration targeted therapy with venetoclax–obinutuzumab can be administered safely to elderly patients with CLL and co-existing comorbidities and provides a superior outcome compared to chlorambucil and obinutuzumab regarding:
Progression free survival.
Overall response rate.
Complete response rate.
MRD negative responses.
In all relevant subgroups including IGVH unmutated, del(17p) or TP53 mutated patients.
In addition, the therapy achieved the highest rate of MRD negative responses that have been observed in a randomised prospective study so far.
Based on these results, venetoclax in combination with obinutuzumab was granted Breakthrough Therapy Designation by the US Food and Drug Administration, reviewed under the Real-Time Oncology Review Pilot Program and subsequently approved for the treatment of previously untreated patients with CLL or small lymphocytic lymphoma on May 15 2019.
These findings support the use of fixed-duration chemotherapy-free treatment venetoclax plus obinutuzumab as first-line therapy in patients with CLL and co-existing comorbidities and establish an alternative treatment option to continuous indefinite BTK inhibitor treatment.