Venetoclax-obinutuzumab combination elicits high response rates in CLL

Previously untreated patients with chronic lymphocytic leukaemia (CLL) and coexisting conditions who received fixed-duration venetoclax plus obinutuzumab had better survival outcomes compared with fixed-duration chemoimmunotherapy, showed results from the international, open-label, phase 3 CLL14 trial [1, 2].

Dr Kirsten Fischer (University of Cologne, Germany) presented the CLL14 trial. The trial included 432 previously untreated patients with CLL and coexisting conditions, and patients were randomly assigned treatment with fixed-duration venetoclax plus obinutuzumab (n=216) or fixed-duration chlorambucil plus obinutuzumab (n=216). 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 overall response rate was significantly higher for the venetoclax plus obinutuzumab arm compared with the chlorambucil plus obinutuzumab arm (84.7% vs 71.3%; P<0.0007); the complete response rate was also significantly higher (49.5% vs 23.1%; P<0.001). At a median follow-up of 28 months, the median progression-free survival (PFS) favoured the venetoclax plus obinutuzumab arm over the chlorambucil plus obinutuzumab arm (HR 0.35; 95% CI 0.23-0.53; P<0.001). The venetoclax plus obinutuzumab arm also had a superior 24-month PFS rate compared with the chlorambucil plus obinutuzumab arm (88% vs 64%; median PFS not reached in both arms). Importantly, the PFS benefit was seen regardless of IGHV or TP53 mutational status. Furthermore, 3 months after the completion of treatment, 76% of the patients in the venetoclax plus obinutuzumab group were confirmed negative for minimal residual disease (MRD) in the blood; the MRD-negative response rate was more than doubled when compared with a negativity rate of 35% of the patients in the standard arm.

In conclusion, 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 with chlorambucil and obinutuzumab regarding:

- progression-free survival,
- overall response rate,
- complete response rate, and
- MRD negative responses

These outcomes were 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. The most common grade 3/4 infection was pneumonia, affecting 4% in each arm. The venetoclax plus obinutuzumab arm had a higher incidence of fatal adverse events compared with the chlorambucil plus obinutuzumab, but this difference was not statistically significant (8% vs 4%). “The increased number of events occurred after completion of therapy,” Dr Fischer added. “We showed that fixed-duration targeted therapy with venetoclax and obinutuzumab can be applied safely to elderly patients with CLL and with relevant comorbidity,” concluded Dr Fischer. “This treatment provides superior outcome compared with chlorambucil and obinutuzumab.”

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   1. Fischer K, et al. Fixed-duration venetoclax plus obinutuzumab improves progression-free survival and minimal residual disease negativity in patients with previously untreated CLL and comorbidities. Abstract S149, 24th Congress of the European Hematology Association, 13-16 June 2019, Amsterdam, the Netherlands.
   2. Fischer K, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236.

 



Posted on 9 June 201925 March 2024