Dr. Al-Sawaf on New Safety Signals With Venetoclax/Obinutuzumab in the CLL14 Trial

Othman Al-Sawaf, MD, a physician with the University Hospital of Cologne in Germany, discusses new safety signals with venetoclax (Venclexta) plus obinutuzumab (Gazyva) in the phase 3 CLL14 trial.

The first impression was a severe drop in any toxicity because, after 1 year, the patients do not require any additional treatment; therefore, all the toxicities that might occur with venetoclax/obinutuzumab and chlorambucil/obinutuzumab, drop, explains Al-Sawaf. No long-term hematological toxicities, such as ongoing neutropenia or anemia, were observed.

What is seen now is a slight increase in secondary malignancies, which was 17% in the venetoclax/obinutuzumab arm versus 10.3% in the chlorambucil/obinutuzumab arm, says Al-Sawaf; although this does not reach any statistical significance, it is fair to be cautious about it and to continue to follow up on this.

No clear pattern has been observed in those secondary malignancies, so there is no increased rate of acute myeloid leukemia or myelodysplastic syndromes—malignancies that are commonly seen following treatment with fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR), for example, says Al-Sawaf. No signal like that was reported, but an overall increase in solid tumors has been observed with venetoclax; this was was not found to reach statistical significance, however. 

Longer follow up with the CLL14 trial is needed, specifically because other trials have even longer follow up with venetoclax, such as the MURANO trial. A similar pattern was not observed there, therefore the field must remain cautious and determine whether this combination is clinically meaningful or not, concludes Al-Sawaf.