Venetoclax plus rituximab compared to a standard therapy of bendamustine plus rituximab significantly improves progression-free survival in patients with relapsed or refractory chronic lymphocytic leukaemia (CLL).
The phase 3 MURANO trial, comprising 389 patients at 109 sites worldwide, found the BCL2 inhibitor extended progression free survival at two years from 36.3% to 84.9%.
The benefit was also seen in pre-specified subgroups with and without chromosome 17p deletion and in secondary outcomes such as event free survival and time to next treatment.
Co-author Dr James D’Rozario, head of haematology at Canberra Hospital, told the limbic the findings were extremely exciting.
“In the fullness of time it will be seen as a key advance in the treatment of CLL and other B cell malignancies. And certainly in this group of refractory, relapsed CLL those results are very exciting and a quantum leap forward I think.”
He said the findings would make it difficult for the drug not to get listed on the PBS despite the crowded space with other classes of drugs including idelalisib and ibrutinib.
He added direct head to head comparisons will be the next important work to be done.
Dr D’Rozario said from a technical viewpoint, the Minimal Residual Disease (MRD) negativity rate was very impressive in the venetoclax and rituximab arm.
“And we know that MRD negativity is very much predictive of a good long term prognosis as well. All those indirect parameters are lining up and tell us this is a very important agent.”
However the study found little difference in overall survival (91.9 v 86.6%) between the two arms.
“It is very often the case in diseases like CLL and low grade lymphoma, which have got an inherently long natural history, that demonstrating an improvement in overall survival is difficult.”
Dr D’Rozario said stringent monitoring and a ramp-up of the dosage were embedded into the study design because of significant concerns about tumour lysis syndrome.
However grade 3 or 4 tumour lysis syndrome rates were low and not significantly different (3.1% v 1.1%).
“In some of the early phase 1 and 2 studies, there were a couple of deaths from tumour lysis syndrome which just underscores its activity but it wasn’t a big deal in the conduct of this study. Initial fears that tumour lysis might limit its applicability didn’t seem to be borne out.”
Other serious adverse events such as fatal infections and Richter’s transformation were similar in both groups.
“While neutropenia grade 3 and above was seen, the actual infection rate was not different in fact smaller in the venetoclax arm and all pretty much manageable.”
The trial results are published in NEJM.