Blood cancers

Venetoclax ‘vaulting over the wall’ of R-CHOP results in DLBCL

Addition of venetoclax to R-CHOP has the potential to improve outcomes for patients with the worst prognosis for diffuse large B-cell lymphoma (DLBCL), those with overexpressed Bcl-2.

In the phase 2 CAVALLI study involving 206 patients with advanced stage DLBCL, the addition of venetoclax to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) resulted in PET complete response (PET-CR) rates of 69%. This compared favourably to rates of 63% seen in comparable studies such as GOYA, in which rituximab was substituted with obinutuzumab.

The addition of venetoclax was also was able to significantly increase 2-year progression free survival (PFS) rate in Bcl-2–positive patients (78% vs 62%) compared to GOYA results (hazard ratio, 0.55; 95% confidence interval, 0.34-0.89), the study investigators said.

The findings, published in Blood suggested that the addition of venetoclax, a selective and potent B-cell lymphoma-2 [Bcl-2] inhibitor, may induce a much deeper response in a subgroup of 25-45% of DLBCL patients who have a poor prognosis with R-CHOP, an accompanying commentary noted.

However the multicentre, multinational study, which included Australian patients from the Concord Hospital, Sydney, also showed that addition of venetoclax was associated with a higher rate of grade 3 to 4 adverse event rates compared with GOYA for neutropenia (68% vs 39%) and infections (23% vs 16%).

These adverse effects of treatment may be manageable with better primary prophylaxis with G-CSF, and would be worth paying if they were balanced with a long-term benefit, said the commentary authors.

In the study, venetoclax was added to R-CHOP in first-line treatment of DLBCL patients who were International Prognostic Index 2 to 5.

PET-CR rates were 69% (143/206) overall, 64% (67/104) in the Bcl-2 overexpression population, and 66% (53/80) in the BCL-2/Myc proteins (double expressor lymphoma, DEL) population.

The study investigators said the findings were encouraging, given that other randomised phase 3 trials of additional agents had failed to show any overall survival benefit over R-CHOP.

The accompanying editorial said that despite the study limitations, the difference in PFS for Bcl-2–positive patients was wide enough to justify further studies with the venetoclax combination.

“This study is particularly exciting because vaulting over the wall of R-CHOP results in DLBCL has been the dream of many researchers for years,” it concluded.

Disclosure: The lead study investigator declared acting as consultant for Roche and receiving honoraria from Bayer, Bristol Myers Squibb, Celgene, Epizyme, F. Hoffmann-La Roche Ltd., Gilead Sciences, and Janssen Pharmaceuticals; and is a member of advisory boards for F. Hoffmann-La Roche Ltd., Celgene, Bristol Myers Squibb, Gilead Sciences, Bayer. and Epizyme. 

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