Chemoimmunotherapy (CIT) is still standard treatment for patients with chronic lymphocytic leukaemia (CLL), particularly when favourable risk factors are present, although this treatment is not suitable for all patients due the severe side effects.
By targeting specific molecular targets associated with development and progression of CLL, the amount of collateral damage to healthy cells is significantly reduced, resulting in more manageable side effects and improved quality and duration of response.
Additionally, intensification of targeted therapies by combining venetoclax plus obinutuzumab with BTK inhibitors such as ibrutinib have recently shown promising outcomes within phase II clinical trials but have not been examined in randomized setting.
The GAIA/CLL 13 study compared the efficacy and safety of chemoimmunotherapy with venetoclax combination treatments in 926 fit patients with treatment-naïve CLL.
Patients under 65 years in the CIT group received a regimen of fludarabine, cyclophosphamide, and rituximab whereas patients over 65 years were treated with bendamustine and rituximab. In the venetoclax arms, patients were randomized to one of the following combinations: (1) venetoclax plus rituximab (RV), (2) venetoclax plus obinutuzumab (GV), or (3) venetoclax plus obinutuzumab and ibrutinib (GIV).
An interim analysis of progression-free survival (PFS) at 61 months after first patient in showed that both GIV and GV treatments were superior to CIT (hazard ratio 0.32 and 0.42, respectively), but PFS did not significantly differ between the RV and CIT groups.
Overall survival rates were comparable across all treatment arms and no differences in haematological side effects were observed.
However, grade 3/4 infections occurred more frequently in patients treated with GIV (21.2%) or CIT (18.5%) compared with GV (13.2%) and RV (10.5%) treatment.
In summary, GIV and GV are superior treatment options with an acceptable safety profile compared with standard CIT in fit patients with treatment-naïve CLL.
Whether triple combination with GIV is superior to the double combination with GV will be evaluated with further follow-up of the trial.