B-cell receptor signaling inhibitors (BCRi), such as Ibrutinib (Ibr) and Idelalisib (Idela), have changed the treatment paradigm for chronic lymphocytic leukemia (CLL), and the BCL-2 inhibitor Venetoclax (Ven) has shown promising efficacy across clinical studies in relapsed/refractory (R/R) CLL. To date, the exact timing on the use of new pathways inhibitors in the real life practice is not well established.
In this multicenter retrospective real life study we evaluated the overall response rate (ORR), progression-free survival (PFS), overall survival (OS) of CLL patients (pts) treated with Ven after one or two BCRi. Also the reasons for BCRi discontinuation - adverse events (AE) vs progressive disease (PD) - were evaluated.
We report a multi-center retrospective analysis that included 76 CLL pts from 18 different Italian centers treated with Ibr and/or Idela prior to Ven for progressive naïve CLL or with relapsed or refractory disease. Twenty-four pts were treated with one BCRi, while 52 pts with both BCRi before Ven. Median age was 63 years (26–87); 78% pts had an unmutated IgVH status, 33% pts had 17p deletion and 32% pts had TP53 mutation. The sequence of the BCRi prior to Ven was the following: Ibr, Idela, Ven in 16 pts; Idela, Ibr, Ven in 8 pts; Ibr, Ven in 37 pts; Idela, Ven in 15 pts.
No statistically significant difference was found in terms of ORR to Ven in patients who had been exposed to one or two BCRi (p = 0.114). At the same time, we observed that pts who received only one BCRi prior to Ven showed a significantly better PFS and OS at 12 months: 76% vs. 35% (p = 0.011) and 88% vs. 57% (p = 0.015), respectively. BCRi treatment was stopped in 70% of pts because of PD and in 30% due to AE. When we considered the impact of the reasons of the first BCRi discontinuation - AE vs PD - on Ven response, we found that the ORR was significantly better in pts who stopped due to AE: 91% vs 49% (p = 0.03). PFS and OS were also significantly better in pts who discontinued treatment due to AE compared to PD, with a PFS of 84% vs 45% (p = 0.003) and an OS of 93% vs 62% (p = 0.028). When we considered the impact of discontinuation of both BCRi on Ven response, the PFS was similar in CLL patients who stopped BCRi due to AE (p = 0.31), while pts who experienced PD to both BCRi showed a worse PFS during Ven (p = 0.06).
The number of BCRi received before BCL2i does not affect ORR to Ven. Single BCRi is better than double BCRi in terms of PFS and OS following Ven treatment, regardless of the BCRi used. Discontinuation of the first BCRi because of AE is associated with a better PFS and OS to Ven compared to pts who experienced PD. The discontinuation of double BCRi for AE did not impact on PFS to Ven. On the other hand, pts who stopped both BCRi for PD showed a tendency to a worse PFS on Ven, without reaching significance. Finally, these preliminary data seem to suggest the use of double BCRi before Ven for pts who discontinued due to AE; on the contrary, we suggest the use of Ven after single BCRi when the reason of discontinuation is disease progression.