Venetoclax Plus Rituximab Supports Immune Recovery in CLL

New research suggests that venetoclax plus rituximab (VR) helps manage relapsed or refractory chronic lymphocytic leukemia (CLL) and supports significant immune system recovery over the long term. The study, published in HemaSphere, compared the immune effects of venetoclax and rituximab (VR) against those of bendamustine plus rituximab (BR), focusing on the restoration of immune function over time.¹

The study, part of the phase 3 MURANO trial, included 389 patients with relapsed or refractory CLL who were randomly assigned to receive VR for 2 years (venetoclax daily for 2 years plus monthly rituximab for the first 6 months) or BR for 6 months. Out of these, 130 patients on VR (n = 194) and 134 on BR (n = 195) completed their treatments without disease progression. Researchers closely monitored immune function by measuring levels of serum immunoglobulins and counts of B cells, T cells, and natural killer (NK) cells throughout treatment. Changes in immunoglobulin levels from baseline to end of combination treatment (EOTC), end of treatment (EOT), and at 12 months and 24 months post EOT were analyzed in the study.

In this new study, impacts on T-cell and natural killer–cell populations were observed in both treatment regimens. | Image Credit: © peshkova-stock.adobe.com

The study findings showed that patients on VR experienced an initial drop in immunoglobulin levels during treatment, but these levels recovered after treatment ended. Researchers found that median immunoglobulin G (IgG) and IgM levels decreased from baseline to EOT:

• IgG: 6.30 g/L to 5.80 g/L (P ≤ .01)
• IgM: 0.25 g/L to 0.18 g/L at EOT (P ≤ .0001)

However, 24 months after EOT, IgG had returned to its baseline level (6.20 g/L) and IgM had increased from baseline (0.41 g/L). Furthermore, median IgA levels increased steadily from baseline throughout the follow-up period: 0.46 g/L at baseline to 0.60 g/L at 12 months post EOT to 0.85 g/L at 24 months post EOT. Researchers noted the addition of rituximab to venetoclax for 6 months did not appear to have affected IgG and IgA levels, but may have affected IgM levels (P ≤ .0001).

On the contrary, patients treated with BR did not show significant changes in IgG, IgA, and IgM levels throughout the study. However, all immunoglobulin levels were above baseline at 12 and 24 months post EOT.

Impacts on T-cell and NK-cell populations were observed in both treatment regimens. In the VR group, CD19-positive (CD19+) B cells were significantly depleted during treatment, with recovery beginning about 1 year post end of combination treatment (EOCT) and stabilizing by approximately 30 months post EOCT. The CD4-positive and CD8-positive T-cell ratios were maintained consistent throughout the study period. In the BR group, CD19+ B cells depleted during treatment but had stabilized by 12 months post EOCT.

The study also reported low rates of severe infections for both treatment groups, with grade 3 or higher infections occurring in 17.5% of patients treated with VR and 21.8% of those treated with BR. The rate of grade 1 to 2 infections was higher among patients who achieved minimal residual disease (MRD) positivity compared with those who achieved undetectable MRD at the end of treatment.

“The reason for this difference in infection risk according to MRD status is not yet known and requires further investigation,” the authors note.

The study points out that the risk of infection was higher for patients with relapsed or refractory disease treated with acalabrutinib or ibrutinib than those who received these drugs as a first-line therapy (risk ratio, 1.49; P = .03).2 However, in this study involving patients with relapsed or refractory CLL, all of whom had received prior chemoimmunotherapy, the overall rate of grade 3 or higher infections remained low “demonstrating the favorable tolerability profile of VR.”

These findings highlight that treatment with VR for CLL not only manages disease progression but may also support the recovery of the immune system.

“Overall, immune recovery was observed with VR and BR, with stabilization of [immunoglobulin] levels after treatment. Posttreatment infection rates were generally low, making these very tolerable therapies for CLL.”

References

1. Kater AP, Eichhorst BF, Owen CJ, et al. Long-term immune changes in patients with relapsed/refractory chronic lymphocytic leukemia following treatment with venetoclax plus rituximab. Hemasphere. 2024;8(8):e146. doi:10.1002/hem3.146

2. Pleyer C, Sun C, Desai S, et al. Reconstitution of humoral immunity and decreased risk of infections in patients with chronic lymphocytic leukemia treated with Bruton tyrosine kinase inhibitors. Leuk Lymphoma. 2020;61(10):2375-2382. doi:10.1080/10428194.2020.1772477