Venetoclax-Based Treatments for Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia Improves PFS Compared With Venetoclax Alone

In their single-institution retrospective analysis, researchers found that a combination of venetoclax-based treatments improved progression-free survival (PFS) compared with venetoclax alone.

Venetoclax, a BCL-2 inhibitor for patients with chronic lymphocytic leukemia (CLL), is FDA approved as a monotherapy or in combination with rituximab specifically for patients with relapsed/refractory (R/R) CLL. But little is known about the combination of venetoclax plus anti-CD20 monoclonal antibodies or bruton tyrosine kinase inhibitors (BTKi), like ibrutinib, as a possible treatment option for this patient population.

For their study, researchers evaluated 98 patients with R/R CLL who were treated with venetoclax alone (43.9% of patients) or in combination with rituximab (19.4%), obinutuzumab (25.5%), or BTKi (11.2%), between 2012 and 2023. Researchers administered FDA-approved dosing standards for patients treated with venetoclax in combination with rituximab or obinutuzumab (400 mg/daily) and BTKi (420 mg/daily). Researchers assessed minimal residual disease (MRD) using multi-parametric peripheral blood flow cytometry.

The median age of study participants was 68 years (range; 46-89 years of age). The median number of months of venetoclax-based treatment was 16.3 (range; 0.9-118.6 months). As of this writing, 14.3% of patients remain on venetoclax. Researchers found that 60.8% of patients had progression after venetoclax-based treatments, with 62.2% requiring additional treatment. Further, 15.3% of patients developed Richter’s Transformation.

In terms of best overall treatment response, 67% of patients had a complete response. Additionally, 24.5% had a partial response, 1.1% had stable disease, and 7.4% had progressive disease. Looking at the best MRD responses, undetected MRD (uMRD) occurred for 66.7% of those treated with venetoclax alone, 82.4% of those treated with venetoclax plus rituximab, 86.4% of those treated with venetoclax plus obinutuzumab, and 70% of those treated with venetoclax plus BTKi.

With a median follow-up of 52 months, the median PFS for the whole cohort was 67.8 months. The researchers found that venetoclax-based treatments had superior PFS (76.6 months) to venetoclax monotherapy (58.9 months; hazard ratio = 0.5037; [95% CI 0.2583 - 0.9635]; p = 0.04).

Examining the just combination treatment approaches, venetoclax plus rituximab demonstrated superior PFS compared with venetoclax monotherapy. Venetoclax plus obinutuzumab and venetoclax plus BTKi also showed trends towards improved PFS, although the median PFS was not reached.

Cytogenetic abnormalities such as del17p/TP53 mutation and MRD positivity 12 months after stopping venetoclax impacted PFS. The median PFS for patients without del17p/TP53 mutation compared with those with del17p/TP53 mutation was 118 months vs 39.7 months, respectfully (HR = 0.2242; [95% CI 0.0533 - 0.8366]; p < 0.0001).

“While venetoclax with rituximab is the current FDA-approved combination regimen for patients with R/R CLL, we found that there was a trend for improved PFS with either venetoclax plus obinutuzumab or venetoclax plus BTKi compared to venetoclax monotherapy,” the authors concluded. “Both the presence of a del17p/TP53 mutation and the presence of MRD 12 months after stopping venetoclax-based treatments significantly adversely affected PFS. However, patients who maintained uMRD 12 months after completing venetoclax had exceptionally durable long-term remission. This has possible implications for employing MRD-adapted treatments for patients with CLL.”

Reference:
Heyman BM, Choi MY, Kipps TJ. Comparison of venetoclax based treatments for patients with relapsed/refractory chronic lymphocytic leukemia. Paper presented at: 65th ASH Annual Meeting & Exposition. San Diego, CA. December 9, 2023. https://ash.confex.com/ash/2023/webprogram/Paper188129.html