How Do Age and Fitness Impact Venetoclax Efficacy in Patients with CLL?

Venetoclax has been shown to be effective in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), including in unfit, untreated patients receiving it in combination with obinutuzumab. However, the effect of age and fitness on efficacy and survival in patients receiving venetoclax treatment remains unknown. A retrospective study presented at the 62nd ASH Annual Meeting & Exposition examined whether these factors played any role on efficacy and survival in venetoclax-treated patients.

The study included 158 patients with CLL treated with venetoclax at 14 Italian centers between February 2017 and May 2020. Comparisons were made by age (<65 years vs. ≥65 years), Chronic Inflammatory Response Syndrome (CIRS; ≤6 vs. >6), major CIRS comorbidity (at least one organ with a CIRS score ≥3 vs. CIRS3+), Eastern Cooperative Oncology Group (ECOG) performance status score (PS; 0-1 vs. >1), and Charlson Comorbidity Index (CCI; <2 vs. ≥2) to determine whether any of these were associated with definitive treatment discontinuation due to toxicity (tox-DTD), permanent dose reduction (PDR), event-free survival (EFS; event: tox-DTD, progression, death), progression-free survival (PFS), and overall survival (OS). The CIRS score calculation did not include CLL itself or any CLL-associated complications.

Patients were observed for a median 11.9 months (range, 2.1-40.2 months) and treated with venetoclax for a median 9.4 months (range, 2.1-40.2 months). Most patients continued therapy (n=111; 70.3%).

About a quarter of patients permanently discontinued venetoclax (n=42; 26.6%) due to reasons including toxicity (n=7) and progressive disease and/or Richter’s transformation (n=25). A similar proportion of patients discontinued treatment for seven days or more (n=41; 25.9%), with a median eight days per patient interruption. Thirty-six patients experienced at least one dose reduction episode (22.8%); 21 patients permanently began receiving venetoclax at a reduced dosage (13.3%).

Most patients received concomitant medications (n=134; 84.8%); 75 patients were taking at least four drugs in addition to venetoclax, and 32 patients were receiving venetoclax concomitantly with CYP3A4 inhibitors/inducers.

Age did not impact tox-DTD, PDR, EFS, PFS, and OS. In older patients, CIRS >6 was significantly associated with PDR, but not tox-DTD. CIRS >6 was not associated with treatment management in younger patients, but CIRS3+ was associated with a higher rate of tox-DTD. Regardless of age classification, CIRS3+ and CIRS >6 did not impact PFS, EFS, and OS. ECOG >1 was associated with more tox-DTD and much shorter PFS, EFS, and OS. Although CCI affected PDR, it did not affect patient outcomes. Patients with del(17p) and/or TP53 mutations had shorter PFS, EFS, and OS. ECOG >1 was an independent risk factor for shorter PFS. Baseline neutropenia and concomitant CYP3A4 inhibitor/inducer treatment was significantly associated with PDR, but compromised renal function was not associated with patients’ management.