Safety profiles of venetoclax + obinutuzumab vs chlorambucil + obinutuzumab in patients with CLL and comorbidities: CLL14 long-term results

The CLL14 clinical trial (NCT02242942) was designed to compare the safety and efficacy of fixed-duration venetoclax plus obinutuzumab (VenG) against treatment with chlorambucil plus obinutuzumab (ClbG) in patients with treatment-naïve chronic lymphocytic leukemia (CLL) and comorbidities. This study is the first to compare a novel, chemotherapy-free, fixed-duration regimen with chemoimmunotherapy for patients with treatment-naïve CLL, including those with del17p or TP53 mutation.

The Lymphoma Hub previously summarized results from the 29-month follow-up of the CLL14 trial which reported the superiority of VenG over ClbG. Additionally, the Lymphoma Hub reported on the prospective analysis of CLL14, which focused on the prognostic value of measurable residual disease (MRD) detection after fixed-duration VenG vs ClbG. This article also outlined the full study design and updated efficacy data from a 39.6-month follow-up; read it here.

Here, we provide a summary of the full safety profile of the two regimens from the long-term follow-up, published by Othman Al-Sawaf and colleagues in Lancet Oncology.¹

Results

• Median follow-up: 39.7 months
• At the time of follow-up, all patients had been off treatment for ≥ 24 months
• Of the 432 patients enrolled in the study, 426 comprised the safety population
  • VenG cohort: n = 212
  • ClbG cohort: n = 214

Data is presented as VenG cohort vs ClbG cohort, unless stated otherwise.

Safety overview

Dose reductions

• Venetoclax and chlorambucil dose reductions due to adverse events (AEs) occurred in 20% and 8% of patients, respectively
• The most common cause of dose reduction was neutropenia, which occurred in 13% vs 6% of patients

Treatment discontinuation

• Treatment discontinuation due to treatment-emergent AEs occurred in 16% of patients in both treatment cohorts
• Venetoclax and chlorambucil discontinuation due to AEs occurred in 13% and 15% of patients, respectively
  • The most common cause of discontinuation was neutropenia, which occurred in 2% of patients across both cohorts
• Obinutuzumab discontinuation due to AEs occurred in 7% vs 8% of patients. The most common AEs leading to obinutuzumab discontinuation were:
  • Neutropenia, thrombocytopenia, and infusion-related reactions (IRRs): 1% across both cohorts
  • Anemia: none vs 1%

Adverse events

• Grade 3 or 4 AEs were observed in 71% vs 72% of patients, the most common being neutropenia (53% vs 48%), IRRs, and thrombocytopenia
• Serious AEs occurred in 54% vs 44% of patients
• Of the patients in the VenG cohort:
  • 14% experienced venetoclax-related serious AEs, most frequently infections (5%)
  • 18% experienced obinutuzumab-related serious AEs, most frequently IRRs (5%) and febrile neutropenia (4%)
  • Venetoclax-related deaths were reported in 1% of patients (sepsis; n = 1)
• Of the patients in the ClbG cohort:
  • 16% experienced chlorambucil-related serious AEs, most frequently infections (6%)
  • 23% experienced obinutuzumab-related serious AEs, most frequently infections (6%) and IRRs (6%)
  • Chlorambucil-related deaths were reported in 1% (septic shock, n = 1; metastatic skin squamous carcinoma, n = 1)

Conclusion

This long-term follow-up of the CLL14 trial confirmed the manageable safety profile of VenG in patients with CLL and comorbidities. Furthermore, less than 5% of patients who received VenG required a next-line therapy within 2 years of treatment termination. Considering the median age of the patients enrolled in this trial (72 years), a proportion of patients receiving VenG may require just one line of therapy in their lifetime, which could be sufficient to preserve their quality of life.

Future directions

The CLL17 trial, investigating continuous ibrutinib vs fixed-duration venetoclax plus obinutuzumab and venetoclax plus ibrutinib, will commence in late 2020.