Oncologists use the measurement of minimal residual disease (MRD) to assess the depth of response during and after treatment of chronic lymphocytic leukemia (CLL) and to understand disease dynamics after treatment. Analysis of clonal growth patterns in patients with CLL can provide insight into the risk of relapse following treatment. Researchers analyzed clonal growth patterns in patients with CLL treated within the CLL14 trial.
In the CLL14 trial, 432 patients with previously untreated CLL and coexisting conditions were randomized to receive chlorambucil or venetoclax until the completion of 12 cycles of treatment and in combination with obinutuzumab for the first 6 cycles.1 The primary end point was progression-free survival (PFS), with MRD as a secondary end point. Peripheral blood samples were collected every 3 to 6 months until 9 years from the time of enrollment of the last patient.
Researchers formed a patient-specific clonal growth rate model. An exponential regression model was fitted to each patient to calculate MRD clone doubling time. Patients who had at least 2 MRD assessments after the end of treatment and had not experienced progressive disease before the end of treatment were included.
Two months after treatment completion, 40% of patients in the venetoclax-obinutuzumab group had undetectable MRD (uMRD) levels <10-6, compared with 7% in the chlorambucil-obinutuzumab group. Most patients who had uMRD levels at the end of treatment already had uMRD levels at cycle 7 after obinutuzumab treatment ceased. In 25% of patients treated with venetoclax-obinutuzumab, MRD response deepened after continuing with 6 cycles of venetoclax monotherapy.
Analysis of data from 4-year follow-up demonstrated a sustained PFS benefit following treatment with venetoclax-obinutuzumab. The 4-year PFS rate in the venetoclax-obinutuzumab group was 74.0% compared with 35.4% in the chlorambucil-obinutuzumab group. The 4-year overall survival rate was similar between the groups, with 85.3% for patients receiving venetoclax-obinutuzumab and 83.1% for patients receiving chlorambucil-obinutuzumab.
Investigators estimated patient-specific clonal growth rates for 123 patients in the venetoclax-obinutuzumab group and 143 patients in the chlorambucil-obinutuzumab group. A very deep response with MRD results below the assay’s limit of quantification was found in 38 patients in the venetoclax-obinutuzumab group and 4 patients in the chlorambucil-obinutuzumab group. These were not included as the growth rate could not be accurately assessed.
The average clonal growth rate among patients in the venetoclax-obinutuzumab group translated into an MRD doubling time of approximately 89 days. For patients in the chlorambucil-obinutuzumab group, the average clonal growth rate corresponded to a doubling time of approximately 71 days. The average rate of growth was lower in patients receiving venetoclax-obinutuzumab compared with those receiving chlorambucil-obinutuzumab.
This analysis of patients treated within the CLL14 trial demonstrated that individual clonal growth rates can be used to estimate MRD doubling time after fixed-duration treatment. Treatment with venetoclax-obinutuzumab was associated with lower clonal growth rates. In addition, treatment with venetoclax-obinutuzumab was found to lead to higher efficacy of MRD eradication and clonal growth eradication. Deepest remission was demonstrated in a considerable subgroup of patients treated with venetoclax-obinutuzumab, in which no clonal growth was measurable during observation.
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