Efficacy of Combination Therapy for Chronic Lymphocytic Leukemia in Patients with Complex Karyotype
A complex karyotype (presence of ≥ 3 chromosomal abnormalities) is a negative prognostic marker in chronic lymphocytic leukemia (CLL). An analysis of the impact of complex karyotype on the efficacy of targeted CLL therapy combining the monoclonal antibody against CD20 antigen obinutuzumab with the BCL2 inhibitor venetoclax or the alkylating cytostatic chlorambucil was published in the journal Blood.
Clinical Study CLL14
A global open-label phase III randomized study involved 432 patients (median age 72 years) with previously untreated CLL and comorbidities. The study demonstrated an improvement in 2-year progression-free survival (PFS) with the venetoclax/obinutuzumab combination (88.2% of patients; 95% confidence interval [CI] 83.7–92.6%) compared to chlorambucil/obinutuzumab (64.1%; 95% CI 57.4–70.8%). Clinical benefit was observed across all high-risk patient groups (including those with p53 protein aberrations and unmutated immunoglobulin heavy-chain variable region genes – IGHV).
Analysis of Treatment Efficacy Based on Patient Karyotype
Karyotyping was successfully performed in 397 (91.9%) patients. A complex karyotype (CK) was found in 15.2% of patients in the chlorambucil arm and 17.0% of those treated with venetoclax/obinutuzumab.
In the chlorambucil arm, the overall response rate (ORR) to treatment 3 months after completing therapy was lower in patients with CK (50.0%) compared to those without CK (78.0%; p = 0.003). The complete response rate (CR) was 10.0% in CK patients and 27.5% in patients without CK (p = 0.041). The median PFS in CK patients was also significantly lower (19.4 months), while the median PFS in patients without CK was not reached in the study (estimated 2-year PFS 36.6% vs. 69.6%).
Conversely, in the venetoclax arm, no differences were observed in ORR (82.4% vs. 87.3%; p = 0.42) or CR (50.0% vs. 51.8%; p = 0.85) based on the presence of CK. The median PFS was not reached in any subgroup, and the estimated 2-year PFS did not significantly differ based on CK presence (78.9% vs. 91.1%).
Conclusion
The presence of CK is a negative prognostic factor in CLL patients treated with chlorambucil-based therapy. Combination therapy with venetoclax and obinutuzumab in the first line shows comparable efficacy regardless of the presence of CK.
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Sources:
1. Fischer K., Al-Sawaf O., Bahlo J. et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019; 380: 2225–2236, doi: 10.1056/NEJMoa1815281.
2. Al-Sawaf O., Lilienweiss E., Bahlo J. et al. High efficacy of venetoclax plus obinutuzumab in patients with complex karyotype and chronic lymphocytic leukemia. Blood 2020 Mar 12; 135 (11): 866–870, doi: 10.1182/blood.2019003451.
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