Early-stage measurable residual disease dynamics and IGHV repertoire reconstitution during venetoclax and obinutuzumab treatment in chronic lymphocytic leukemia

Abstract

In chronic lymphocytic leukemia, measurable residual disease (MRD) depth following fixed-duration treatment is associated with progression-free survival. MRD is usually reported at the end of treatment as a static parameter, but successive MRD measurements allow more accurately characterization of MRD dynamics, which may reveal additional prognostic information. To study the value of MRD dynamics, we used the IGHV leader-based NGS assay to longitudinally measured MRD in 60 patients treated in the HOVON-139/GIVE trial, in which previously untreated patients received two cycles of pre-induction with obinutuzumab, followed by one year induction treatment with obinutuzumab and venetoclax, followed by randomization to consolidation treatment with venetoclax or MRD-conditional consolidation. Induction treatment resulted in undetectable MRD (uMRD) (<10-5) in 93% of assessed patients, with 85% and 74% of patients retaining uMRD at six and twelve months after randomization. High levels of early-stage MRD, assessed during venetoclax ramp up, were associated with failure of achieving uMRD after induction treatment, whereas low levels of early-stage MRD predicted a low probability of loss of uMRD and disease progression after randomization. Venetoclax consolidation treatment significantly impaired polyclonal IGHV repertoire reconstitution after induction treatment with venetoclax and obinituzumab. In conclusion, very early-stage MRD levels were associated with treatment outcomes.