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

Background: In chronic lymphocytic leukemia, the depth of measurable residual disease (MRD) following fixed-duration treatment is associated with progression-free survival (PFS). MRD is often reported as a static parameter, cross-sectionally assessed at the end of treatment. However, as treatment is initiated and subsequently withheld, MRD levels are expected to follow a parabular trajectory, rapidly decreasing to a nadir at time of maximum response and eventually rising again after cessation of treatment. We hypothesized that successive MRD measurements, which more comprehensively capture these MRD dynamics, may reveal additional valuable prognostic information. Aims: Using our previously developed IGHV leader-based NGS assay, we aimed to evaluate the value of MRD dynamics in the setting of fixed-duration treatment with venetoclax and obinutuzumab (O-Ven). Additionally, besides MRD detection, IGHV sequencing captures the entire IGHV repertoire, a proxy of the diversity of the healthy B cell pool. As such we also aimed to evaluate polyclonal IGHV repertoire reconstitution following treatment with O-Ven. Methods: We 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 O-Ven, followed by randomization to consolidation treatment with venetoclax or MRD-conditional consolidation. MRD measurements were performed using the IGHV-leader NGS assay with a limit of detection of MRD 10-5. MRD was measured at four timepoints: during the fourth week of venetoclax ramp up (11 weeks after the start of treatment), after the end of induction treatment, and six and twelve months after randomization. Results: Induction treatment resulted in undetectable MRD (uMRD) (<10-5) in 40/43 (93%) of assessed patients, with 45/53 (85%) and 39/53 (74%) of patients retaining uMRD at six and twelve months after randomization. High levels of early MRD (>10-2), measured during venetoclax ramp up, were associated with failure of achieving uMRD after induction treatment (2/3 versus 0/22, P=0.01). Conversely, low levels of early MRD (<10-4) predicted a low probability of loss of uMRD twelve months after randomization (0/9 versus 8/18, P=0.03, negative predictive value = 100%) and were associated with a 100% 40-month PFS rate (95%CI 100-100), compared to 83% for patients with early MRD >10-4 (95%CI 67-99, P=0.048)(see Figure). Venetoclax consolidation treatment, compared to no consolidation treatment, significantly impaired polyclonal IGHV repertoire reconstitution after induction treatment with O-Ven (mean Shannon’s H 1.97 [1.41-2.53] versus 5.54 [3.56-7.52], P=0.002).Summary/Conclusion: High levels of early MRD (>10-2, measured during venetoclax ramp up) predicted failure to achieve uMRD (<10-5) after induction treatment with O-Ven, whereas low levels of early MRD (<10-4) were associated with a low probability of loss of uMRD and a 100% 40-month PFS rate. In addition, venetoclax consolidation treatment impaired polyclonal IGHV repertoire reconstitution after induction treatment with O-Ven. Keywords: Chronic lymphocytic leukemia, Minimal residual disease (MRD), Venetoclax, Obinutuzumab