Long term follow-up and results of retreatement after obinutuzumab-venetoclax in first-line CLL patients with coexisting conditions

Abstract Introduction In the HOVON 139/GiVe trial previously untreated CLL patients unfit for FCR received 2 cycles of obinutuzumab monotherapy for debulking, followed by 6 cycles of obinutuzumab plus venetoclax and 6 cycles of venetoclax monotherapy. Patients who achieved partial (PR) or complete response (CR) were randomized to arm A (n = 32), receiving 12 cycles of venetoclax maintenance irrespective of MRD status, or arm B (n=30), receiving MRD-guided venetoclax maintenance for up to 12 cycles. As previously published after median follow-up of 35.2 months no clear benefit was seen of these Venetoclax maintenance arms (https://doi.org/10.1016/s2352-3026(22)00034-5). Here we report the long-term efficacy of MRD-guided O-Ven treatment at a median follow-up of 90 months. Results In total 67 patients were included, majority high-risk CLL-IPI, including 13% TP53 aberrations. At a median follow up of 90 months (IQR 85 - 97 months), the median PFS was 86,4 months (95% CI 72 months – not reached); 5-, 6- and 7 year PFS rates were 78%, 63% and 53%, respectively. Among randomized patients (n=62, 5 patients dropped out before randomization), PFS at 4, 5 and 6 years after randomization in arm A and arm B was 75% and 87%, 63% and 67%, and 53% and 57%, respectively (no comparison between arms was performed). Patients reaching CR (n=20) versus those with PR (n=42) at randomization demonstrated a PFS of 86% and 77%, 71% and 59% and 57% and 51% after 4, 5 and 6 years, respectively. The median OS was not reached; OS rates at 4-, 5-, and 6-year were 93%, 91% and 88%, respectively. In total 11 of 67 patients died (Richter's transformation (2), progression CLL (1), pneumonia (2), COVID (2), myocardial infarction (1) and 3 unknown (3)). After 6 cycles of obinutuzumab-venetoclax combination, 57 of 64 evaluable patients (89%) achieved undetectable peripheral blood (u)MRD (<10-4), increasing to 95% after 6 cycles of venetoclax monotherapy. At 15 months post-randomization, 41 of 58 evaluable patients (71%) remained uMRD. Patients reaching uMRD after 6 cycles of obinutuzumab-venetoclax, after 6 cycles of venetoclax monotherapy and at 15 months after randomization did not demonstrate a better PFS than those who did not reach uMRD at these timepoints. In addition, no correlation was found between baseline characteristics (age, sex, Binet stage, IGHV mutational status, TP53 aberrations and CLL-IPI) and PFS, possibly due to a relative low statistical power. At a median follow-up of 90 months 21 patients (31%) received second line treatment for CLL with a median time to next treatment of these 21 patients of 70 months (IQR: 41 – 78). The secondline treatment regimens included acalabrutinib-venetoclax in the HOVON 159 study (n=8), ibrutinib (n=7), acalabrutinib (n=2), venetoclax (n=1), (R-) chemotherapy (n=2), and CAR-T cell infusion (n=1). The ORR was 76% (6 patients CR and 10 patients PR). After second line treatment 7 patients experienced a PFS event (two deaths and five disease progression, of whom two died after progression). The median PFS from start of second line treatment to progression or death was 41 months (95% CI:12 - not reached). The remaining 17 alive patients had a median post-retreatment follow-up of 20 months (IQR: 5–30). Discussion and conclusions MRD-guided O-Ven leads to durable disease control in previously untreated CLL patients unfit for FCR, with a median PFS of over 7 years, irrespective of maintenance arm. No clear association between MRD status at fixed time points and PFS was seen, likely due to the high rate of undetectable MRD achieved during induction. Only 31% of patients required retreatment within 90 months, with most achieving renewed disease control. These results suggest that first-line time limited O-Ven can induce durable remissions and allows for effective retreatment, even in less-fit patients.