Discussion
toxicity, toxicities
CLL, REMISSIONS, DISEASE, DEL(17P), REMISSION, DELETION, TRISOMY 12
The venetoclax-obinutuzumab regimen is the first fixed-duration frontline treatment without chemotherapy in CLL. Long-term observations are therefore of high interest, since they allow to gain an understanding of disease dynamics and clinical outcomes after cessation of therapy. In particular, the biological characteristics and determinants of MRD response and non-response to limited exposure to BCL2 inhibition have not been elucidated so far.The first aim of this report was to analyse the long-term efficacy and durability of a fixed-duration regimen with Ven-Obi, compared to chemoimmunotherapy with Clb-Obi. All patients were off study treatment for at least 4 years. The majority of patients who had received Ven-Obi have remained in remission 4 years after treatment completion, suggesting possible achievement of long-term disease control in this group of elderly and unfit patients. In addition, over 70% of the patients in the Ven-Obi arm have not yet required another line of treatment suggesting that many patients might only require one line of CLL treatment in their lifetime. Furthermore, all treatment-related toxicity occurred during treatment exposure, with no long-term toxicity observed after end of treatment, concluding the fixed-duration approach was associated with reduced toxicity. This finding might avoid issues of cumulative toxicities observed with continuous treatment exposurePatients with del(17p) and/or While almost all patients in the Clb-Obi arm had experienced an MRD conversion to MRD levels ≥10In light of the strong prognostic impact of follow-up month 3 MRD status, the transcriptional profiles of patients before treatment were classified into MRD responders and non-responders. Clustering according to gene expression showed that patients were grouped according to IGHV status, trisomy 12 and also deletion 13q, which has also been previously observed in CLLAn open question is how the fixed-duration approach generally compares to the other cornerstone of CLL management, which is continuous BTK inhibitor therapyIn summary, these 5-year results suggest that in patients with previously untreated CLL, fixed-duration treatment with Ven-Obi continues to lead to significantly longer progression-free survival compared to chemoimmunotherapy with Clb-Obi. This finding was associated with a significant decrease in toxicity after treatment cessation and continuous deep remissions with high rates of undetectable MRD. Upregulation of inflammatory pathways and resistance markers such as 