P619: tracking disease parameters by mrd, ct and pet in first line cll patients treated with fixed duration ibrutinib-venetoclax; interim analysis of the first 30 patients in hovon 158/next step trial.

Background: HOVON 158/NEXT STEP trial is a phase 2 study in patients with previously untreated chronic lymphocytic leukemia (CLL), evaluating the efficacy and safety of adding 6 cycles of ibrutinib-obinutuzumab to patients who are not in complete remission (CR) and/or have minimal residual disease (MRD) after fixed-duration ibrutinib-venetoclax (IV). Combination of IV is known for its synergistic mechanism of action to eradicate CLL from the different tissue compartments: lymph node (LN), spleen, peripheral blood (PB) and bone marrow (BM). However, bio-clinical significance of minimally enlarged LN on CT after IV harbour a high uncertainty. Although FDG-PET has proven predictive value in lymphomas, clinical significance in CLL is not determined. Aims: This pre-planned 2nd interim-analysis of the first 30 patients evaluates safety and efficacy of IV, before ibrutinib-obinutuzumab consolidation. Moreover, MRD and (PET-) CT are explored for tracking clearance of CLL parameters from different compartments. Methods: Eligible patients with untreated CLL receive IV (3 cycles I lead in, followed by 12 cycles IV). IwCLL responses are centrally assessed after cycle 8 and 15 with specification of partial remission (PR) based on CT and BM histology. MRD is centrally assessed by 8-colour flow cytometry (undetectable [u]MRD <10-4). All PET-CT’s are centrally reviewed. Results: Between Dec2020 and Aug2021, 85 patients were registered. Of the first 30 patients, median age was 69 years (range 34-85), 70% were male. CIRS score > 6 was found in 6 patients (20%), CLL-IPI score was high/very high in 20 (66%), 17 (57%) patients had mutated IGHV and 12 (40%) unmutated IGHV. Del (17p)/TP53 mutation was found in 3 patients (10%) and genomic complexity (≥ 3 aberrations) in 3 patients (10%). After 15 cycles, 13 patients (43%) had CR, 12 (40%) PR, due to remaining LN in half of them. Thirteen patients (43%) obtained uMRD in PB and 10 (33%) in BM (Figure). CT scan at baseline (n=30) showed LN in combination with liver/spleen involvement in the majority of patients, 4 (13%) CT’s showed only LN involvement, 3 (10%) CT’s showed enlarged spleen only and 1 (3%) CT was normal. Already after cycle 8 (n=29), 11 (38%) CT’s were normal, 13 (45%) CT showed LN ≥ 1,5cm and only 5 (17%) CT’s showed abnormal spleen and/or liver. At cycle 15 (n=25) 17 (68%) CT’s were normal, 5 (20%) with enlarged LN and 3 (12%) with abnormal spleen and/or liver. PET at baseline showed increase uptake (Deauville ≥ 4) in 46% of scans. After cycle 8 and cycle 15, a complete metabolic response was observed in 86% and 88% of scans, respectively. Five patients discontinued due to adverse events (n=3), death (n=1) and patient’s decision (n=1). Dose modifications during treatment were common. Cumulative intended dose <75% was 40% for venetoclax and 20% for ibrutinib. Grade 3 and 4 adverse events occurred in 43% and 37% of patients, respectively. Most common were laboratory abnormalities (53%), infections (20%), haematological toxicities (17%) and gastrointestinal disorders (13%). Adverse events of clinical interest were infections in 17 (57%) patients, 8 of whom grade 3 (27%) and 1 grade 5 (3%), due to COVID-19. Two patients had a grade 3 bleeding event (7%), 3 patients had cardiac arrhythmia’s (10%) of which one was grade 4. Summary/Conclusion: Fixed-duration IV is an effective and safe treatment combination, although dose reductions are common. Detailing responses by CT reveal kinetics of CLL clearance, with faster normalisation of spleen and liver than LN. PET provides additional information on activity of residual CLL sites.Keywords: Venetoclax, Chronic lymphocytic leukemia, ibrutinib, Minimal residual disease (MRD)