SAKK – YOUNG ONCOLOGY ACADEMY

EHA 2023

Highlights in CLL

CLL14 6-year follow up: Long-term PFS benefit with the time-limited chemotherapy-free 1st line treatment venetoclax-obinutuzumab
This phase 3 trial enrolled 432 patients with previously untreated CLL and coexisting medical conditions. The patients were randomized 1:1 to receive either venetoclax plus obinutuzumab or chlorambucil combined with the same obinutuzumab regimen.
Venetoclax-obinutuzmab demonstrates clinically significant efficacy across all risk groups In this updated analysis with a median follow-up of 76.4 months, the median PFS (primary endpoint) at data-cutoff was 76.2 months in the venetoclax-obinutuzumab arm and 36.4 months in the chlorambucil-obinutuzumab arm (HR: 0.40; 95 %-CI: 0.31–0.52, p < 0.0001). The 6-year PFS rate was significantly better with 53.1 % for patients receiving venetoclax-obinutuzumab compared to 21.7 % for patients after therapy with chlorambucil-obinutuzumab. High-risk subgroups harboring a TP53 mutation/deletion (median PFS: 51.9 vs. 20.8 months; p = 0.03) or unmutated IGHV (median PFS: 64.8 vs. 26.9 months; p < 0.001) also had a significant benefit from venetoclax-obinutuzmab. Six-year OS rate was in favor of venetoclax-obinutuzumab, but did not (yet) reach a statistically significant difference (78.7 % vs. 69.2 %, HR: 0.69; 95 %-CI: 0.48–1.01, p = 0.052). No new safety signals or late toxicities were reported, although a trend towards an increased rate of secondary malignancies was observed. MRD at treatment cessation correlates with PFS and OS In addition, the results revealed that the achievement of an undetectable MRD (defined as 10-4) at the end of treatment was associated with a prolonged PFS and OS for patients receiving venetoclax-obinutuzumab (HR 3.42, 95 %-CI 1.65-7.06, p < 0.001), allowing the identification of high-risk patients with shorter OS even if salvaged with a BTKi. CLL12: Final data on BTKi therapy in early-stage higher-risk CLL patients The CLL12 trial challenged the concept of watch & wait in asymptomatic patients with early-stage CLL in the era of targeted therapies and enrolled 515 patients with 152 low-risk patients allocated to the observational cohort and 182 and 181 randomly assigned to receive ibrutinib or placebo (treatment cohort), respectively. Ibrutinib significantly improves PFS but yields similar OS and higher toxicities At a median follow-up of 69.3 months median PFS was not reached in the ibrutinib arm compared with 14.0 months in patients under placebo (HR 0.174, 95 % CI 0.12-0.25, p < 0.001). However, 5-year-OS rates were 93.3 % with ibrutinib and 93.6 % with placebo (HR 0.791, 95 %-CI 0.36-1.75, p = 0.562). Patients receiving ibrutinib experienced higher rates of toxicities, e.g. bleeding (36.5 %), arrythmia (22.4 %), and other cardiac events (17.6 %) leading to death in 4 patients (2.4 %). These data show the effectiveness of ibrutinib, but do not justify changing the current standard of watch & wait with early-stage CLL. Author: Dr. med. Kevin Hofer, Resident in Hematology, University Hospital Zurich Mentor: Prof. Dr. med. Gabriela Baerlocher Hematology, University of Bern, today Member of commission ­Eruopean Council References: 1. Al-Sawaf O et al.: Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized cll14 study. EHA 2023, Abstract S145. 2. Langerbeins P et al.: Ibrutinib versus placebo in patients with asymptomatic, treatment-naïve early stage chronic lymphocytic leukemia (cll): final results of the phase 3, double-blind, placebo-controlled cll12 trial. EHA 2023, Abstract S200. SCHWEIZER ZEITSCHRIFT FÜR ONKOLOGIE 1/2024 21