P641: RETREATMENT WITH VENETOCLAX AFTER VENETOCLAX, OBINUTUZUMAB +/- IBRUTINIB: POOLED ANALYSIS OF 13 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREATED IN GCLLSG TRIALS (2022)

Background: Fixed duration venetoclax (V)-containing therapies are commonly used in CLL, either combined with obinutuzumab (Ven-G) for treatment-naïve or with rituximab for relapsed/refractory disease. Current clinical trials also combine Ven-G with ibrutinib (GIVe) or acalabrutinib (GAVe) to increase efficacy and possibly shorten treatment duration with minimal residual disease (MRD)-guided discontinuation strategies. Aims: There is only little evidence regarding the best sequence of currently available therapies and if time-limited therapies can be repeated at progression. Therefore, we pooled the patients (pts) with two consecutive V-containing treatment lines from GCLLSG trials, to study efficacy and safety of a re-treatment with V-based regimens. Methods: Thirteen pts with two sequential V-containing lines (V1 and V2) were identified within the following 5 multicenter phase-II or -III trials: 3 pts each received V1 in CLL2-BAG and CLL2-GIVe, 2 Ven-G in CLL13 (excluded from time-to event analyses due to unavailable data) and 1 in CLL14; all were subsequently treated in CLL2-BAAG (V2). Four additional pts received V1 and V2 in CLL2-BAG. Results: At the start of V1, the median age was 58 (range 49-65) years and 11 pts (92%) had a high/very high CLL-IPI, all 13 pts had an unmutated IGHV, 8 (62%) a del(17p) and/or TP53mut and 6 (46%) a complex karyotype. Four pts had already received a median of 2.5 (range 1-4) prior treatment lines (chemo(immuno)therapies only). V1 was Ven-G in 10 pts, including 4 pts with a bendamustine debulking, and GIVe in 3 pts. Median duration of V1 was 13 (range 11-29) months for all pts and 14 (range 13-26) months in the 9 pts with a MRD-guided discontinuation strategy who achieved uMRD, one pt failed to achieve uMRD in bone marrow and had to stop after approximately 2.5 years as per protocol. Three pts received V1 with a fixed duration of approximately one year. V2 was GAVe in 9 pts, including 2 with a bendamustine debulking, and Ven-G or Ven in 2 each, all with a MRD-guided discontinuation. Thus far, 5 pts have stopped V2: two pts due to uMRD and one each due to adverse events (allergic skin reactions), planned allogeneic stem cell transplantation and end of study treatment after approximately 2.5 years. Median treatment duration was 16 (range 8-30) months for V2, which is already longer than with V1 (see above) but 8 pts still continue V2. All pts experienced adverse events (AEs) during V1 and V2, AEs CTC °III/IV occurred in 11 and 8 pts during V1 and V2, respectively and serious AEs in 6 and 4, respectively. Hematological AEs °III/IV occurred in 6 and 2 pts during V1 and V2, tumor lysis syndromes °III in 2 and 3 pts and infections °III/IV in 2 each. All pts responded to V1 and V2, uMRD in PB was achieved at the end of V1 in 12/13 pts (92%) and thus far with V2 in 9/13 pts (69%). Median time between end of V1 and start of V2 was 29 (range 15-55) months. Median progression-free survival from start of V1 was 42 months and after V2 no progressions occurred so far at a median follow up time of 19 (range 8-33) months. All pts are alive, see also Fig. 1. Image:Summary/Conclusion: In this pooled analysis of 13 pts with two consecutive time-limited V-containing therapies, which includes mainly pts with adverse risk factors and a short remission duration, V-based re-treatment appeared to be safe and efficacious: no increased rate of AEs was seen so far and all pts responded with at least 2/3 even achieving uMRD again.