PS1161 EFFICACY AND SAFETY OF IBRUTINIB IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS PREVIOUSLY TREATED WITH VENETOCLAX IN THE MURANO STUDY
Authors: Greil R. , Fraser G. , Leber B. , Marks R. , Quaresmini G. , Middeke J. Moritz , Semenzato G. , Schary W. , Boyer M. , Breuleux M. , Crompton N. , Humphrey K. , Marlton P. 
Published: June 2019

Background:The BCL2 inhibitor venetoclax (Ven) and the Bruton's tyrosine kinase inhibitor ibrutinib (IBR) have complementary mechanisms of action in chronic lymphocytic leukemia (CLL). As data with targeted agents become available for earlier therapy lines, it is important to understand how to sequence these new regimens best in CLL.Aims:To present a post‐hoc series, obtained after follow‐up from the randomized, phase 3 MURANO study (NCT02005471), of patients (pts) with relapsed/refractory (R/R) CLL who received IBR following fixed‐duration treatment with Ven+rituximab (VenR).Methods:389 pts with R/R CLL were enrolled in MURANO and received 6 cycles of bendamustine (B)+R or 6 cycles of VenR followed by Ven monotherapy once daily for up to 2 years. Primary endpoint was investigator‐assessed progression‐free survival (PFS). This case series reports outcomes for pts treated with VenR in MURANO (IBR‐naïve at study inclusion) who developed progressive disease (PD) and were treated subsequently with IBR.Results:PFS was significantly longer in pts who received fixed‐duration VenR compared with those treated with BR (hazard ratio for overall MURANO population: 0.16 [95% confidence interval: 0.12–0.23]; p < 0.001). As of the May 8, 2018 data cut‐off (median follow‐up: 36 months), 28% of pts (55/194) in the VenR arm had experienced a PFS event (i.e. progression or death, whichever occurred first). Eight pts who had received VenR and experienced a PD event were treated subsequently with IBR (median treatment duration at last follow‐up: 13.5 months [range 3–42]). For these pts, the median number of therapy lines preceding VenR treatment was 1 (range: 1–4). Before VenR treatment, 7 pts had received fludarabine+cyclophosphamide+R (FCR), of whom 3 had achieved complete response (CR), 3 partial response (PR), and 1 had stable disease (SD) on FCR. Two FCR‐treated pts (1 with PR and 1 with CR on VenR) were considered refractory to FCR prior to VenR treatment.Before VenR treatment, 3 pts had a chromosome 17p deletion, 5 had mutated TP53, 1 had chromosome 11q deletion, 4 had unmutated IGVH, 6 had lymph nodes (LN) >10 cm and 2 had LN ≥5–<10 cm. Baseline lymphocyte counts ranged from 0.14 to 388.6 × 109/L, platelets from 59 to 228 × 109/L, and neutrophils from 0.38 to 4.37 × 109/L. Best response to VenR included CR in 3 and PR in 5 pts; 5 pts achieved minimal residual disease negativity at some point during VenR treatment. Chromosomal status and blood cell counts before IBR treatment were unavailable. All 8 pts achieved a response to IBR (7 PR, 1 very good PR). At last follow‐up, 6 pts were still on treatment (of whom 1 was due to stop due to PD after 40 months), 2 had stopped due to PD after approx. 3.5 and 7 months; no pts had died.Four pts had IBR dose modification or interruption due to neutropenia (n = 2), clarithromycin treatment (n = 1), or cutaneous nevus biopsy (n = 1). Multiple skin abscesses were observed in 1 pt. Two pts had arthralgia, 1 case of which had nearly resolved on follow‐up, 1 pt had atrial fibrillation, 1 had pneumonia (without hospital admission), and no instances of major bleeding were reported.Summary/Conclusion:IBR demonstrated an acceptable tolerability profile with no new safety signals as well as good clinical activity in this series of R/R CLL pts who received IBR following VenR treatment in MURANO. IBR treatment, therefore, seems an acceptable option for pts with CLL who relapse following VenR. More data will be gathered from the MURANO study for pts treated with VenR who progress and subsequently receive treatment with IBR.image