S108 SAFETY ANALYSIS OF VENETOCLAX AND IBRUTINIB FOR PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (R/R CLL): SECOND INTERIM ANALYSIS FROM THE PHASE II VISION HO141 TRIAL
Authors: A.P. Kater, J. Dubois, S. Kersting, L. Enggaard, G.J. Veldhuis, R. Mous, C.H. Mellink, J.A. Dobber, C.B. Poulsen, H. Frederiksen, A. Janssens, S.R. Janssen, I. Schjødt, E.C. Dompeling, T. Salmi, M. Mattsson, M. Bellido, H.T. Tran, K. Nasserinejad, M.‐D. Levin, C.U. Niemann
Journal: HemaSphere (2019)

Background: Novel treatment options for patients with R/R CLL are either based on continuous treatment ( e.g. the BTK inhibitor ibrutinib) or fixed duration treatment regardless of the level of response ( e.g. the Bcl‐2 inhibitor venetoclax + rituximab). Neither treatment accounts for biological differences between patients and might result in unnecessary medical and economic costs and development of resistance. Post‐treatment minimal residual disease (MRD) has proven to predict outcome in patients receiving chemo‐immunotherapy. Aims: The aim of the VISION / HOVON 141 study is to evaluate feasibility of MRD‐guided treatment cessation and reinitiation in patients with R/R CLL after induction treatment with venetoclax + ibrutinib. Methods: Patients are treated with ibrutinib monotherapy (420 mg daily) for two (28 days) cycles. In cycle 3 venetoclax is ramped up weekly to the final dosage of 400 mg daily from start of cycle 4. Combination of venetoclax + ibrutinib is given for a total of 15 cycles; patients achieving undetectable (uMRD) on blood and bone marrow (by central flow cytometry, &lt; 10 −4 level) are randomized thereafter 1:2 between maintenance ibrutinib or observation (stopping therapy). Registered at clinicaltrials.gov: NCT03226301. Results: Enrollment is complete with 230 patients. This preplanned interim analysis includes data for the first 9 induction cycles in the first 51 eligible patients with focus on safety, including the incidence of adverse events (AEs) of special interest (atrial fibrillation (AF), bleeding and tumor lysis (TLS)), and initial response evaluation including MRD results available until the end of cycle 12. The median age was 67 years (40 – 83), 36 (71%) were male, 33 (65%) had WHO performance status 0, and 43 (84%) were Binet stage B/C. Eight (16%) had centrally assessed TP53 aberrations (12 unknown, 24%) and 29 (57%) were IGHV unmutated (six not interpretable, 12%). Fifteen patients (29%) were classified as high and 30 (59%) as medium risk of TLS. The median prior lines of treatment was 1 (range 1 – 3). Of these 51 patients, 49 completed the first two cycles of ibrutinib monotherapy and the third cycle of ibrutinib combined with venetoclax ramp up; one stopped treatment through own decision, one suddenly died after two weeks of ibrutinib induction from an unknown cause. Of 49 patients who started cycle 4, 45 completed cycle 9 and four went off protocol, of whom one for excessive toxicity. Eleven (22%) patients experienced grade 2 AEs, 21 (42%) grade 3 and 12 (24%) grade 4 AEs. Of the 51 patients, 6 (12%) experienced laboratory TLS at cycle 3 venetoclax ramp up, four (8%) AF events were reported from cycle 4 to 6 and there were no bleeding events. Of 51 patients at month 9, thirty‐one (61%) achieved a complete remission (CR) and 15 (29%) patients achieved a partial remission (PR). Improvement in median hemoglobin and platelet count were seen while the median white blood cell count normalized from 87.5 (range 5 – 425) x 10‐E9/L to 4 (range 2.2 – 77) x 10‐E9/L at end of cycle 9. MRD results were available for 42 patients at end of cycles 9 and 12. Peripheral blood uMRD was found in 33% and 52% of patients at end of cycle 9 and 12 respectively (see Figure). The uMRD rate at end of cycle 15 in 25 patients with MRD results available was 48% (data not shown). Summary/Conclusion: Treatment with ibrutinib and venetoclax in the setting of R/R CLL shows a favorable benefit‐risk profile and a complete remission in 61% of patients after 9 cycles of treatment with an increasing uMRD rate to 52% after one year of treatment. The DSMB recommends continuing of the study. image