SAFETY ANALYSIS OF VENETOCLAX AND IBRUTINIB FOR PREVIOUSLY TREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): FIRST INTERIM ANALYSIS FROM THE PHASE II VISION HO141 TRIAL
Author(s): ,
Carsten U Niemann
Affiliations:
Department of Hematology,Rigshospitalet, Copenhagen University Hospital,Copenhagen,Denmark
,
Mark-David Levin
Affiliations:
Department of Internal Medicine,Albert Schweitzer ziekenhuis ,Dordrecht,Netherlands
,
Kazem Nasserinejad
Affiliations:
HOVON Data Center,Rotterdam,Netherlands
,
Ann MH Janssens
Affiliations:
UZ Leuven ,Leuven,Netherlands
,
Lisbeth Enggaard
Affiliations:
Herlev Hospital,Copenhagen,Denmark
,
Sabina Kersting
Affiliations:
HagaZiekenhuis,van Den Haag,Netherlands
,
Gerrit J Veldhuis
Affiliations:
Antonius Ziekenhuis ,Sneek,Netherlands
,
Rogier Mous
Affiliations:
Universitair Medisch Centrum Utrecht ,Utrecht,Netherlands
,
Clemens HM Melink
Affiliations:
AMC,Amsterdam,Netherlands
,
Johan A Dobber
Affiliations:
AMC,Amsterdam,Netherlands
,
Ida Schjødt
Affiliations:
Department of Hematology,Rigshospitalet, Copenhagen University Hospital,Copenhagen,Denmark
,
EC Dompeling
Affiliations:
Isala,Zwolle,Netherlands
,
Christian B Poulsen
Affiliations:
Roskilde Sygehus,Roskilde,Denmark
,
Hoa TT Tran
Affiliations:
Akershus,Oslo,Norway
,
Tommi Salmi
Affiliations:
Turku University Hospital,Turku,Finland
,
Mattias Mattsson
Affiliations:
Uppsala University Hospital,Uppsala,Sweden
Arnon P Kater
Affiliations:
AMC,Amsterdam,Netherlands
EHA Library. Niemann C. Jun 15, 2018; 214819; PF346
Carsten Niemann
Carsten Niemann
Contributions
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Abstract

Abstract: PF346

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
Standard of care for patients with relapsed or refractory CLL (RR CLL) is rapidly changing. For patients with late relapse > 2-3 years from 1st-line, repeated fixed duration therapy with chemoimmunotherapy may be used, while patients with early relapse or TP53 aberrations are treated with novel targeted agents until toxicity or progression. Thus, chemotherapy-free regimens with the option to safely stop treatment are warranted.

Aims
The aim of the VISION / HOVON 141 study is to evaluate whether combination treatment with venetoclax + ibrutinib in patients with RR CLL can lead to minimal residual disease (MRD) negativity, allowing MRD-guided treatment cessation. We here report on a preplanned safety interim analysis.

Methods
Patients were treated with ibrutinib monotherapy (420 mg daily) for the first two cycles of 28 days,  in cycle 3 venetoclax was ramped up weekly from 20 mg to the final dosage of 400 mg daily from start of cycle 4. All patients are treated for 15 cycles; MRD negative patients (blood and bone marrow, by central flowcytometry, 10-4 level) are randomized 1:2 between maintenance ibrutinib or observation thereafter, MRD positive patients continue ibrutinib monotherapy. Patients in the observation arm are assessed for blood MRD every three months; venetoclax + ibrutinib is reinitiated upon MRD >10-2. Enrollment is ongoing, 62 of 207 planned patients enrolled. This interim analysis includes data for the first 3 induction cycles of the first 15 eligible patients in the study with focus on safety including the incidence of adverse events (AEs) of special interest (atrial fibrillation, bleeding and tumor lysis) and initial response evaluation. Only grade 2 and above AEs were reported as per protocol. Registered at clinicaltrials.gov: NCT03226301.

Results
The median age for the first 15 patients was 59 years (range 40-79), eight (53%) were male, 11 (73%) showed WHO performance status 0, 14 (93%) were classified as Binet stage B/C, five (33%) as high and nine (60%) as medium risk of tumor lysis (one unknown), six (40%) had centrally assessed TP53 aberrations and nine (60%) were IGHV unmutated (one unknown). All patients completed the first two cycles of ibrutinib monotherapy and the third cycle of ibrutinib combined with venetoclax ramp up. Three and two patients had dose modifications of ibrutinib and venetoclax, respectively, no patients stopped treatment. Three (20%) patients experienced grade 2 AEs, three (20%) grade 3 and two (13%) grade 4 AEs, no grade 5 AEs were reported. Two (13%) patients experienced an SAE during ibrutinib monotherapy (febrile neutropenia, adenocarcinoma of the lung) while no SAEs were reported during cycle 3 venetoclax ramp up. No tumor lysis, atrial fibrillation or bleeding events reported. Eight (53%) patients achieved a clinical complete remission (CR) and six (40%) patients achieved a partial remission (PR) while one (7%) achieved PR with lymphocytosis as assessed by the local investigator at end of cycle 3 (the day before the ramp up to 400 mg venetoclax in the 4th cycle). Improvement in median hemoglobin and platelet count were seen while the median white blood cell count decreased from 260 to 8 x 10-E9 after an initial ibrutinib induced lymphocytosis.

Conclusion
Treatment with ibrutinib and ramp up with venetoclax in the setting of RR CLL was manageable without any unexpected AEs; all patients responded, 53% had a clinical complete response within the first three cycles of treatment, before reaching the final dosage of venetoclax. The DSMB recommends continuing of the study.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Apoptosis, B cell chronic lymphocytic leukemia, Minimal residual disease (MRD), Targeted therapy

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