OBINUTUZUMAB PRE-INDUCTION ABROGATES HIGH TUMOR LYSIS RISK OF VENETOCLAX IN TREATMENT NAÏVE FCR-UNFIT PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: A PLANNED INTERIM ANALYSIS.
Author(s): ,
Mark-David Levin
Affiliations:
Internal Medicine,Albert Schweitzer hospital,Dordrecht,Netherlands
,
Sabina Kersting
Affiliations:
Internal Medicine,HAGA hospital,the Hague,Netherlands
,
Yvette van Norden
Affiliations:
Statistics,Erasmus MC Institute HOVON data centre,Rotterdam,Netherlands
,
Johan Dobber
Affiliations:
Laboratory special hematology,Academic Medical Center,Amsterdam,Netherlands
,
Clemens Mellink
Affiliations:
Laboratory of clinical genetics ,Academic Medical Center,Amsterdam,Netherlands
,
Ludo Evers
Affiliations:
Laboratory special hematology,Academic Medical Center,Amsterdam,Netherlands
,
Francien Croon - de Boer
Affiliations:
Internal Medicine,Ikazia hospital,Rotterdam,Netherlands
,
John Schreurs
Affiliations:
Internal Medicine,Martini hospital,Groningen,Netherlands
,
Ellen van der Spek
Affiliations:
Internal Medicine,Rijnstate hospital,Arnhem,Netherlands
,
Hein Visser
Affiliations:
Internal Medicine,Northwest Clinics,Alkmaar,Netherlands
,
Cecile Idink
Affiliations:
Internal Medicine,ZorgSaam hospital,Terneuzen,Netherlands
,
Shulamiet Wittebol
Affiliations:
Internal Medicine,Gelderland Valley hospital,Ede,Netherlands
,
Mels Hoogendoorn
Affiliations:
Internal Medicine,Medical Center Leeuwarden,Leeuwarden,Netherlands
,
Sanne Tonino
Affiliations:
Hematology,Academic Medical Center,Amsterdam,Netherlands
Arnon P. Kater
Affiliations:
Hematology,Academic Medical Center,Amsterdam,Netherlands
EHA Library. Levin M. Jun 15, 2018; 214821; PF348
Mark David Levin
Mark David Levin
Contributions
Abstract

Abstract: PF348

Type: Poster Presentation

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

Location: Poster area

Background
Combination of chlorambucil and obinutuzumab is currently the most effective treatment for CLL patients unfit for fludarabine or bendamustine containing regimens with 1/3 of patients reaching peripheral blood (PB) minimal residual disease negativity (MRD-). Early data on venetoclax containing regimens show promising results with deep remissions but are hampered by risk of tumor lysis syndrome (TLS). Whether optimal duration of venetoclax treatment can be guided by MRD- is currently unknown. We perform a randomized phase 2 study to address 1) whether TLS-risk can be mitigated in an unfit population by introducing pre-induction and 2) whether MRD-guided duration of venetoclax treatment is a feasible and efficacious approach.  

Aims
Here we report on a planned interim safety analysis (especially TLS risk before and after obinutuzumab pre-induction) and MRD data of the first 30 patients in this HOVON 139 / GIVE trial. 

Methods
Treatment regimen is as follows: Pre-induction (figure 1): 2 cycles of obinutuzumab monotherapy (C1 d1:100 mg, d2: 900 mg, d8:1000 mg, d15: 1000mg and C2 d1: 1000 mg); Induction I: 6 cycles obinutuzumab (C3-8 d1: 1000 mg) in combination with venetoclax (C3: ramp-up weekly 20-50-100-200mg and 400mg daily thereafter); Induction II: 6 cycles venetoclax monotherapy (C9-14: 400 mg daily); MRD-guided maintenance: randomization of patients with at least partial remission (PR) after induction II: 12 additional cycles of venetoclax irrespective of MRD or venetoclax maintenance only in MRD+ patients. All cycles are 28 days. MRD–: <1 CLL cell/104 leukocytes (L) by flowcytometry. TLS risk groups according to Roberts. 

Results
Until the 29th of January 2018, 46 patients were included in this trial. Thirty patients were followed for at least 3 cycles (median age 70, range 57-79 years) and are reported here, of whom 73% was male, 47% had RAI stage ≥3 and median CIRS-score was 3 (range 0-16). IGHV was mutated  in 13 (43%) and unmutated in 13 (43%) patients (non-conclusive in 4 (13%). Deletion 17p was found in 3 (10%), 7 (24%) patients showed a TP53-mutation (≥10%) and 9 (30%) had complex karyotype. Baseline TLS risk scores are depicted in table 1. Downgrading of TLS risk occurred in 25 patients (83%): 3 from high to medium, 3 from high to low and 19 from medium to low risk. Laboratory TLS grade 1 occurred in 4 times in 3 patients: 2 times during pre-induction with obinutuzumab, both with medium TLS risk and 2 times during venetoclax ramp-up with low TLS risk after pre-induction, of whom 1 with high and 1 with medium TLS risk at baseline. All TLS resolved with protocolled hydration, allopurinol +/- rasburicase. During pre-induction 9 patients (30%) experienced grade 3-4 toxicities, but none in the second pre-induction cycle. The intended dose of 3000 mg obinutuzumab in the first pre-induction cycle was reached in 28 patients (93%). During the first induction cycle 3 patients (10%) developed grade 3-4 toxicity. In addition, all patients received the total intended dose of venetoclax ramp-up. First PB MRD data showed  21 of 25 patients (84%) MRD-, 3 (12%) MRD intermediate (10-4–<10-2) and 1 (4%) MRD+ after 6 cycles of induction treatment and 4 of 4 (100%) MRD- after 12 cycles of induction treatment (see table 2). 

Conclusion
Obinutuzumab pre-induction is well tolerated in elderly patients and results in abrogating high TLS risk in all patients. MRD-negativity is seen in 84% of patients after 6 cycles and in all patients reaching 12 cycles of induction treatment with obinutuzumab and venetoclax.

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

Keyword(s): BCL2, Minimal residual disease (MRD), Obinutuzumab, Tumor lysis

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