IBRUTINIB, VENETOCLAX PLUS OBINUTUZUMAB IN NEWLY DIAGNOSED MANTLE CELL LYMPHOMA PATIENTS
Author(s): ,
Steven Le Gouill
Affiliations:
hematology,CHU de Nantes,Nantes,France;CRCINA INSERM,Nantes,France
,
franck Morschhauser
Affiliations:
CHU de Lille,Lille,France
,
krimo Boua
Affiliations:
CHU de Bordeaux,Bordeaux,France
,
guillaume cartron
Affiliations:
CHU Montpellier,Montpellier,France
,
olivier casasnovas
Affiliations:
chu de Dijon,Dijon,France
,
thomas gastinne
Affiliations:
CHU de Nantes,Nantes,France
,
dedric Rossi
Affiliations:
CHU de Dijon,Dijon,France
,
emmanuelle Tchernonog
Affiliations:
CHU de Montpellier,Montpellier,France
,
Rory Mac Culloch
Affiliations:
Plymouth University hospital,plymouth,United Kingdom
,
charles herbaux
Affiliations:
CHU de Lille,Lille,France
,
david chiron
Affiliations:
INSERM CRCINA,Nantes,France
,
mary callanan
Affiliations:
CHU de Dijon,Dijon,France
simon rule
Affiliations:
Plymouth University Hospital,Plymouth,United Kingdom
(Abstract release date: 05/14/20) EHA Library. Le Gouill S. 06/12/20; 295048; S228
Steven Le Gouill
Steven Le Gouill
Contributions
Abstract

Abstract: S228

Type: Oral Presentation

Session title: Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Background

Novel targeted therapies have demonstrated high efficacy in relapse and/or refractory (R/R) MCL. Ibrutinib, a first in class BTK inhibitor, is approved for R/R MCL. Venetoclax, a first in class bcl-2 inhibitor. Obinutuzumab is a type II glycol-engineered, humanized anti-CD20 antibody. Pre-clinical investigations have demonstrated the utility of combining these three molecules in MCL (Chiron et al, Blood 2016).

Aims

The OAsIs trial (NCT02558816) is a multicenter, non-randomised, phase I study designed to assess the safety, tolerability and efficacy of Ibrutinib/ Venetoclax/Obinutuzumab in both R/R MCL and in newly diagnosed MCL. Herein, we present the safety, clinical and MRD results for untreated patients.

Methods

Obinutuzumab was given at 1000mg IV C1D1, 8, 15, C2-6 D1 and every 2 months until C23. Ibrutinib was given as a standard dose (560mg/d) from C1D2 and until progression. The dose of Venetoclax was 400mg (according to step B analysis and DSMC recommendations) and administered from C1-bis (to prevent TLS: C1-bis W1-20mg, C1-bis W2-50, C1-bis W3-100, C1-bis W4-200) and at 400mg from C2 to C23. Response was assessed by cheson 99 criteria at C2, C4 and C6 and by Lugano criteria at Cycle 6. MRD by ASO-qPCR (assay sensitivity 10-5) was measured at the end of C3 and 6 in blood and / or bone marrow. DLTs were assessed during the first 3 months (C1, C1-bis and C2) of treatment.

Results

Fifteen untreated MCL patients were enrolled from August 2018 to April 2019. Median age at inclusion was 65y (range 51-77). All patients presented with stage III/IV disease and nodal disease (four patients had tumor mass >5cm). The MIPI score was high in 9 cases, intermediate in 5 and low in one case. One patient presented with pleomorphic variant. TP53 status at diagnosis was assessed in 14 patients (one was not informative) of these two presented TP53 mutation. IGHV status was mutated in two cases including the p53mutcase and not mutated in 10 (not informative in 3 cases). During the first three months of treatment (C1, C1-bis and C2), the relative dose intensity (ratio of delivered to the planned dose intensity) was 87% for Ibrutinib, 93% for Obinutuzumab and 100% for Venetoclax. During this period, non-hematological grade 3-4 AEs were hepatobiliary disorders (n=4; 3 patients with raised GGT-grade 3-, alanine -grade 3- and aspartate -grade 4- aminotransferase and one with biological cytolysis – grade 4) and rash (n=1; grade 3). Hematological grade 3-4 AEs were lymphocytosis (n=1; grade 3) and neutropenia (n=1; grade 4). All (n=15) patients are in response (including CR/uCR in 8 cases) at end of cycle 2 according to Cheson 99 criteria. In terms of MRD status, 12 patients (3 were not informative for MRD) were assessed at end of cycle 3 and all were MRD negative in blood including the p53mutpatient. Fourteen patients completed 6 cycles and one progressed at C4, eleven reached CR according to Lugano criteria (one PR, and 2 missing) and were MRD neg (in blood and/or BM; ongoing for one and not informative for 2), including the P53mut patient. At date of last contact (JAN 2020), no disease progression is reported and all patients remain under the planned treatment.

Conclusion
Ibrutinib/Venetoclax/Obinutuzumab combination therapy has a very good safety profile and shows high efficacity rates at the molecular level in untreated patients. Oasis step C is the first trial that report the use of Ibrutinib/Venetoclax/Obinutuzumab as frontline therapy in MCL.

Session topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Abstract: S228

Type: Oral Presentation

Session title: Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Background

Novel targeted therapies have demonstrated high efficacy in relapse and/or refractory (R/R) MCL. Ibrutinib, a first in class BTK inhibitor, is approved for R/R MCL. Venetoclax, a first in class bcl-2 inhibitor. Obinutuzumab is a type II glycol-engineered, humanized anti-CD20 antibody. Pre-clinical investigations have demonstrated the utility of combining these three molecules in MCL (Chiron et al, Blood 2016).

Aims

The OAsIs trial (NCT02558816) is a multicenter, non-randomised, phase I study designed to assess the safety, tolerability and efficacy of Ibrutinib/ Venetoclax/Obinutuzumab in both R/R MCL and in newly diagnosed MCL. Herein, we present the safety, clinical and MRD results for untreated patients.

Methods

Obinutuzumab was given at 1000mg IV C1D1, 8, 15, C2-6 D1 and every 2 months until C23. Ibrutinib was given as a standard dose (560mg/d) from C1D2 and until progression. The dose of Venetoclax was 400mg (according to step B analysis and DSMC recommendations) and administered from C1-bis (to prevent TLS: C1-bis W1-20mg, C1-bis W2-50, C1-bis W3-100, C1-bis W4-200) and at 400mg from C2 to C23. Response was assessed by cheson 99 criteria at C2, C4 and C6 and by Lugano criteria at Cycle 6. MRD by ASO-qPCR (assay sensitivity 10-5) was measured at the end of C3 and 6 in blood and / or bone marrow. DLTs were assessed during the first 3 months (C1, C1-bis and C2) of treatment.

Results

Fifteen untreated MCL patients were enrolled from August 2018 to April 2019. Median age at inclusion was 65y (range 51-77). All patients presented with stage III/IV disease and nodal disease (four patients had tumor mass >5cm). The MIPI score was high in 9 cases, intermediate in 5 and low in one case. One patient presented with pleomorphic variant. TP53 status at diagnosis was assessed in 14 patients (one was not informative) of these two presented TP53 mutation. IGHV status was mutated in two cases including the p53mutcase and not mutated in 10 (not informative in 3 cases). During the first three months of treatment (C1, C1-bis and C2), the relative dose intensity (ratio of delivered to the planned dose intensity) was 87% for Ibrutinib, 93% for Obinutuzumab and 100% for Venetoclax. During this period, non-hematological grade 3-4 AEs were hepatobiliary disorders (n=4; 3 patients with raised GGT-grade 3-, alanine -grade 3- and aspartate -grade 4- aminotransferase and one with biological cytolysis – grade 4) and rash (n=1; grade 3). Hematological grade 3-4 AEs were lymphocytosis (n=1; grade 3) and neutropenia (n=1; grade 4). All (n=15) patients are in response (including CR/uCR in 8 cases) at end of cycle 2 according to Cheson 99 criteria. In terms of MRD status, 12 patients (3 were not informative for MRD) were assessed at end of cycle 3 and all were MRD negative in blood including the p53mutpatient. Fourteen patients completed 6 cycles and one progressed at C4, eleven reached CR according to Lugano criteria (one PR, and 2 missing) and were MRD neg (in blood and/or BM; ongoing for one and not informative for 2), including the P53mut patient. At date of last contact (JAN 2020), no disease progression is reported and all patients remain under the planned treatment.

Conclusion
Ibrutinib/Venetoclax/Obinutuzumab combination therapy has a very good safety profile and shows high efficacity rates at the molecular level in untreated patients. Oasis step C is the first trial that report the use of Ibrutinib/Venetoclax/Obinutuzumab as frontline therapy in MCL.

Session topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

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