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A RANDOMISED COMPARISON OF CPX-351 AND FLAG-IDA IN HIGH RISK ACUTE MYELOID LEUKAEMIA. RESULTS FROM THE NCRI AML19 TRIAL
Author(s): ,
Nigel Russell
Affiliations:
Guy's and St Thomas' NHS Foundation Trust, Department of Haematology,London,Royaume-uni;Guy's and St Thomas' NHS Foundation Trust, Department of Haematology,London,Vereinigtes Königreich;Guy's and St Thomas' NHS Foundation Trust, Department of Haematology,London,Regno Unito;Guy's and St Thomas' NHS Foundation Trust, Department of Haematology,London,United Kingdom;Guy's and St Thomas' NHS Foundatio
,
Charlotte Wilhelm-Benartzi
Affiliations:
Centre for Trials Research,Cardiff University,Cardiff,Royaume-uni;Centre for Trials Research,Cardiff University,Cardiff,Vereinigtes Königreich;Centre for Trials Research,Cardiff University,Cardiff,Regno Unito;Centre for Trials Research,Cardiff University,Cardiff,United Kingdom;Centre for Trials Research,Cardiff University,Cardiff,Reino Unido;Centre for Trials Research,Cardiff University,Cardiff,Ve
,
Steve Knapper
Affiliations:
School of Medicine,Cardiff University,Cardiff,Royaume-uni;School of Medicine,Cardiff University,Cardiff,Vereinigtes Königreich;School of Medicine,Cardiff University,Cardiff,Regno Unito;School of Medicine,Cardiff University,Cardiff,United Kingdom;School of Medicine,Cardiff University,Cardiff,Reino Unido;School of Medicine,Cardiff University,Cardiff,Verenigd Koninkrijk;School of Medicine,Cardiff Uni
,
Leona Batten
Affiliations:
Centre for Trials Research,Cardiff University,Cardiff,Royaume-uni;Centre for Trials Research,Cardiff University,Cardiff,Vereinigtes Königreich;Centre for Trials Research,Cardiff University,Cardiff,Regno Unito;Centre for Trials Research,Cardiff University,Cardiff,United Kingdom;Centre for Trials Research,Cardiff University,Cardiff,Reino Unido;Centre for Trials Research,Cardiff University,Cardiff,Ve
,
Joanna Canham
Affiliations:
Centre for Trials Research,Cardiff University,Cardiff,Royaume-uni;Centre for Trials Research,Cardiff University,Cardiff,Vereinigtes Königreich;Centre for Trials Research,Cardiff University,Cardiff,Regno Unito;Centre for Trials Research,Cardiff University,Cardiff,United Kingdom;Centre for Trials Research,Cardiff University,Cardiff,Reino Unido;Centre for Trials Research,Cardiff University,Cardiff,Ve
,
Emily Hinson
Affiliations:
Centre for Trials Research,Cardiff University,Cardiff,Royaume-uni;Centre for Trials Research,Cardiff University,Cardiff,Vereinigtes Königreich;Centre for Trials Research,Cardiff University,Cardiff,Regno Unito;Centre for Trials Research,Cardiff University,Cardiff,United Kingdom;Centre for Trials Research,Cardiff University,Cardiff,Reino Unido;Centre for Trials Research,Cardiff University,Cardiff,Ve
,
Ulrik Malthe Overgaard
Affiliations:
Copenhagen University Hospital,Copenhagen,Danemark;Copenhagen University Hospital,Copenhagen,Dänemark;Copenhagen University Hospital,Copenhagen,Danimarca;Copenhagen University Hospital,Copenhagen,Danemark;Copenhagen University Hospital,Copenhagen,Dinamarca;Copenhagen University Hospital,Copenhagen,Denemarken;Copenhagen University Hospital,Copenhagen,Dinamarca;Copenhagen University Hospital,Copenha
,
Jad Othman
Affiliations:
Department of Medical and Molecular Genetics,Kings College London,London,Royaume-uni;Department of Medical and Molecular Genetics,Kings College London,London,Vereinigtes Königreich;Department of Medical and Molecular Genetics,Kings College London,London,Regno Unito;Department of Medical and Molecular Genetics,Kings College London,London,United Kingdom;Department of Medical and Molecular Genetics,K
,
Richard Dillon
Affiliations:
Department of Medical and Molecular Genetics,Kings College London,London,Royaume-uni;Department of Medical and Molecular Genetics,Kings College London,London,Vereinigtes Königreich;Department of Medical and Molecular Genetics,Kings College London,London,Regno Unito;Department of Medical and Molecular Genetics,Kings College London,London,United Kingdom;Department of Medical and Molecular Genetics,K
,
Priyanka Mehta
Affiliations:
University Hospitals of Bristol and Weston NHS Trust,Bristol,Royaume-uni;University Hospitals of Bristol and Weston NHS Trust,Bristol,Vereinigtes Königreich;University Hospitals of Bristol and Weston NHS Trust,Bristol,Regno Unito;University Hospitals of Bristol and Weston NHS Trust,Bristol,United Kingdom;University Hospitals of Bristol and Weston NHS Trust,Bristol,Reino Unido;University Hospitals
,
Panos Kottaridis
Affiliations:
University College London Hospitals NHS Foundation Trust,London,Royaume-uni;University College London Hospitals NHS Foundation Trust,London,Vereinigtes Königreich;University College London Hospitals NHS Foundation Trust,London,Regno Unito;University College London Hospitals NHS Foundation Trust,London,United Kingdom;University College London Hospitals NHS Foundation Trust,London,Reino Unido;Univer
,
Jamie Cavenagh
Affiliations:
Department of Haematology,St Bartholomew's Hospital,London,Royaume-uni;Department of Haematology,St Bartholomew's Hospital,London,Vereinigtes Königreich;Department of Haematology,St Bartholomew's Hospital,London,Regno Unito;Department of Haematology,St Bartholomew's Hospital,London,United Kingdom;Department of Haematology,St Bartholomew's Hospital,London,Reino Unido;Department of Haematology,St Ba
,
Claire Hemmaway
Affiliations:
Aukland Hospital,Aukland,Nouvelle-zélande;Aukland Hospital,Aukland,Neuseeland;Aukland Hospital,Aukland,Nuova Zelanda;Aukland Hospital,Aukland,新西兰;Aukland Hospital,Aukland,Nueva Zelanda;Aukland Hospital,Aukland,Nieuw Zeeland;Aukland Hospital,Aukland,Nova Zelândia;Aukland Hospital,Aukland,Новая Зеландия;Aukland Hospital,Aukland,Nya Zeeland
,
Claire Arnold
Affiliations:
Belfast City Hospital,Belfast,Royaume-uni;Belfast City Hospital,Belfast,Vereinigtes Königreich;Belfast City Hospital,Belfast,Regno Unito;Belfast City Hospital,Belfast,United Kingdom;Belfast City Hospital,Belfast,Reino Unido;Belfast City Hospital,Belfast,Verenigd Koninkrijk;Belfast City Hospital,Belfast,Reino Unido;Belfast City Hospital,Belfast,Соединённое Королевство;Belfast City Hospital,Belfast,
Mike Dennis
Affiliations:
The Christie NHS Foundation Trust. On behalf of the NCRI AML Working Group,Manchester,Royaume-uni;The Christie NHS Foundation Trust. On behalf of the NCRI AML Working Group,Manchester,Vereinigtes Königreich;The Christie NHS Foundation Trust. On behalf of the NCRI AML Working Group,Manchester,Regno Unito;The Christie NHS Foundation Trust. On behalf of the NCRI AML Working Group,Manchester,United Ki
(Abstract release date: 05/12/22) EHA Library. Russell N. 06/11/22; 356992; S128
Prof. Nigel Russell
Prof. Nigel Russell
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S128

Type: Oral Presentation

Session title: Novel insights into AML treatment

Background
Liposomal daunorubicin and cytarabine (CPX-351) has shown a survival advantage for older patients (>60years) with secondary AML compared to 3+7 chemotherapy however in younger patients there is a lack of randomised evidence for benefit. We have previously reported improved survival with FLAG-Ida treatment as treatment intensification for younger patients identified with high risk (HR) AML following induction therapy and for patients with secondary AML (Burnett AK et al. Leukemia. 2018 Dec;32(12):2693-2697) and considered this regimen an appropriate comparator for trials in younger patients.

Aims
We compared CPX-351 with FLAG-Ida in a randomised fashion in patients who were either HR at trial entry based on cytogenetics or identified as HR following induction or at relapse.

Methods
The AML19 trial (ISRCTN78449203) randomised CPX-351 vs FLAG-Ida in 635 patients mainly <60 years with HR AML or MDS (>10% blasts) (median age 53.6 yrs). Three groups of HR patients were randomised 2:1 in favour of CPX with the aim of proceeding to allogeneic transplant. Group 1 (n=195) had known adverse risk cytogenetics (Grimwade et al, Blood 2010,116, 354) and were randomised at diagnosis between 4 courses of CPX-351 and 2 courses of FLAG-Ida followed by MACE/MidAC consolidation. Group 2 (n=263) were HR by validated risk score, had FLT3-ITD without an NPM1 mutation,  had refractory disease and were randomised after induction course 1. Group 3 (n=177) were randomised after course 2 if they had persisting MRD  at the time of relapse. Here we present results for Group 1. Group 1 was not powered to claim statistical significance; therefore, these results are intended to be exploratory and hypothesis generating.

Results
Group 1 included 49.2% with de novo AML 20.3% patients with secondary AML and 30.5% with HR MDS.

The Overall response rate(CR/CRi) was 64.8% for CPX-351 and 74.4% for FLAG-Ida (univariate OR:0.57, 95%CI 0.30-1.10, p=0.09).  Overall survival (OS) at 3 years was 32% and 24%, median OS was 13.3 months vs 10.2 months (univariate HR:0.83, 95%CI 0.58-1.18, p=0.3) for CPX -351 and FLAG-Ida respectively (Figure 1a).  Event free survival (EFS) was not significantly different (HR:0.91 95%CI: 0.50-1.64, p=0.76). Relapse free survival (RFS) at 3 years was 43% and 28%, median RFS was 22.1 months vs 14 months (univariate HR:0.66, 95%CI 0.41-1.06, p=0.09) for CPX -351 and FLAG-Ida respectively (Figure 1b). RFS was significant when adjusting for NPM1 mutation status or FLT3 mutation status using multivariable cox regression model with RFS being better with CPX-351 compared to FLAG-Ida (HR:0.58, 95% CI0.36-0.95, p=0.03). Median duration of remission favoured CPX and was 319.5 days vs 167 days (p=0.046) for CPX vs FLAG-Ida respectively. Haematological toxicity was greater in course 1 with CPX-351 with platelet recovery to 100x109/L at 34.5 days versus 29 days (p<0.001) and neutrophil recovery to 1.0x109/L at 32 days vs 30 days.(p=0.12). Day 30 and day 60 mortality were not significantly different between arms with 4.8% vs 7.3% (p=0.46) and 12.4% vs 11.0% (p=0.77) for CPX-351 and FLAG-Ida respectively.Compliance was better with CPX-351 with 90.7% vs 83.0% receiving the scheduled course 1 dose. More patients receiving CPX-351 were transplanted (50.5% vs 41.5%) with the median number of courses given prior to transplant 2 in both arms.

Conclusion
In patients with adverse cytogenetics CPX-351 did not improve response, OS or EFS compared to FLAG-Ida but was associated with better duration of remission and RFS. Further follow-up is needed to determine the clinical significance of those differences.

Keyword(s):

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S128

Type: Oral Presentation

Session title: Novel insights into AML treatment

Background
Liposomal daunorubicin and cytarabine (CPX-351) has shown a survival advantage for older patients (>60years) with secondary AML compared to 3+7 chemotherapy however in younger patients there is a lack of randomised evidence for benefit. We have previously reported improved survival with FLAG-Ida treatment as treatment intensification for younger patients identified with high risk (HR) AML following induction therapy and for patients with secondary AML (Burnett AK et al. Leukemia. 2018 Dec;32(12):2693-2697) and considered this regimen an appropriate comparator for trials in younger patients.

Aims
We compared CPX-351 with FLAG-Ida in a randomised fashion in patients who were either HR at trial entry based on cytogenetics or identified as HR following induction or at relapse.

Methods
The AML19 trial (ISRCTN78449203) randomised CPX-351 vs FLAG-Ida in 635 patients mainly <60 years with HR AML or MDS (>10% blasts) (median age 53.6 yrs). Three groups of HR patients were randomised 2:1 in favour of CPX with the aim of proceeding to allogeneic transplant. Group 1 (n=195) had known adverse risk cytogenetics (Grimwade et al, Blood 2010,116, 354) and were randomised at diagnosis between 4 courses of CPX-351 and 2 courses of FLAG-Ida followed by MACE/MidAC consolidation. Group 2 (n=263) were HR by validated risk score, had FLT3-ITD without an NPM1 mutation,  had refractory disease and were randomised after induction course 1. Group 3 (n=177) were randomised after course 2 if they had persisting MRD  at the time of relapse. Here we present results for Group 1. Group 1 was not powered to claim statistical significance; therefore, these results are intended to be exploratory and hypothesis generating.

Results
Group 1 included 49.2% with de novo AML 20.3% patients with secondary AML and 30.5% with HR MDS.

The Overall response rate(CR/CRi) was 64.8% for CPX-351 and 74.4% for FLAG-Ida (univariate OR:0.57, 95%CI 0.30-1.10, p=0.09).  Overall survival (OS) at 3 years was 32% and 24%, median OS was 13.3 months vs 10.2 months (univariate HR:0.83, 95%CI 0.58-1.18, p=0.3) for CPX -351 and FLAG-Ida respectively (Figure 1a).  Event free survival (EFS) was not significantly different (HR:0.91 95%CI: 0.50-1.64, p=0.76). Relapse free survival (RFS) at 3 years was 43% and 28%, median RFS was 22.1 months vs 14 months (univariate HR:0.66, 95%CI 0.41-1.06, p=0.09) for CPX -351 and FLAG-Ida respectively (Figure 1b). RFS was significant when adjusting for NPM1 mutation status or FLT3 mutation status using multivariable cox regression model with RFS being better with CPX-351 compared to FLAG-Ida (HR:0.58, 95% CI0.36-0.95, p=0.03). Median duration of remission favoured CPX and was 319.5 days vs 167 days (p=0.046) for CPX vs FLAG-Ida respectively. Haematological toxicity was greater in course 1 with CPX-351 with platelet recovery to 100x109/L at 34.5 days versus 29 days (p<0.001) and neutrophil recovery to 1.0x109/L at 32 days vs 30 days.(p=0.12). Day 30 and day 60 mortality were not significantly different between arms with 4.8% vs 7.3% (p=0.46) and 12.4% vs 11.0% (p=0.77) for CPX-351 and FLAG-Ida respectively.Compliance was better with CPX-351 with 90.7% vs 83.0% receiving the scheduled course 1 dose. More patients receiving CPX-351 were transplanted (50.5% vs 41.5%) with the median number of courses given prior to transplant 2 in both arms.

Conclusion
In patients with adverse cytogenetics CPX-351 did not improve response, OS or EFS compared to FLAG-Ida but was associated with better duration of remission and RFS. Further follow-up is needed to determine the clinical significance of those differences.

Keyword(s):

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