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GEMTUZUMAB-BASED INDUCTION CHEMOTHERAPY COMBINED WITH MIDOSTAURIN FOR FLT3 MUTATED AML. RESULTS FROM THE NCRI AML19 'MIDOTARG' PILOT TRIAL
Author(s): ,
Nigel Russell
Affiliations:
Haematology,Guy's and St Thomas' NHS Foundation Trust,London,Royaume-uni;Haematology,Guy's and St Thomas' NHS Foundation Trust,London,Vereinigtes Königreich;Haematology,Guy's and St Thomas' NHS Foundation Trust,London,Regno Unito;Haematology,Guy's and St Thomas' NHS Foundation Trust,London,United Kingdom;Haematology,Guy's and St Thomas' NHS Foundation Trust,London,Reino Unido;Haematology,Guy's and
,
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
,
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
,
Nicola Potter
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
,
Jelena Jovanovic
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
,
Amanda Gilkes
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 M 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 L 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
,
Panos Kottaridis
Affiliations:
Haematology,University College London Hospitals NHS Foundation Trust,London,Royaume-uni;Haematology,University College London Hospitals NHS Foundation Trust,London,Vereinigtes Königreich;Haematology,University College London Hospitals NHS Foundation Trust,London,Regno Unito;Haematology,University College London Hospitals NHS Foundation Trust,London,United Kingdom;Haematology,University College Lon
,
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 Arnold
Affiliations:
Haematology,Belfast City Hospital,Belfast,Royaume-uni;Haematology,Belfast City Hospital,Belfast,Vereinigtes Königreich;Haematology,Belfast City Hospital,Belfast,Regno Unito;Haematology,Belfast City Hospital,Belfast,United Kingdom;Haematology,Belfast City Hospital,Belfast,Reino Unido;Haematology,Belfast City Hospital,Belfast,Verenigd Koninkrijk;Haematology,Belfast City Hospital,Belfast,Reino Unido;
,
Mike Dennis
Affiliations:
Haematology,The Christie NHS Foundation Trust,Manchester,Royaume-uni;Haematology,The Christie NHS Foundation Trust,Manchester,Vereinigtes Königreich;Haematology,The Christie NHS Foundation Trust,Manchester,Regno Unito;Haematology,The Christie NHS Foundation Trust,Manchester,United Kingdom;Haematology,The Christie NHS Foundation Trust,Manchester,Reino Unido;Haematology,The Christie NHS Foundation T
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
(Abstract release date: 05/12/22) EHA Library. Russell N. 06/11/22; 356990; S126
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: S126

Type: Oral Presentation

Session title: Novel insights into AML treatment

Background
Following the RATIFY study Midostaurin in combination with “7+3” like chemotherapy has become the standard of care for patients with newly diagnosed FLT3 mutated AML. The ALFA 0701 trial also suggested a benefit for Gemtuzumab Ozogamicin (GO) in FLT3 mutated AML however the combination of GO-based induction with Midostaurin has not been formally assessed.  

Aims
To assess the safety of midostaurin in combination with Gemtuzumab and intensive induction therapy and to assess impact of the combination on MRD kinetics

Methods
 The NCRI AML19 trial randomised patients to receive DA 3+10 (Daunorubicin 60mg/m2 on days 1,3,5 plus AraC 100mg/m2 bd on days 1-10) plus a single dose of GO 3mg/m2 on day 1 (DAGO1) or 2 doses (3mg/m2, maximum 5mg) on days 1 and 4 (DAGO2) plus 50mg bd of midostaurin (m) for 14 days following completion of chemotherapy. Eligibility included age 18-60 years with a FLT3-ITD or TKD mutation.  Enhanced pharmacovigilance (PV) was performed for four weeks following the first induction course. Midostaurin was also given following second induction (DA 3+8 without GO) and 2 courses of HDAC consolidation and as maintenance for 12 cycles in non-transplanted patients. From November 2020 to November 2021, 77 patients were enrolled into the Midotarg pilot receiving DAGO1m (n=39) or DAGO2m (n=38). 59 had a FLT3 ITD and 22 a FLT3-TKD (and 4 had both). 59 patients have completed course 1 and are evaluable. RT-qPCR MRD monitoring for patients with an NPM1 mutation (n=48) was performed following each cycle of chemotherapy. A descriptive comparison is presented here of toxicity and MRD kinetics with FLT3 mutated patients receiving DAGO1 or DAGO2 without Midostaurin in the same trial.  

Results
Treatment compliance in course 1 was 88% for DAGO1m and 100% for DAGO2m. One patient did not receive any Midostaurin because of colitis during induction. Dose interruption for QTc prolongation occurred in 1 patient. A total of 17 SAEs (CTC grade 3 or greater) were reported (GO1, n=11, GO2 n= 6).  Day 60 mortality was 0%.  No cases of VOD were reported. Blood count recovery was not delayed. Time to neutrophil recovery to 1 x 109/L was 31 and 32 days with DAGO1m and DAGO2m compared to 31 and 32 days in DAGO1 and DAGO2 .. Time to platelet recovery to 100 x 109/L was 28 and 29 days with DAGO1m and DAGO2m respectively compared to 30 days in DAGO1 and DAGO2.  

Complete remission (CR plus CRi) was achieved in 51/59 (88%) evaluable patients who have completed induction with DAGOm. In 44 evaluable patients in remission with NPM1 mutation, 34 (74%) were MRD negative in the peripheral blood after course 2. This compares with 63% in 54 evaluable patients with DAGO only. Bone marrow NPM1 transcript levels after courses 1 to 4 were compared with  FLT3 mutated patients receiving DAGO1 and DAGO2 without Midostaurin (Figure 1) with a higher proportion of patients becoming MRD negative from course 2 onwards and 81% being MRD negative after course 4.

Conclusion
The addition of midostaurin to DAGO using a single or fractionated dose of GO was well tolerated with no evidence of increased toxicity, high response rate and with encouraging clearance of NPM1 mutant transcripts. A randomised study of DAm versus DAGOm in FLT3 mutated AML is planned

Keyword(s): Acute myeloid leukemia, Flt3-ITD, Gemtuzumab ozogamicin

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: S126

Type: Oral Presentation

Session title: Novel insights into AML treatment

Background
Following the RATIFY study Midostaurin in combination with “7+3” like chemotherapy has become the standard of care for patients with newly diagnosed FLT3 mutated AML. The ALFA 0701 trial also suggested a benefit for Gemtuzumab Ozogamicin (GO) in FLT3 mutated AML however the combination of GO-based induction with Midostaurin has not been formally assessed.  

Aims
To assess the safety of midostaurin in combination with Gemtuzumab and intensive induction therapy and to assess impact of the combination on MRD kinetics

Methods
 The NCRI AML19 trial randomised patients to receive DA 3+10 (Daunorubicin 60mg/m2 on days 1,3,5 plus AraC 100mg/m2 bd on days 1-10) plus a single dose of GO 3mg/m2 on day 1 (DAGO1) or 2 doses (3mg/m2, maximum 5mg) on days 1 and 4 (DAGO2) plus 50mg bd of midostaurin (m) for 14 days following completion of chemotherapy. Eligibility included age 18-60 years with a FLT3-ITD or TKD mutation.  Enhanced pharmacovigilance (PV) was performed for four weeks following the first induction course. Midostaurin was also given following second induction (DA 3+8 without GO) and 2 courses of HDAC consolidation and as maintenance for 12 cycles in non-transplanted patients. From November 2020 to November 2021, 77 patients were enrolled into the Midotarg pilot receiving DAGO1m (n=39) or DAGO2m (n=38). 59 had a FLT3 ITD and 22 a FLT3-TKD (and 4 had both). 59 patients have completed course 1 and are evaluable. RT-qPCR MRD monitoring for patients with an NPM1 mutation (n=48) was performed following each cycle of chemotherapy. A descriptive comparison is presented here of toxicity and MRD kinetics with FLT3 mutated patients receiving DAGO1 or DAGO2 without Midostaurin in the same trial.  

Results
Treatment compliance in course 1 was 88% for DAGO1m and 100% for DAGO2m. One patient did not receive any Midostaurin because of colitis during induction. Dose interruption for QTc prolongation occurred in 1 patient. A total of 17 SAEs (CTC grade 3 or greater) were reported (GO1, n=11, GO2 n= 6).  Day 60 mortality was 0%.  No cases of VOD were reported. Blood count recovery was not delayed. Time to neutrophil recovery to 1 x 109/L was 31 and 32 days with DAGO1m and DAGO2m compared to 31 and 32 days in DAGO1 and DAGO2 .. Time to platelet recovery to 100 x 109/L was 28 and 29 days with DAGO1m and DAGO2m respectively compared to 30 days in DAGO1 and DAGO2.  

Complete remission (CR plus CRi) was achieved in 51/59 (88%) evaluable patients who have completed induction with DAGOm. In 44 evaluable patients in remission with NPM1 mutation, 34 (74%) were MRD negative in the peripheral blood after course 2. This compares with 63% in 54 evaluable patients with DAGO only. Bone marrow NPM1 transcript levels after courses 1 to 4 were compared with  FLT3 mutated patients receiving DAGO1 and DAGO2 without Midostaurin (Figure 1) with a higher proportion of patients becoming MRD negative from course 2 onwards and 81% being MRD negative after course 4.

Conclusion
The addition of midostaurin to DAGO using a single or fractionated dose of GO was well tolerated with no evidence of increased toxicity, high response rate and with encouraging clearance of NPM1 mutant transcripts. A randomised study of DAm versus DAGOm in FLT3 mutated AML is planned

Keyword(s): Acute myeloid leukemia, Flt3-ITD, Gemtuzumab ozogamicin

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