preheader BJH 1

Gemtuzumab-based induction chemotherapy combined with midostaurin for FLT3-mutated AML

Thus far, the combination of gemtuzumab ozogamicin (GO)-based induction with midostaurin has not been formally assessed in patients with FLT3-mutated acute myeloid leukaemia. Results from the NCRI AML19 Midotarg pilot trial now demonstrated that the addition of midostaurin to daunorubicin, cytarabine and GO was well tolerated with no evidence of increased toxicity, a high response rate and encouraging clearance of NPM1 mutant transcripts.

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 acute myeloid leukaemia (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. Therefore, the Midotarg pilot study aimed to assess the safety and feasibility of combining midostaurin with a single or fractionated schedule of gemtuzumab incorporated into intensive chemotherapy induction with daunorubicin and cytarabine (DA 3+10).

Study design

The NCRI AML19 trial randomised de novo AML patients to receive DA 3+10 (daunorubicin 60 mg/m2 on days 1,3,5 plus cytarabine 100 mg/m2 bd on days 1-10) plus a single dose of GO 3 mg/m2 on day 1 (DAGO1) or 2 doses (3 mg/m2, maximum 5 mg) on days 1 and 4 (DAGO2) plus 50 mg bd of midostaurin (m) for 14 days following completion of each course and maintenance. GO was not given beyond course 1. Eligibility included age 18-60 years with a FLT3-internal tandem duplication (ITD) or FLT3-tyrosine kinase domain (TKD) mutation. Enhanced pharmacovigilance 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.

RT-qPCR minimal residual disease (MRD) monitoring for patients with an NPM1 mutation (N= 48) was performed following each cycle of chemotherapy. A descriptive comparison of toxicity and MRD kinetics with FLT3-mutated patients receiving DAGO1 or DAGO2 without midostaurin in the same trial is presented here.


From November 2020 to November 2021, 185 patients were screened and 77 were enrolled into the Midotarg pilot, receiving DAGO1m (N= 39) or DAGO2m (N= 38). Of them, 59 had a FLT3-ITD and 22 a FLT3-TKD mutation (4 had both). In total, 59 patients have completed course 1 and are evaluable. Treatment compliance was 87% for DAGO1m and 100% for DAGO2m. There were no cases of VOD while QTc prolongation was only a minor problem with one case each in the DAGO1m and DAGO2m arms. Day 60 mortality was 0%. Blood count recovery was not delayed compared to patients receiving DAGO without midostaurin and the data monitoring committee review after 25 and 50 patients raised no non-haematological toxicity concerns. Complete remission (CR plus CRi) was achieved in 51 out of 59 (88%) evaluable patients who had completed course 1 induction with DAGOm. CR/Cri was 83% for DAGO1m and 93% for DAGO2m. This compared favourably with 84.5% (DAGO1) and 80.7% (DAGO2) in 120 FLT3-positive patients in AML19v1 who received DAGO1 (N= 61) or DAGO2 (N= 59) without midostaurin.

In 44 evaluable patients in remission with NPM1 mutation, 34 (74%) were MRD-negative in the peripheral blood after course 2. This compares favourable 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, with a higher proportion of patients becoming MRD-negative from course 2 onwards and 81% being MRD-negative after course 4.


The addition of midostaurin to DAGO using a single (GO1) or fractionated dose (GO2) of gemtuzumab ozogamicin was well tolerated in FLT3-positive AML, with no evidence of increased toxicity or reduced compliance. There was a high response rate post course 1 and with encouraging evidence of clearance of NPM1 mutant transcripts and reduction in the number of high-risk patients post course 2. As it is still too early to assess the impact on survival, longer-term survival analysis will take place later this year. A randomised study of DAm versus DAGOm in FLT3-mutated AML is planned.


Russell N, et al. Gemtuzumab-based induction chemotherapy combined with midostaurin for FLT3 mutated AML. Results from the NCRI AML19 “midotarg” pilot trial. Presented at EHA 2022; Abstract S126.

Speaker Nigel Russell

Nigel Russell

Nigel Russell, MD, PhD, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom


See: Keyslides


Back to Top