Midostaurin Plus DA and Gemtuzumab Ozogamicin Show High Efficacy, Safety in AML

Findings from the UK National Cancer Research Institute (NCRI) AML19 trial (ISRCTN 78449203) demonstrated that adding the FLT3 inhibitor midostaurin (Rydapt) to a regimen of daunorubicin, cytarabine (DA; CPX351), and gemtuzumab ozogamicin (GO; Mylotarg) yielded favorable safety and efficacy in patients with acute myeloid leukemia (AML).^1,2

The combination therapy, referred to as DAGO+m, yielded a 91% overall response rate and a promising 2-year overall survival (OS) rate of 77%, with no increase in toxicity compared to treatment without midostaurin and a day-60 mortality of 0%.

The addition of midostaurin significantly deepened the molecular response for patients with NPM1 mutations. Patients with co-mutations in NPM1 or with core binding factor AML had high survival rates, with 2-year OS rates of 88% and 100%, respectively. The regimen was also effective and well-tolerated in the 16 patients aged > 60 years, who achieved a 2-year OS of 69%.

A particularly striking finding was the profound impact of midostaurin on clearing molecular minimal residual disease (MRD), a critical factor for preventing relapse. After the second course of therapy, 81% of evaluable patients receiving the triplet therapy plus midostaurin were MRD-negative in peripheral blood, compared with just 68% in the cohort treated with the triplet combination alone. The 2-dose gemtuzumab ozogamicin schedule was more effective at clearing MRD. The rate of peripheral blood MRD negativity after course 2 was 86% for arm 1 vs 75% for arm 2.

A similar benefit was observed in clearing the primary FLT3-ITD mutation, assessed via highly sensitive next-generation sequencing. After 2 cycles, 79% of patients receiving daunorubicin, cytarabine, gemtuzumab ozogamicin plus midostaurin achieved MRD negativity in the bone marrow.

Critically, 100% of patients had an FLT3-ITD variant allele frequency below the clinically significant threshold of 0.01%. In contrast, 17% of patients treated with daunorubicin, cytarabine, and gemtuzumab ozogamicin alone remained MRD positive above this level (P =.017).

The enhanced MRD clearance achieved by the patients in arm 2 is particularly important, as it may reduce the proportion of patients who require an allogeneic stem cell transplant (allo-SCT) in first remission.

Regarding safety, there was no significant difference in hematological or non-hematological toxicity between patients who received midostaurin and patients who contemporaneously received daunorubicin, cytarabine, and gemtuzumab ozogamicin alone. No cases of veno-occlusive disorder were reported.

Further, the addition of midostaurin did not delay the time to neutrophil or platelet recovery compared with daunorubicin, cytarabine, and gemtuzumab ozogamicin alone. Compliance with the oral midostaurin component was high, with 83% of patients receiving all or all but one of their prescribed doses during the first induction course.

Study Overview and Rationale

Activating mutations in the FLT3 gene are present in approximately 1/3 of patients with AML and are associated with suboptimal outcomes due to high rates of relapse. Previous landmark studies incorporating FLT3 inhibitors, such as RATIFY (NCT00651261)³ and QUANTUM-First (NCT02668653)⁴, reported 4-year OS rates of only 51% and 48%, respectively, with relapse being the primary cause of treatment failure.

“It is difficult to compare our results with those reported with for induction chemotherapy with an FLT3 inhibitor but without [gemtuzumab ozogamicin] due to differences in the patient populations enrolled,” Russell et al noted in the study.¹ “Crudely, the 2-year OS of 78% reported here compares favorably with the reported 2-year OS of 62% for [daunorubicin plus cytarabine] plus midostaurin in the RATIFY study (which included more adverse-risk patients but was limited to those aged <60 years) and 55% for [daunorubicin plus cytarabine] plus quizartinib [Vanflyta] in the QUANTUM-First study (which was limited to patients with FLT3-ITD but included older patients).”

This study was designed to address the need for improved treatment strategies by exploring a novel combination. Gemtuzumab ozogamicin has been shown to improve survival in patients with favorable and intermediate-risk cytogenetics. Blasts from FLT3mut AML express high levels of CD33, the molecular target of gemtuzumab ozogamicin, suggesting these patients could derive particular benefit from its inclusion. Despite this, the combination of an FLT3 inhibitor and gemtuzumab ozogamicin with intensive chemotherapy has not been routinely used due to limited data on its safety and efficacy.

Study Design

The NCRI AML19 trial was amended to evaluate this combination in a substudy named "Midotarg." The study enrolled younger adults (median age, 51 years) with newly diagnosed AML fit for intensive chemotherapy. A notable portion (21%) of patients were over 60 years of age.

Between November 2020 and November 2021, 195 patients were randomized to receive induction chemotherapy with daunorubicin and cytarabine plus either 1 dose of gemtuzumab ozogamicin (DAGO1) or 2 fractionated doses of gemtuzumab ozogamicin (DAGO2). Of these, 77 patients with centrally confirmed FLT3 mutations consented to the Midotarg substudy and received the triplet therapy (39 patients in arm 1 and 38 patients in arm 2).

Patients received midostaurin for 14 days following each chemotherapy course and subsequently as maintenance for 1 year unless they proceeded to allo-SCT.

Next Steps in Research

As next steps, the investigators plan to perform a randomized comparison of the treatment combination with 2 fractionated doses of gemtuzumab ozogamicin against other intensive regimens in the forthcoming OPTIMISE-FLT3 trial (ISRCTN 34016918).⁵

REFERENCES

1.Russell N, Othman J, Cumming O et al. Safety and efficacy of combining midostaurin and gemtuzumab ozogamicin with induction chemotherapy in FLT3-mutated AML. Published December 12, 2025. Accessed January 5, 2026. Blood Adv (2025) 9 (24): 6455–6466.doi: 10.1182/bloodadvances.2025017244.

2.Adults with acute myeloid leukemia or high-risk myelodysplastic syndrome (AML19). ISRCTN.com. Updated January 10, 2025. Accessed January 5, 2026. https://www.isrctn.com/ISRCTN78449203

3.Daunorubicin, cytarabine, and midostaurin in treating patients with newly diagnosed acute myeloid leukemia. ClinicalTrials.gov. Updated August 18, 2021. Accessed January 5, 2026. https://clinicaltrials.gov/study/NCT00651261

4.Quizartinib with standard of care chemotherapy and as continuation therapy in patients with newly diagnosed FLT3-ITD (+) acute myeloid leukemia (AML) (QuANTUM-First). ClinicalTrials.gov. Updated August 6, 2024. Accessed January 5, 2026. https://clinicaltrials.gov/study/NCT02668653

5.Optimising therapy in FLT3-mutated acute myeloid leukemia. ISRCTN.com. Updated May 16, 2025. Accessed January 5, 2026. https://www.isrctn.com/ISRCTN34016918