Acute myeloid leukemia (AML) is a clonal malignant disorder which is characterized by the expansion of leukemic blasts in the bone marrow and the peripheral blood, which goes along with a suppression of normal hematopoiesis including granulopoiesis, erythropoiesis and thrombocytopoiesis. The prognosis is largely determined by cytogenetic and molecular risk factors, age, performance status and antecedent myelodysplastic syndrome (MDS). With the exception of old and frail patients, most AML patients are eligible for intensive chemotherapy, which is given in curative intent consisting of induction and consolidation therapy. However, despite intensive therapy, the long-term outcome of AML patients remains poor, with less than 30% of patients achieving long lasting remission and even cure. This poor outcome is largely due to refractoriness to induction chemotherapy as well as relapses during and after completion of intensive induction and consolidation therapy. Regarding refractoriness, about 20-30% of AML patients under the age of 60 years and about 50% of older patients fail to attain complete remission (CR) following cytarabine plus anthracycline based standard induction therapy. In addition, patients having achieved CR are at a high risk of relapse, particularly within the first two years after completion of chemotherapy. Allogeneic hematopoietic cell transplantation (allo-HCT) is currently the only treatment strategy to offer the prospect of cure in relapsed/refractory (r/r)-AML; but outcome after allo-HCT is largely determined by the remission state before allo-HCT. With the aim to induce a CR before allo-HCT, salvage chemotherapy regimens are administered in r/r-AML. Typically, these salvage regimens are based on high dose cytarabine (HiDAC), which is frequently combined with either mitoxantrone (HAM regimen) or fludarabine plus idarubicin (idaFLA regimen). However, there is still no commonly accepted standard salvage regimen and overall CR rates remain low with less than one third of the patients achieving a CR. Apart from already known clinical unfavorable prognostic parameters in relapsed AML such as short first CR duration, older age and previous allo-HCT, FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory AML. Recently midostaurin has been approved by the FDA and EMA for the treatment of newly diagnosed AML with activating FLT3 mutations. But still roughly one quarter of patients, who received midostaurin, was refractory to induction therapy and relapse rate at 2 years excited 40%. Thus, new treatment options are urgently needed, particularly in r/r-AML with FLT3-ITD.

The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is very specific for FLT3, has a high capacity for sustained FLT3 inhibition and an acceptable toxicity profile. Furthermore, single agent quizartinib doubled the response rate as compared to standard of care in a randomized study in r/r-AML. Although survival was also improved in this study the difference was only marginal.

In this protocol we evaluate the efficacy of quizartinib in combination with HAM (high-dose cytarabine, mitoxantrone) as compared to historical controls based on the matched threshold crossing approach followed by randomized prophylactic versus MRD-triggered continuation therapy with quizartinib including consolidation (chemotherapy as well as allo-HCT) and maintenance.