Tolerability and Efficacy of Midostaurin to 10-day Decitabine in Unfit Adult AML and High Risk MDS Patients

Prior treatment

• Diagnosis of any previous or concomitant malignancy is an exclusion criterion:
• except when the patient completed successfully treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to randomization. OR
• Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period ( ≤ 5 days) with Hydroxyurea is allowed
• Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.)
• History of stroke or intracranial hemorrhage within 6 months prior to randomization.
• Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study.

Other illness

• Patient has a history of human immunodeficiency virus or active infection with Hepatitis C or B.
• Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance.
• Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Lab values

• Cardiac dysfunction as defined by:
  • Myocardial infarction within the last 3 months of study entry, or
  • Reduced left ventricular function with an ejection fraction \< 40% as measured by MUGA scan or echocardiogram or
  • Unstable angina or
  • New York Heart Association grade IV congestive heart failure or
  • Unstable cardiac arrhythmias.

Other

• Acute promyelocytic leukemia.
• Acute leukemia's of ambiguous lineage according to WHO 2016
• Patient has symptomatic central nervous system (CNS) leukemia (NO routinely lumbar puncture required to investigate CNS involvement)
• Blast crisis of chronic myeloid leukemia.
• except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix
• Patients known to be pregnant

• Patients with:
  • a diagnosis of AML and related precursor neoplasms according to WHO 2016 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or
  • a diagnosis of myelodysplastic syndrome with excess of blasts (MDS) and International Prognostic Score System (IPSS) \> 4.5
• Patients 18 years and older.
• Patients NOT eligible for standard chemotherapy, defined as hematopoietic cell transplantation comorbidity index (HCT-CI) ≥ 3.
  • or Patients NOT eligible for standard chemotherapy for other reasons (wish of patient).
• White blood cell (WBC) ≤ 30 x109/L (prior hydroxyurea allowed for a maximum of 5 days, stop 2 days before start decitabine treatment)
• Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
  • Serum creatinine ≤ 221.7 µmol/L (≤ 2.5 mg/dL ), unless considered AML-related
  • Serum bilirubin ≤ 2.5 x upper limit of normal (ULN), unless considered AML-related or due to Gilbert's syndrome
  • Alanine transaminase (ALT) ≤ 2.5 x ULN, unless considered AML-related
• WHO performance status 0, 1 or 2.
• Patient is willing and able to use adequate contraception during and until 5 months after the last protocol treatment.
• Written informed consent.
• Patient is capable of giving informed consent.