Precision Therapy Versus Standard Therapy in AML and MDS in Elderly

Inclusion Criteria: * 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 and therapy-related AML (not if they have received antileukemic/mds treatment)), or * acute leukemias of ambiguous lineage according to WHO 2016 or a diagnosis of myelodysplastic syndrome (MDS) with IPSS-R \> 4.5.1 * Patients 60 years and older. * Patients must NOT be eligible for intensive chemotherapy or allogeneic stem cell therapy (See Chapter 23.3) * WBC ≤ 25 x109/L (prior hydroxyurea allowed for a maximum of 14 days, stopped before start of treatment) * Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values: * WHO performance status 0, 1 or 2 for subjects ≥ 75 years of age OR 0 to 3 for subjects ≥ 60 to 74 years of age. * Life-expectancy above 3 months * Signed Informed Conscent * Male Subjects Only: Male subjects who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice contraception with condom. Male subjects must agree to refrain from sperm donation from initial study drug administration until at least 90 days after the last dose of study drug. Exclusion Criteria: * Acute promyelocytic leukemia. * AML with favourable cytogenetic or genetic changes in patients who are fit for intensive chemotherapy. Favourable genetics are: t(8;21)(q22;q22.1); RUNX1-RUNX1T1; inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11; mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†; Biallelic mutated CEBPA * Patients previously treated for AML or MDS (any antileukemic therapy or MDS treatment including investigational agents). * Patients where it is not possible to get bone-marrow for NGS, i.e., "dry tap". * 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. * Blast crisis of chronic myeloid leukemia. * Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.) * Cardiac dysfunction as defined by: * Unstable angina or * New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue,palpitations, dyspnea, or angina pain or * Unstable cardiac arrhythmias * Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance with the study protocol and follow-up schedule. * Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent. * Patients who do not understand the Written Informed Consent (e.g., language problems) * Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea. * Subject is known to be positive for HIV (HIV testing is not required). * Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required). * AML subjects that has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of venetoclax treatment. * Subject has a malabsorption syndrome or other condition that precludes enteral route of administration. Additional exclusion criteria at the time of randomization * WHO performance status \> 2 for subjects ≥ 75 years of age OR \> 3 for subjects ≥ 60 to 74 years of age. * Progressive disease according to ELN criteria (see chapter 12 Response evaluation) * Initial treatment has made the patient eligible for allogeneic stemcell transplantation * In addition, it will be specific exclusion criteria for the patients receiving targeted therapies related to the Summary of Product Characteristics (SPC) of each drug.