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 2016classification (excluding acute promyelocytic leukemia) including secondary AML (afteran antecedent hematological disease and therapy-related AML (not if they have receivedantileukemic/mds treatment)), or
• acute leukemias of ambiguous lineage according to WHO 2016 or a diagnosis ofmyelodysplastic syndrome (MDS) with IPSS-R > 4.5.1
• Patients 60 years and older.
• Patients must NOT be eligible for intensive chemotherapy or allogeneic stem celltherapy (See Chapter 23.3)
• WBC ≤ 25 x109/L (prior hydroxyurea allowed for a maximum of 14 days, stopped beforestart of treatment)
• Adequate renal and hepatic functions unless clearly disease related as indicated bythe 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 practicecontraception with condom. Male subjects must agree to refrain from sperm donationfrom initial study drug administration until at least 90 days after the last dose ofstudy drug.

Exclusion Criteria:

• Acute promyelocytic leukemia.
• AML with favourable cytogenetic or genetic changes in patients who are fit forintensive 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 orwith FLT3-ITDlow†; Biallelic mutated CEBPA
• Patients previously treated for AML or MDS (any antileukemic therapy or MDS treatmentincluding 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: exceptwhen the patient completed successfully treatment (chemotherapy and/or surgery and/orradiotherapy) with curative intent for this malignancy at least 6 months prior torandomization.
• 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 inwhich patients are comfortable at rest but ordinary physical activity results infatigue,palpitations, dyspnea, or angina pain or
• Unstable cardiac arrhythmias
• Patients with a history of non-compliance to medical regimens or who are consideredunreliable with respect to compliance with the study protocol and follow-up schedule.
• Patients who have senile dementia, mental impairment or any other psychiatric disorderthat 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 thanhydroxyurea.
• 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 ofthose with an undetectable viral load within 3 months. (Hepatitis B or C testing isnot required).
• AML subjects that has received strong and/or moderate CYP3A inducers within 7 daysprior to the initiation of venetoclax treatment.
• Subject has a malabsorption syndrome or other condition that precludes enteral routeof 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 stemcelltransplantation
• In addition, it will be specific exclusion criteria for the patients receivingtargeted therapies related to the Summary of Product Characteristics (SPC) of eachdrug.