Venetoclax in Addition to Sequential Conditioning With Fludarabine / Amsacrine / Ara-C (FLAMSA) + Treosulfan for Allogeneic Blood Stem Cell Transplantation in Patients With MDS, CMML or sAML

Inclusion Criteria: Subjects must voluntarily sign and date an informed consent, approved by an independent ethics committee (IEC), prior to the initiation of any study-specific procedures MDS, CMML or sAML (marrow blast count <30%) according to WHO classification (revised version 2016) with a marrow blast count >5% and high-risk genetic features (e.g. bad risk karyotype according to the IPSS-R / ELN classification or presence of unfavorable somatic mutations (e.g. TP53, RUNX1, IDH1, IDH2, KMT2A, DEK-NUP214 or RAS pathway mutations including NRAS, KRAS, PTPN11, CBL, NF1, RIT1 or KIT), falling into the "high" or "very high" risk category of the IPSS-R or IPSS-M), or a marrow blast count >20% any time between diagnosis and inclusion Untreated except for oral Hydroxyurea <60 days or a maximum of 2 courses of treatment with Azacytidine or Decitabine alone or in combination with Venetoclax Identification of a well matched (10 out of 10, A, B, C, DR, DQ) donor either related or unrelated Age ≥18 HCT-CI < 3 (except former treatment of a solid tumor) ECOG performance status ≤ 2 at study entry no active, uncontrolled infection at inclusion able to adhere to the study visit schedule and other protocol requirements Female of childbearing potential (FCBP) must: Understand that based on embryo-foetal toxicity studies in animals venetoclax may harm the foetus when administered to pregnant woman Agree to have a medically supervised pregnancy test at Screening and within 72 hours prior treatment start Avoid becoming pregnant while receiving Venetoclax Use effective contraception during treatment with Venetoclax and for at least 1 months after the last dose, Understand that is currently unknown whether venetoclax may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method Notify her study doctor immediately if there is a risk of pregnancy Males must: agree to use condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through at least 30 days after the last dose of study drug. Agree to notify the investigator immediately, if pregnancy or a positive pregnancy test occurs in his partner during study participation Exclusion Criteria: sAML with known FLT3 mutation (ITD or TKD) Marrow blast count >30% at the time of screening Peripheral white blood count >20,000 per microliter despite treatment with Hydroxyurea previous cytotoxic therapy exceeding oral Hydroxyurea >60 days or >2 courses of treatment with Azacytidine, Decitabine or low dose Ara-C alone or in combination with Venetoclax previous allogeneic blood stem cell transplantation symptomatic CNS-involvement with MDS; CMML or sAML any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form pregnant or lactating females Refusal to use safe contraceptive methods during the study period Cardiac history of CHF (>NYHA 2) requiring treatment or Ejection Fraction < 40% or chronic stable angina Forced expiratory volume in 1 second (FEV1) <50% of expected corrected for hemoglobin and/or volume Diffusing capacity of the lungs for carbon monoxide (DLCO) <50% of expected corrected for hemoglobin and/or volume any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study: Impaired renal function (GFR < 45 ml/min) Impaired hepatic function, as follows Aspartate aminotransferase (AST) ≥3 x ULN or Alanine aminotransferase (ALT) ≥3 x ULN or Total bilirubin ≥1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) or Alkaline Phosphatase ≥3 x ULN known hypersensitivity to Venetoclax, Fludarabine, Amsacrine, Ara-C or Treosulfan concurrent use of other anti-cancer agents or treatments except Hydroxyurea and a maximum of 2 courses of Azacytidine or Decitabine positive for HIV or replicating infectious hepatitis, type A, B, C or E prior history of malignancy other than MDS, CMML, sAML (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 2 years participation in another study with ongoing use of unlicensed investigational product from 28 days or <5 half-lifes of the investigational product before study enrollment No planned or executed/given treatment with any of the following within 7 days prior to the first dose of study drug (or ramp-up prophase): Steroid therapy for anti-neoplastic intent moderate or strong cytochrome P450 3A (CYP3A) inhibitors moderate or strong CYP3A inducers Refusal to avoid consumption of any of the following within 3 days prior to the first dose of study drug: grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), star fruit. Persons with any kind of dependency on the investigator or employed by the sponsor or investigator Persons held in an institution by legal or official order