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

Exclusion Criteria27

• 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 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