This trial aims to find the MTD of Venetoclax when added to Fludarabin, Amsacrine and Ara-C + Treosulfan and to evaluate whether the addition of Venetoclax to sequential conditioning with FLAMSA + Treosulfan is safe for allogeneic blood stem cell transplantation in patients with high-risk MDS, CMML or sAML (FLAMSAClax)
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 according to WHO classification (revised version 2016) with a marrow blast count >5% and/or 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) any time between diagnosis and inclusion
Untreated except for oral Hydroxyurea 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
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
Single group
Venetoclax
DrugStudy treatment consists of the conditioning therapy including 6 or 8 days of Venetoclax treatment.
Amsacrine
DrugAmsacrine is part of the conditioning therapy and is administered on day -10 to -7 before allogeneic blood stem cell transplantation
Ara-C
DrugAra-C is part of the conditioning therapy and is administered on day -10 to -7 before allogeneic blood stem cell transplantation
Tacrolimus
DrugTacrolimus is used for prophylaxis of acute and chronic graft-versus-host-disease according to institutional standards.
Mycophenolate Mofetil
DrugMycophenolate Mofetil is used for prophylaxis of acute and chronic graft-versus-host-disease according to institutional standards.
The primary target variable is safety, defined as the maximal organ toxicity to each organ system according to CTC criteria as well as the number of AEs of grade III or greater within the first 30 days (± 3) after transplantation
maximal organ toxicity to each organ system according to CTC criteria as well as the number of AEs of grade III or greater within the first 30 days (± 3) after transplantation
Safety, defined as the maximal organ toxicity to each organ system according to CTC criteria as well as the number of AEs of grade III or greater until day +100 (± 7) after transplantation
maximal organ toxicity to each organ system according to CTC criteria as well as the number of AEs of grade III or greater until day +100 (± 7) after transplantation
Graft failure at day +30 (± 3) after transplantation
Number of patients with graft failure (no donor chimerism at day +30 (± 3) after transplantation)
Incidence of aGvHD during the first 2 years after transplantation
Incidence of aGvHD during the first 2 years after transplantation
Course of aGvHD during the first 2 years after transplantation
Course of aGvHD during the first 2 years after transplantation (response/no response to steroids)
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Heinrich-Heine University, Duesseldorf
Lead sponsor
Koordinierungszentrum für Klinische Studien - Duesseldorf
Collaborator
