Venetoclax- Augmented Treosulfan-Based Reduced Intensity Conditioning Before Allogeneic Stem Cell Transplantation

Inclusion Criteria

• •1. Age between 18 and 75 years at the time of signing the Informed Consent
• •2. Patient is fluent in German
• •3. Signed written Informed Consent with the cognitive ability to understand all consequences of trial participation and to comply with all trial related procedures
• •4. Diagnosis of AML,MDS/AML (according to ICC 20226) or HRMDS (IPSS-R7 \>3.5 or IPSS-M8 \>0; according to ICC 20226 and IWG 20232)
• •5. Myeloid neoplasm (AML, MDS/AML or HR-MDS according to ICC 20226) under control\* at time of screening, defined as one of the following:
• •5.1. AML (ICC 20226):
• •• Scheduled for alloHCT after prior Remission
• •Induction ± Consolidation:
• •* Achievement of at least MLFS\*\* (according to ELN 20221 criteria) after up to two cycles of intensive, anthracycline-based induction chemotherapy OR
• •* Achievement of at least MLFS\*\* (according to ELN 20221 criteria) after intensive, anthracycline-based induction chemotherapy folllowed by up to three cycles of cytostatic consolidation therapy OR
• •* Achievement of at least MLFS\*\* (according to ELN 20221) after less intensive, HMA-based treatment (up to six cycles) OR
• •* Achievement of at least MLFS\*\* (according to ELN 20221) after a combination of intensive and less intensive treatments (up to six cycles in total) 5.2. MDS/AML (ICC 20226):• Scheduled for alloHCT after prior Remission
• •Induction ± Consolidation:
• •* Achievement of at least MLFS\*\* (according to ELN 20221 criteria) after up to two cycles of intensive, anthracycline-based induction chemotherapy OR
• •* Achievement of at least MLFS\*\* (according to ELN 20221 criteria), after intensive, anthracycline-based induction chemotherapy folllowed by up to three cycles of cytostatic consolidation therapy OR
• •* Achievement of at least MLFS\*\* (according to ELN 20221 criteria) after less intensive, HMA-based treatment (up to six cycles and including HMA monotherapy) OR
• •* Achievement of at least MLFS (according to ELN 20221 criteria) after a combination of intensive and less intensive treatments (up to six cycles in total)• Scheduled for upfront alloHCT:
• •* ≤19% bone marrow blastsAND• ≤19% peripheral blood blastsAND• ≤15.000/µl peripheral blood Leukocytes 5.3. HR- MDS (ICC 20226, IWG 20232)
• •* Scheduled for alloHCT after prior therapy:
• •* up to six cycles of a less intensive HMAbased treatment or HMA monotherapy AND
• •* ≤9% bone marrow blastsAND• ≤9% peripheral blood blasts• Scheduled for upfront alloHCT:
• •* ≤9% bone marrow blasts AND
• •* ≤9% peripheral blood blasts \*The disease is considered clinically controlled, when it is either aggressive but has proven responsive to cytostatic chemotherapy (e.g. AML with achievement of at least MLFS) or slowly progressive ( e.g. suitable for upfront alloHCT in cases of MDS/AML) or is both slowly progressive and responsive to therapy
• •6. Eligiblity for alloHCT according to a board of experienced haematologists
• •7. Karnofsky Performance Index ≥60%
• •8. Planned alloHCT with Peripheral Blood Stem Cells (PBSC)
• •9. Infusion of allogeneic stem cells schedulded between day 14 and day 28 after Screening
• •10. Availability of a suitable donor, defind as one of the following:
• •10.1. HLA-identical sibling (MSD)OR 10.2. HLA-compatible (9/10 antigens matched for HLA-A, -B, -C, -DRB1, and -DQB1) unrelated donor (MUD) with completed confirmatory typing.
• •OR 10.3. Two unrelated donors with \>90% probability of a 9/10 match for HLA- A, -B, -C, -DRB1, and -DRQB1, according to OptiMatch list (MUD)
• •11. Documented diffusion lung capacity for carbon monoxide (DLCO) \>40% (adjusted for hemoglobin, if available) and FEV1/FVC \>50%
• •12. Left ventricular ejection fraction (LVEF) ≥40%
• •13. GFR (CKD-EPI) ≥ 30 ml/min/1,73 m2
• •14. Bilirubin ≤3x ULN and AST ≤5x ULN
• •15. Thoracic imaging (either X-ray or computed tomography (CT)) without evidence of active infection or second malignancy
• •16. Subject (male or female) is willing to use highly effective methods during treatment and for 6 months (male or female) after the end of treatment (adequate: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner1, sexual abstinence2). Female participants using homonal contraceptives should use a barrier method as well.1 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success2 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
• •17. Absence of pregnancy confirmed by a highly sensitive pregnancy test not older than 3 days at time of screening (only FCBP).
• •18. Subject agrees not to share medication.