Addition of Hydroxyurea to Fludarabine, Cytarabine, Idarubicin and Venetoclax Salvage Therapy for Adults With Relapsed or Refractory Acute Myeloid Leukemia

Inclusion criteria

• A diagnosis of either:

• Refractory AML defined as having > 10% bone marrow blasts after induction with one cycle of intensive chemotherapy or no CR after two cycles of chemotherapy.
• Relapsed disease (including extramedullary disease) according to the 2022 ELN criteria (see appendix A).
• MRD relapse defined as evidence of measurable (minimal) residual disease (MRD) at a level of ≥5%, as determined by either molecular assays or multiparameter flow cytometry.
• Age 18 years or older.
• ECOG Performance Status ≤ 2.
• Adequate renal and hepatic functions as indicated by the following laboratory values:

• Creatinine clearance ≥ 30 mL/min calculated by the Cockcroft Gault formula.
• Serum bilirubin ≤ 3 x upper limit of normal (ULN), unless due to Gilbert's syndrome.
• Alanine aminotransferase (ALAT) ≤ 5 x ULN.
• Considered fit for intensive chemotherapy.
• Male patients must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid fathering a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control.
• Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
• Female patients of nonchildbearing potential must be postmenopausal (defined as at least 1 year without any menses), documented surgically sterile prior to screening.
• Female patients of childbearing potential must agree to avoid pregnancy during the study and for 6 months after the final study drug administration and have a negative urine or serum pregnancy test at screening, and if heterosexually active, agree to consistently apply one highly effective method of birth control in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration.
• The subject has given their written consent to participate in the trial.
• Patient is capable of giving informed consent.

Exclusion criteria

• Acute promyelocytic leukemia.
• WBC ≥30; pretreatment with HU to reduce the level of WBC <30 is allowed in part B/phase II of the trial.
• TP53 double hit mutation / biallelic TP53 inactivation.
• CNS leukemia.
• Relapse within 3 months from the date of allo-HCT.
• Uncontrolled infection.
• ECOG Performance Status > 2.
• Major organ failure precluding administration of planned chemotherapy
• Cardiac dysfunction as defined by:

• Myocardial infarction within the last 3 months of study entry, or
• Reduced left ventricular function with an ejection fraction < 50% as measured by echocardiogram (will only be performed when clinically suspected) or
• Unstable angina or
• New York Heart Association (NYHA) grade III or IV congestive heart failure (see appendix C) or
• Severe cardiac arrhythmias
• Age 75 years or older.
• Known intolerance to any of the chemotherapeutic drugs in the protocol.
• Positive pregnancy test.
• Lactating female or female of childbearing potential not using adequate contraception.
• Known inherited bone marrow failure syndromes (e.g., Fanconi anemia, Dyskeratosis congenita and related telomeropathies (e.g., TERT, TERC, DKC1 mutations).
• Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance.