Azacitidine in Combination With Low Dose Intensity Venetoclax in Patients With AML Incl. Explorative AML Profiling

Prior treatment

• Prior venetoclax treatment for myeloid malignancy.
• Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment).

Other illness

• HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection that is not controlled with antiviral medication with the definition hereof at the discretion of the investigator.
• Cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in palpitations, fatigue, dyspnea, or anginal pain.
• Evidence of clinically significant condition(s), which at the investigator's discretion would adversely affect the patient's participation in this study (including but not limited to):
  • Chronic respiratory disease that requires continuous oxygen use.
  • Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal).
  • Malabsorption syndrome or other condition that precludes enteral route of administration.
  • Uncontrolled GVHD.
• Previous malignancies with the exception of previous malignancy treated successfully with curative intent and indolent/smoldering malignancies (defined at the investigator's discretion).
• Known hypersensitivity to venetoclax or azacitidine or excipients of any of the drugs.

Age

• Fertile men or women of childbearing potential unless:
  • Surgically sterile or ≥ 2 years after the onset of menopause.
  • Willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index \<1) and one additional effective (barrier) method during study treatment and for 3 months after the end of study treatment.

Other

• Acute promyelocytic leukemia (APL).
• Patients with 4th or higher AML relapse.
• Leukemic cell content (blast percentage) in bone marrow/peripheral blood \< 10 %.
• ECOG \>3.
• AML patients with CNS involvement (note: cerebrospinal fluid or radiological investigations are not required without clinical suspicion).

• Written informed consent.
• Patients who present with one of the following (except acute promyelocytic leukemia).
  • De novo or secondary AML unfit for standard induction therapy
  • Relapsed/refractory AML after at least 1 line of prior therapies
• Written informed consent to participate in an exploratory research protocol including bio-banking, comprehensive AML profiling (genomics, transcriptomics, proteomics, etc.) and ex vivo drug sensitivity testing to assess venetoclax and other drug sensitivities.
  • All patients are treated with azacitidine+venetoclax irrespective of the ex vivo screening results.
• ECOG Performance status ≤ 2 for patients ≥ 75 years of age OR ≤ 3 for patients ≥ 18 to 74 years of age.
• Leukocyte count \< 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion
• Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.
• Adequate liver function as demonstrated by
  • alanine aminotransferase (ALT) ≤ 4.0 × ULN.
  • bilirubin ≤ 1.5 × ULN.
• Specific inclusion criteria for elderly/unfit AML patients:
  • ≥ 70 years of age OR
  • ≥ 18 to 69 years of age and ineligible for intensive chemotherapy meeting at least one of the following criteria:
  • Clinically significant comorbidities, as reflected by at least 1 of the following criteria:
  • Left ventricular ejection fraction (LVEF) \< 50%.
  • Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected.
  • Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected.
  • Chronic stable angina or congestive heart failure controlled with medication.
  • Alanine aminotransferase (ALT) 3.0-4.0 × ULN.
  • Other contraindication(s) to anthracycline therapy (must be documented).
  • Adverse risk genetics (ELN criteria) associated with poor outcome with standard chemotherapy.
  • Patient declines intensive chemotherapy.
  • Secondary AML after previous disease modifying treatment (i.e. HMA/induction chemotherapy and/or allogeneic stem cell transplantation) of clonal myeloid diseases such as MDS, MDS/MPN, or MPN.
• Specific inclusion criteria for relapsed AML patients:
  • ≥ 55 years of age with non-CBF AML relapse OR
  • ≥ 18 of age and meeting at least one of the following criteria:
  • Not candidate for intensive chemotherapy (see criterion 8).
  • Relapse after chemotherapy, or monotherapy with HMA, or allogeneic stem cell transplantation. (note: patients with 4th or higher relapse are excluded).
  • Patient declines intensive chemotherapy.
• Specific inclusion criteria for refractory AML patients:
  • Patients who fail to achieve a complete or partial remission after previous monotherapy with HMA or induction chemotherapy (at least 1 cycle of chemotherapy containing cytarabine or clofarabine, in combination with a topoisomerase II inhibitor (e.g. anthracycline or mitoxantrone).