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

Ki vehet részt

• 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)

Ki nem vehet részt

• 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)
• 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
• 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
• 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)