Overview
The treatment of older unfit patients with acute myeloid leukemia (AML) is challenging. The hypomethylating agents (HMA) azacitidine and decitabine have relatively mild side effects and have proven to be feasible for the treatment of older patients and patients with co-morbidities. Currently, venetoclax added to an HMA agent is the new standard of treatment. Since this new standard comes with a substantial societal financial burden, there is a rational to optimize the venetoclax dosing schedule. The CYP3A4 inhibitor cobicistat (COBI) can be used to increase venetoclax exposure, thereby allowing to reduce the dose of venetoclax and thus costs substantially.
Eligibility
Inclusion Criteria:
In order to be eligible to participate in this study, a patient must meet all of the
following criteria:
- Patients with: a diagnosis of AML and related precursor neoplasms according to
ICC-2022 classification (excluding acute promyelocytic leukaemia) (appendix A).
Patients may have had previous treatment with erythropoiesis stimulating agents (ESA)
for an antecedent phase of MDS. ESAs must be stopped at least two weeks before
registration.
- Patients 18 years and older who are considered not fit for intensive chemotherapy or
who decline the option of intensive chemotherapy.
- WHO performance status 0, 1 or 2 (appendix E).
- Adequate renal and hepatic functions unless clearly disease related as indicated by
the following laboratory values:
- Adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min;
calculated by the Cockcroft Gault formula or measured by 24 hours urine
collection.
- Serum bilirubin ≤ 3 x upper limit of normal (ULN), unless considered AML-related
or due to Gilbert's syndrome.
- Alanine transaminase (ALT) ≤ 3 x ULN, unless considered AML-related.
- Male subjects who are sexually active, must agree, from Study Day 1 until at least 90
days after the last dose of study drug, to practice the protocol specified
contraception. Male subjects must agree to refrain from sperm donation from initial
study drug administration through at least 90 days after the last dose of study drug.
- Female subjects must be either postmenopausal defined as: Age >55 years with no menses
for ≥12 months, without an alternative medical cause. OR willing and able to use
adequate contraception during and until 180 days after the last protocol treatment.
- Written informed consent.
- Patient is capable of giving informed consent.
- Patient agrees not to participate in another interventional study while on treatment
without approval of the (co-) Principal Investigator.
Exclusion Criteria:
A patient who meets any of the following criteria cannot be included in this study:
- Acute promyelocytic leukemia.
- Myelodysplastic syndrome (MDS).
- Patients previously treated for AML or MDS (any anti-leukemic therapy including
investigational agents; excluding: 1) erythropoiesis stimulating agents (ESAs); 2)
hydroxyurea (hydroxyurea is allowed for the control of peripheral leukemic blasts in
patients with leukocytosis).
- Diagnosis of any previous or concomitant malignancy is an exclusion criterion:
- except when the patient successfully completed treatment (chemotherapy and/or
surgery and/or radiotherapy) with curative intent for this malignancy at least 24
months prior to registration;
- except for basal and squamous cell carcinoma of the skin or in situ carcinoma of
the cervix.
- Blast crisis of chronic myeloid leukemia.
- Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes,
infection, hypertension, pulmonary disease etc.).
- Cardiac dysfunction as defined by:
- Myocardial infarction within the last 3 months of study entry, or
- Reduced left ventricular function with an ejection fraction < 40% as measured by
MUGA scan or echocardiogram, or
- Unstable angina or New York Heart Association (NYHA) grade IV congestive heart
failure (see Appendix G), or
- Unstable cardiac arrhythmias.
- History of stroke or intracranial haemorrhage within 6 months prior to registration.
- Symptomatic central nervous system (CNS) leukemia (NO routinely lumbar puncture
required to investigate CNS involvement).
- History of non-compliance to medical regimens or considered unreliable with respect to
compliance.
- Senile dementia, mental impairment or any other psychiatric disorder that prohibits
the patient from understanding and giving informed consent.
- Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than
hydroxyurea.
- Any psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule.
- Unreplaceable use of strong inhibitors or inducers of CYP3A or CYP3A/p-GP substrates
with a narrow therapeutic window (e.g. cobicistat or ritonavir for HIV treatment).
Please check with Appendix I.
- Intolerability, contra-indication or allergy to one of the study drugs.