Predicting response to alvocidib by mitochondrial profiling
Inventors
Warner, Steven L. • Bearss, David J.
Assignees
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Publication Number
US-10624880-B2
Publication Date
2020-04-21
Expiration Date
Abstract
The present disclosure provides diagnostic methods useful for predicting a patient's response to alvocidib and guiding a physician decision to administer alvocidib to the patient.
Core Innovation
The disclosure relates to diagnostic and response-prediction methods for treating acute myeloid leukemia (AML) that is dependent on MCL-1 by using mitochondrial BH3 profiling of bone marrow-derived cancer cells. The methods determine an MCL-1 priming level by subjecting bone marrow cells to a BH3 mimetic that is selective for MCL-1 and determining a corresponding mitochondrial polarization or mitochondrial depolarization readout associated with MCL-1 priming.
A treatment decision is made based on the measured MCL-1 priming level, including administering alvocidib, cytarabine, and mitoxantrone to a mammal when the bone marrow cells have MCL-1 priming of at least 15%. The disclosure also includes dependent refinements with threshold levels at least 20%, 25%, 30%, and 35%, and clinical contexts such as refractory and/or relapsed/refractory AML.
The disclosure frames the problem as predicting and improving response in AML in which dependence on MCL-1 is relevant, including differences between bone marrow and peripheral blood measurements. The patient cohort analysis is described as showing an association between bone marrow NOXA priming and clinical outcomes such as complete remission, with improved predictive performance compared with peripheral blood or single-peptide metrics, and it includes an algorithmic selection between regimens using bone marrow NOXA priming and peripheral blood bone marrow/peripheral blood BIM 0.1.
Claims Coverage
The partial content provides two independent claims (clm-00001 and clm-00009). Both claims center on treating MCL-1-dependent AML using a bone marrow MCL-1 priming measurement with an MCL-1-selective BH3 mimetic and mitochondrial polarization or depolarization as the readout, with a decision threshold of at least 15% for administering alvocidib, cytarabine, and mitoxantrone.
Treatment of MCL-1-dependent AML guided by MCL-1 priming threshold
Administer alvocidib, cytarabine, and mitoxantrone to a mammal with acute myeloid leukemia (AML) dependent on MCL-1 when bone marrow cells have MCL-1 priming of at least 15%, where MCL-1 priming is determined by subjecting the bone marrow cells to an MCL-1-selective BH3 mimetic and determining the percentage change in mitochondrial polarization corresponding to the MCL-1 priming.
MCL-1 priming-based treatment workflow using mitochondrial depolarization readout
Acquire a plurality of bone marrow cells; determine an MCL-1 priming of the bone marrow cells by subjecting cells to an MCL-1-selective BH3 mimetic and determining the percentage change in mitochondrial depolarization corresponding to the MCL-1 priming; administer alvocidib, cytarabine, and mitoxantrone if the bone marrow cells have the MCL-1 priming of at least 15%.
Across both independent claims, the inventive coverage is the same decision principle: using an MCL-1-selective BH3 mimetic with a mitochondrial readout to quantify MCL-1 priming in bone marrow cells and administering the alvocidib/cytarabine/mitoxantrone regimen when the measured priming meets or exceeds a defined threshold, with dependents specifying higher thresholds and clinical narrowing to refractory and/or relapsed/refractory AML.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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