Predicting response to alvocidib by mitochondrial profiling
Inventors
Warner, Steven L. • Bearss, David J.
Assignees
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Publication Number
US-10357488-B2
Publication Date
2019-07-23
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 invention relates to methods of treating acute myeloid leukemia (AML) whose disease is dependent on MCL-1 by using a patient-specific MCL-1 priming measurement from bone marrow cells to guide administration of alvocidib, cytarabine, and mitoxantrone. Cells from the mammal’s bone marrow are subjected to a BH3 mimetic that is selective for MCL-1, and an MCL-1 priming value is determined.
The method correlates this MCL-1 priming with mitochondrial polarization or mitochondrial depolarization to support treatment selection. In the disclosed approach, the determination is based on the percentage change in mitochondrial polarization or mitochondrial depolarization that corresponds to the MCL-1 priming produced by exposure to the MCL-1-selective BH3 mimetic.
Treatment with alvocidib, cytarabine, and mitoxantrone is administered when the bone marrow cells have MCL-1 priming of at least 40%. The invention further includes acquiring a plurality of bone marrow cells from the mammal and performing the MCL-1 priming determination as part of a treatment workflow.
Claims Coverage
The provided set includes two independent claims (clm-00001 and clm-00005), both directed to treating an AML patient whose disease is dependent on MCL-1 using alvocidib, cytarabine, and mitoxantrone conditioned on an MCL-1 priming threshold measured with an MCL-1-selective BH3 mimetic and a mitochondrial polarization/depolarization readout. Across the independent claims, the main inventive focus is the selection of patients based on bone-marrow-derived MCL-1 priming measured by a BH3 mimetic and quantified via mitochondrial polarization/depolarization percentage change, using a threshold of at least 40%.
Patient selection using MCL-1 priming by an MCL-1-selective BH3 mimetic with mitochondrial polarization readout
Administering alvocidib, cytarabine, and mitoxantrone to a mammal with AML dependent on MCL-1 when bone marrow cells have MCL-1 priming of at least 40%, wherein the MCL-1 priming is determined by subjecting the bone marrow cells to a BH3 mimetic selective for MCL-1 and determining the percentage change in mitochondrial polarization corresponding to the MCL-1 priming.
MCL-1 priming threshold-based treatment after acquiring bone marrow cells with mitochondrial depolarization readout
Acquiring a plurality of bone marrow cells, determining an MCL-1 priming by subjecting the bone marrow cells to a BH3 mimetic selective for MCL-1 and determining the percentage change in mitochondrial depolarization corresponding to the MCL-1 priming, and administering alvocidib, cytarabine, and mitoxantrone if the bone marrow cells have the MCL-1 priming of at least 40%.
Both independent claims cover treating MCL-1-dependent AML with alvocidib, cytarabine, and mitoxantrone when bone marrow cells meet an MCL-1 priming threshold of at least 40%, where the priming is measured using an MCL-1-selective BH3 mimetic and quantified by percentage change in mitochondrial polarization or mitochondrial depolarization.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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