Treatment of acute myeloid leukemia (AML) with venetoclax failure
Inventors
Bearss, David J. • Anthony, Stephen Patrick • MCCULLAR, Michael Vincent • SMITH, Susan Carol
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11793802-B2
Publication Date
2023-10-24
Expiration Date
Abstract
Provided herein are various regimens for treating acute myeloid leukemia (AML) in subjects (e.g, patients) who have undergone one or more prior anti-AML therapies involving venetoclax, and have shown disease progression after the one or more prior therapies. The treatment regimens disclosed herein involve alvocidib, either as a monotherapy, or in combination with cytarabine or a hypomethylating agent, such as decitabine or azacitidine. The treatment regimens disclosed herein do not involve combination therapy of alvocidib with venetoclax.
Core Innovation
The described invention relates to methods of treating acute myeloid leukemia (AML) in a subject in need thereof. The methods administer an effective amount of alvocidib to the subject in the absence of venetoclax, where the subject has refractory, resistant, or relapsed AML after one or more prior therapies, including at least one therapy comprising venetoclax and a hypomethylating agent. The disclosure further characterizes alvocidib as Formula (I) or Formula (I-b) and links the treatment to MCL-1 and MCL-1 dependency in AML.
The disclosure also provides treatment regimens in which alvocidib is combined with low-dose cytarabine or used with hypomethylating agents in treatment cycles. The methods include alvocidib monotherapy and sequential alvocidib, cytarabine, and alvocidib courses, and are described in the context of dosing and scheduling across treatment cycles, including 28-day cycle structures and drug holiday period concepts.
A further aspect of the invention is methods for addressing tumor lysis syndrome (TLS) in a subject. The disclosure describes TLS risk-reduction and monitoring concepts in which alvocidib is administered in the absence of venetoclax, and identifies TLS-related methods together with laboratory monitoring panels and thresholds using laboratory markers including serum potassium, serum phosphate, serum uric acid, serum calcium, serum creatinine, and lactate dehydrogenase (LDH).
Claims Coverage
The partial content includes three independent claims. Across these, the claims cover alvocidib administration in the absence of venetoclax for refractory, resistant, or relapsed AML after prior venetoclax and hypomethylating agent therapy, including a sequential alvocidib-cytarabine-alvocidib regimen, and a separate claim directed to inhibiting development of tumor lysis syndrome (TLS) and reducing TLS-related mortality and severity/incidence by administering alvocidib within a specified dose range.
Alvocidib without venetoclax after venetoclax-and-hypomethylating-agent prior therapy
Administering an effective amount of alvocidib to the subject in the absence of venetoclax, wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax and a hypomethylating agent.
Sequential alvocidib-cytarabine-alvocidib courses in venetoclax-absent AML treatment
Administering in the absence of venetoclax an effective amount of alvocidib in a first course of treatment, an effective amount of cytarabine in a second course of treatment, and an effective amount of alvocidib in a third course of treatment, wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax and a hypomethylating agent.
Tls prevention, reduction, and incidence control with alvocidib dosing in the absence of venetoclax
Administering alvocidib at a first dose of from about 15 mg/m2 to about 40 mg/m2 in the absence of venetoclax, wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax, for inhibiting development of tumor lysis syndrome (TLS), reducing severity, decreasing mortality from TLS, reducing incidence of TLS, preventing TLS, or treating AML in a subject without high risk for developing TLS.
The independent claims collectively define venetoclax-absent treatment strategies using alvocidib for refractory, resistant, or relapsed AML following prior venetoclax plus hypomethylating agent therapy, including a sequential alvocidib/cytarabine/alvocidib regimen, and a separate claim directed to inhibiting TLS development and reducing TLS-related mortality by administering alvocidib in the absence of venetoclax within a specified dose range.
Stated Advantages
Overcoming venetoclax failure in venetoclax failure settings described in the document.
Reducing tumor lysis syndrome (TLS) risk.
Reducing TLS mortality.
Inhibiting development of tumor lysis syndrome (TLS).
Reducing the severity of TLS.
Decreasing mortality from TLS.
Reducing the incidence of TLS.
Preventing TLS.
Treating AML in a subject without high risk for developing TLS.
Documented Applications
Treating AML in a subject with refractory, resistant, or relapsed disease after prior therapies comprising venetoclax and a hypomethylating agent by administering alvocidib in the absence of venetoclax.
Inhibiting development of tumor lysis syndrome (TLS) and/or reducing severity, incidence, and mortality from TLS by administering alvocidib in the absence of venetoclax.
Managing AML treatment regimens as described, including alvocidib monotherapy and sequential course regimens involving alvocidib and cytarabine, in venetoclax-absent contexts.
Treating acute myeloid leukemia (AML) in a subject with refractory, resistant, or relapsed disease after prior therapies comprising venetoclax and a hypomethylating agent, including contexts described as venetoclax-failure AML.
Methods for inhibiting development of tumor lysis syndrome (TLS), reducing severity of TLS, decreasing TLS-related mortality, reducing incidence of TLS, preventing TLS, or treating AML without high risk for developing TLS.
Kit/instruction concepts for treating venetoclax-failure AML with extensive example/supportive clinical-study embodiments and dosing schedules.
Interested in licensing this patent?