Phorbol ester compositions and methods of use for treating or reducing the duration of cytopenia

1. A method of treating neutropenia and/or anemia comprising administering to a mammalian subject in need thereof, a combination of a phorbol ester of Formula I, pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, or polymorph thereof,

wherein R 1 and R 2 are selected from the group consisting of hydrogen, hydroxyl,

wherein the alkyl group contains 1 to 15 carbon atoms,

wherein the lower alkenyl group contains 1 to 7 carbon atoms,

and

R 3 is hydrogen or

and a granulocyte-colony stimulating factor (G-CSF); wherein said phorbol ester of Formula I is administered in an effective amount from about 10 and 1500 μg of said phorbol ester of Formula I per day, and said G-CSF is administered in an effective amount from 150 μg to 400 μg; wherein the G-CSF is administered to said mammalian subject in a coordinate administration protocol, simultaneously with, or after administration of said phorbol ester of Formula I; and wherein the combination of phorbol ester of Formula I and G-CSF is administered at least two times.

2. A method of treating neutropenia and/or thrombocytopenia comprising administering to a mammalian subject in need thereof, a combination of a phorbol ester of Formula I, pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, or polymorph thereof,

wherein R 1 and R 2 are selected from the group consisting of hydrogen,

wherein the alkyl group contains 1 to 15 carbon atoms,

wherein the lower alkenyl group contains 1 to 7 carbon atoms, and

R 3 is hydrogen or

and a granulocyte-colony stimulating factor (G-CSF); wherein said phorbol ester of Formula I is administered in an effective amount from about 10 and 1500 μg of said phorbol ester of Formula I per day, and said G-CSF is administered in an effective amount from 150 μg to 400 μg; wherein the G-CSF is administered to said mammalian subject in a coordinate administration protocol, simultaneously with, or after administration of said phorbol ester of Formula I; and wherein the combination of phorbol ester of Formula I and G-CSF is administered at least two times.

3. The method according to claim 1 or 2 , wherein R 1 or R 2 is

the remaining R 1 or R 2 is

and R 3 is hydrogen.

4. The method according to claim 1 or 2 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.

5. The method according to claim 1 or 2 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate (TPA).

6. The method according to claim 1 or 2 , further comprising administering at least one secondary or adjunctive therapeutic agent.

7. The method according to claim 1 or 2 , wherein said phorbol ester of Formula I is administered every day or every other day.

8. The method according to claim 1 or 2 , wherein said phorbol ester of Formula I is administered in an effective amount comprising between about 150 to 500 μg of said phorbol ester compound of Formula I every day or every other day.

9. The method according to claim 1 or 2 , wherein the combination increases absolute neutrophil count (ANC) of the mammalian subject to above 1500/mm 3 .

10. The method according to claim 1 or 2 , wherein the combination increases platelet levels of the mammalian subject to above 100,000/μl.

11. The method according to claim 1 or 2 , wherein the mammalian subject is a human with acute myeloid leukemia (AML).