BIOMARKER AND PATIENT SELECTION IN TREATMENT FOR MYELOFIBROSIS
Transfusion independence in, and overall survival of, myelofibrosis patients can be improved by selecting a patient specific treatment method. A patient's baseline ferritin level can be used as a biomarker to select a first line treatment. The patient's ferritin levels during treatment can inform decisions about terminating treatment or changing treatments to maintain transfusion dependence and/or convert a patient to transfusion independent from transfusion requiring or transfusion dependent.
1 . A method of treating myelofibrosis in a subject, the method comprising:
administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as having (i) myelofibrosis, and (ii) a ferritin level greater than 90 ng/mL.
2 . The method of claim 1 , wherein the subject is identified as having a ferritin level greater than 90 ng/mL and less than 650 ng/mL.
3 . The method of claim 1 , wherein the subject is identified as having a ferritin level greater than 650 ng/mL.
4 . The method of claim 3 , further comprising administering a therapeutically effective amount of a second therapeutic agent to the subject.
5 . The method of claim 1 , further comprising determining the level of ferritin in a sample of a subject having myelofibrosis.
6 . The method of claim 1 , wherein the momelotinib or a pharmaceutically acceptable salt thereof is administered for a treatment period of a plurality of weeks.
7 . The method of claim 1 , further comprising steps of determining the level of ferritin in a sample of the subject once a month, or twice a month, or once weekly during a treatment period.
8 . The method of claim 7 , wherein the subject is assessed as maintaining a ferritin level within a predetermined range during the treatment period; or
wherein the subject is assessed as having a ferritin level that is not within a predetermined range during the treatment period; or
wherein the subject is assessed as having a ferritin level that is not within a predetermined range during the treatment period and wherein the method further comprises the step of terminating administration of the momelotinib or a pharmaceutically acceptable salt thereof, and/or the optional second therapeutic agent; or
wherein the subject is assessed as having a ferritin level that is not within a predetermined range during the treatment period and wherein the method further comprises the steps of
terminating administration of the momelotinib or a pharmaceutically acceptable salt thereof, and/or the optional second therapeutic agent; and
administering a second line treatment comprising:
administering a therapeutically effective amount of a JAK inhibitor to the subject wherein the subject is assessed as having a ferritin level less than 90 ng/mL; or
administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to the subject wherein the subject is assessed as having a ferritin level greater than 90 ng/mL and less than or equal to 650 ng/mL; or
administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent, to the subject wherein the subject is assessed as having a ferritin level greater than 650 ng/mL.
9 . The method of claim 8 , wherein the predetermined range of ferritin level during the treatment period is greater than or equal to 90 ng/mL, or wherein the predetermined range of ferritin level during the treatment period is greater than or equal to 90 ng/mL and less than or equal to 650 ng/mL; or
wherein the predetermined range of ferritin level during the treatment period is greater than 650 ng/mL.
10 . A method of maintaining transfusion independence in a subject being treated for myelofibrosis, the method comprising
a) administering a therapeutically effective amount of a JAK inhibitor to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) as having a ferritin level less than 90 ng/mL; or
b) administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) as having a ferritin level greater than 90 ng/mL and less than or equal to 650 ng/mL; or
c) administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) as having a ferritin level greater than 650 ng/mL.
11 . A method of converting a subject being treated for myelofibrosis from transfusion requiring or from transfusion dependent to transfusion independent, the method comprising
a) administering a therapeutically effective amount of a JAK inhibitor to a subject identified as (i) having myelofibrosis, (ii) being transfusion requiring or transfusion dependent, and (iii) as having a ferritin level less than 90 ng/mL; or
b) administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion requiring or transfusion dependent, and (iii) as having a ferritin level greater than 90 ng/mL;
c) administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion requiring or transfusion dependent, and (iii) as having a ferritin level greater than 90 ng/mL and less than or equal to 650 ng/mL; or
d) administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion requiring or transfusion dependent, and (iii) as having a ferritin level greater than 650 ng/mL.
12 . The method of claim 10 , wherein the JAK inhibitor is chosen from momelotinib or a pharmaceutically acceptable salt thereof, ruxolitinib or fedratinib.
13 . The method of claim 4 , wherein the second therapeutic agent is a BET protein inhibitor, or is a BRD4 inhibitor.
14 . A method of treating or preventing anemia in a subject being treated for myelofibrosis comprising
administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified (i) as having myelofibrosis, and (ii) as having anemia or as being at risk for becoming anemic, and (iii) as having a ferritin level greater than or equal to 90 ng/mL.
15 . The method of claim 10 , further comprising in earlier step of determining the level of ferritin in a sample of a subject having myelofibrosis; and/or
wherein the momelotinib or a pharmaceutically acceptable salt thereof is administered for a treatment period of a plurality of weeks.
16 . The method of claim 10 , further comprising steps of determining the level of ferritin in a sample of the subject once a month, or twice a month, or once weekly during a treatment period.
17 . The method of claim 16 , wherein the subject is assessed as maintaining a ferritin level within a predetermined range during the treatment period; or
wherein the subject is assessed as having a ferritin level that is not within a predetermined range during the treatment period; or
wherein the subject is assessed as having a ferritin level that is not within a predetermined range during the treatment period and wherein the method further comprises the step of terminating administration of the JAK inhibitor, or the momelotinib or a pharmaceutically acceptable salt thereof, and/or the optional second therapeutic agent; or
wherein the subject is assessed as having a ferritin level that is not within a predetermined range during the treatment period and wherein the method further comprises the steps of
terminating administration of the JAK inhibitor, or the momelotinib or a pharmaceutically acceptable salt thereof, and/or the optional second therapeutic agent; and
administering a second line treatment comprising:
administering a therapeutically effective amount of a JAK inhibitor to the subject wherein the subject is assessed as having a ferritin level less than 90 ng/mL; or
administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to the subject wherein the subject is assessed as having a ferritin level greater than 90 ng/mL; or
administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to the subject wherein the subject is assessed as having a ferritin level greater than 90 ng/mL and less than or equal to 650 ng/mL; or
administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent, to the subject wherein the subject is assessed as having a ferritin level greater than 650 ng/mL.
18 . The method of claim 17 , wherein the predetermined range of ferritin level during the treatment period is greater than or equal to 90 ng/mL, or wherein the predetermined range of ferritin level during the treatment period is greater than or equal to 90 ng/mL and less than or equal to 650 ng/mL; or
wherein the predetermined range of ferritin level during the treatment period is greater than 650 ng/mL.
19 . The method of claim 1 , wherein the subject has previously been treated with JAK inhibitor therapy other than momelotinib; or
wherein the subject has previously been treated with ruxolitinib.
20 . The method of claim 19 , wherein the subject has had an inadequate response to or is intolerant of ruxolitinib; and/or
wherein the subject failed to respond or ceased to respond to previous ruxolitinib therapy; and/or
wherein the subject is naïve to JAK inhibitor therapy.
21 . The method of claim 1 , wherein the therapeutically effective amount is between 50 mg/day and 200 mg/day.