COMBINATION TREATMENT OF CHRONIC MYELOMONOCYTIC LEUKEMIA IN PATIENTS WITH RAS PATHWAY MUTATIONS
Provided herein are methods for treating a subject having chronic myelomonocytic leukemia (CMML), the method comprising: (a) identifying a RAS pathway mutation in tumor cells of the subject, wherein the RAS pathway mutation is a NRAS, KRAS, PTPN-11 and/or CBL mutation; (b) identifying a dominant CBL mutation of CBL variant allele frequency of from <5% to >10%; and (c) administering to the subject identified in step (a) a therapeutically effective amount of an anti-hGM-CSF antibody. Also provided herein are methods for treating a subject having chronic myelomonocytic leukemia (CMML), the method comprising: (a) identifying a RAS pathway mutation in tumor cells of the subject, wherein the RAS pathway mutation is a NRAS, KRAS, PTPN-11 and/or CBL mutation; (b) identifying a dominant CBL mutation of CBL variant allele frequency of from <5% to >10%; and (c) administering to the subject identified in step (a) a therapeutically effective amount of an anti-hGM-CSF antibody lenzilumab and a therapeutically effective amount of a second therapeutic agent. The subject may have a RAS pathway mutation or a RAS pathway mutation and at least one TET2 mutation identified in the tumor cells, an increased percentage of CD116 and CD131 in CD34 + stem and progenitor cells in the subject compared to a healthy subject and/or an increased percentage of CD14 + cells in the subject compared to a healthy subject. A therapeutically effective amount of a hypomethylating agent or hydroxyurea may be further administered according to the provided methods.
1 . A method for treating a subject having chronic myelomonocytic leukemia (CMML), the method comprising:
a) identifying a RAS pathway mutation in tumor cells of the subject, wherein the RAS pathway mutation is a NRAS, KRAS, PTPN-11 and/or CBL mutation;
b) identifying a dominant CBL mutation of CBL variant allele frequency of from <5% to >10%; and
c) administering to the subject identified in steps (a) and (b) or solely in step (b) a therapeutically effective amount of an anti-hGM-CSF antibody.
2 . The method of claim 1 , further comprising administering a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is a hypomethylating agent or a chemotherapy drug.
3 . The method of claim 2 , wherein the hypomethylating agent is administered for five to seven days starting on day one of administration of the anti-hGM-CSF antibody.
4 . The method of claim 2 , wherein the chemotherapy drug is hydroxyurea and wherein the hypomethylating agent is selected from the group consisting of azacytidine, decitabine, and a combination of decitabine and cedazuridine.
5 . The method of claim 1 , further comprising identifying an increased percentage of CD116 and CD131 in CD34 + stem and progenitor cells in the subject compared to a healthy subject or further comprising identifying an increased percentage of CD14 + cells in the subject compared to a healthy subject.
6 - 7 . (canceled)
8 . The method of claim 1 , wherein the anti-hGM-CSF antibody is selected from the group consisting of lenzilumab, Namilumab, Otilimab, Gimsilumab, and TJM2 (TJ003234).
9 . (canceled)
10 . The method of claim 2 , wherein the anti-hGM-CSF antibody is selected from the group consisting of lenzilumab, Namilumab, Otilimab, Gimsilumab, and TJM2 (TJ003234).
11 . (canceled)
12 . The method of claim 8 , wherein the anti-hGM-CSF antibody is administered on day one and day 15 of cycle 1 and on day one only for all subsequent cycles, and wherein the all subsequent cycles consist of a total of 24 cycles, and each cycle consists of 28 days.
13 . The method of claim 10 , wherein the anti-hGM-CSF antibody is administered on day one and day 15 of cycle 1 and on day one only for all subsequent cycles, and wherein the all subsequent cycles consist of a total of 24 cycles, and each cycle consists of 28 days.
14 . The method of claim 1 , wherein the subject has a RAS pathway mutation and a TET2 mutation identified in the tumor cells or wherein the subject has a RAS pathway mutation and two TET2 mutation variants identified in the tumor cells.
15 . (canceled)
16 . The method of claim 8 , wherein the anti-hGM-CSF antibody is administered intravenously (IV) at a dose of from 552 mg to 1656 mg, wherein the dose of 552 mg is administered over a 1 hour IV infusion and the dose of 1656 mg is administered over 2 hour(s) IV infusion or is administered at a dose of 552 mg over a 1 hour IV infusion.
17 . The method of claim 8 , wherein the anti-hGM-CSF antibody lenzilumab is administered intravenously (IV) at a dose of from 552 mg to 1656 mg, wherein the dose of 552 mg is administered over a 1 hour IV infusion and the dose of 1656 mg is administered over 2 hour(s) IV infusion or is administered at a dose of 552 mg over a 1 hour IV infusion.
18 . The method of claim 7 , wherein the hypomethylating agent is administered subcutaneously at a dose of 75 mg/m 2 .
19 . The method of claim 2 , wherein the administration demonstrates a complete response (CR) plus partial response (PR) of 50-90% compared to complete response (CR) plus partial response (PR) of 7-21% achieved with sole administration of a hypomethylating agent; and wherein the response is a complete response or a partial response during 6 first cycles.
20 . (canceled)
21 . The method of claim 19 , wherein the CR or PR result in improved survival and progression-free survival at two years after treatment compared to survival and progression-free survival at two years after administration of a hypomethylating agent alone.
22 . The method of claim 2 , wherein the administration demonstrates/achieves clinical benefit at any point during 24 cycles, wherein the clinical benefit comprises impact on physical and functional capacity of the subject, social well-being of the subject, hematological and non-hematologic safety and combinations thereof.
23 . (canceled)
24 . The method of claim 22 , wherein the hematological safety comprises (a) a decrease in C-reactive protein (CRP) by at least 50% within six months of administering the therapeutically effective amount of the therapeutically effective amount of the anti-hGM-CSF antibody and the hypomethylating agent compared to baseline CRP prior to treatment, and (b) an improvement in hematological parameters; (c) an improved bone marrow response of less than 5% blasts within 12 months or (d) a complete response in subjects having a medium increase in GM-CSF and pro-inflammatory cytokines found in an innate immune response and M1 macrophage activation compared to levels of GM-CSF and pro-inflammatory cytokines and M1 macrophage activation in healthy subjects within 12 months; and/or (e) a decrease in a variant allele frequency (VAF) of at least one identified RAS-pathway mutation, wherein the RAS-pathway mutation is a KRAS and/or CBL mutation; and wherein the clinical benefit comprising impact on the physical capacity of the subject comprises a reduction in splenomegaly.
25 - 27 . (canceled)
28 . The method of claim 2 , further comprising treating the subject with an allogeneic transplant.
29 . A method for treating a subject having chronic myelomonocytic leukemia (CMML), the method comprising:
a) identifying a RAS pathway mutation in tumor cells of the subject, wherein the RAS pathway mutation is a NRAS, KRAS, PTPN-11 and/or CBL mutation;
b) identifying a dominant CBL mutation of CBL variant allele frequency of from <5% to >10%; and
c) administering to the subject identified in steps (a) and (b) or solely in step (b) a therapeutically effective amount of an anti-hGM-CSF antibody and a therapeutically effective amount of a second therapeutic agent.
30 . The method of claim 29 , wherein the second therapeutic agent is a hypomethylating agent or a chemotherapy drug, wherein the hypomethylating agent is selected from the group consisting of azacytidine, decitabine, and a combination of decitabine and cedazuridine and wherein the chemotherapy drug is hydroxyurea; and wherein the anti-hGM-CSF antibody is selected from the group consisting of lenzilumab, Namilumab, Otilimab, Gimsilumab, and TJM2 (TJ003234).
31 . The method of claim 30 , wherein the hypomethylating agent is administered for five to seven days starting on day one of administration of the anti-hGM-CSF antibody.
32 - 57 . (canceled)