Page 36 - Haematologica Vol. 110 - January 2025

REVIEW ARTICLE - Molecular pathogenesis and novel treatments for CMML L. Marando et al. Table 1. Results of investigational therapies in chronic myelomonocytic leukemia.
Trial number (Eponym)
Phase
Target(s)
Agent(s)
N
ORR %
CR %
mOS months
Reference
Standard of care
NCT02214407 (DACOTA)
III
DNMT1
Decitabine
84
63
8
18.4
Itzykson, 202397
Epigenetic modifiers
NCT01613976
I
HDAC
Azacitidine + panobinostat
4
0
0
-
Kobayashi, 201898
NCT02877277
I
TET2
Azacitidine + ascorbic acid
3
-
-
-
Gillberg, 201999
NCT03418038
II
TET2
Ascorbic acid
2
-
-
-
Xie, 2023100
Chromatin modifiers
-
I
Aurora kinase A
ENMD-2076
1
0
0
-
Yee, 2016101
NCT01926587
I
PLK1
Azacitidine + rigosertib
1
0
0
-
Navada, 2020102
RNA processing inhibitors
NCT02159872
II
Ribosome A-site
Omacetaxine mepesuccinate (homoherringtonine)
8
33
0
7.5
Short, 2019103
NCT02841540
I
SF3B1
H3B-8800
4
0
0
-
Steensma, 2021104
JAK inhibitors
NCT01787487
II
JAK2
Ruxolitinib + azacitidine
17
65
-
15.1
Assi, 2018105
NCT01776723
I/II
JAK2
Ruxolitinib
50
38
2
24.7
Hunter, 2021106
NCT01776723
II
JAK2
Ruxolitinib
29
17
0
24
Padron, 2022107
RAS superfamily agents
NCT00920140
I/II
MEK1/2
Trametinib
11
27
9
14.5
Borthakur, 2016108
NCT00034684
II
Farnesyl- transferase
Lonafarnib
35
29
6
-
Feldman, 2008109
EudraCT 2004-004685-32
II
Farnesyl- transferase
Lonafarnib
2
0
0
-
Ravoet, 2008110
Protein degradation agents
NCT00744536
II
E3 ubiquitin ligase
Lenalidomide + melphalan
12
25
0
8.5
Buckstein, 2014111
ACTRN-12607000283471
II
E3 ubiquitin ligase
Azacitidine + thalidomide
16
63
19
-
Kenealy, 2017112
NCT01368757 (AGMT CMML-1)
I
E3 ubiquitin ligase
Lenalidomide
20
8
0
28.9
Burgstaller, 2018113
NCT01522976 (SWOG S1117)
II
E3 ubiquitin ligase HDAC
Azacitidine + lenalidomide Azacitidine + vorinostat
19 16
68 12
-
NR
Sekeres, 2017114
NCT01342692 (AZA PLUS)
II
E3 ubiquitin ligase HDAC dsDNA
Azacitidine + lenalidomide Azacitidine + valproic acid Azacitidine + idarubicin
456
35
18
19.7
Ades, 2022115
NCT00580242
I
E3 ubiquitin ligase, proteasome
Lenalidomide + bortezomib
-
0
0
-
Attar, 2013116
NCT02610777
II
NEDD8
Azacitidine + pevonedistat
9
78
33
-
Sekeres, 2021117
NCT03862157
I/II
NEDD8
Azacitidine + venetoclax + pevonedistat
2
100
0
-
Short, 2023118
Cytokine & growth factor derivatives
NCT02268253
I/II
CD123 (IL-3R)
Tagraxofusp
36
11
0
-
Patnaik, 2021119
NCT02546284
I
GM-CSF
Lenzilumab
15
33
0
-
Patnaik, 2020120
ACTRN-12621000223831 (PREACH-M)
II/III
GM-CSF
Lenzilumab + azacitidine ± ascorbic acid
11
73
55
-
Hiwase, 2023121
Immune checkpoint inhibitors
NCT03066648
I
TIM-3
Sabatolimab + azacitidine/ decitabine
15
67
27
7.6*
Brunner, 2024122
Many studies have enrolled diverse populations including patients with both myelodysplastic syndromes and chronic myelomonocytic leuke- mia (CMML). The data tabulated here represent only prospective studies that reported CMML-specific outcomes. Three retrospective studies (with 6, 27, and 51 patients) have described the combination of venetoclax with either azacitidine or decitabine, with overall response rates ranging from 50-90%, complete response rates of 0-22%, and median overall survivals of 10.3-25.1 months.123-125 *The study by Brunner et al. reported only median progression-free survival. The hyphen symbol (-) indicates that these data were not reported for the CMML-specific population. ORR: overall response rate; CR: complete response; mOS: median overall survival; HDAC: histone deacetylase. NR: not reached; GM-CSF: granulocyte-macrophage colony-stimulating factor.
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