Leucémie myélomonocytaire chronique - Cancéropole Ile de France Journée Cancers Rares, 11 février 2021 - canceropole-idf.fr
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Leucémie myélomonocytaire chronique
Cancéropole Ile de France
Journée Cancers Rares, 11 février 2021
LES CANCERS RARES : DE L'ÂGE PÉDIATRIQUE À L'ÂGE ADULTE
JMML CMML
Monocytosis
Splenomegaly
Myeloid/erythroid precursors on PB smears
Hemoglobin F increased
GM-CSF hypersensitivity
STAT5 hyper-phosphorylation
Somatic mutation in RAS path / -7
LES CANCERS RARES : DE L'ÂGE PÉDIATRIQUE À L'ÂGE ADULTE
GM-CSF–dependent pSTAT5 sensitivity
Padron E et al, Blood, 2013
Padron E et al, Clin Cancer Res 2016
Jeudi 11 février 2021
Patnaik M et al, Blood 2020
Immature myeloid cells in the peripheral blood
****
****
Immature
NS
CD3,CD19,CD56- CD16- Granulocytes
Monocytes
CD11b
CD15
SSC
SSC
FSC CD16 CD33 CD66b
Young Aged CMML
Selimoglu-Buet D et al, ongoing
Typically,
a 72-y man
routine blood test
Simple definition
Blood monocytes > 1000/µL showing a monocytosis
> 1,000 / mm3
> 10% WBC
Severe prognosis According to the WHO, if monocytosis
(median OS, 20-30 months) persists for at least 3 months w/o other
explanation: CMML
Typically,
a 72-y man
routineCMML
blood test
Simple definition
Blood monocytes > 1000/µL showing a monocytosis
Relative survival (%)
> 1,000 / mm3
> 10% WBC
Severe prognosis According to the WHO, if monocytosis
(median OS, 20-30 months) persists for at least 3 months w/o other
Months
explanation: CMML
Srour SA et al, Brit J Haematol, 2016
Whole genome
sequencing
at least two genomic
signatures in every
patient
Both indicate an
ageing-related
process
Merlevede et al, Nat Commun 2016
Before HMA After HMA
An epigenetically
defined phenotype
e.g. monocyte subset
CD16
repartition: a
MIR150/TET3
deregulated pathway
CD14
Selimoglu-Buet D et al, Nature Commun 2018
Hypomethylating agents do not reduce mutation burden in responders
Eric Padron
Merlevede et al, Nat Commun 2016
Most frequent order of mutation accumulation in CD34+ HSPCs
Epigenetic Splicing Signalling
NRAS
TET2 SRSF2
KRAS
Itzykson R et al, Blood 2013JMML as a Severe CMML as a
RASopathy RASopathy?
Monocytosis
Splenomegaly
Myeloid/erythroid precursors on PB smears
Hemoglobin F increased
GM-CSF hypersensitivity
STAT5 hyper-phosphorylation
Somatic mutation in RAS path / -7
LES CANCERS RARES : DE L'ÂGE PÉDIATRIQUE À L'ÂGE ADULTEBlast cell fraction in the blood and BM
PB BM
CMML-0 < 2% < 5%
CMML-1 2-4% 5-9%
Two 5-9% 10-19%
CMML-2
WHO-recognized
prognostic
WBC count
criteria
Dysplastic WBC < 13 G/L
Proliferative WBC = or > 13 G/LNRAS mutations
correlate with
proliferation
and
blastic transformation
Carr RM et al, Nature Commun, in revision,
cohort of 521 patientsHES CD123 pDCs in excess (20%) are part of the leukemic clone associate with RAS pathway mutations
pDCs excess correlates with Treg increase
and leukemic transformation risk
80
60
AML transformation (%)
40 P = 0.01
pDC rich
20
pDC poor
0
Months)
Lucas N et al, Leukemia 2019TET2-mutated monocytes produce more MIF
Niyongere S et al, Leukemia 2019
Droin N et al, ongoingApoptosis-resistant monocytes can be targeted
by inhibiting both MCL-1 and MEK
hCD34 Untreated Combo
or MCL1 inhitor i.v., once a week
hBMNC MEK inhibitor p.o., 5days a week
Annexin V negative cells (%)
100 ****
Propidium negative
80 7 weeks 3 weeks
day 0
60
40 400 40
* *** 300
**
x 103/ µL peripheral blood
Number of hCD45+ cells
20
Number of human cell
300 30
Spleen weight (mg)
/ spleen x 106
200
0 200 20
Controls CMML 100 10
100
(n=102) (n=75)
0 0 0
Vehicle Combo Vehicle Combo Vehicle Combo
Sevin M, Debeurme F et al, Blood, in revision
Sevin M et al, Blood, in revisionAging CMML
mutated / epimutated
HSCs
Erythro MK Lc Mc DCs Erythro MK Lc Mc DCs
PNN PNN1 – Optimized use of hypomethylating agents
New HMAs: guadecitabine, CC-846 (oral azacytidine), ASTX727 (Aza + cedazuridine)
Combined with venetoclax? with IDH1/2 inhibitors? with lenalidomide?
2 – New treatments of cytopenias
Anemia, with ligand traps for activins and GDF11 (luspatercept)
Thrombocytopenia, with eltrombopag
3 – Targeting GM-CSF signaling
Lenzilumab (KB003), an IgG1k with high affinity for GM-CSF (phase 1)
Ruxolitinib (phase 2 using PDX models as avatars)
4 – Targeting RAS-MAPK pathway
Tipifarnib (farnesyltransferase inhibitor) : off-target effect
MEK inhibitors : trametinib + AZA, cobimetinib in TET2/NRAS
5 – Targeting other signaling pathways
PLK1 inhibitor volasertib in RAS-mutant CMML
Dasatinib in CBL gain of function mutants that activate Lyn
6 – Other targeted drugs
Spliceosome : H3B-8800, no signal
CD123 : Tagraxofusp
Telomerase : ImetestatLeucémie myélomonocytaire chronique
Cancéropole Ile de France
Journée Cancers Rares, 11 février 2021
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