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CCO 300606

REVIEW

CURRENT
OPINION Current management of patients with chronic
myelomonocytic leukemia
Elvira Mora a and Guillermo F. Sanz a,b

Purpose of review
The present review focuses on the current management of patients with chronic myelomonocytic leukemia
(CMML) and the most recent developments in the field.
Recent findings
CMML is a heterogeneous malignant myeloid disorder sharing features of myelodysplastic syndromes
(MDS) and myeloproliferative neoplasms and characterized by peripheral blood monocytosis and
increased risk of progression to acute leukemia. Its natural course is highly variable and use of CMML-
specific prognostic scoring systems is strongly recommended for tailoring treatment. Multiple recent studies
have showed that somatic mutations, which are almost always present have a relevant and independent
impact on survival but lack a clear role in predicting the response to currently available drugs.
Summary
The incorporation of somatic mutations to prognostic scoring systems has improved the prediction of
patients’ outcomes. Current treatment for CMML remains unsatisfactory. Allogeneic hematopoietic cell
transplantation is the only curative option but is applicable to a minority of patients. Usually higher-risk
patients displaying MDS-like characteristics are treated with hypomethylating agents (HMAs), whereas
those with myeloproliferative features generally receive hydroxyurea or HMAs but none of these drugs
substantially modify the natural history of CMML. Newer therapies are clearly needed.
Keywords
chronic myelomonocytic leukemia, hematopoietic cell transplantation, hypomethylating agents, mutations,
prognosis, treatment

INTRODUCTION exclusion of reactive monocytosis. Differential diag-

Chronic myelomonocytic leukemia (CMML) is a rare
clonal hematological malignancy with characteris-
tics of both myelodysplastic and myeloproliferative
disorders and a highly variable clinical course. For-
merly classified among myelodysplastic syndromes
(MDS), CMML is currently included in the MDS/
myeloproliferative (MPN) neoplasms by the World
Health Organization (WHO) classification [1].
In the present article, we do not intend to pro-
vide an exhaustive description of the disease, but
rather to focus on recent relevant issues related to
the management of patients with CMML and offer
currently available evidence to assist physicians in
decision-making.
Diagnosis
The diagnosis of CMML requires a 3-month persis-
tent monocytosis, defined as an absolute monocyte
count more than 1  109/l that should represent
more than 10% of the WBC differential [2], after
nosis should also include other malignant myelo-
proliferative disorders as outlined in the 2008 WHO
criteria [1] and the 2016 revision [2] for the diagnosis
of CMML, as shown in Table 1. The latter revision
incorporated the CMML-0 category (<5% bone mar-
row blasts), based on a study that showed that
CMML-0 had a significantly better prognosis than
CMML-1 [3]. Interestingly, this finding has not been
confirmed in a large series recently reported [4].
Careful cytomorphological evaluation of blast
percentage, including myeloblasts, monoblasts, and
promonocytes, in the peripheral blood and bone
a
Hospital Universitario y Politécnico La Fe, Valencia and bCIBERONC,
Instituto Salud Carlos III, Madrid, Spain
Correspondence to Guillermo F. Sanz, MD, PhD, Hematology Depart-
ment, Hospital Universitario y Politécnico La Fe, Torre F, Planta 7, Avenida
Fernando Abril Martorell, 106, 46026 Valencia, Spain.
Tel: +34 96 124 4925; e-mail: sanz_gui@gva.es
Curr Opin Oncol 2018, 30:000–000
DOI:10.1097/CCO.0000000000000486

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Hematologic malignancies
KEY POINTS
 Flow cytometry immunophenotyping of peripheral
blood monocytes and the presence of cytogenetic
abnormalities or somatic gene mutations are powerful
tools for establishing the diagnosis of CMML.
 Several specific somatic mutations are clearly
associated with long-term outcomes and may be
valuable for establishing a more accurate prognosis in
the individual patient. In contrast, the relevance of
somatic mutations for predicting response to HMAs
is unclear.
 Allogeneic hematopoietic cell transplantation is the only
potentially curative treatment approach for patients with
CMML but relevant questions regarding the procedure
remain unanswered.
 Hydroxyurea and HMAs are the most commonly used
treatment alternatives for CMML patients who are not
candidates to allo-HCT but they do not modify the
natural history of the disorder.
 The development of new treatment strategies
is essential.
Table 1. WHO diagnostic criteria for chronic myelomonocytic leukemia and categories
WHO 2008 [1]
Criteria Persistent (3 months) peripheral blood
monocytosis 1  109/l
Lack of Philadelphia chromosome or BCR-ABL
fusion gene
No evidence of PDGFRA or PDGFRB
rearrangements in cases with eosinophilia
<20% blasts in the peripheral blood and bone
marrowa
At least one of the following: (a) Myelodysplastic
features in at least one cell line. (b) Presence of
an acquired clonal cytogenetic or mutational
abnormality in hematopoietic cells. (c) All other
causes of monocytosis have been excluded.
WHO categories
CMML-0 – <2% blasts in peripheral blood and <5% blasts in bone
CMML-1 <5% blasts in peripheral blood and/or <10%
blasts in bone marrow
CMML-2 5–19% blasts in peripheral blood, 10–19% in
bone marrow, and/or when any Auer rods are
present
FAB categories
MD-CMML WBC <13  109/l
9
MP-CMML WBC 13  10 /l
Changes in the 2016 revision are in bold.
WHO, World Health Organization; FAB, French-American-British; WBC, white blood cell; CML, chronic myeloid leukemia; PMF, primary myelofibrosis; ET:
essential thrombocythemia.
a
Count of blasts includes myeloblasts, monoblasts, and promonocytes (mature monocytes displaying atypical cytologic features are common and are excluded
from the blast count).
2 www.co-oncology.com
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marrow aspirate smears as well as the detection of
myelodysplastic features in at least one hematopoi-
etic cell lineage are essential for diagnosis. A bone
marrow biopsy is strongly recommended by many
experts and considered as mandatory in case of ‘dry
tap’ bone marrow aspiration to assess bone marrow
fibrosis. The presence of myelofibrosis in CMML has
recently been associated with inferior overall sur-
&
vival (OS) [5 ,6], presence of myeloproliferative
(MP)-like features, and more frequent JAK2 muta-
tions [6].
Flow cytometry immunophenotyping (FCI) in
CMML has been recognized as a valuable tool for
CMML diagnosis and for monitoring response to
therapy [7,8]. The presence of classical CD14þ/
CD16- monocytes in peripheral blood more than
94% of total monocytes constitutes a simple, rapid
and robust diagnostic marker to distinguish CMML
from other causes of monocytosis, with a sensitivity
and specificity of 90.6 and 95.1%, respectively [9].
This approach has been recently validated in two
&
smaller studies [10,11 ], which stress the importance
of performing the analysis within the first 24 h after
sampling to avoid false negative results [10] and the
WHO 2016 [2]
Persistent peripheral blood monocytosis 1  109/l, with
monocytes accounting for 10% of the WBC count
Not meeting WHO criteria for BCR-ABL1þ CML, PMF,
polycythemia vera, or ET
No evidence of PDGFRA, PDGFRB, or FGFR1 rearrangements
or PCM1-JAK2 fusions in cases with eosinophilia
<20% blasts in the peripheral blood and bone marrowa
At least one of the following: (a) Myelodysplastic features in
at least one cell line. (b) Presence of an acquired clonal
cytogenetic or mutational abnormality in hematopoietic
cells. (c) All other causes of monocytosis have been
excluded.
marrow
2–4% blasts in peripheral blood and/or 5–9% blasts in
bone marrow
5–19% blasts in peripheral blood, 10–19% in bone marrow,
and/or when any Auer rods are present
WBC <13  109/l
WBC 13  109/l
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Current management of patients with CMML Mora and Sanz

capacity to distinguish CMML from other MPN with
& &
associated monocytosis [11 ]. It has therefore been
suggested that the current cautious recommenda-
tion of a 3-month delay for CMML diagnosis could
be avoided by using this FCI criteria [9,10].
Cytogenetic and mutational profiles
Cytogenetic abnormalities and somatic mutations
are found respectively in 25–30% [12–14] and up to
& &&
95% [15 ,16,17 ,18–25] of CMML patients, provid-
ing definitive evidence of clonality and supporting
the correct diagnosis in doubtful cases.
The most frequent cytogenetic abnormalities
are trisomy 8, loss of Y chromosome, abnormalities
of chromosome 7, and complex karyotypes. Cyto-
genetic findings have a strong influence in OS and a
validated CMML-specific cytogenetic risk classifica-
tion recognizes three risk categories: low risk (nor-
mal karyotype or loss of Y chromosome as a single
anomaly), high risk (presence of trisomy 8 or abnor-
malities of chromosome 7, or complex karyotype),
and intermediate risk (all other abnormalities) [13].
On the other hand, therapy-related CMML (t-
CMML) has been associated with a higher frequency
of both abnormal karyotypes and higher-risk
chromosomal abnormalities, resulting in shorter
OS and leukemia-free survival (LFS) [15 ].
A large number of gene mutations have been
found in CMML, illustrating its molecular heteroge-
neity and improving our knowledge of the biology of
the disease. As shown in Table 2, which depicts the
relative frequencies of these mutations, the most
frequently mutated genes are TET2, SRSF2, and
ASXL1, followed by mutations in RUNX1 and RAS
&&
pathway [16,17 ,18]. The range of cellular pathways
affected by those gene mutations includes epigenetic,
splicing, transcription, tumor suppression, and cell
signaling regulation. Although none of them is dis-
ease-specific, the high frequency of some mutations
certainly confirms that CMML is an MDS-indepen-
dent entity. Recent findings suggest that ancestral
mutations that drive the pathogenesis of the disease
are frequently TET2, SRSF2, and ASXL1 while others
are predominantly secondary mutations, that can
& &
trigger disease progression [19 ,20 ].
Signaling-associated mutations (JAK2 and RAS
pathway mutations) are more common in MP-
& &
CMML [11 ,16,20 ]. The distribution of gene muta-
tions or frequency of mutations in TP53 in t-CMML
&
and de-novo CMML are similar [15 ]. Although
TET2 mutations are broadly prevalent, only one

Table 2. Relative frequencies of somatic mutations in patients with chronic myelomonocytic leukemia

Class of genetic Itzykson et al. Elena et al. Patnaik et al.

&& &
mutation Gene 2013 [16] (n ¼ 173–312) 2016 [17 ] (n ¼ 214) 2018 [15 ] (n ¼ 265)

Detection of 1 somatic mutation 95% 93% NA

Epigenetic regulators TET2 58 44 58
DNMT3A 2 NA 6
IDH1 0.4 NA 2
IDH2 6 6 6
Chromatin regulation ASXL1a 40 37 51
EZH2 5 7 3
Splicing SRSF2 46 39 48
SF3B1 6 6 6
U2AF1 5 4 7
ZRSR2 8 4 3
Cell signaling NRAS 11 12 15
KRAS 8 9 5
CBL 10 8 13
PTPN11 NA NA 3
JAK2 V617F 8 7 8
FLT3 3 3
Transcription factors RUNX1 15 8 8
Tumor suppressor genes TP53 1 7 3
Other SETBP1 NA 9 14

NA, not available.

a
Nonsense and frameshift mutations.

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CCO 300606

Hematologic malignancies

marrow blasts 5%;

usseldorf scoring system; MPM, Mayo prognostic model; CPSS, CMML-specific prognostic scoring system; GFMM, Groupe Français des Myélodysplasies model; MMM,
WBC 13  109/l;
study suggests a favorable OS in the absence of

(CPSS cytogenetics
CPSS-Mol [17 ]

þ ASXL1, NRAS,
Gene risk groups

mutations.; bone
SETBP1, RUNX1
&&

RBC transfusion
ASLX1 mutation [21]. Frameshift and nonsense

dependence

Mayo molecular model; CPSS-Mol, Molecular CMML-specific prognostic scoring system; Hb, hemoglobin; Plt, platelets; IMC, immature myeloid cells; ALC, absolute lymphocyte count, LDH: lactate dehydrogenase;
ASXL1 mutations have been correlated to adverse

214

NR
64
37
18
OS in several studies [16,18]. In addition, the co-
occurrence of EZH2 and ASXL1 has been associated
with shorter OS in comparison to ASXL1mt patients
alone [22]. Similarly, DNMT3A mutations may

dl; Plt <100  109/

AMC >10  109/l;

blood; Hb <10 g/
&
adversely impact on OS and LFS [23 ]. The number

l; ASXL1 mutations
IMC in peripheral
of driver mutations also determines survival out-

MMM [18]
comes, as recently demonstrated in a study where

466

59
97

31
16
a shorter OS was observed in CMML patients with
&
three or more concomitant mutations [24 ]. Not
unexpectedly, TP53 mutation, although uncom-
mon in CMML (4%), has been also associated with

<10 or 11 g/dl (by sex);

WBC >15  109/l; Hb
&
poorer OS [24 ]. Conversely, a recent meta-analysis

Plt <100  109/l;

ASXL1 mutations
Age >65 years;
revealed no significant effect on prognosis of SRSF2

GFMM [16]
mutations in CMML patients [25].

312

NR
38

14
Assessment of prognosis
The use of one of the prognostic scoring indexes that
are offered in Table 3 is strongly recommended for risk

CMML WHO type;

assessment of the individual patient with CMML.

CMML FAB type;

RBC transfusion
CMML-specific
cytogenetics;

dependence
Most of them have been externally validated and have CPSS [29]
shown a comparable performance when tested in a
578

31
72

13
5
large international dataset [26]. Among those CMML-

CMML, chronic myelomonocytic leukemia; WBC, white blood cell; AMC, absolute monocyte count; NR, not reached.
specific prognostic tools, some of them include only
peripheral blood and bone marrow characteristics,
which are readily available for practically all CMML
AMC >10  109/l; IMC

patients [12,27,28]. The more recently developed also

in peripheral blood;

Plt <100  109/l

Hb <10 g/dl;

include cytogenetics [29,30], gene mutations [16,18],

MPM [28]

&&
or both cytogenetics and gene mutations [17 ]. The
226

18
32

10
Table 3. Prognostic scoring systems for chronic myelomonocytic leukemia

mutational status of ASXL1 has recently been incor-

porated into two models developed by the Groupe
Francophone des Myelodysplasies [16] and Mayo
Clinic [18]. The so-called CMML-specific prognostic
scoring system (CPSS)-Molecular, integrates the
>5%; LDH >200 U/l;
bone marrow blasts

genetic score (that includes the CPPS cytogenetic risk

Hb <9 g/dl; Plt
<100  109/l
DUSS [27]

score and the mutational status of not only ASXL1 but

288

also NRAS, SETBP1, and RUNX1) along with RBC

26
93

11

transfusion requirements, WBC and bone marrow

&&
blast counts [17 ]. Potential reasons for using the
classical CPSS [29] is that is relatively simple and the
MDAPS, MD Anderson prognostic score; DUSS, D€

only one that has also been validated in the transplan-

Hb < 12 g/dl; IMC
in peripheral blood;
ALC >2.5  109/l;

&&
tation setting [31,32 ]. Furthermore, this prognostic
bone marrow
MDAPS [12]

blasts >10%

score is able to segregate 4 risk groups with signifi-

Risk groups, median OS in months
213

cantly different OS. Patients with low- or intermedi-

15
24

8
5

ate-1 risk by CPSS are considered as lower-risk patients,

whereas those with intermediate-2 or high-risk are
deemed as higher-risk and, thus, as potential candi-
dates for a curative treatment approach.
Prognostic score

Intermediate-1
Intermediate-2
No. of patients

included

Current treatment approach

Variables

High
Low

There is a lack of evidence-based recommendations

for the selection of treatment in patients with

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Current management of patients with CMML Mora and Sanz

CMML, since most data on efficacy and safety are
from small uncontrolled studies or from clinical trials
designed for MDS. Further, the criteria used for assess-
ing response in these trials did not consider end
points related to the control of the myeloproliferative
component of CMML. An international consortium
proposed in 2015 specific response criteria for MDS/
MPN [33] that has been recently retrospectively vali-
dated for CMML [34]. Finally, the variable clinical
course of the disease, advanced age, and disappoint-
ing long-term efficacy of currently available treat-
ment alternatives, complicate treatment choice.
Allogeneic hematopoietic cell transplantation
Allogeneic hematopoietic cell transplantation (allo-
HCT) is the only potentially curative therapy for
patients with CMML, but only a minority of patients
are candidates for transplantation. In addition, most
available data regarding the role of allo-HCT in
CMML come from a limited number of retrospective
&&
studies [32 ,35–42] that are shown in Table 4. Over-
all, these studies show that allo-HCT is a valid
treatment option for selected patients, resulting in
long-term remission in up to 40% of transplanted
patients. However, they do not allow drawing defin-
itive conclusions on the timing of transplantation,
patients who may benefit most from this procedure,
need and type of pretreatment, most appropriate
conditioning regimen, and best hematopoietic cell
source. An international expert panel position
report recommends to perform allo-HCT in CMML
patients with intermediate-2 or high-risk score by
&&
CPSS [43 ] after assessing the allo-HCT associated
mortality risk by the HCT-comorbidity index [44].
In lower-risk patients, transplantation could be
delayed until disease progression. All symptomatic
younger patients should be offered the opportunity
to discuss the indication of allo-HCT shortly after
diagnosis. Regarding disease status at transplanta-
tion, a large registry-based study [40] reported a
better outcome in patients who were transplanted
in complete remission compared to those with
active disease, whereas another study [39] did not
find this relationship. The potential advantage of
using a particular treatment modality before trans-
plant is unclear. A recent single-institution retro-
spective study on 83 patients showed a lower
incidence of relapse and better disease-free survival
in patients treated with HMAs before transplanta-
tion than in those receiving chemotherapy or sup-
portive care [42]. In contrast, in a large CIBMTR
&&
study [32 ] on 209 patients, outcomes of treated
or untreated patients prior to transplantation were
similar. Reasons for these discrepant results have
been the subject of a recent commentary [45]. The
presence of RAS-pathway mutations has been signif-
icantly associated with worse OS after transplanta-
tion in patients with MDS/MPN [46] but this finding
requires confirmation.

Table 4. Allogeneic hematopoietic cell transplantation in the treatment of chronic myelomonocytic leukemia
Condition- Type of Outcome
ing (%) donor (%) (%)
Complete
Study No. of Median remission
References Institution period patients age (Range) at HCT (%) MAC RIC Related Unrelated OS DFS

Elliot et al. 2006 [35] Mayo Clinic 1992–2004 17 50 (26–60) 6 94 6 82 18 18 (3y) 18 (3y)
Ocheni et al. Hamburg 2003–2007 12a 56 (37–66) 17 54 46 15 85 75 (3y) 50 (3y)
2009 [36] University
Krishnamurthy et al. Kings College 1998–2007 18 54 (38–66) <50% 17 83 39 61 31 (3y) 31 (3y)
2010 [37]
Eissa et al. FHCRC 1986–2008 85 51.7 (1–69) NA 68 32 45 55 40 (10y) 38 (10y)
2011 [38]
Park et al. SFGM-TC 1992–2009 73 53 (29–67) 21 41 59 58 42 32 (3y) 29 (3y)
2013 [39]
Symeonidis et al. EBMT 1988–2009 513 53 (18–75) 26 52 48 56 44 33 (4y) 27 (4y)
2016 [40]
Sharma et al. Mayo Clinic 1990–2014 36 53 (18–66) NA 61 39 NA NA NA NA
2015 [41]
Kongtim et al. MDACC 1991–2013 83 57 (18–78) 29 77 23 36 64 32–36 (3y) NA
2016 [42]
&&
Liu et al. 2017 [32 ] CIBMTR 2001–2012 209 57 (23–74) NA 51 49 35 64 38 (3y) 27 (3y)

NA, not available; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; OS, overall survival; DFS, disease-free survival; FHCRC, Fred
Hutchinson Cancer Research Center; SFGM-TC, Societé Francaise de Greffe de Moelle et Therapie Cellulaire; EBMT, European Blood and Marrow Transplant;
MDACC, MD Anderson Cancer Center; CIBMTR, Center for International Blood and Marrow Transplant Research.
a
One patient received two transplants.

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Hematologic malignancies
Hypomethylating agents and other
treatments
The currently available treatment for those CMML
patients who are not candidates for allo-HCT is
symptom-directed and does not substantially mod-
ify the natural history of the disease. Schematically,
treatment options are limited to hypomethylating
agents (HMAs), such as azacitidine and decitabine;
cytoreductive therapy (hydroxyurea and other
cytotoxic drugs), as well as supportive care, includ-
ing erythropoiesis-stimulating agents (ESAs) and
transfusions.
Myelodysplastic (MD)-CMML patients are usu-
ally managed as those with MDS. In the only avail-
able study specifically analyzing the efficacy of ESAs
in CMML, the erythroid response rate was 64%
(median duration, 8 months) and RBC transfusion
independence was 31%. The CPSS and EPO levels
were found adequate tools to select CMML patients
with symptomatic anemia who may benefit from
treatment with ESAs (low and intermediate-1 risk by
the CPSS and low endogenous serum EPO levels)
[47].
The use of HMAs in CMML patients is supported
by several noncomparative clinical trials [48–
&
58,59 ] (Table 5). In these studies, the proportion
of FAB and WHO subtypes were heterogeneous and
HMAs were frequently used after prior treatment
had failed (35–70%). The overall response rate
(ORR) ranged from 38 to 69% with decitabine and
from 39% to 54% with azacitidine, but complete
remission rates were significantly more modest.
Recently, a large retrospective study compared
CMML patients treated with azacitidine or decita-
bine as first line therapy, with an ORR of 75%,
including a complete remission of 41% and a
&
median OS of 20 months [55 ]. Patients treated with
decitabine showed significantly higher complete
remission rates (54.8 vs. 23.0%, P < 0.001), although
no statistically significant differences between both
drugs were observed in OS. Yet, another recent study
that compared complete remission between azaci-
tidine and decitabine found no differences [21].
Therefore, currently there are not sufficient data
to support the choice of one HMA over the other.
Cytoreductive therapy with hydroxyurea is con-
sidered the mainstay of therapy for symptomatic
MP-CMML patients. Although the specific role of
HMAs in MP-CMML is not yet established, it is
generally assumed that these agents are less active
&
in MP-CMML compared with MD-CMML [56 ].
However, the ORR reported in three studies with
azacitidine [48,50,51] for patients with MP-CMML
(32, 48, and 68%) were not significantly different
from those observed in the MD-CMML setting
(55, 40, and 35%, respectively) (Table 5). A recent
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retrospective study compared azacitidine with
hydroxyurea as first-line treatment and showed a
trend for better OS with azacitidine [51]. The results
of the ongoing prospective randomized DACOTA
trial (NCT02214407), comparing decitabine to
hydroxiurea in MP-CMML patients, are eagerly
awaited.
A major goal of research is the identification of
biomarkers to predict treatment response after
HMAs. However, up to date the relationship
between somatic mutations and response to HMAs
& &
in CMML is unclear [20 ,56 ,57]. A large study of 174
CMML patients has showed that ASXL1 mutations
predicted lower ORR to HMAs, whereas TET2mut/
ASXL1wt genotype predicted a higher complete
remission rate and OS [21]. Nonetheless, those
results were not confirmed by another study that,
remarkably, found that patients with at least three
somatic mutations had a shorter median response
&
duration [24 ]. Interestingly, it seems that response
to azacitidine has no effect on somatic mutation
burden and early clonal evolution with expansion of
subclones has been detected even under treatment
&
and irrespective of clinical response [19 ]. One study
has found that a specific DNA methylation pattern
could predict response to decitabine in CMML [57],
but this result requires confirmation. New method-
ologies to determine the intracellular dynamics of
azacitidine therapy, such as multiparameter mass
spectrometry, are under development, aiming to
understand the mechanisms of azacitidine refracto-
riness [58].
Intensive chemotherapy is used for fitted
patients with extreme myeloproliferative features
or those progressing to AML, especially as a bridge
to allo-HCT. However, their survival is dismal,
regardless of response to therapy, and with minimal
&
benefit for patients undergoing an allo-HCT [59 ].
Novel therapies in chronic myelomonocytic
leukemia
Given the lack of therapeutic options, multiple clini-
cal trials in CMML are ongoing. Some of them are
assessing drugs such as rigosertib or guadecitabine as
well as combinations of HMAs with the NEDD8-
activating enzyme inhibitor pevonedistat. Luspater-
cept and sotatercept, two modified activin receptor
IIB fusion proteins, are under investigation for ane-
mic patients [60]. Other studies are evaluating the
combination of HMAs with histone deacetylase
inhibitors (vorinostat or panobinostat [61]) or
immune checkpoint inhibitors. While RAS inhibitors
like tipifarnib or MEK inhibitors such as trametinib
could be useful due to the high prevalence of RAS-
pathway mutations [62], other specific molecular
Volume 30  Number 00  Month 2018
 Table 5. Hypomethylating agents in the treatment of chronic myelomonocytic leukemia

Response (myelodys-
plastic/
WHO CMML sub- myeloprolif
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type (%) FAB CMML subtype (%) erative) (%)

Drug No. of Median Prior Median Overall Complete Median
References (schedule) patients age (range) therapy (%) cycles (range) CMML-1 CMML-2 Myelodysplastic Myeloproliferative response remission OS (months)

Costa et al. Azacitidine 38 70.5 (36–83) 56 5 (1–>50) 73 27 30 70 39 (55/32) 11 12

2011 [48] (75D7/100D5)
Fianchi et al. Azacitidine (50D7/ 31 69 (53–84) 35 6 (2–31) 44 56 65 35 51 42a 37
2013 [49] 75D7/F100D5/
F100D7)
Adès et al. Azacitidine 76 70 (33–85) 46 6 (1–40) 55 45 54 46 43 (40/48) 17 29
2013 [50] (75D5/75D7)
Pleyer et al. Azacitidine (75D7/ 48 71 (38–87) 50 5.5 (1–65) 40 60 42 58 54 (35/68) 13 10
CCO 300606

2014 [51] 75D5/ F100D7)

Aribi A et al. Decitabine 19 66 (44–82) 47 9 (1–18) 79 21 68 32 69 58a 19

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2007 [52] (20D5/ 10D10)
Wijermans Decitabine (45D3) 31 71 (53–81) NA 4 (0–6) 58 42 24 76 44 10 15
et al. 2008 [53]
Braun et al. Decitabine (20D5) 39 71 (54–88) 41 10 (1–24) 44 56 18 82 38 10 18.5
2011 [54]
Alfonso et al. Azacitidine 151 69 (50–88) 0 8 (1–71) 39 35 43 57 75 41 24
&
2017 [55 ] Decitabine
Santini et al. Decitabine (20D5) 42 72 (42–84) NA 6 (1–34) 62 38 33 67 48 17 17
&
2018 [56 ]

NA, not available; OS, overall survival; 50D7, azacitidine 50 mg/m2 daily for 7 days; 75D5, azacitidine 75 mg/m2 daily for 5 days; 75D7, azacitidine 75 mg/m2 daily for 7 days; 100D5, azacitidine 100 mg/m2
daily for 5 days; F100D5/F100D7, ‘flat’ azacitidine 100 mg daily for 5 or 7 days, 20D5, decitabine 20 mg/m2 daily intravenous or subcutaneous for 5 days; 10D10, decitabine 10 mg/m2 daily intravenous for 10
days; 45D3, decitabine 15 mg/m2/8 h intravenous for 3 days.
a
Complete remission and marrow complete remission were considered together.

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7
Current management of patients with CMML Mora and Sanz

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CE: Tripti; CCO/300606; Total nos of Pages: 9;
CCO 300606
Hematologic malignancies
targets, such as IDH1/2 inhibitors, might be a thera-
peutic option in occasional patients. Finally, other
clinical trials are currently assessing the potential role
of agents targeting the JAK/STAT pathway or granu-
locyte macrophage colony stimulating factor (GM-
CSF), such as lenzilumab [63]. Regarding the former,
the preliminary results of a phase I clinical trial with
the JAK inhibitor ruxolitinib are encouraging, with
an ORR up to 35% and showing some benefit for the
management of constitutional symptoms or spleno-
megaly [64]. Therefore, the combination of ruxoliti-
nib with azacitidine is currently being explored.
CONCLUSION
Treatment of CMML remains largely unsatisfactory
for most patients. For this reason, the design of
CMML-specific clinical trials aiming to find more
effective agents able to modify the natural history of
the disorder are clearly needed. For this purpose, a
large international cooperative effort will be
required. A better understanding of the molecular
mechanisms involved in the pathogenesis of CMML
and in driving disease progression will undoubtedly
contribute to identifying new therapeutic targets
and to develop more accurate prognostic models
for better stratifying CMML patients regarding
treatment.
Acknowledgements
None.
Financial support and sponsorship
This work was partially financed with FEDER funds
(CIBERONC (CB16/12/00284)).
Conflicts of interest
G.F.S. has participated as consultant for Abbvie, Amgen,
Boehringer Ingelheim, Celgene, Helsinn Healthcare,
Janssen, Novartis, and Roche. E.M. has no conflicts of
interest to disclose.
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