Increasing recognition and emerging therapies argue for dedicated clinical trials in chronic myelomonocytic leukemia

Aline Renneville1, Mrinal M. Patnaik 2, Onyee Chan 3, Eric Padron 3 and Eric Solary

1INSERM U1287, Gustave Roussy Cancer Campus, Villejuif, France. 2Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. 3Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA. 4Faculty of Medicine, Université Paris-Sud, Le Kremlin-Bicêtre, France. 5Department of Hematology, Gustave
Roussy Cancer Campus, Villejuif, France. ✉email: [email protected]
Received: 9 March 2021 Revised: 11 June 2021 Accepted: 14 June 2021


Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Median overall survival of this aggressive myeloid malignancy is only 2–3 years, with a 15–30% risk of acute leukemic transformation. The paucity of clinical trials specifically designed for CMML has made therapeutic management of CMML patients challenging. As a result, treatment paradigms for
CMML patients are largely borrowed from MDS and MPN. The standard of care still relies on hydroxyurea, hypomethylating agents (HMA), and allogeneic stem cell transplantation, this latter option remaining the only potentially curative therapy. To date, approved drugs for CMML treatment are HMA, including azacitidine, decitabine, and more recently the oral combination of decitabine and cedazuridine. However, HMA treatment does not meaningfully alter the natural course of this disease. New treatment approaches for improving CMML-associated cytopenias or targeting the CMML malignant clone are emerging. More than 25 therapeutic agents are currently being evaluated in phase 1 or phase 2 clinical trials for CMML and other myeloid malignancies, often in combination with a HMA backbone. Several novel agents, such as sotatercept, ruxolitinib, lenzilumab, and tagraxofusp have shown promising clinical efficacy in CMML. Current evidence supports the idea that effective treatment in CMML will likely require combination therapy targeting multiple pathways, which emphasizes the need for additional new therapeutic options. This review focuses on recent therapeutic advances and innovative treatment strategies in CMML, including global and molecularly targeted approaches. We also discuss what may help to make progress in the design of rationally derived and disease-modifying therapies for CMML.


CMML is a rare cancer

The development of new therapies in rare cancers, defined as diseases with a prevalence of fewer than five cases out of a population of 10,000, requires clinical trials involving many cooperative centers to meet accrual targets. As such, rare cancers are alternatively included as part of a larger, heterogenous group of malignancies, precluding any specific analysis or path to agency approval. This is well exemplified by chronic myelomonocytic leukemia (CMML), a disease classified as a myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndrome in the last iteration of the World Health Organization (WHO) classification of Tumors of Hematopoietic and Lymphoid Tissues [1]. While being the most frequent MDS/MPN, CMML remains a rare disease as its annual incidence is only 0.4/100,000 in Western countries [2–6].

CMML characteristics and subtypes

CMML is characterized by persistent peripheral blood (PB) mono- cytosis (≥1× 109/L with monocytes accounting for ≥10% of the white blood cell count) [1]. This disease typically affects older adults, with a median age of 72 at diagnosis, and demonstrates a male predominance [2, 3, 7]. CMML is one of the most aggressive chronic myeloid leukemias, with a median overall survival of ~2–3 years, and a lifetime inherent risk of transformation to acute myeloid leukemia (AML) of 15–30% [6, 8]. In 1976, the French-American-British Cooperative group designated CMML as a dysmyelopoietic syndrome [9], imprinting the perception that CMML was a variant of MDS while the proliferative component of the disease was neglected. This perception led to the repeated enrollment of small numbers of CMML patients in MDS-dedicated clinical trials, precluding specific therapeutic attention for decades. This biased attitude was enforced by the low annual incidence of CMML, limiting the development of dedicated clinical trials. CMML diagnosis is currently based on the 2016 WHO criteria [1]. According to the blast cell proportion in PB and bone marrow (BM), this classification distinguishes CMML-0 (PB blasts <2%, BM < 5% blasts) from CMML-1 (PB blasts = 2–4%, BM blasts = 5–9%) and CMML-2 (PB blasts = 5–19%, BM blasts = 10–19%). A blast cell fraction of 20% or more in either compartment is consistent with AML. This classification also distinguishes myeloproliferative (MP-CMML) and myelodysplastic (MD-CMML) CMML subtypes, depending on the peripheral leukocyte count (≥13 × 109/L, or <13 × 109/L, respectively) [1] (Fig. 1).

Fig. 1 Treatment goals for CMML according to the myelodysplastic or myeloproliferative disease subtype. WBC white blood cell, pDC plasmacytoid dendritic cells, GM-CSF granulocyte-macrophage colony-stimulating factor.

Prognostic assessment

CMML is typically associated with a rapid adverse outcome but there is considerable heterogeneity in the clinical course, with a median overall survival that may range from less than 12 to over 50 months [10, 11]. Therefore, adequate management of patients with newly diagnosed CMML requires an accurate prognostic assessment. Although several CMML-specific prognostic scoring systems (MDAPS [12], GFM [13], CPSS [14], CPSS-Mol [15], Mayo molecular [10]) have been proposed, none of them has emerged as clearly superior and no single model is universally adopted [4, 16]. Moreover, these different prognostic scoring systems have a limited predictive value at the patient level [17] and therefore are not directing therapeutic choices in CMML, as opposed to what is routinely done with the revised international prognostic scoring system for MDS. Additional biological parameters, such as
DNA methylation pattern, cytokine profiling, and clonal cell microenvironment, are being explored in CMML and could be considered in the future to improve existing prognostic scoring

Treatment goals

The clinical management of CMML patients remains challenging [4, 5]. The current therapeutic strategy is based on risk-adapted approaches for allogeneic stem cell transplantation (allo-SCT) decision and symptom-directed approaches in all other situations [16] (Fig. 2). Allo-SCT is the only potentially curative therapy for CMML and should be considered in most patients with inter- mediate to high-risk disease. However, advanced age at diagnosis and comorbidities preclude the use of this therapeutic approach in most patients (only 10% are eligible) [8]. To date, no drug has demonstrated to be able to modify the natural history of this rapidly lethal disease. Response to intensive chemotherapy is usually poor and transient [17, 18]. The available drug treatments are intended for palliation of symptoms or tumor burden reduction, possibly as a bridge to allo-SCT [4, 18]. In a non-transplant setting, treatment goals are essentially to correct cytopenia(s) in MD-CMML and control proliferative features and constitutional symptoms in MP-CMML (Fig. 1). Red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESA) are used in low-risk CMML patients with anemia. Hydroxyurea can be used in MP-CMML to manage symptoms and control leukocytosis [17, 18], (Fig. 2) but does not eradicate the leukemic clone [19]. Hypomethylating agents (HMA), including 5-azacytidine (AZA) and decitabine (DAC), are commonly considered as the standard of care therapy for symptomatic CMML. Both drugs have been approved by the Food and Drug Administration (FDA) for CMML, based on phase 3 randomized trials dedicated to MDS with a low number of CMML included. In Europe, AZA is approved exclusively for dysplastic CMML-2 [20, 21]. Most of the evidence of the effect of HMA in CMML comes from small, non-randomized clinical trials [22–24], indicating a 40–50% overall response rate (ORR) and less than 20% complete responses (CR) [6]. Importantly, HMA have no impact on mutational allele burden or leukemic transformation, even in responding patients, and all responders ultimately relapse [25, 26].
Thus, CMML is a disease in which there is an unmet need for effective, disease-modifying therapeutic approaches.
Based on recent insights into disease pathogenesis, there is a newfound interest in evaluating novel therapeutic approaches in CMML. This review focuses on emerging strategies that deserve dedicated clinical trials. We also discuss how to make progress in rationally designed and disease-modifying therapies for CMML.

What is the optimal first-line therapy for CMML?

Because of the lack of data, the optimal first-line therapy for CMML still remains a matter of debate. Only one randomized clinical trial specifically dedicated to CMML has ever been published so far, showing the superiority of hydroxyurea over oral etoposide [27].
Preliminary results of a second prospective randomized phase 3 trial (DACOTA trial, NCT02214407) comparing DAC to hydroxyurea as a frontline treatment of poor-prognosis CMML patients failed to demonstrate any advantage of DAC regarding event-free survival and overall survival. Furthermore, compared to hydroxyurea, DAC treatment was associated with a higher incidence of non- hematological adverse events, including cardiac events [28]. In contrast, a recent retrospective cohort study published by Pleyer et al. suggests that HMA are the preferred therapy for patients with higher-risk CMML and those with myeloproliferative features.
In this study, HMA were not found to confer a survival advantage for patients classified as having lower-risk disease [29]. Therefore, whether or not HMA treatment provides a clinical benefit in CMML patients and in which disease subgroup(s) remains to be confirmed by future prospective studies.

An emerging interest for new therapies

Given the currently limited therapeutic options and the limited efficacy of HMA in CMML, new therapeutic approaches are urgently needed. Fortunately, there is an emerging interest in renewing the therapeutic approaches in CMML. More than 25 therapeutic agents are currently being evaluated in phase 1 or phase 2 clinical trials that are recruiting CMML patients. Once again, with the exception of a few dedicated trials, CMML continues to be pooled with other myeloid malignancies, and many of these drugs are tested in combination with an HMA backbone. Novel therapeutic agents with proven or promising activity in clinical trials are indicated in Table 1. When available, results with these novel agents are discussed below. A list of actively recruiting and not yet recruiting interventional clinical trials is provided in Table 2. Small molecules that have recently shown anti-proliferative effects in preclinical models are listed in Table 3.

Intensive chemotherapy

CMML is basically a chemoresistant disease that cannot be cured with intensive chemotherapy alone. Except for CMML-2 as a bridge to allo-SCT, this therapeutic approach is not recommended [17]. The novel agent CPX-351 (Vyxeos), a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 molar ratio, has been FDA-approved for the

Fig. 2 Therapeutic strategies for CMML patients. Allo-SCT allogeneic stem cell transplantation, ESA erythropoiesis-stimulating agent, NGS next-generation sequencing, HMA hypomethylating agents, MDS myelodysplastic syndrome, AML acute myeloid leukemia, TKI tyrosine kinase inhibitors, GM-CSF R granulocyte-macrophage colony-stimulating factor receptor. Asterisk indicates allo-SCT for patients with CMML-0/1 has to be discussed on an individual basis, taking into account patient characteristics and other disease parameters, such as somatic mutations. Hash indicates although HMA have been approved for CMML, recent data suggest that their use is questionable.
treatment of newly diagnosed therapy-related AML or AML with myelodysplasia-related changes [30]. This new formulation is currently tested in clinical trials for patients with high-risk CMML or secondary AML (NCT04802161, NCT03672539) (Table 2) and its efficacy to bridge a severe CMML to transplant would deserve to be tested.

Optimized use of hypomethylating agents

Predictive biomarkers for HMA response. As mentioned above, the currently used HMA have limited efficacy in modifying CMML course. A first question is whether we could improve their clinical interest by selecting patients that are more prone to benefit from these drugs. A study based on 174 HMA-treated CMML patients suggested that the combined ASXL1 wild-type/
TET2 mutated genotype was associated with a significantly higher CR rate [31]. Another pivotal study including 40 CMML patients who were responsive or resistant to DAC identified a specific molecular signature consisting of 167 differentially methylated regions of DNA at baseline that distinguished responders from non-responders, allowing the development of an epigenetic classifier that accurately predicted DAC response at the time of diagnosis [32]. The utility of these predictive biomarkers of CMML response to HMA has not yet been validated in routine clinical practice [17].
Next-generation HMA. Could we improve HMA efficacy in CMML treatment? AZA and DAC are not readily orally bioavailablebecause of rapid clearance by cytidine deaminase (CDA) in the gut and the liver. Next-generation HMA with alternative modes of administration have been developed, as well as strategies combining HMA with other compounds. Unfortunately, all these optimizing strategies are being tested in trials that lump CMML cases with a large number of MDS cases. Guadecitabine (SGI-110), a prodrug dinucleotide comprising DAC and deoxyguanosine that can be injected subcutaneously, has a longer in vivo exposure time than intravenous DAC and is clinically active with acceptable tolerability in higher-risk MDS and CMML patients (NCT01261312) (Table 1) [33]. Oral HMA, such as CC-486 (oral azacitidine) and ASTX727, a combination of oral DAC with the CDA inhibitor cedazuridine, have also been investigated in MDS and CMML. In July 2020, the FDA approved the oral combination of DAC (35 mg)/cedazuridine (100 mg) for adult patients with MDS and CMML, based on the results from two randomized crossover trials (NCT02103478 and NCT03306264) showing that systemic DAC exposure, DNA demethylation, safety, and efficacy were similar to intravenous DAC (Table 1) [34, 35]. These oral HMA formulations, which have the potential to offer a convenient alternative to injectable HMA, could gradually replace their injectable counter- parts. That said, given their limited activity [25], HMA alone may not be an obligate comparator any more in CMML-dedicated clinical trials, thereby opening more possibilities for innovative trial design. Combination therapy with HMA. A commonly tested strategy in an attempt to increase their efficacy is to combine HMA with other drugs. Phase 2 trials failed to demonstrate so far any advantage in combining HMA with a variety of histone deacetylase inhibitors [36]. More promising results were obtained with lenalidomide, a thalidomide analog with clinical efficacy in MDS, particularly in the setting of chromosome 5q deletion [37]. The North American Intergroup conducted a phase 2/3 multicenter trial that randomly assigned 277 patients with high-risk MDS or CMML to AZA, AZA + lenalidomide, or AZA + vorinostat (NCT01522976). Results of the phase 2 part of the trial indicated AZA + vorinostat was not effective in the CMML subgroup, with only 12% ORR and increased toxicity. In contrast, the AZA + lenalidomide combina- tion was well tolerated (without increasing serious adverse events as compared with monotherapy) and, in the subgroup of CMML patients (n = 53), increased the ORR as compared to AZA alone (68% vs. 28%) [38]. Nonetheless, given the inherent biases of such subgroup analysis, the efficacy of the AZA + lenalidomide combination remains to be confirmed in future studies dedicated to CMML.

A. Renneville et al.
4 Therapeutic agent(s) Mechanism of action Phase study Intervention Disease(s) Reference
Lenzilumab Anti-hGM-CSF antibody 1 Lenzilumab monotherapy CMML NCT02546284 48 Ruxolitinib JAK1 and JAK2 inhibitor 2 Ruxolitinib monotherapy CMML NCT03722407 52 Lenalidomide CRBN modulator 2 Azacitidine ± lenalidomide CMML, MDS NCT01522976 38 Tagraxofusp (SL-401) CD123-directed cytotoxin 2 Tagraxofusp monotherapy CMML, myelofibrosis NCT02268253 73 Sotatercept Ligand trap for activin II 2 Sotatercept monotherapy Anemia due to CMML NCT01736683 43
receptor A or LR MDS Guadecitabine (SGI-110) Subcutaneous DNMT inhibitor 1/2 Guadecitabine monotherapy CMML, MDS, AML NCT01261312 33 Decitabine + DNMT1 inhibitor + CDA 1/2 Oral decitabine + cedazuridine CMML, MDS NCT02103478 34
cedazuridine inhibitor monotherapy Decitabine + DNMT1 inhibitor + CDA 3 Oral decitabine + cedazuridine vs. IV CMML, MDS, AML NCT03306264 35
cedazuridine inhibitor decitabine

Another potentially important drug in combination with HMA is venetoclax, an orally bioavailable selective small-molecule BCL2 inhibitor. AZA was suspected to synergistically inhibit the prosurvival proteins MCL1 and BCL-XL, thereby increasing the dependence of leukemia cells on BCL2. Venetoclax combined with HMA has recently emerged as a new standard of care for newly diagnosed AML patients who are ineligible for intensive che- motherapy [39], with NPM1 or IDH1/2 mutated AMLs being particularly responsive to the combined treatment, that is now being evaluated in CMML (and MDS) patients (NCT04160052, NCT03404193) (Table 2). However, a recent study reported that resistance to AZA + venetoclax in AML can arise due to biological properties intrinsic to monocytic differentiation. Resistant mono- cytic AML (sub)clones were found to lose expression of the venetoclax target BCL2 and rely on MCL1 to mediate oxidative phosphorylation and survival. Furthermore, preliminary evidence suggests that genetic factors, such as RAS mutations may contribute to venetoclax resistance either through epistatic mechanisms and/or by driving monocytic differentiation [40].
Finally, HMA could be combined with targeted therapies. Although rare, IDH2 and, to a lesser extent, IDH1 mutations are identified in a small subset of CMML, often preceding leukemic transformation. IDH1/2 inhibitors could be an option for these patients and their combination to AZA could potentially improve their efficacy. This approach is currently being tested in a clinical trial combining AZA with the IDH2 inhibitor enasidenib, notably in CMML patients (NCT03683433, NCT03383575) (Table 2). If the efficacy of personalized drug combinations is validated in subsets of CMML patients, currently developed oral HMA could make them easier to use [41].

New treatments for CMML-associated cytopenias

The management of CMML-associated cytopenias can be a challenge. Sotatercept (ACE-011) and luspatercept (ACE-536) are ligand traps for activin II receptors A and B, respectively, that both inhibit negative regulators of late-stage erythropoiesis. These novel agents are recombinant fusion proteins consisting of the extracellular domain of the human activin receptor type IIA or IIB linked to the human immunoglobulin G1 Fc domain. Both drugs act as ligand traps by competitively binding and neutralizing transforming growth factor β superfamily ligands, such as activins and growth differentiation factors including GDF11, known to inhibit late-stage erythroid maturation through phosphorylation and activation of Smad 2/3 transcription factors. Early promising

Table 2. On-going clinical trials in CMML.
Agents tested
Epigenetic modifiers Mechanism of action Phase study Intervention Disease(s) ClinicalTrials. Identifier gov
NTX-301 Oral DNMT1 inhibitor 1 NTX-301 monotherapy CMML, AML, MDS NCT04167917
Vitamine C (ascorbic acid) Cofactor of TET dioxygenases NA Monotherapy with oral vitamin C CMML-1, LR MDS NCT03682029
Vitamine C (ascorbic acid) Cofactor of TET dioxygenases 2 Vitamine C or placebo + azacitidine CMML, MDS, AML NCT03999723
ASTX030 DNMT1 inhibitor + CDA inhibitor 2/3 Cedazuridine + azacytidine CMML, AML, MDS NCT04256317
ASTX727 DNMT1 inhibitor + CDA inhibitor 3 Oral cedazuridine + decitabine vs. IV decitabine CMML, MDS, AML NCT03306264
ASTX727 DNMT1 inhibitor + CDA inhibitor 1/2 ASTX727 + itacitinib (JAK1 inhibitor) (arm 1) MDS/MPN NCT04061421
1/2 ASTX727 + INCB053914 (Pan-PIM inhibitor) (arm 2) MDS/MPN NCT04061421
1/2 ASTX727 + INCB059872 (LSD1 inhibitor)
(arm 3) MDS/MPN NCT04061421
ASTX727 DNMT1 inhibitor + CDA inhibitor 1/2 ASTX727 + venetoclax CMML, MDS NCT04655755
Seclidemstat LSD1 inhibitor 1/2 Seclidemstat + azacitidine CMML, MDS NCT04734990
Signaling pathways
Ruxolitinib JAK1 and JAK2 inhibitor 2 Ruxolitinib monotherapy CMML NCT03722407
NMS-03592088 FLT3, CSF1R, and KIT inhibitor 1/2 NMS-03592088 monotherapy CMML, R/R AML NCT03922100
Cobimetinib Oral MEK1 and MEK2 inhibitor 2 Cobimetinib monotherapy CMML with RAS pathway mutations NCT04409639
Trametinib Oral MEK1 and MEK2 inhibitor 2 Trametinib + azacitidine + venetoclax R/R CMML, MDS, AML NCT04487106
Quizartinib Selective FLT3 inhibitor 1/2 Quizartinib + azacitidine MDS/MPN with FLT3 or CBL mutations NCT04493138
Glasdegib Oral SMO inhibitor 3 Azacitidine ± glasdegib CMML, MDS, AML NCT04842604

Canakinumab Anti-IL-1β monoclonal antibody 2 Canakinumab ± azacitidine after four cycles CMML, MDS NCT04239157
MBG453 Anti-TIM-3 monoclonal antibody 3 MBG453 or placebo + azacytidine CMML-2, MDS NCT04266301
Cusatuzumab Anti-CD70 monoclonal antibody 2 Cusatuzumab or placebo + azacytidine CMML, HR MDS NCT04264806
Bevacizumab Anti-VEGF-A monoclonal antibody 1 Bevacizumab + abaloparatide CMML, MDS NCT03746041
IO-202 LILRB4 blocking antibody 1 IO-202 ± azacitidine R/R CMML, monocytic AML NCT04372433

SNS-301 Cancer vaccine 2 SNS-301 monotherapy CMML-2, HR MDS NCT04217720
BLEX 404 (BLI-1401) Immunostimulant 2 BLEX 404 + azacitidine CMML, MDS NCT02944955

Ubiquitin-Proteasome system
TAK-243 (MLN7243) E1 ubiquitin ligase inhibitor 1 TAK-243 monotherapy CMML, R/R AML, MDS NCT03816319
Pevonedistat (MLN4924) NEDD8-activating enzyme inhibitor 1 Pevonedistat + azacitidine CMML, MDS, AML NCT03814005
Pevonedistat (MLN4924) NEDD8-activating enzyme inhibitor 3 Azacitidine ± pevonedistat CMML, HR MDS, low-blast AML NCT03268954 Others
Tagraxofusp (SL-401) CD123-directed cytotoxin 2 Tagraxofusp monotherapy CMML, myelofibrosis NCT02268253
Enasidenib IDH2 inhibitor 2 Enasidenib + azacitidine CMML, MDS, acute leukemia NCT03683433

Table 2 continued
Agents tested
Enasidenib Mechanism of action
IDH2 inhibitor Phase
2 study Intervention
Enasidenib ± azacitidine Disease(s)
CMML, MDS, AML ClinicalTrials. Identifier
NCT03383575 gov
LY3410738 Covalent IDH inhibitor 1 LY3410738 monotherapy CMML, MDS, AML, MPN NCT04603001
Venetoclax BCL2 inhibitor 1/2 Venetoclax + azacitidine CMML, HR or R/R MDS NCT04160052
Venetoclax BCL2 inhibitor 2 Venetoclax + decitabine CMML-2, R/R AML, HR MDS, BPDCN NCT03404193
Ceralasertib (AZD6738) ATR kinase inhibitor 1 Ceralasertib monotherapy CMML, MDS NCT03770429
CB-839 Glutaminase inhibitor 1b/2 CB-839 + azacitidine CMML, HR MDS, AML NCT03047993
CPX-351 Liposomal cytarabine-daunorubicin 1 CPX-351 monotherapy CMML, HR R/R MDS NCT03896269
CPX-351 Liposomal cytarabine-daunorubicin 2 CPX-351 ± pomalidomideCMML, MDS, MPN, AML, t-AML NCT04802161
Salsalate NSAID 2 Salsalate + venetoclax + decitabine or azacitidine CMML-2, AML, MDS/MPN NCT04146038
CFI-400945 Oral inhibitor of polo-like kinase 4 1/2 CFI-400945 ± decitabine or azacitidine CMML, MDS, AML NCT04730258
Actively recruiting and not yet recruiting interventional studies registered in the database are listed.
R/R relapsed/refractory, HR high-risk, LR low-risk, BPDCN blastic plasmacytoid dendritic cell neoplasm, t-AML therapy-related acute myeloid leukemia, NSAID nonsteroidal anti-inflammatory drug.

Table 3. Small molecules with anti-proliferative effects in preclinical models.
Agent(s) tested
Pacritinib Mechanism of action
JAK2/FLT3 inhibitor Cell types
CMML primary cells Observations
Pacritinib inhibits the growth of CMML cells in vitro and in vivo in PDX models Reference
Binimetinib MEK inhibitor TET2 and N-RAS-
mutated cells Mouse and human TET2/NRAS double-mutant leukemia show preferential sensitivity to MEK inhibition 58
Volasertib PLK1 inhibition RAS-mutated CMML cells Pharmacologic inhibition of PLK1 is able to kill CMML cells in vitro and in RAS-mutant PDX models 46
Dasatinib Tyrosine kinase inhibitor targeting LYN CBL-mutated CMML cells LYN inhibition by dasatinib has in vitro and in vivo efficacy in CBL-mutant cell lines and primary CMML cells 64
Azacitidine + Trametinib Hypomethylating agent + MEK inhibitor RAS-mutated CMML cells Azacitidine and trametinib additively inhibited ERK phosphorylation and prolonged survival of CMML mice compared to single-agent treatment 59
S63845 + MEK
inhibitors MCL1 inhibitor + MEK inhibitors CMML primary cells Combined MCL1 and MEK inhibition restores CMML monocyte apoptosis and decreases leukemic burden in PDX models 60
PDX patient-derived xenograft. results have been reported with these novel agents for treating anemia in lower-risk MDS patients, and higher responses were observed among patients with ring sideroblasts and SF3B1 mutation. A recent phase 3 randomized trial with luspatercept demonstrated significant hemoglobin responses in MDS patients [42]. A phase 2 dose-finding study evaluating sotatercept in patients with anemia due to lower-risk MDS or non-proliferative CMML after failure with ESAs [43] identified a hematologic improvement in 49% (36/74) of patients while grade 3–4 adverse events were observed in only 5% of them (4/74). This trial provided a proof-of-principle that sotatercept can restore ineffective erythropoiesis in patients with low-risk MDS and CMML with an acceptable safety profile (Table 1). Altogether, activin receptor II ligand traps may represent a new paradigm for anemia treatment in low-risk CMML with cytopenia (Fig. 2).
Another commonly observed cytopenia in CMML is thrombo- cytopenia, which can be difficult to manage. The oral thrombo- poietin receptor agonist eltrombopag has been explored in a multicenter phase 2 trial in patients with CMML-0 and platelet count < 50 × 109/L (NCT02323178). The final results of this trial indicate eltrombopag treatment is safe and induces frequent but mostly transient responses without increasing the risk of CMML progression. Eltrombopag could be considered in lower-risk CMML patients with isolated thrombocytopenia (Fig. 2). Phase 3 studies may be useful to confirm the role of eltrombopag in CMML patients with thrombocytopenia [44].

Novel-targeted approaches

Comprehensive analysis of the genomic CMML landscape demonstrated an average of 14 ± 5 mutations in coding sequences per patient, which is similar to AML but much lower than the average number of mutations in solid tumors [25, 45]. This relative genetic simplicity is combined with low intraclonal heterogeneity [19]. Moreover, about 40% of CMML cases harbor somatic gain-of-function mutations that are amenable to pharma- cological inhibition. Collectively, these features suggest CMML may be particularly suitable for molecularly targeted approaches. This is especially true for the MP-CMML subtype, where activating mutations in signaling pathways are highly enriched [46].

Therapies targeting GM-CSF signaling pathways

Like observed in juvenile myelomonocytic leukemia (JMML), a pediatric disease closely related to CMML, CMML cell proliferation is related to myeloid progenitor hypersensitivity to granulocyte- macrophage colony-stimulating factor (GM-CSF), which elicits a cascade of downstream signaling and transcription factor activa- tion to include the induction and activation of STAT5 [47]. About 90% of CMML primary samples demonstrate hypersensitivity to GM-CSF by hematopoietic colony formation assays and phospho-
STAT5 flow cytometry, which likely contributes to the monocytic phenotype. This phenomenon is enhanced by signaling- associated mutations, such as N-/KRAS, CBL, and JAK2 mutations with high variant allele frequency, but not limited to cases harboring those mutations. These findings suggest that the divergent molecular alterations in CMML may mediate responses that converge within the GM-CSF signaling pathway[47]. This pathway can be targeted using different approaches, including immunotherapies and small molecules inhibitors of downstream components of the GM-SCF receptor signaling pathway (Figs. 2–3). Lenzilumab (KB003) is a novel, engineered human IgG1κ monoclonal antibody, with high affinity for human GM-CSF thathas activity in preclinical models of CMML [47]. Patnaik et al. have recently reported a multicenter phase 1 clinical trial testing the safety and preliminary efficacy of single-agent lenzilumab in 15 CMML patients who were refractory, intolerant or deemed ineligible for HMA or hydroxyurea therapy. The drug was well tolerated, without any drug-related grade 3–4 adverse events, and durable clinical benefit was achieved in four (33%) patients. One patient with a partial marrow response was bridged to allo-SCT, providing a proof-of-concept that GM-CSF inhibition is a viable therapeutic strategy in CMML. Responses were seemingly better in RAS-pathway mutant CMML patients and in those who demon- strated GM-CSF hypersensitivity in colony-forming assays and robust patient-derived xenograft (PDX) engraftment. Future studies will better identify CMML patients who are more likely to respond to this immunotherapy and suggest rational combina- tion strategies [48]. Mavrilimumab, a GM-CSF receptor alpha- directed mononclonal antibody that has been successfully tested in rheumatoid arthritis patients [49], could also be considered as an additional therapeutic option in CMML patients.
Since JAK2 is a sentinel tyrosine kinase in the GM-SCF pathway, JAK2 inhibition is another attractive approach to antagonize GM- CSF hypersensitivity. Ruxolitinib is a JAK1/2 inhibitor that is already approved in MPNs, including myelofibrosis, based on phase 3 data demonstrating improved disease-free survival and symptom control [50, 51]. Notably, responses were seen even in the absence of a detectable JAK2 mutation. A phase I trial evaluating ruxolitinib as monotherapy in 20 CMML-1 patients either as first- line therapy or after HMA failure did not identify any dose-limiting toxicity [52]. Although the trial was not designed to assess efficacy, objectives responses, including spleen reduction, improvement of constitutional symptoms, and hematologic improvement, were observed in seven patients (35%) [52]. A phase 2 trial evaluating the efficacy of ruxolitinib monotherapy in CMML is ongoing (NCT03722407) (Table 1), but the preliminary data of combining ruxolitinib and AZA in MDS/MPN overlap syndromes (NCT01787487) indicated a good tolerance of the combination and a response rate of 57% in patients with MDS/MPNs, of which 17/35 (48%) had CMML [53].
Pacritinib, a JAK2/FLT3 inhibitor, showed efficacy in reducing pSTAT5 levels in response to GM-CSF stimulation in primary CMML cells. Pacritinib also demonstrated anti-proliferative and pro-apoptotic effects in CMML cells both in vitro and in PDX models (Table 3). These data further confirm the importance of targeting GM-CSF cytokine stimulation as a therapeutic approach in CMML [54].

Therapies targeting RAS-MAPK pathway

Oncogenic RAS pathway mutations in genes including NRAS, KRAS, CBL, and PTPN11 mutations, are identified in ~30–40% of CMML patients and frequently drive a proliferative CMML phenotype [46, 55]. In many respects, CMML appears to be a RASopathy of the elderly, developing in the genetic background of epigenetic and splicing somatic alterations, contrasting with JMML, a RASopathy of children with germline or somatic RAS pathway alteration. Targeting the RAS-MAPK pathway is therefore an attractive therapeutic approach in CMML [56].
Tipifarnib is a potent and selective inhibitor of farnesyltransfer- ase (FT), an enzyme required for post-translational attachment of farnesyl groups for localization of signaling proteins, including all RAS enzymes, to the inner cell membrane. The caveat of this pharmacological strategy is that NRAS and KRAS can undergo an alternative pathway for prenylation, enabling the cancer cells to overcome signaling inhibition by FT inhibition alone. Since N-/ KRAS mutations are involved in at least 30% of CMML cases, tipifarnib was investigated in this disease[57]. Surprisingly, tipifarnib may be more effective in RAS-wild-type CMML cells, suggesting an off-target effect. Tipifarnib as a single agent has been tested in a phase 2 trial in CMML patients (NCT02807272) but results were suboptimal and the study is now closed.
MEK1/2 inhibitors, including trametinib, binimetinib, and cobimetinib, have shown promising clinical activity in various cancers and represent an active area of investigation in CMML. A CMML-specific phase 2 trial is ongoing to assess the efficacy of cobimetinib in newly diagnosed or HMA-treated CMML patients
with RAS pathway mutations (NCT04409639). Of particular interest for CMML, Tet2/Nras double-mutant mouse models responded to MEK inhibition, which was also observed in patient samples [58], providing a rationale for mechanism-based therapy in CMML carrying these two concomitant mutations. Furthermore, a novel combination therapy with trametinib and AZA was shown to additively inhibit ERK phosphorylation and significantly prolonged survival of CMML mice compared to single-agent treatment [59]. Finally, recent findings indicate that the combined inhibition of MAPK and MCL1 is a promising therapeutic approach to slow down CMML progression by inducing leukemic monocyte apoptosis [60] (Table 3).

Fig. 3 Targeting cell-autonomous mechanisms in CMML. Schematic representation of the activity of currently available therapeutic agents at the cell level. pUb polyubiquitin, 5-mC 5-methylcytosine, 5-hmC 5-hydroxymethylcytosine.

Targeting other signaling pathways

Hedgehog signaling is critical for the maintenance and expansion of cancer stem cells and has attracted a great deal of attention as a therapeutic target in solid and hematologic malignancies [61]. Glasdegib, an oral inhibitor of sonic hedgehog receptor smooth- ened, has been approved in the USA and Europe in combination with low-dose cytarabine to treat patients with newly diagnosed
AML unable to receive intensive chemotherapy due to comorbid- ities or age (≥75 years). Phase 2 trials are evaluating glasdegib in MDS and CMML patients, either in monotherapy (NCT01842646) or in combination with AZA (NCT02367456). The addition of glasdegib to AZA for patients with newly diagnosed higher-risk
MDS, AML, or CMML ineligible for intensive chemotherapy showed promising CR and overall survival rates [62]. Recently, we observed that RAS pathway mutations caused increased expression of the mitotic checkpoint kinase PLK1 through enrichment of H3K4me1 at the PLK1 gene promoter, a process regulated by the lysine methyltransferase KMT2A (MLL1). PLK1 inhibition with volasertib efficiently reduced the formation of progenitor colonies derived from NRAS mutant proliferative CMML cells, and demonstrated anti-leukemic activity in RAS-mutant CMML PDX models (Table 3) [46]. These results are consistent with prior work showing that PLK1 is a therapeutic vulnerability in RAS-mutated cells [63]. Given that volasertib has an established safety record in myeloid malignancies, these findings provide immediate therapeutic perspectives especially for RAS-mutant proliferative CMML.
A recent study provided evidence that gain-of-function CBL mutations activate the SRC-family kinase LYN, which in turn stimulates PI3K/AKT signaling pathways. Pharmacological inhibi- tion of LYN by dasatinib showed in vitro and in vivo efficacy in CBL-mutant cell lines and primary CMML cells (Table 3), suggesting a novel therapeutic opportunity for the treatment of CBL-mutant CMML. Ongoing studies aimed at determining whether dasatinib may have broader inhibitory effects in diseased cells, independent of CBL mutations [64].
PI3k-δ is the most abundant PI3K subunit amongst monocytic leukemia samples, including CMML samples. Combination therapy with the PI3K-δ inhibitor umbralisib and the JAK1/2 inhibitor ruxolitinib was recently shown to synergistically decrease growth in CMML primary samples in vitro. This dual inhibition had the unique ability to decrease STAT5, ERK, S6, and AKT signaling simultaneously. These findings suggest co-inhibition of PI3K-δ and JAK1/2 has promising activity and deserves further investigation in CMML [65].

Targeting the spliceosome

Mutations in spliceosome genes, such as SRSF2, SF3B1, and U2AF1 are involved in over half of CMML patients. In contrast to signaling pathway mutations, these mutations are typically early events in CMML pathogenesis, which suggest an opportunity to target the founder clone [66]. Several studies suggested that cancer cells with spliceosome mutations are preferentially susceptible to additional splicing perturbations in vivo as compared to cells without such mutations, thus providing a therapeutic window in spliceosome mutant malignancies [67]. The orally bioavailable modulator of the SF3b complex H3B-8800 was shown to induce lethality in spliceosome-mutant malignancies in preclinical models [68]. A phase 1 trial testing H3B-8800 in AML, MDS, and CMML patients (NCT02841540) has demonstrated safety, even with prolonged dosing. However, efficacy results have been disap- pointing since no objective complete or partial responses were achieved. Decreased RBC or platelet transfusion requirements were still observed in 12/84 (14%) of enrolled patients [69].

General and/or empirical treatment approaches

The concept of cancer precision medicine in CMML is limited to a subset of patients harboring druggable mutations. Moreover, the vast majority of druggable targets identified in CMML so far, which belong to signaling pathway mutations, are mostly late and often subclonal events in CMML evolution. Treatment approaches that may be synergistic or complementary to molecularly targeted therapies may be therefore of utmost importance in order to improve the disease outcome.
Tagraxofusp (formerly SL-401) is a CD123-directed cytotoxin consisting of recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin. The IL-3 domain binds to CD123 (the alpha chain of the IL-3 receptor heterodimer) and translocates diphteria toxin into the cytosol, which leads to cell death. In December 2018, tagraxofusp was FDA-approved for the treatment of blastic plasmacytoid dendritic cell neoplasm, a rare and aggressive hematologic malignancy with strong CD123 expression [70]. CD123 is also a potential therapeutic target in various myeloid malignancies, including AML and MDS [71]. CD123 is highly expressed on primary blasts and monocytes from CMML patients [72]. A phase 2 trial evaluating the safety and efficacy of tagraxofusp in CMML patients is under way (NCT02268253), with preliminary data demonstrating a 80% spleen response rate and a 30% BM CR rate (Table 1) [73]. Plasmacytoid dendritic cells (pDC) accumulate in the BM of ~20% of CMML patients and were recently shown to be part of the leukemic clone. The presence of pDC in CMML correlates with the presence of RAS pathway mutations and an increased risk of acute leukemia transformation [74]. Tagraxofusp has thus the potential to target both typical CMML cells and, in some cases, the associated clonal pDC population.
Previous studies have established a role for indoleamine 2,3- dioxygenase 1/2 in regulating pDC and myeloid DC plasticity. IDO is an immune-checkpoint enzyme that induces systemic immune tolerance through multiple mechanisms, including regulatory T-cell (Treg) expansion and tryptophan catabolism. A recent study using CMML patient samples highlighted the association of BM IDO- positive DC aggregates with a T-cell compartment shift toward a
Treg phenotype. Future research will reveal whether this finding might be exploited therapeutically using IDO pathway inhibitors, such as indoximod and/or CD123-directed therapies [75].
Imetelstat, a 13-mer lipid-conjugated oligonucleotide targeting the RNA template of human telomerase reverse transcriptase, is a first-in-class telomerase inhibitor currently in clinical development for myeloid malignancies. Imetelstat has shown remarkable efficacy in patients with essential thrombocythemia [76] and primary myelofibrosis [77]. A phase 2/3 multicenter study is ongoing to evaluate the efficacy and safety of imetelstat in transfusion- dependent patients with low or intermediate-1 risk MDS who are relapsed/refractory to ESA (NCT02598661), with preliminary data showing a 8-week transfusion independence rate of 42% for a median duration of 20 months and limited side effects [78]. Further studies are required to determine the potential of imetelstat in CMML patients, identify the underlying genetic susceptibilities to telomerase inhibition therapy, and evaluate rational therapeutic combinations with telomerase inhibitors.

The (lack of) CMML models

Comprehensive biological studies and therapeutic advances in CMML have been considerably hampered by the lack of appropriate CMML models. First, a cancer cell line representative of CMML has not been generated yet. Second, the short-life span of primary CMML cells ex vivo does not allow high-throughput screening. Third, the limited development of mouse models so far represents an additional barrier to the development of novel therapies.
The generation of induced pluripotent stem cell clones from CD34+ cells from CMML patients has recently been tested as an alternative approach to model the disease. However, this experimental system has proven to be difficult to work with and revealed functional heterogeneity between individual clones [79, 80]. In 2017, two groups reported the great capacity of primary CMML cells to engraft in immunocompromised mice with transgenic expression of three human cytokines including GM-SCF in the NOD/SCID-Il2rcγnull background (NSG-SGM3), with PDX that closely phenocopied human disease and genetic characteristics of the primary samples [54, 81]. Although the demonstration of robust PDX models in NSG-SGM3 mice was a significant progress in the field, serial transplantation still remains challenging. To address this concern, Kloos et al. utilized oncogenic supplementation using lentiviral expression of the human oncogene Menin- gioma 1 in primary CMML cells, allowing serial transplantation up to five generations. This efficient engraftment enabled an in vivo targeted RNA interference screening and the identification of a novel combination therapy with AZA and trametinib that has demonstrated additive effect in vivo (Table 3) [59].

Future research directions

Development of CMML model systems. The limited availability of CMML models is a major bottleneck that limits basic and translational research, including target identification and drug discovery. Future work should focus on the development of new model systems that would serve as a basis for high-throughput genetic or drug screening approaches. Efforts dedicated to the creation of CMML cell lines should be pursued. Co-culture systems with BM mesenchymal stromal cells [82] should be explored for CMML stem cells. PDX models are assumed to faithfully recapitulate the cellular and molecular features of primary CMMLs and represent an extremely valuable tool for in vivo preclinical studies [54]. The use of CMML PDX models should be encouraged to improve preclinical evaluation of novel treatment strategies and our ability to predict patient responses in clinical trials.
Identification of novel therapeutic targets. Understanding key pathophysiological mechanisms implicated in CMML will help to identify novel therapeutic targets and design alternative or adjuvant treatments to optimize existing therapeutic strategies. For instance, a better understanding of the role of the immune system in CMML pathogenesis could also lay the foundation for future therapeutic strategies, such as immune-checkpoint inhibi- tors. Single-cell analysis of clonal architecture evolution under therapy, combining genotyping, gene expression, and epigenetic changes, could reveal novel therapeutic vulnerabilities allowing selective targeting of CMML cells. Another advantage of single-cell technologies is to allow the identification of residual normal stem cells, a potential reservoir to restore functional hematopoiesis [83]. Finally, deciphering the key molecular mechanisms underpinning acute leukemia transformation will be instrumental in tailoring . novel treatments that could be proposed to prevent CMML progression to AML.

Fig. 4 Targeting non-cell autonomous mechanisms in CMML. Schematic representation of potential therapeutic strategies that could be developed to target non-cell autonomous features in CMML. MSC mesenchymal stem cells, LSC leukemic stem cells, MPP multipotent progenitors, CMP common myeloid progenitors, CLP common lymphoid progenitors, pDC plasmacytoid dendritic cells

(1) Which cell type(s) should be targeted?

An open question in CMML is which cell type(s) should be targeted. Although CMML originates from a stem/progenitor leukemic cell, targeting the mature cells of the malignant clone could also be envisioned. Monocytes belonging to the CMML clone can produce proinflammatory cytokines that ultimately redirects leukemic progenitor cell fate towards the myeloid lineage, establishing a positive feedback loop that sustains leukemic development, as observed with IL-6 in chronic myeloid leukemia [84]. Similarly, CMML derived BM macrophages likely contribute to modify the BM niche and affect disease development or progression. Another therapeutic opportunity could be to target the clonal pDC population or immature neutrophils that behave as myeloid- derived suppressive cells, but this will require a deeper understanding of their contributions to the disease.

(2) Which mechanisms should be targeted?

To date, most efforts to treat CMML have been focused on targeting cell-autonomous features, essentially target- ing cell surface receptors or intracellular proteins within individual CMML cells (Fig. 3). Targeting non-cell autono- mous mechanisms, including cell–cell interactions and soluble factors, may also be exploited in the future. This could be achieved by targeting interactions between the CMML cells and their BM microenvironment, or targeting signaling molecules between mature and stem/progenitor CMML cells, or alternatively targeting molecular mediators that have been shown or suggested to play an important role in CMML monocyte biology, such as CCL2 (MCP-1), CCL3 (MIP1α), IL-1α/β, IL-6, and IL-17 (Fig. 4) [85–88].
Development of innovative treatment modalities. Existing ther- apeutic agents for CMML mainly consist of small-molecule inhibitors of signaling pathways, or receptor agonists/antagonists. Immunotherapy approaches are in development and several monoclonal antibodies and immunostimulants are currently tested in clinical trials (Table 2). The fact that allo-SCT can cure some CMML patients provides evidence that other immunother- apeutic approaches have the potential to be curative in future non-transplant settings. Further studies are required to identify
which biological subtypes of CMML are more likely to benefit from allo-SCT or alternative immunotherapy approaches.
Another active area of research is targeted protein degradation approaches that utilize the ubiquitin-proteasome system to degrade proteins of interest, including those previously thought to be undruggable, such as transcription factors. This pharmaco- logical strategy has revolutionized the treatment of other myeloid malignancies, namely acute promyelocytic leukemia [89] and del (5q) MDS [90], and may be employed in the future for CMML. The field of small interfering RNA therapeutics is also rapidly evolving and has the ability to target specific missense mutations [91], which could be helpful to target recurrent point mutations, for example N/KRAS p.G12D or SRSF2 p.P95H mutations.
Finally, translating these scientific advances into clinical benefits for CMML patients will require the intervention of the MDS/MPN international working group (IWG) to set up
international dedicated trials, supported by consensual prog- nostic tools and treatment response criteria. It is anticipated that the 2015 IWG response assessment guidelines proposed for adult MDS/MPN [92] will require further refinement and validation in the context of CMML. Standardizing outcome assessment will help to better evaluate the impact of novel therapies for CMML.


Standard treatment options for CMML are limited. Current clinical management still relies on supportive care, hydroxyurea, HMA, and allo-SCT, the latter remaining the only path to a potential cure. To address the question of which CMML patient might benefit from allo-SCT and when should allo-SCT be recommended, we advocate for better biological annotations in transplant registries and more transplant studies.
The inclusion of patients in CMML-dedicated clinical trials must be strongly encouraged to identify innovative therapeutic strategies taking into account the proliferative component of the disease together with cell dysplasia and the altered immune and tissue environment. The unmet need in CMML treatment triggers sufficient interest to anticipate that phase 3 randomized clinical trials are indeed feasible in CMML, as demonstrated by the DACOTA trial [28].
Targeted therapy in CMML is in its infancy, but multiple novel agents are being investigated in clinical trials and some of them have shown promising activity in CMML patients. Current evidence supports the idea that effective treatment in CMML will likely require combination therapy targeting multiple pathways, which emphasizes the need for additional new therapeutic options.
Development of new CMML model systems, identification of novel therapeutic targets, and innovative treatment modalities should help designing rationally derived and disease-modifying therapies for CMML. These efforts should be pursued in the frame of IWGs to move the CMML field forward.


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AR wrote the original draft and made figures. MMP, OC, EP, and ES revised the manuscript. ES supervised the work.

ES group was supported by research grants from Stemline and from Servier laboratories. EP has research funding from Incyte, Kura, and BMS. EP has received honorarium from Novartis, Taiho, Stemline, and Blueprint medicines.

Correspondence and requests for materials should be addressed to E.S.
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