{"entity":{"id":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","aka":["CMML","MDS/MPN","Myelodysplastic/myeloproliferative neoplasms","Atypical CML (BCR-ABL1-negative)","MDS/MPN with ring sideroblasts and thrombocytosis","MDS/MPN with SF3B1 mutation and thrombocytosis","Juvenile myelomonocytic leukaemia (JMML)"],"tldr":"Chronic myelomonocytic leukaemia and its relatives are bone-marrow cancers that behave partly like myelodysplasia (poorly made blood cells) and partly like a proliferative disease (an excess of monocytes or platelets). Hypomethylating agents produce responses in a minority and stabilise counts in more, transplant can cure the fit, and RAS-pathway and JAK inhibitors are in trials.","summary":"The myelodysplastic/myeloproliferative neoplasms combine dysplasia and cytopenias with proliferation. Chronic myelomonocytic leukaemia (CMML) is the prototype: persistent monocytosis (above 0.5 x 10^9/L and at least 10 percent of leukocytes under WHO 2022) with dysplasia, absence of BCR-ABL1 and of PDGFRA/B, FGFR1 or JAK2 rearrangements, and a characteristic mutational profile: TET2 and SRSF2 co-mutation in around half, with ASXL1, RUNX1, SETBP1 and RAS-pathway (NRAS, KRAS, CBL) mutations driving the proliferative phenotype and worse outcome. The other members are atypical CML (SETBP1, ETNK1; dysplastic neutrophilia), MDS/MPN with SF3B1 mutation and thrombocytosis (ring sideroblasts, often with JAK2 V617F), MDS/MPN not otherwise specified, and in children juvenile myelomonocytic leukaemia (JMML; RAS-pathway, neurofibromatosis type 1 and Noonan syndrome). Risk is scored by CPSS and the molecular CPSS-Mol, which incorporate blast count, white count, transfusion need, cytogenetics and ASXL1, NRAS, RUNX1 and SETBP1 mutations.\n\nAllogeneic transplant is the only curative therapy and is offered to fit patients with higher-risk disease. Hypomethylating agents are the drug standard: azacitidine and decitabine are approved for CMML (the oral decitabine-cedazuridine label also includes CMML), producing responses in a minority and stabilising counts in more, without clear evidence that they change the mutational clone. Hydroxyurea controls proliferative disease and splenomegaly and was as good as etoposide in the only randomised trial. JMML is treated with azacitidine as a bridge to transplant, the only cure. For MDS/MPN with ring sideroblasts, luspatercept and JAK inhibitors are used by extension from MDS and MPN. Trials are testing RAS-pathway inhibition (MEK inhibitors), JAK inhibition (ruxolitinib in proliferative CMML), the anti-GM-CSF antibody lenzilumab, venetoclax combinations for accelerated disease, and hypomethylating-agent combinations.\n\nOpen problems: transformation to AML in a substantial minority, the lack of disease-modifying drugs, and the fact that trials rarely enrol these patients specifically.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Chronic_myelomonocytic_leukemia","links":[{"label":"NCI PDQ: myelodysplastic/myeloproliferative neoplasms","url":"https://www.cancer.gov/types/myeloproliferative/patient/mds-mpn-treatment-pdq"},{"label":"NCCN: Myelodysplastic Syndromes (includes CMML)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"},{"label":"WHO 5th edition haematolymphoid tumours (Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01613-1"},{"label":"Hydroxyurea vs etoposide in CMML (Blood 1996)","url":"https://doi.org/10.1182/blood.V88.7.2480.bloodjournal8872480"}],"tags":["nci-coverage","rare","haematologic"],"related":["mds","myeloproliferative-neoplasms","aml","cml","systemic-mastocytosis","cll"],"cancers":[],"sections":[],"technologies":["allogeneic-hsct","epigenetic-drugs","cytogenetics-fish","flow-cytometry-mrd","ngs-bioinformatics-software","transfusion-support"],"targets":["jak2","kras","bcl2"],"drugs":["azacitidine","decitabine-cedazuridine","hydroxyurea","ruxolitinib","venetoclax","luspatercept","lenzilumab"],"companies":[],"institutions":[],"pathways":["ras-mapk","jak-stat","epigenetic-reprogramming","clonal-haematopoiesis","rna-splicing"],"terms":["hma","blasts","cytopenias","cytogenetics","conditioning-regimen"],"trials":["nct04256317"],"people":[],"bottlenecks":["b-rare-cancers","b-aging-comorbidity"],"keyPapers":["paper-wattel-blood"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"CMML affects roughly four people per million per year, almost all over 60; the overlap neoplasms are together rarer than either MDS or the classical MPNs (SEER; WHO).","subtypes":["CMML, dysplastic type (WBC under 13 x 10^9/L)","CMML, proliferative type (WBC 13 or more; RAS-pathway mutations, splenomegaly)","CMML-1 and CMML-2 by blast percentage","Atypical chronic myeloid leukaemia, BCR-ABL1-negative","MDS/MPN with SF3B1 mutation and thrombocytosis (formerly MDS/MPN-RS-T)","MDS/MPN not otherwise specified","Juvenile myelomonocytic leukaemia (paediatric)"],"biomarkers":["Monocyte count and percentage; flow cytometric monocyte subset partitioning (classical monocytes above 94 percent)","Bone marrow blasts and dysplasia","Cytogenetics (trisomy 8, -7/del(7q), complex)","NGS: TET2, SRSF2, ASXL1, RUNX1, SETBP1, NRAS, KRAS, CBL, JAK2, SF3B1; exclusion of BCR-ABL1 and PDGFRA/B rearrangements","CPSS and CPSS-Mol risk score","Germline NF1, PTPN11, CBL in JMML"],"standardOfCare":[{"setting":"Higher-risk CMML, fit with a donor","approach":"Allogeneic haematopoietic stem cell transplant, often after hypomethylating-agent cytoreduction; the only curative option.","refs":["allogeneic-hsct","azacitidine"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Myelodysplastic Syndromes (CMML section); EHA/ELN CMML recommendations","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Higher-risk or symptomatic CMML, not transplant candidate","approach":"Azacitidine or decitabine (or oral decitabine-cedazuridine) until progression; supportive care with transfusion and growth factors.","refs":["azacitidine","decitabine-cedazuridine","hma","transfusion-support"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: MDS (CMML)"}},{"setting":"Proliferative CMML with symptomatic leucocytosis or splenomegaly","approach":"Hydroxyurea (superior to etoposide in the randomised GFM trial); ruxolitinib in trials for symptomatic proliferative disease.","refs":["hydroxyurea","ruxolitinib"],"guideline":{"version":"Wattel et al., Blood 1996 (hydroxyurea vs etoposide)","url":"https://doi.org/10.1182/blood.V88.7.2480.bloodjournal8872480"}},{"setting":"Juvenile myelomonocytic leukaemia","approach":"Allogeneic transplant; azacitidine as bridging therapy (EMA approval 2019 for JMML); watchful waiting for some CBL- or Noonan-associated cases that regress spontaneously.","refs":["azacitidine","allogeneic-hsct"],"guideline":{"version":"EWOG-MDS / COG JMML recommendations"}}],"stateOfArt":["WHO 2022 and the ICC redefined CMML with a lower monocyte threshold and molecular criteria, and split it into dysplastic and proliferative types with distinct biology.","CPSS-Mol brings mutations into risk assessment and guides transplant timing.","Hypomethylating agents remain the only approved drugs; oral decitabine-cedazuridine makes them easier to take but the clone usually persists.","RAS-pathway biology (also the driver of JMML) is the therapeutic target of the decade: MEK inhibitors, GM-CSF blockade and combinations with hypomethylating agents are in trials."],"history":[{"year":1982,"title":"FAB classification includes CMML within MDS","refs":[]},{"year":1996,"title":"Hydroxyurea beats etoposide in CMML","note":"GFM randomised trial (Wattel et al., Blood).","refs":["hydroxyurea"]},{"year":2001,"title":"WHO creates the MDS/MPN category","note":"CMML, atypical CML and JMML grouped as overlap neoplasms.","refs":[]},{"year":2004,"title":"Azacitidine approved for MDS including CMML","refs":["azacitidine"]},{"year":2013,"title":"CPSS risk score for CMML","note":"Such and colleagues; CPSS-Mol adds mutations in 2016.","refs":[]},{"year":2020,"title":"Oral decitabine-cedazuridine approved for MDS and CMML","refs":["decitabine-cedazuridine"]},{"year":2022,"title":"WHO 5th edition and ICC redefine CMML","note":"Monocyte threshold lowered to 0.5 x 10^9/L with molecular support; dysplastic vs proliferative subtypes formalised.","refs":[]}],"pipeline":["ruxolitinib","venetoclax","azacitidine","allogeneic-hsct","jbi-802","tuspetinib","bexmarilimab"],"openProblems":["No drug alters the disease course; RAS-pathway inhibitors, GM-CSF antibodies and venetoclax combinations are in early trials.","Transformation to AML in a substantial minority; sequential mutation tracking to intervene earlier is being studied.","Transplant is curative but most patients are old; reduced-intensity conditioning and better donor availability widen access.","Trials usually lump CMML with MDS or exclude it; dedicated CMML cohorts and registries (such as the European Hematology Association consortium) are the response."],"parent":"leukaemia"},"route":"/cancers/cmml/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"advanced-systemic-mastocytosis","kind":"cancer","name":"Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia)","route":"/cancers/advanced-systemic-mastocytosis/"},{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","route":"/cancers/cml/"},{"id":"histiocytoses","kind":"cancer","name":"Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms","route":"/cancers/histiocytoses/"},{"id":"leukaemia","kind":"cancer","name":"Leukaemia (all types)","route":"/cancers/leukaemia/"},{"id":"mds","kind":"cancer","name":"Myelodysplastic syndromes / neoplasms (MDS)","route":"/cancers/mds/"},{"id":"myeloproliferative-neoplasms","kind":"cancer","name":"Myeloproliferative neoplasms (PV, ET, myelofibrosis)","route":"/cancers/myeloproliferative-neoplasms/"},{"id":"systemic-mastocytosis","kind":"cancer","name":"Systemic mastocytosis","route":"/cancers/systemic-mastocytosis/"}],"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"ngs-bioinformatics-software","kind":"technology","name":"Clinical NGS bioinformatics and variant interpretation","route":"/technologies/ngs-bioinformatics-software/"},{"id":"cytogenetics-fish","kind":"technology","name":"Cytogenetics and FISH","route":"/technologies/cytogenetics-fish/"},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"},{"id":"flow-cytometry-mrd","kind":"technology","name":"Multiparameter flow cytometry MRD","route":"/technologies/flow-cytometry-mrd/"},{"id":"transfusion-support","kind":"technology","name":"Transfusion support and anaemia management","route":"/technologies/transfusion-support/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"dnmt1","kind":"target","name":"DNMT1 (DNA methyltransferase 1)","route":"/targets/dnmt1/"},{"id":"jak2","kind":"target","name":"JAK2","route":"/targets/jak2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"nras","kind":"target","name":"NRAS","route":"/targets/nras/"},{"id":"pdgfrb","kind":"target","name":"PDGFRB","route":"/targets/pdgfrb/"}],"drug":[{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/"},{"id":"bexmarilimab","kind":"drug","name":"Bexmarilimab","route":"/drugs/bexmarilimab/"},{"id":"decitabine-cedazuridine","kind":"drug","name":"Decitabine + cedazuridine (oral)","route":"/drugs/decitabine-cedazuridine/"},{"id":"hydroxyurea","kind":"drug","name":"Hydroxyurea (hydroxycarbamide)","route":"/drugs/hydroxyurea/"},{"id":"jbi-802","kind":"drug","name":"JBI-802","route":"/drugs/jbi-802/"},{"id":"lenzilumab","kind":"drug","name":"Lenzilumab","route":"/drugs/lenzilumab/"},{"id":"luspatercept","kind":"drug","name":"Luspatercept","route":"/drugs/luspatercept/"},{"id":"ruxolitinib","kind":"drug","name":"Ruxolitinib","route":"/drugs/ruxolitinib/"},{"id":"tuspetinib","kind":"drug","name":"Tuspetinib","route":"/drugs/tuspetinib/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"pathway":[{"id":"clonal-haematopoiesis","kind":"pathway","name":"Clonal haematopoiesis (CHIP)","route":"/pathways/clonal-haematopoiesis/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"jak-stat","kind":"pathway","name":"JAK-STAT signalling","route":"/pathways/jak-stat/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"rna-splicing","kind":"pathway","name":"RNA splicing","route":"/pathways/rna-splicing/"}],"term":[{"id":"blasts","kind":"term","name":"Blasts (leukaemic blast cells)","route":"/terms/blasts/"},{"id":"conditioning-regimen","kind":"term","name":"Conditioning regimen (myeloablative, reduced-intensity)","route":"/terms/conditioning-regimen/"},{"id":"cytogenetics","kind":"term","name":"Cytogenetics and karyotype","route":"/terms/cytogenetics/"},{"id":"cytopenias","kind":"term","name":"Cytopenias and myelosuppression","route":"/terms/cytopenias/"},{"id":"hma","kind":"term","name":"Hypomethylating agents (azacitidine, decitabine)","route":"/terms/hma/"},{"id":"sf3b1-mutation","kind":"term","name":"SF3B1 mutation","route":"/terms/sf3b1-mutation/"}],"trial":[{"id":"nct04256317","kind":"trial","name":"A Multi-phase Study of ASTX030 (Azacitidine and Cedazuridine) in Myeloid Neoplasm Alone or in Combination With Venetoclax in AML (AZTOUND Study)","route":"/trials/nct04256317/"},{"id":"nct04730258","kind":"trial","name":"A Study of CFI-400945 With or Without Azacitidine in Patients With AML, MDS or CMML","route":"/trials/nct04730258/"},{"id":"nct05428969","kind":"trial","name":"A Study to Assess Safety, Tolerability and Preliminary Efficacy of Bexmarilimab in Combination With Standard of Care in Patients With Hematological Malignancies","route":"/trials/nct05428969/"},{"id":"nct03850574","kind":"trial","name":"Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tuspetinib (HM43239) in Patients With Relapsed or Refractory Acute Myeloid Leukemia","route":"/trials/nct03850574/"},{"id":"nct07033598","kind":"trial","name":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia","route":"/trials/nct07033598/"},{"id":"nct07612280","kind":"trial","name":"Phase 1/ Phase 2 Study to Assess Safety and Efficacy of Orally Administered JBI-802 in Subjects With Myeloproliferative Neoplasms (MPN) and Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) With Thrombocytosis","route":"/trials/nct07612280/"},{"id":"nct04581512","kind":"trial","name":"Study to Evaluate the Safety and Tolerability of EP0042","route":"/trials/nct04581512/"}],"bottleneck":[{"id":"b-aging-comorbidity","kind":"bottleneck","name":"Older and multimorbid patients are excluded and undertreated","route":"/bottlenecks/b-aging-comorbidity/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"}],"paper":[{"id":"paper-wattel-blood","kind":"paper","name":"A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Français des Myélodysplasies and European CMML Group","route":"/key-papers/paper-wattel-blood/"}],"journal":[{"id":"current-hematologic-malignancy-reports","kind":"journal","name":"Current hematologic malignancy reports","route":"/journals/current-hematologic-malignancy-reports/"},{"id":"leukemia-research","kind":"journal","name":"Leukemia research","route":"/journals/leukemia-research/"}]}}