Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms
These are bone-marrow cancers that behave partly like myelodysplasia (poorly made blood cells) and partly like a proliferative disease (too many monocytes or platelets). Drugs that reprogramme the marrow's gene control (hypomethylating agents) help many patients, a stem cell transplant can cure the fit, and the driver mutations now being mapped point to targeted drugs.
Overview
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.
Allogeneic 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.
Open problems: transformation to AML in a substantial minority, the lack of disease-modifying drugs, and the fact that trials rarely enrol these patients specifically.
State of the art today
- 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.
Where it starts and where it drains
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
- Bone marrow (leukaemia, MDS, MPN, myeloma)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)
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- cervical
- axillary
- mediastinal
- para-aortic and mesenteric
- inguinal
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD)
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).
- AI in radiologyEstablished
- cfDNA fragmentomicsEstablished
- Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)Standard of care
- DNA methylation profilingEstablished
- HCC surveillance in cirrhosis (ultrasound + AFP)Standard of care
- High-risk pancreatic surveillance (CAPS / PRECEDE)Established
- A 28-day national pathway for people with a positive multi-cancer blood test
- A breath test to rule out cancer in people with vague symptoms
- A cancer blood test for older people arriving at A&E with unexplained symptoms
- A legislated, publicly reported 28-day standard from urgent referral to diagnosis
- A live national dashboard of stage at diagnosis as the scorecard for early detection
- A single 'cancer check at 60' appointment bundling all screening tests
Background: Alpha-fetoprotein (AFP), Barrett's oesophagus, CA 19-9, Early detection, Faecal immunochemical test (FIT). Also on OnCo: Symptoms and red flags · Early detection roadmap.
Where the cases are
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
Allogeneic haematopoietic stem cell transplant, often after hypomethylating-agent cytoreduction; the only curative option.
Azacitidine or decitabine (or oral decitabine-cedazuridine) until progression; supportive care with transfusion and growth factors.
Hydroxyurea (superior to etoposide in the randomised GFM trial); ruxolitinib in trials for symptomatic proliferative disease.
Allogeneic transplant; azacitidine as bridging therapy (EMA approval 2019 for JMML); watchful waiting for some CBL- or Noonan-associated cases that regress spontaneously.
Subtypes & biomarkers
top- 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)
- 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
Target prevalence in this cancer
- 1982FAB classification includes CMML within MDS
- 1996Hydroxyurea beats etoposide in CMML
GFM randomised trial (Wattel et al., Blood).
- 2001WHO creates the MDS/MPN category
CMML, atypical CML and JMML grouped as overlap neoplasms.
- 2004Azacitidine approved for MDS including CMML
- 2013CPSS risk score for CMML
Such and colleagues; CPSS-Mol adds mutations in 2016.
- 2020Oral decitabine-cedazuridine approved for MDS and CMML
- 2022WHO 5th edition and ICC redefine CMML
Monocyte threshold lowered to 0.5 x 10^9/L with molecular support; dysplastic vs proliferative subtypes formalised.
Open problems, and what is being done about each
No drug alters the disease course; RAS-pathway inhibitors, GM-CSF antibodies and venetoclax combinations are in early trials.
and how the field plans to fix it →What is being done about thisCancers without a drug targetAvailable now- AdagrasibApproved
- CRISPR functional genomicsEstablished
- DaraxonrasibApproved
- KRAS & RAS inhibitorsApproved
- PROTACs & molecular glues (targeted protein degradation)Approved
- RevumenibApproved
In trials- AI-driven drug & target discoveryPhase 2
- CodeBreaK 200Positive
- ELI-002 7PPhase 2
- ElironrasibPhase 2
- KRYSTAL-12Positive
- MRTX1133Phase 1
Ideas and roadmaps- A drug screen that only rewards killing sleeping cancer cells
- A guaranteed purchase prize for the first drug against a named hard target
- A precompetitive consortium for the twenty hardest cancer targets
- A synthetic lethality map for every cancer driver in every tissue context
- A target de-risking index that counts failures as well as successes
- AI-designed proteins that grip the floppy parts of cancer drivers
Background: RAS / RAF / MEK / ERK (MAPK), p53 / RB / cell-cycle checkpoint. Also on OnCo: Targets · KRAS roadmap.
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.
and how the field plans to fix it →What is being done about thisCost and accessAvailable now- HPV & HBV vaccinationStandard of care
- ImatinibApproved
- Trastuzumab biosimilarsApproved
In trials- Gefitinib vs gefitinib plus pemetrexed-carboplatin in EGFR-mutant lung cancer (Tata Memorial)Positive
- IARC India HPV vaccine dose study (one, two or three doses)Positive
- IMAGINE (varnimcabtagene autoleucel, Immuneel)Positive
- Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)Positive
- Low-dose olanzapine for cancer anorexia (Tata Memorial)Positive
- METRO PLUS (Tata Memorial Centre, Varanasi)Positive
Ideas and roadmaps- 90-day reliance approval for cancer drugs cleared by two stringent regulators
- A cheap old tablet to restore appetite
- A combination pricing rule so two-drug regimens are not priced as two monopolies
- A coordinated reserve and shared schedule for the world's medical isotope reactors
- A dedicated global financing window for cancer, modelled on the Global Fund
- A delinked market-entry reward paid by payers when a repurposed generic wins approval
Background: Accelerated approval, Biosimilar, Real-world evidence. Also on OnCo: Financial help and assistance navigator · Coverage by country · HTA decisions.
Trials usually lump CMML with MDS or exclude it; dedicated CMML cohorts and registries (such as the European Hematology Association consortium) are the response.
Trials
topRecruiting now (live from ClinicalTrials.gov)
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Expert centres
topCentres linked to this cancer in OnCo
- via Allogeneic stem cell transplantation
- HOVONRotterdam, NLvia Venetoclax
- Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolis, IN, USNCI comprehensivevia Allogeneic stem cell transplantation
- Juravinski Cancer Centre / Escarpment Cancer Research InstituteHamilton, ON, CAvia Allogeneic stem cell transplantation
- via Allogeneic stem cell transplantation
- via Ruxolitinib
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterBaltimore, MD, USNCI comprehensivevia Allogeneic stem cell transplantation
- via Azacitidine
- Walter and Eliza Hall Institute of Medical ResearchMelbourne, AUvia Venetoclax
Questions to ask
topQuestions to ask your oncologist about Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example Monocyte count and percentage; flow cytometric monocyte subset partitioning, Bone marrow blasts and dysplasia, Cytogenetics, 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), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include CMML, dysplastic type, CMML, proliferative type, CMML-1 and CMML-2 by blast percentage.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Higher-risk CMML, fit with a donor
- For my situation (higher-risk cmml, fit with a donor), which of the standard options do you recommend and why?Why: Guideline options include: Allogeneic haematopoietic stem cell transplant, often after hypomethylating-agent cytoreduction; the only curative option.
- Am I a candidate for Azacitidine, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Higher-risk or symptomatic CMML, not transplant candidate
- For my situation (higher-risk or symptomatic cmml, not transplant candidate), which of the standard options do you recommend and why?Why: Guideline options include: Azacitidine or decitabine (or oral decitabine-cedazuridine) until progression; supportive care with transfusion and growth factors.
- Am I a candidate for Azacitidine, Decitabine + cedazuridine (oral), and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Proliferative CMML with symptomatic leucocytosis or splenomegaly
- For my situation (proliferative cmml with symptomatic leucocytosis or splenomegaly), which of the standard options do you recommend and why?Why: Guideline options include: Hydroxyurea (superior to etoposide in the randomised GFM trial); ruxolitinib in trials for symptomatic proliferative disease.
- Am I a candidate for Hydroxyurea (hydroxycarbamide), Ruxolitinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Juvenile myelomonocytic leukaemia
- For my situation (juvenile myelomonocytic leukaemia), which of the standard options do you recommend and why?Why: Guideline options include: Allogeneic transplant; azacitidine as bridging therapy (EMA approval 2019 for JMML); watchful waiting for some CBL- or Noonan-associated cases that regress spontaneously.
- Am I a candidate for Azacitidine, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Ruxolitinib, Venetoclax, Azacitidine, Allogeneic stem cell transplantation?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “No drug alters the disease course; RAS-pathway inhibitors, GM-CSF antibodies and venetoclax combinations are in early trials”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Transformation to AML in a substantial minority; sequential mutation tracking to intervene earlier is being studied”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
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3drugs
6companies
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5terms
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2Latest papers
topQuery for this cancer: (TITLE:"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms" OR ABSTRACT:"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms" OR TITLE:"CMML" OR ABSTRACT:"CMML" OR TITLE:"MDS/MPN" OR ABSTRACT:"MDS/MPN" OR TITLE:"Myelodysplastic/myeloproliferative neoplasms" OR ABSTRACT:"Myelodysplastic/myeloproliferative neoplasms" OR TITLE:"Atypical CML BCR-ABL1-negative" OR ABSTRACT:"Atypical CML BCR-ABL1-negative" OR TITLE:"MDS/MPN with ring sideroblasts and thrombocytosis" OR ABSTRACT:"MDS/MPN with ring sideroblasts and thrombocytosis") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, not a curated reading list.
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