Myelodysplastic/Myeloproliferative Diseases is a group of myeloid neoplasms that have both dysplastic features characterized by abnormal cell morphology and cytopenia in one or more cell lines as well as proliferative features characterized by marrow hypercellularity and increased numbers of circulating cells in one or more lineages at diagnosis and are difficult to assign to either myelodysplastic or myeloproliferative groups.

WHO classification MDS/MPD diseases

1. Chronic myelomonocytic leukaemia.
2. Juvenile myelomonocytic leukaemia.
3. Atypical chronic myeloid leukaemia.
4. Refractory anaemia with ringed sideroblasts and thrombocytosis (RARS-T) (JAK2 V617F)
5. MDS/MPN, unclassified.

Classification of paediatric MDS:

1. Juvenile myelomonocytic leukaemia (JMML)
2. Down’s syndrome (DS)
3. Transient abnormal myelopoiesis (TAM)
4. Myeloid leukaemia of DS
5. Myelodysplastic syndrome (MDS)
6. Refractory cytopenia (RC)
7. Refractory anaemia with excess blasts (RAEB)
8. Refractory anaemia with excess blasts in transformation (RAEB-t).

Differential diagnosis of proliferative MDS:

	CML	CMML	Atypical CML
Dysplasia	<10% except in transformation	+	++
Monocytosis	Absolute monocytosis but <3%	+	+
Immature granulocytes	Myelocyte peak	<15%	>15%
Basophilia	+	–	±
BCR–ABL rearrangement ± Ph chromosome	Yes	No	No
RAS mutations	No	40%	?

Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic malignancy characterized by persistent monocytosis (>1 × 10⁹/L), myeloid cell proliferation with myeloid cell dysplasia, ineffective haematopoiesis, and a propensity to transform into acute myeloid leukaemia (AML). It is a very heterogeneous disease, with haematological characteristics ranging from those of a myelodysplastic syndrome (MDS) with peripheral monocytosis, to very proliferative forms, characterized by high WBC counts, splenomegaly, and/or other forms of extramedullary disease.

Causes of monocytosis:

• Infections: Tuberculosis, malaria, kala-azar, enteric fever, bacterial endocarditis, PUO, syphilis, protozoal infection.
• Autoimmune conditions: SLE, rheumatoid arthritis, temporal arteritis, polyarteritis nodosa, inflammatory bowel disease, sarcoidosis, myositis.
• Malignant disorders:
  • Acute myelomoncytic and monocytic leukaemia
  • Chronic myelomonocytic leukaemia and other myeloproliferative disorders
  • Myelodysplastic syndrome
  • Hodgkin’s lymphomas
  • Histiocytoses
  • Carcinomas.
• Miscellaneous
  • Post splenectomy
  • Cyclic neutropenia
  • Chronic idiopathic neutropenia
  • Kostmann’s syndrome.

Presentation of CMML:

Predominantly presents in >60 age group with male predominance. Median age of presentation is 72 years; only 10% of cases present under the age of 60. Often asymptomatic and found on routine FBC. Weight loss, fatigue, night sweats may occur. Maculopapular skin and gum infiltration or serous effusions (pericardial, pleural, ascitic and synovial) may occur in high PB monocyte count. Splenomegaly (50%) and hepatomegaly (up to 20%) occur usually only in cases with leucocytosis and symptoms.

Investigation and diagnosis: Investigation as for MDS:

• CBC: Mild anaemia and thrombocytopenia are common; variable WBC count ranging from normal to >80 x 10⁹/L, marked in 50%; monocyte count >1.0 x 10⁹/L is diagnostic minimum with normal morphology or may have agranular cytoplasm and/or abnormal nuclear lobation; reactive causes of monocytosis must be excluded; neutrophilia in some patients; platelets usually normal or decreased.
• Bone marrow: Typically, hypercellular with blasts <20%; typical trilineage dysplastic features are found in >80% cases; cytochemical studies may aid the distinction between monocyte and granulocyte precursors.
• Cytogenetic abnormalities: Cytogenetic abnormalities are detected in 30–40% of cases but not specific for CMML; the most frequent being trisomy 8, loss of chromosome Y, monosomy 7, deletion 7q, trisomy 21, and del(20q). 5q- is rare. Chromosomal translocations involving 8p11 or 5q31 are found in a minority, usually presenting with marked eosinophilia.
• Molecular aberrations affect mostly epigenetic, splicing, and signalling genes. Gene sequencing detects a clonal abnormality in >90% of cases. Hypermethylation and reduced expression of the p15 gene (in marrow trephines) is found in 50% cases. RAS mutations is found higher (40%) than in other forms of myelodysplasia. Typically, the disease genomic fingerprint combines mutations in TET2, SRSF2, and ASXL1 and genes of the RAS signalling pathway. The association of SRSF2 and TET2 mutations is highly specific for CMML. 
• Flow cytometry: CMML is characterized by an increase in classical (CD14+/CD16−) fraction (≥94%), whereas intermediate (CD14+/CD16+) and nonclassical (CD14−/CD16+) monocytes are increased in benign reactive monocytosis. Therefore, flow cytometry can exclude a benign reactive monocytosis without waiting for 3 months.
• Lysozyme raised in serum and urine.
• Hypokalaemia may be present.

WHO diagnostic criteria for CMML:

1. Persistent peripheral blood monocytosis of >1×10⁹/L, with monocytes accounting for ≥10% of the white blood cell count.
2. BCR-ABL1 rearrangement and WHO criteria for ET, PV, and PMF must be absent. The presence of MPN features in the bone marrow and/or mutations in JAK2, CALR, or MPL tend to support MPN with monocytosis rather than CMML.
3. In cases with eosinophilia, no evidence of PDGFRA, PDGFRB, or FGFR1 rearrangement or PCM1-JAK2.
4. <20% blasts (myeloblasts, monoblasts, and promonocytes) in the bone marrow and peripheral blood.
5. Dysplasia in one or more lineages; or, in absence of or minimal myelodysplasia,
   1. An acquired clonal cytogenetic abnormality present in BM cells; or,
   1. Monocytosis persistent for ≥3 months and all other causes excluded.

Differential diagnosis and borderline diseases:

1. CML: BCR-ABL1 rearrangement is a must, very rarely presents with >10% monocytes in the WBC differential count, and generally has a higher percentage of circulating IMC than CMML.
2. Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2.
3. M4 AML: can be challenging and requires expert pathologic review; presence of Auer rods or of an NPM1 mutation favours diagnosis of M4 AML.
4. Proliferative cases of MDS/MPN-unclassifiable, chronic neutrophilic leukaemia, and atypical CML (sometimes also typical CML) can present with clonal, sustained monocytosis of >1 × 10⁹/L.

Prognosis and Prognostic Subgroups of CMML:

Median survival: Ranges from <1 year in older patients to almost 3 years in youngers.

Leukemic transformation rate: 15% to 30%.

FAB (1994) prognostic subtypes: This subtype is based on WBC count.

Prognostic type	Features	Outcome
MP-CMML	WBC count ≥13 × 109/L; RAS/MAPK signalling pathway is frequently activated	Worse outcome
MD-CMML	WBC count <13 × 109/L	Better outcome

WHO (2016) prognostic subtypes: This subtyping is based on blast cell percentage in peripheral blood and bone marrow.

Prognostic type	Features	Outcome
CMML-0	(<2% blasts in PB and <5% in BM	Better outcome
CMML-1	2% to 4% in PB and/or 5% to 9% in BM
CMML-2	5% – 19% blasts in PB and/or 10% – 19% in BM, or presence of Auer rods irrespective of blast count	Worse outcome

CMML-specific cytogenetic risk classification: This is based on cytogenetic pattern.

Prognostic type	Features	5-year survival	Median survival (mo)
Low risk	Normal karyotype or loss of Y	35%	37
Intermediate risk	Others abnormality	26%	18
High risk	Trisomy 8 or abnormal 7 or complex karyotype	4%	11

CMML-specific Prognostic Scoring System (CPSS): This subtyping is based combinedly on WBC count (FAB subtype), blast cell percentage (WHO classifications), CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. All these variables add a score as follows-

Variable	Scores=0	Scores=1	Scores=2
FAB subtype	MDS-CMML	MPN-CMML
WHO subtype	CMML-1	CMML-2
CMML-specific cytogenetic risk classification	Low	Intermediate	High
RBC transfusion dependency (at least 1 transfusion every 8 weeks over a period of 4 months), or Haemoglobin level <10 g/dL	No	Yes

Risk group	Overall Score	Median survival in month	Risk of AML evolution at 2 years (%)	Risk of AML evolution at 5 years (%)
Low	0	61	8	24
Intermediate-1	1	31	25	41
Intermediate-2	2-3	15	49	52
High	4-5	9	100	100

Patient-related prognostic factors: These are applicable as for other malignancies-

1. Age,
2. Functional ability (performance status),
3. Comorbidities,
4. Physical reserves (frailty),
5. Nutritional status and cognition, and
6. Quality of life.

Monitoring parameters for treatment:

1. CBC and differential,
2. Assessment of splenomegaly and extramedullary disease (serous effusions, skin lesions, etc.) preferably using the same morphological test,
3. Evaluation of general symptoms with a standardized questionnaire
4. BM examination with cytogenetic profiling should be performed if a change in the above evaluation is identified.

Management:

Current therapies aim to improve symptom burden using a personalized strategy guided by cytopenia-induced or proliferation-associated symptoms. Inclusion of CMML patients in clinical trials is strongly encouraged at all stages of the disease.

Watchful-waiting strategy: Stable isolated monocytosis (CMML-0), i.e. asymptomatic cases with near normal haematology apart from monocytosis, require no intervention and should simply be monitored; therapy otherwise supportive.

Indications of treatment:

1. Hb level <10 g/dL, as generally poorly tolerated by elderly patients,
2. Platelet count falls below 30 × 10⁹/L or in case of bleeding symptoms,
3. Major or symptomatic splenomegaly,
4. Presence of other extramedullary disease, typically cutaneous involvement or serous effusions, and
5. Constitutional symptoms in MP-CMML, no consensus WBC threshold to start treatment.

Treatment modalities:

1. Allogeneic stem cell transplantation (ASCT),
2. Erythropoiesis-stimulating agents (ESAs) and RBC transfusion in anaemic patients,
3. Cytoreductive drugs in proliferative diseases, and
4. Hypomethylating agents (HMAs) in the most severe CMML, especially when cytopenias predominate.

Allogeneic stem cell transplantation: Currently available therapeutic agents can lead to survival prolongation but no cure of CMML. Therefore, allogeneic HSCT is used as a curative treatment option. Candidate for HSCT:

• Medically fit patients bellow the age of 70 with a donor,
• No major contraindication to transplant,
• Higher-risk CMML, or lower-risk patients with poor prognostic factors that include severe cytopenia, several poor-risk somatic mutations (especially ASXL1, RUNX1, SETBP1, NRAS).

Hypomethylating agents: In patients MD-CMML, ineligible for transplant, especially with excess of marrow blasts, should be considered for azacytidine or decitabine. In patients eligible for transplant, the recommendation of HMA is unclear.

Low-dose cytoreductive chemotherapy: Patients with MP-CMML having significant leucocytosis or organomegaly, in the absence of major cytopenia or excess of marrow blasts, are still treated with low-dose cytoreductive therapy. Hydroxyurea is preferred to etoposide. Low-dose hydroxyurea (1 g/d) shows higher response rates and better survival than etoposide (150 mg/wk), with median OS of 20 and 9 months, respectively.

Intensive chemotherapy: Intensive chemotherapy is not recommended, except in CMML-2 patients as a bridge to HSCT, or when the disease appears to be very close to M4 AML (presence of Auer rods, NPM1 mutation).

Younger patients with adverse features: Treatment options not optimal and, therefore, patients should be put into clinical trials. Myeloablative allogeneic SCT offers the only curative option. Alternatively, AML-type induction followed by consolidated with autologous SCT.

Chromosomal translocations involving 8p11 or 5q31: Respond well to imatinib mesylate but not to conventional chemotherapy.

Red cell transfusion: Red cell transfusion is indicated for symptomatic anaemia (usually Hb <80 g/L), either in the absence of suitable disease-modifying therapy or in conjunction with active therapeutic intervention. No consistent single haemoglobin target value is recommended and the transfusion frequency depends upon symptomatic benefit.

Other management of cytopenia:

• For symptomatic anaemia in patients with cytopenia (MD-CMML), ESA or red cell transfusion may be considered.
• Cytoreductive drug induced severe neutropenia is treated by tapering and/or interrupting the drug. Safe use of G-CSF in CMML patients with HMA-induced neutropenia is uncertain, although may be considered in febrile patients not responding to antibiotics.
• A short steroid course may be attempted if an immune component of thrombocytopenia is suspected, e.g. severe thrombocytopenia in the absence of anaemia and excess of marrow blasts. Thrombopoietin (TPO) agonist eltrombopag may be considered under clinical trial.

Iron chelation therapy: It may be considered for transfusion-dependent patients with CMML belonging to CPSS lower-risk categories and a serum ferritin level higher than 1000 ng/mL, after 25 units of red cell, in the absence of patient-related (non-MDS) factors anticipated to reduce life expectancy to <3 years.

Newer drugs on trial: TPO agonists (eltrombopag), JAK2 inhibitors (ruxolitinib, farnesyltransferase inhibitors (tipifarnib), histone deacetylase inhibitors (tefinostat), GM-CSF cytokine (lenzilumab), second-generation HMA (guadecitabine), isocitrate dehydrogenase inhibitors and spliceosome inhibitors.

References:

https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2017-04-736421

https://ashpublications.org/blood/article/128/10/1408/35302/Integrating-clinical-features-and-genetic-lesions

https://ashpublications.org/blood/article/127/20/2391/35255/The-2016-revision-to-the-World-Health-Organization

https://ashpublications.org/blood/article/121/15/3005/31363/Development-and-validation-of-a-prognostic-scoring

http://www.haematologica.org/content/96/3/375.long

https://journals.lww.com/hemasphere/Fulltext/2018/12000/Diagnosis_and_Treatment_of_Chronic_Myelomonocytic.7.aspx