Chapter 2: MYELODYSPLASTIC /

MYELOPROLIFERATIVE DISEASES

Chronic Myelomonocytic Leukemia (CMML)

General

Monoclonal hematopoietic disorder of bone marrow stem cells in which monocytosis is a major defining feature.

Diagnostic criteria

· Persistent monocytosis (>1 x 10⁹/L) in PB

· No Ph or BCR/ABL

· <20% blasts in PB or BM (CMML Blasts: Myeloblasts, monoblasts and promonocytes)

· Dysplasia in one or more myeloid lineages (not necessary)

· If dysplasia is minimal or absent, CMML can be diagnosed if:

o Clonal cytogenetic abnormality in marrow cells, or

o Monocytosis persistent for at least 3 mo, and all other causes of monocytosis have been excluded (such as tumor, infection, or inflammation)

Epidemiology

· 3/100,000 over the age of 60, annually

· Median age at diagnosis 65-75 years

· Male predominance 1.5-3:1

Clinical features

· Sites of involvement

o PB and BM always involved

o Most common sites of extramedullary leukemic infiltration: spleen, liver, skin, and LNs

· ~50% of patients

o WBC count normal or slightly decreased

o MDS-like picture

· ~50% of patients

o WBC count increased

o MPD-like picture

· Fatigue, weight loss, fever, night sweats, infection, and bleeding

Etiology

· Unknown

· Occupational or environmental carcinogens, ionizing irradiation and cytotoxic agents in some cases

PB Morphology

· Monocytosis (>1 x 10⁹/L), hallmark of CMML

· Monocytes >10% of WBC

· Monocytes are usually mature with unremarkable morphology, but can exhibit:

o Abnormal granulation

o Unusual nuclear lobation

o Finely dispersed chromatin

· Blasts <20% of WBC

· WBC count decreased, normal, or increased

· Promyelocytes and myelocytes <10% of WBC

· Mild basophilia

· Eosinophils normal or slightly increased.

· If >1.5 x 10⁹/L, then DX: CMML with eosinophilia

· Dysgranulopoiesis present in most cases, and may be more prominent in cases with normal or low WBC count

· Neutrophil nuclear hypolobation

· Neutrophil abnormal cytoplasmic granulation

· Mild anemia, common

· Moderate thrombocytopenia with atypical platelets often present

BM Morphology

· Hypercellular in >75% of cases

· Granulocytic proliferation

· Monocytic proliferation

o Alpha naphthyl acetate esterase

o Alpha naphthyl butyrate esterase +/- naphthol ASD chloroacetate esterase

· Dysgranulopoiesis in most cases

· Dyserythropoiesis (>50% of cases)

o Megaloblastic changes, abnormal nuclear contours, ringed-sideroblasts

· Megakaryocytic dysplasia (up to 80% of cases)

o Abnormal nuclear lobation and micromegs

· Variable degree of fibrosis (30% of cases)

Other organ systems

· Splenic enlargement

o Red pulp infiltration by leukemic cells

· Lymph nodes

o Uncommon involvement

o If seen→ sign of transformation to a more acute phase

o LN may be diffusely infiltrated by myeloid blasts

· Plasmacytoid monocytes

o Sometimes diffusely infiltrate LNs or spleen

o Generalized lymphadenopathy due to plasmacytoid monocyte infiltration may be presenting manifestation of CMML

o Proposed to be of monocytic lineage, but not proven to be clonally related to the neoplastic cells of CMML

Classification

· CMML-1

o Blasts <5% in PB or <10% in BM

· CMML-2

o Blasts 5-19% in PB or 10-19% in BM (or Auer rods with <20% blasts in BM or PB)

o May be at risk of rapid transformation to acute leukemia and poor prognosis

· CMML with eosinophilia:

o CMML criteria + PB eosinophilia > 1.5 x 10⁹/L

o May have extensive tissue damage related to eosinophil degranulation

a/w t(5;12)

o Tx with Gleevec

Immunophenotype

· CD33 and CD13 + , variable CD14, CD64, and CD68

· Increased % of CD34+ cells may be associated with early transformation to acute leukemia

· Plasmacytoid monocytes

o Characteristic phenotype: CD14, CD43, CD56, CD68, and CD4

o CD2, CD5 often present, but T-cell derivation disproved

Genetics

Nonspecific cytogenetic abnormalities in 20-40%

· +8

· -7/del (7q)

· Structural abnormalities of 12p

· Abnormalities of 11q23 uncommon (suggest acute leukemia)

· i(17q) more aggressive course

· RAS point mutations (40%)

· t(5;12)(q31;p12)

o -Result in TEL/PDGFßR abnormal fusion gene

o -<1-2% of CMML cases

o -Marked eosinophilia

Prognosis/predictive factors

· Prognosis

o Median survival 20-40 months

o 15-30% progress to acute leukemia

· Predictive factors

o PB and BM blast % (most imp. survival determinant)

o Splenomegaly

o Severity of anemia

o Degree of leukocytosis

Atypical Chronic Myeloid Leukemia (aCML)

General

· Leukemic disorder with MDS and MPD features at initial diagnosis

· Leukocytosis with principle involvement of dysplastic immature and mature neutrophils

· Multilineage dysplasia common

· No Ph or BCR/ABL

Epidemiology

· Unknown incidence

· Estimated 1-2 cases for every 100 cases of Ph+, BCR/ABL+ CML

· Median age 7th-8th decades

· M:F = 1-2.5:1

Sites of involvement

· PB and BM always involved

· Spleen and liver involvement common

Clinical features

· Few reports

· Most patients have symptoms related to

o Anemia

o Thrombocytopenia

o Splenomegaly

Etiology

· Unknown

Diagnostic criteria

· PB leukocytosis (mature and immature neutrophils)

· Prominent dysgranulopoiesis (major feature): pseudo Pelger-Huet cells, abnormally condensed nuclear chromatin, abnormal nuclear segmentation, or abnormal granules.

· No Ph or BCR/ABL

· Neutrophil precursors (promyelos, myelos, metamyelos) ¾10% of WBC

· Basophils <2% of WBC

· Monocytes < 10% of WBC

· Hypercellular BM with granulocytic proliferation and dysplasia +/- erythroid and megakaryocytic dysplasia

· <20% blasts in PB and BM

BM morphology

· BM megakaryopoiesis and erythropoiesis are variable in quantity

· M:E >10:1

· Increased reticulin fibers at diagnosis or later in course of disease

Cytochemistry/Immunophenotype

· No specific abnormalities

Genetics

· +8, +13, del(20q), i(17q), del(12p)

o 80% of cases

o Not specific

o No Ph or BCR/ABL

Course and prognosis

· Median survival < 20 months

· Poor prognostic factors

o Thrombocytopenia

o Marked anemia

· 25-40% evolve to acute leukemia

· Remainder die of marrow failure

aCML Variant: Syndrome of abnormal chromatin clumping

· PB morphology

o High % of immature and mature neutrophils with exaggerated clumping of chromatin

o Nuclear hypolobation and cytoplasmic hypogranularity are common

o WBC count usually increased

o Severe anemia and thrombocytopenia

· BM morphology

o Hypercellular

o Granulocytic proliferation with nuclear abnormalities similar to PB

o Moderate dysplasia in erythroid and megakaryocytic lineages

· Survival is similar to aCML

Juvenile Myelomonocytic Leukemia (JMML)

General

· Monoclonal hematopoietic disorder of childhood characterized by proliferation of the granulocytic and monocytic lineages

· Erythroid and megakaryocytic abnormalities common

· Bone marrow stem cell with multilineage potential in the myeloid series

Diagnostic Criteria

· PB monocytosis > 1 x 10⁹/L

· Blasts < 20% of WBCs in the blood and of the nucleated bone marrow cells

· No Ph chromosome or BCR/ABL

· Plus two or more of the following:

o Hemoglobin F increased for age

o Immature granulocytes in PB

o WBC>10 x 109/L

o Monoclonal chromosomal abnormality

o GM-CSF hypersensitivity of myeloid progenitors in vitro

Epidemiology

· 1.3 per million children ages 0-14, annually

· <2-3% of all childhood leukemias

· 20-30% of all cases of myeloproliferative and myelodysplastic diseases in patients less than 14 years old.

· 75% occur in children <3 years old

· Male predominance of ~ 2:1

· 10% of patients have NF-1

Sites of Involvement

· PB and BM always involved

· Leukemic infiltration

o Liver and spleen, virtually in all cases

o LN

o Skin

o Respiratory tract

Clinical Features

· Constitutional symptoms (including malaise, pallor, and fever or infection)

· Bleeding

· Bronchitis or tonsillitis in (50%)

· Maculopapular skin rash (40-50%)