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) ľ10% 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%)

·        Café-au-lait spots in pts with NF-1

·        Hepatosplenomegaly (~100%)

 

Etiology

·        Unknown

·        Some genetic predisposition

·        Association with neurofibromatosis type 1

 

PB Morphology

·        Leukocytosis

o       WBC 25-35 x 109/L

o       >100 x 109/L in 5-10%

o       Neutrophils (including promyelocytes and myelocytes) and monocytes

o       Blasts usually < 5%, always < 20%

o       Eosinophilia and basophilia in minority

·        Anemia

o       nRBCs frequent

o       RBCs typically normocytic, but may be microcytic, or macrocytic (a/w monosomy 7)

·        Thrombocytopenia (may be severe)

 

BM Morphology

·        Hypercellular bone marrow

o       Granulocytic proliferation

o       Monocot’s usually 5-10%

o       Blasts < 20%

§         No Auer rods

·        Dyspoiesis/dysplasia usually minimal

o       Pseudo-Pelger-Huet neutrophils

o       Hypogranularity of neutrophil cytoplasm

o       Megaloblastic changes in erythroid precursors

 

  Morphology in Other Organs

·        Leukemic infiltration

o       Skin

§         Superficial and deep dermis

o       Lung

§         Peribronchial lymphatics into adjacent alveolar septae

o       Spleen

§         Red pulp

§         Predilection for trabecular and central arteries

o       Liver

§         Sinusoids and portal tracts

 

Cytochemistry/Immunophenotype

·        No specific abnormalities

·        Lysozyme should be used for detection

o       Myelo-peroxidase may be weakly expressed

·        Alpha naphthyl acetate esterase

·        Butyrate esterase +/- napthol ASD chloroacetate esterase

·        LAP scores decreased in 50% of cases, not helpful for Dx

 

 

Genetics

·        No Ph or BCR/ABL

·        Monosomy 7 (30-40%)

·        Point mutations in RAS (20%)

·        Loss of NF1 allele

o       Associated with NF-1

·        Loss of heterozygosity for NF1

o       Patients lacking NF-1 phenotype

 

Prognosis

·        Overall poor prognosis

·        Better Prognosis:

o       <1 year of age

·        Worse prognosis:

o       2 years old

o       PLT <33 x 109/L

o       Hbg F >15%

·        If untreated, 30% die in one year

·        Median survival from 5 months to 4 years

·        Most die from organ failure (leukemic infiltration)

·        10-20% evolve to acute leukemia

·        Response to chemotherapy often poor

·        BMT demonstrated to improve survival time

 

 

Myelodysplastic/myeloproliferative disease, unclassifiable 

(MDS/MPD, U)

General

·        Cases with clinical, laboratory and morphologic features that support a diagnosis of both MDS and MPD, but do not meet criteria for other entities in the MDS/MPD category

·        Proliferation of one or more myeloid lineages that is ineffective and/or dysplastic

      and, simultaneously effective proliferation +/- dysplasia in one or more of the other
  lineages

 

Diagnostic Criteria

·        Features of MDS (RA, RARS, RCMD, RAEB), and

·        Features of MPD (eg, plt>600k, WBC≥13k), and

·        No h/o CMPD or MDS, no drug causes, no Ph or BCR/ABL, del (5q), t(3;3)(q21;q26) or inv(3)(q21q26)

 OR

·        Features of MDS and MPD, but cannot be assigned to any other MDS, CMPD or MDS/MPD

 

Exclusion Criteria

·        Patients with a previous, well-defined myloproliferative disease who develop dysplastic features associated with transformation to a more aggressive phase

·        Ph, BCR/ABL

 

Incidence

·        Unknown

 

Sites of Involvement

·        BM and PB always involved

·        Spleen

·        Liver

·        Other extramedullary tissues

 

Clinical Findings

·        Similar to those of both MDS and MPD patients

·        Splenomegaly and hepatomegaly

 

Etiology

·        Unknown

 

PB Morphology

·        Anemia +/- macrocytosis

o       Dimorphic RBCs

·        Evidence of effective proliferation in one or more lineages

o       Thrombocytosis ( >  600 x 109/L)

o       Leukocytosis ( > 13 x 109/L)

·        Dysplasia

·        Giant or hypogranular platelets

·        Blasts < 20%

o       >10% indicates transformation to aggressive phase

 

BM Morphology

·        Hypercellular bone marrow

·        Proliferation of one or all of the myeloid lineages

·        Dysplastic features present simultaneously in at least one cell line

 

 

Provisional entity: MDS/MPD, U-Refractory anemia with ringed-sideroblasts (RARS) associated with marked thrombocytosis

·        Clinical and morphologic features of RARS

·        Markedly elevated platelet count (>600 x 109/L)

·        BM Morphology

o       >15% of erythroid precursors are ringed-sideroblasts

o       Megakaryocytic proliferation

§         Normal or enlarged megs, similar to those in ET

·        ? Distinct entity

·        ? Spectrum of RARS

·        ? Simultaneous occurrence of two diseases

·        Disease entities with similar findings

o       5q- syndrome

o       MDS or AML and abnormalities of 3q21q26

§         Thrombocytosis with micromegs

·        Genetics

o       Not specific

·         No Ph, BCR/ABL

·        Cell of origin

o       Unknown

·        Prognosis/predictive factors

o       Unknown