Myeloproliferative, Myelodysplastic, and AML

CML - Chronic Myelogenous Leukemia

Median Age

• 46-53 (m)

Clinical Manifestations

• asymptomatic/symptomatic-

  • Malaise

  • fullness of upper abdomen

  • weight loss

  • night sweats

  • bone tenderness

  • leukostasis

  • pruritus

  • diarrhea

  • refractory peptic ulcer disease

Pathophysiology

• Abnormal Ph chromosome (chrom 22) from chemicals/radiation

  • ABL protein located on chromosome 9, BCR1 protein located on chrom 22, Fusion oncoprotein created drives myeloid proliferation

  • (mutation causing translocation of chr 9 and 22 that forms the BCR-ABL fusion gene, which causes uncrontrolled myeloid proliferation)

Blood and BM Findings

• PB: increased WBC (N, B, Mega) maybe nRBC

• BM: hyper, increased granulocytes and mega, decreased normoblasts, pseudo gaucher, marrow fibrosis

Cytogenetic, molecular studies, immunophenotyping

• t(9;22) - philadelphia chromosome present in most

• detection of fusion (ABL-BCR) gene

Treatment

• Chemo

• BM transplant

• Imatinib

• 2nd/3rd gen tyrosine kinase inhibitors for resistance

PV - Polycythemia Vera

Median Age

• 60 (m)

Clinical Manifestations

• Asymptomatic- thrombosis/bleeding, headache, epistaxis, hemorrhagic stroke, angina, myocardial infarction, splenomegaly

Pathophysiology

• uncontrolled proliferation of, erythroid, granulocytes, megakaryocyte cells due to JAK2 mutation causing erythropoietin independence

• Neoplastic clinal stem cells are hypersensitive to/functionally independent of erythropoietin. 

• JAK2 Gene mutation

Blood and BM Findings

• PB: Plts>400, WBC>12 (no fever or infection), increased Hgb/Hct/RBC volume

• BM: hyper, erythroid, granulocytic, and mega proliferation, reduced iron stores

Cytogenetic, molecular studies, immunophenotyping

• presence of JAK2 mutation (or other similar)

  • Point mutation replaces guanine w. Thymine (changes from valine to phenylalanine)

Treatment

• Phlebotomy, aspirin, hydroxyuria/busulfan, JAK inhibitors,

ET - Essential Thrombocythemia

Median Age

• 60 (w)

Clinical Manifestations

• Asymptomatic

• vascular occlusion

• hemorrhage

• splenomegaly

Pathophysiology

• Increased plt production due to mutation that causes constant growth signaling

  • JAK2 Mutation

Blood and BM Findings

• PB: Thrombocytosis, giant plt, slight increased N, Slight decreased hgb/hct w/ normal RBC volume

• BM: mega hypercellularity and clustering

Cytogenetic, molecular studies, immunophenotyping

• JAK2 or other clonal mutation

• cytogenetic abnormalities

• abnormal thrombopoietin

Treatment

• Control bleeding

• plateletpheresis

• hydroxyurea

• aspirin

• JAK 2 inhibitors

PM - Primary Myelofibrosis

Median Age

• 67

Clinical Manifestations

• Fever

• anorexia

• weight loss

• night sweats

• bone pain

• weakness

• lethargy

Pathophysiology

• fibrosis (scaring) in the marrow causes cell production to happen in other organs (spleen and liver), causing immature RBC and WBCS w/ abnormal shapes.

• JAK2 mutation results in abnormal megakaryocytes that release growth factors

Blood and BM Findings

• PB: teardrops, nRBCs, granulocytes, variable plts, micromegakaryocytes

  
  

  BM: fibrosis, granulocytic and megakaryocytic hypercellularity, dysmegakaryopoiesis, dysgranulopoiesis

Cytogenetic, molecular studies, immunophenotyping

• JAK2 mutation involved

Treatment

• Targets anemia and hepatosplenomegaly, JAK2 inhibitors, Nusulfan hydroxyurea, radiotherapy, splenectomy, chemo, allogenic stem transplant

CNL - Chronic Neutrophilic Leukemia

Median Age

• ?

Clinical Manifestations

• Hepatosplenomegaly, mucocutaneous bleeding, gout, and pruritis

Pathophysiology

• X

Blood and BM Findings

• PB: increased WBC >25 w/ left shift, neutrophils may have toxic granules, normal rbc/plt

  
  

  BM: hypercellular w/ predominate proliferation of neutrophils, myeloid:erythroid =20:1

Cytogenetic, molecular studies, immunophenotyping

• X

Treatment

• X

CEL - Chronic Eosinophilic Leukemia

Median Age

• X

Clinical Manifestations

• fever, cough, fatigue, angioedema, muscle pain, pruritus, hepatosplenomegaly

Pathophysiology

• Clonal proliferation of eos that dominate BM and PB, they release cytokines which cause damage to tissue

Blood and BM Findings

• PB: eosinophilia, neutrophilia, maybe mild monocytosis & basophilia

• BM: hypercellular, Charcot-leyden crystals, fibrosis

Cytogenetic, molecular studies, immunophenotyping

• X

Treatment

• X

Mastocytosis

• Cutaneous Mastocytosis

• Systemic Mastocytosis

• Mast cell Tumors

Median Age

• all

• cutaneous - children

• systemic - after 2nd decade

Clinical Manifestations

• Skin involvement in 80%

• urticarial lesions, skin lesions (melanin pigmentation), skin manifestations

• fatigue, weight loss, mediator-related systemic events, musculoskeletal complaints

• anemia, leukocytosis, thrombocytopenia

Pathophysiology

• clonal neoplastic proliferation of mast cells, accumulating in one or more organ systems due to a genetic mutation in KIT gene

Blood and BM Findings

• leukocytosis (eosinophilia, neutropenia), thrombocytosis

Cytogenetic, molecular studies, immunophenotyping

• X

Treatment

• X

Myelodysplastic Syndrome

Median Age

• 70

Clinical Manifestations

• can be asymptomatic

• splenomegaly is rare

• infections

• fatigue, weakness, malaise

Pathophysiology

• Abnormal division, maturation, and proliferation of erythrocytes, granulocytes, monocytes, and plts

• primary or due to therapy

• abnormal myeloid stem cell - usually erythroid, myeloid, and megakaryocytic lines affected

• may result from environment (chemicals, radiation, infection), or smoking

Blood and BM Findings

• progressive cytopenias despite cellular BM

• Dyspoiesis in one or more cell lines
  

Cytogenetic, molecular studies, immunophenotyping

• loss of genetic material
  

Treatment

• X

Dyserythropoiesis

PB

• oval macrocytes

• hypochromic microcytes

• dimorphic RBC

• pokilocytosis

• baso stippining

• howell-jolly bodies

• siderocytes

BM:

• RBC precursors

  • multiple nucleus

  • abnormal nuclear shapes

  • lobes/buds

• nuclear fragments in cytoplasm

• internuclear bridging

• ring sideroblasts

• megaloblastoid cellular development

Dysmyelopoiesis

PB

• Nuclear-cytoplasm asynchrony

• abnormal granulation

  • large

  • hypogranulation

• abnormal nuclear features

  • hyposeg

  • hyperseg

  • nuclear rings

BM

• nuclear cytoplasm asynchrony

• cytoplasmic changes

  • uneven stain

  • lack of granules

  • large primary granules

  • auer rods

• abnormall nuclear findings

  • hypo or hyperseg

  • ring-shaped nuclei

• granulocytic hypoplasia or hyperplasia

Dysmegakaryopoiesis

PB

• Giant Plts

• abnormal plt granulation

  • hypo

  • hyper

  • large fused

• micromegakaryocytes

BM

• large mononuclear megakaryocytes

• micromegakaryocytes

• micromegakaryoblasta

• bilobed/separated nuclei

Refractory Cytopenia w. Unilineage Dysplasia (RCUD)

Criteria

• blasts <1% in PB and <5% in BM

• Dysplasia present in >10% of single myeloid lineage

• <15% eyrthroid precursors are ring sideroblasts

• No specific cytogenetic abnormalities

Refractory anemia w/ ring sideroblasts (RARS)

Criteria:

• Anemia

• Dyserythropoiesis

• >15% bone marrow erythroid precursors are ring sideroblasts

• Dimorphic PB – hypochromic and normochromic

Refractory cytopenia with multilineage dysplasia (RCMD)

Criteria:

• One or more cytopenias

• Dysplasia in two or more myeloid cell lines

• Blasts <1% in PB and <5% in BM

• No Auer rods

• May have >15% ring sideroblasts

• More aggressive disease

Refractory anemia with excess blasts (RAEB-1)

Criteria:

• Trilineage cytopenias

• Dysmyelopoiesis and/or dysmegakaryopoiesis

• Blasts 2-19% in PB and 5-19% in BM

Two types:

• RAEB-1 – Blasts 2-4% in PB and 5-9% in BM

• RAEB-2 – Blasts 5-19% in PB and 10-19% in BM; if Auer rods present automatically type 2

Myelodysplastic syndrome with isolated del(5q)

Criteria:

• Anemia without other cytopenias

• Thrombocytosis

• Hypolobulated megakaryocytes

• Erythroid hypoplasia

• Blasts <1% in PB and <5% in BM

• Deletion of 5q

• Revlimid is an effective treatment

Myelodysplastic syndrome, unclassifiable (MDS-U)

• Subtypes of MDS that initially lack specific changes to place them in a specific subtype

Criteria:

• Cytopenias

• Unequivocal dysplasia in <10% of cells in one or more myeloid cell line

• Blasts <1% in PB and <5% in BM

Childhood myelodysplastic syndrome

• Very rare

• in children

• some have similar characteristics as adults

Myelodysplastic/myeloproliferative neoplasms

• has characteristics of MDS and MPD

• 4 types

  • chronic myelomonocytic leukemia

  • atypical chronic myeloid leukemia, BCR/ABL1 neg

  • juvenile myelomonocytic leukemia

  • myelodysplastic/myeloproliferative neoplasm, unclassifiable

chronic myelomonocytic leukemia

Criteria:

• Persistent monocytosis >1.0 x 109

• Absence of BCR/ABL1 fusion gene

• <20% blasts and promonocytes in PB and BM

• Dysplasia in one or more myeloid cell line

• Increased leukocyte count with absolute monocytosis

• Dysgranulopoiesis

• Splenomegaly

• No specific cytogenetic abnormality

• Prognosis depends on number of blasts

atypical chronic myeloid leukemia, BCR/ABL1 neg

Criteria:

• Leukocytosis

• Morphologically dysplastic neutrophils and precursors

• Basophilia may be present

• Multilineage dysplasia is common

• BCR/ABL1 fusion gene not present

• Dyspoiesis in all cell lines – neutrophils most affected

Prognosis

• Poor usually will progress to AML or bone marrow

failure

juvenile myelomonocytic leukemia

Criteria

• Proliferation of granulocytic and monocytic cell lines

• Children 1 month to 14 years of age

• Allogeneic stem cell transplant effective in about

50% of patients

myelodysplastic/myeloproliferative neoplasm, unclassifiable

Cases that meet criteria for MDS/MPD but don’t fit a specific subcategory

Explain how prognosis of MDS is determined.

• uses the International Prognostic Scoring System (IPSS) to produce a risk score and median survival

  • very low = <1.5 (8.8 yr survival)

  • Low = >1.5-3

  • Intermediate = >3-4.5

  • High = >4.5-6

  • Very High = >6 (0.8 yr survival)

Discuss treatment of MDS

• Improve quality of life/prolong survival (depends on prognosis)

  • supportive care

  • stem cell transplant

  • drugs: lenalidomide, azacitidine, decitabine

Acute leukemia

Key Characteristics

• sudden onset

• fatal in 6mo if untreated

• loss of BM function

• often discovered after treatment for weakness, bleeding, flu

Types:

• Acute Lymphoid Leukemia

• Acute Myeloid Leukemia

  • WBC 5-30×10^9/L

  • myeloblasts in PB

  • pallor, fatigue, fever, bruising, bleeding

  • splenomegaly

  • increased uric acid and phosphorus

  • decreased calcium and potassium

M0 AML, minimally differentiated

Median age of onset

• X

Clinical findings

• x

Incidence and risk factors

• X

Pathophysiology

• X

Prognosis

• X

Blood and bone marrow findings

• blasts no distinctive myeloid features; doesnt show typical cytochemical stains

Cytogenetic, molecular, and immunophenotyping

• CD13, CD33, CD34, CD117 – myeloid lineage-specific

• CD3, CD79a, and CD22 – lymphoid lineage-specific

M1 AMP w/o maturation

Median age of onset

• X

Clinical findings

• X

Incidence and risk factors

• X

Pathophysiology

• X

Prognosis

• X

Blood and bone marrow findings

• X

Cytogenetic, molecular, and immunophenotyping

• X

M2 AML w/ maturation

Median age of onset

• X

Clinical findings

• X

Incidence and risk factors

• X

Pathophysiology

• X

Prognosis

• X

Blood and bone marrow findings

• X

Cytogenetic, molecular, and immunophenotyping

• X

M3 acute promyelocytic

Median age of onset

• X

Clinical findings

• X

Incidence and risk factors

• X

Pathophysiology

• X

Prognosis

• X

Blood and bone marrow findings

• X

Cytogenetic, molecular, and immunophenotyping

• X

M4 Acute myelomonocytic

Median age of onset

• X

Clinical findings

• X

Incidence and risk factors

• X

Pathophysiology

• X

Prognosis

• X

Blood and bone marrow findings

• X

Cytogenetic, molecular, and immunophenotyping

• X

M4eoacute myelomonocytic w/ eosinophilia

Median age of onset

• X

Clinical findings

• X

Incidence and risk factors

• X

Pathophysiology

• X

Prognosis

• X

Blood and bone marrow findings

• X

Cytogenetic, molecular, and immunophenotyping

• X

M5a acute monocytic leukemia, poorly differentiated

M5b acute monocytic leukemia, well differentiated

M6 acute erythroleukemia

M7 acute megakaryocytic leukemia