Myelodysplastic/ Myeloproliferative Neoplasms (MDS/MPN)

Myelodysplastic/myeloproliferative neoplasms(MDS/MPN)

MDS/MPN DiseasesChronic Myelomonocytic LeukemiaAtypical Chronic Myeloid Leukemia,bcr/abl1 negJuvenile Myelomonocytic LeukemiaMDS / MPN, Unclassified

MDS/MPN: WHO ClassificationMonoclonal hematopoietic neoplasms withclinical, laboratory or morphologic findingsof both myelodysplastic syndromes andchronic myeloproliferative diseases

MDS/MPD: General featuresHypercellular bone marrow– Proliferation of one or more myeloid lineagesMay be effective and functional with increased circulatingcellsOr morphologically and functionally dysplasticCytopenias– Ineffective proliferation of other lineagesBlasts 20%Splenomegaly and hepatomegaly

MDS/MPD: Exclusion criteriaPatients with well-definedmyeloproliferative diseases who developdysplasia and ineffective hematopoiesisPh or Bcr/Abl

Chronic MyelomonocyticLeukemia (CMML)

CMML: DefinitionMonoclonal hematopoietic disorder ofbone marrow stem cells in whichmonocytosis is a major defining feature.

CMML: Etiology/EpidemiologyUnknownOccupational or environmentalcarcinogens, ionizing irradiation andcytotoxic agents3/100,000 over the age of 60, annuallyMedian age at diagnosis: 65-75 yearsMale predominance, M:F 1.5-3:1

CMML: Diagnostic criteriaPersistent monocytosis ( 1 x 109/L,or 1 x 103/uL) in PB, Monocytes 10% ofWBCsNo Ph or Bcr/Abl 20% blasts in PB or BM, 20% mayinclude:– Myeloblasts– Monoblasts– PromonocytesMay have dysplasia in one or moremyeloid lineages (not necessary)

CMML: Diagnostic criteriaIf dysplasia is minimal or absent, CMMLcan be diagnosed if:– Monoclonal cytogenetic abnormality inmarrow cells, or– Monocytosis persistent for at least 3 mo, and– All other causes of monocytosis are excluded

CMML: Diagnostic criteriaDysgranulopoiesis present in most cases,and may be more prominent in cases withnormal or low WBC count– Neutrophils with nuclear hypolobation– Neutrophils with abnormal cytoplasmicgranulationMild anemiaModerate thrombocytopenia with atypicalplatelets

CMML: Clinical featuresSymptoms: fatigue,weight loss, fever,night sweats, infection, bleedingSites of involvement– PB and BM always involved– Most common sites of extramedullaryleukemic infiltrationSpleenLiverSkinLNs

Monoblasts

Promonocytes

CMML: PB morphologyMonocytosis, dysplastic PMNs

CMML: BM MorphologyHypercellular in 75% of casesGranulocytic proliferationMonocytic proliferation: positive for thesenon-specific esterases (NSE)– Alpha naphthyl acetate esterase– Alpha naphthyl butyrate esterase

Butyrate

CMML: BM MorphologyDysgranulopoiesis in most casesDyserythropoiesis ( 50%)– Megaloblastic changes, abnormal nuclearcontours, ringed-sideroblastsMegakaryocytic dysplasia (80%)– Abnormal nuclear lobation and micromegsVariable degree of fibrosis (30%)

CMML: BM Morphology

CMML: Clinical featuresIn about 50%– WBC count normal or slightly decreased– “MDS-like” pictureIn about 50%– WBC count increased– “MPD-like” picture

CMML: Clinical features“MDS-CMML” and “MPD-CMML”– Arbitrary cut-off for leukocyte count(13,000/µl)Little evidence of clinical relevanceDuration of survival times similarNo cytogenetic or molecular differencesMDS-type may become more proliferative

CMML: Morphology; otherorgan systemsSpleen– Red pulp infiltration by leukemic cellsLymph node involvement– Uncommon– Sign of transformation to a more acute phase– LN may be diffusely infiltrated by myeloidblasts

CMML: ClassificationCMML-1– PB blasts 5% of WBC and 10% of nucleated BMcellsCMML-2– PB blasts 5-19% or BM blasts 10-19% or with Auerrods– May be at risk of rapid transformation to acuteleukemia and poor prognosisAML– PB and/or BM blasts 20% or more

CMML-1 50% of cases: WBC with minimaldysgranulopoiesis 50% of cases: Normal WBC withabsolute monocytosis,neutropenia and dysgranulopoiesis.Degree of leukocytosis, neutrophilia and dysplasia isvariable.

CMML-2 Blasts 5-19% in the blood Blasts 20% in BM Auer rods present

CMML: ImmunophenotypeCD33/13 ( ), variable CD14/64/68Increased percentage of CD34( ) cells may beassociated with early transformation to acuteleukemia

CMML: GeneticsNonspecific cytogenetic abnormalities in20-40%– Trisomy 8– del (7q)– Structural abnormalities of 12p– JAK2 V617F uncommon– Abnormalities of 11q23 uncommon - suggestacute leukemia

CMML: GeneticsRAS point mutations (40%)i(17q)– More aggressive courseCases that may resemble CMML with markedeosinophilia:-t(5;12)(q31;p12) resulting in ETV6/PDGFRBabnormal fusion gene - MPN with eosinophiliaand ETV6/PDGFRB mutation-del(4)(q12) resulting in FIP1L1/PDGFRAabnormal fusion gene - MPN with eosinophiliaand FIP1L1/PDGFRA mutation

CMML: prognosis/predictivefactorsPrognosis– Median survival 20-40 months– 15-30% progress to acute leukemiaPredictive factors––––PB and BM blast percentage (most important factor)SplenomegalySeverity of anemiaDegree of leukocytosis

Atypical Chronic MyeloidLeukemia (aCML),bcr/abl1 negative

aCML: Characteristic featuresLeukocytosis with dysplastic immature andmature neutrophilsMultilineage dysplasiaNo Ph or Bcr/Abl

aCML: EpidemiologyUnknown incidenceEstimated 1-2 cases for every 100 Ph( )CMLMedian age: 7th-8th decadesM:F 1-2.5:1

aCML: Diagnostic criteriaPB leukocytosis (mature and immatureneutrophils), WBC 13 x109/L (13 x103/uL )Prominent dysgranulopoiesis (majorcharacteristics)No Ph or Bcr/AblNo rearrangement of PDGFRA or PDGFRBNeutrophil precursors (promyelocytes,myelocytes, metamyelocytes) 10% of WBCsBasophils 2% of WBCs

aCML: Diagnostic criteriaMonocytes 10% of WBCHypercellular BM with granulocyticproliferation and dysplasia, with or withouterythroid and megakaryocytic dysplasiaSome cases may have megakaryocytessimilar to those in CML 20% blasts in PB and BM

aCML: Clinical featuresPB and BM always involvedSpleen and liver involvement: commonMost patients have symptoms related to– Anemia– Thrombocytopenia– Splenomegaly

aCML: PB morphology

aCML, BM Hypercellularity due granulocyticproliferation. Bone marrow biopsy.

aCML: BM morphologyBM megakaryopoiesis and erythropoiesisare variable in quantityM:E 10:1Increased reticulin fibers at diagnosis orlater in course of disease

aCML:Cytochemistry/ImmunophenotypeNo specific abnormalities

aCML: Genetics 8, 13, del(20q), i(17q), del(12p)– 80% of cases– Not specific– No Ph or Bcr/Abl1– Some cases with JAK2 V617F– 30% of cases with NRAS or KRAS

aCML: Course and prognosisMedian survival 20 monthsPoor prognostic factors– Thrombocytopenia– Marked anemia25-40% evolve to acute leukemiaThe remaining patients die of marrowfailure

aCML: VariantSyndrome of abnormal chromatinclumping– PB morphologyhigh percentage of immature and matureneutrophils with exaggerated clumping ofchromatin (“chromatin condensation”)nuclear hypolobation and cytoplasmichypogranularity are commonWBC count usually increasedSevere anemia and thrombocytopenia

aCMLSyndrome of abnormal chromatinclumping– BM morphologyhypercellulargranulocytic proliferation with nuclearabnormalities similar to PBModerate dysplasia in erythroblastic andmegakaryocytic lineages– Survival is similar to aCML

aCML: Peripheral Blood SmearAbnormal chromatin clumping

aCML: Aspirate Smear

aCML: Aspirate Smear

–Uncommon –Sign of transformation to a more acute phase –LN may be diffusely infiltrated by myeloid blasts . CMML: Classification . hypogranularity are common WBC count usually increased Severe anemia and thrombocytopenia . aC