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Surgical Pathology Criteria

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Chronic Myelogenous Leukemia (CML)


  • Pluripotent myeloproliferative neoplasm associated with BCR-ABL1 fusion gene in the Philadelphia chromosome

Alternate/Historical Names

  • Chronic granulocytic leukemia
  • Chronic myeloid leukemia

Diagnostic Criteria

  • CML is characterized by a chronic phase that generally progresses to a blast phase, frequently passing through an accelerated phase
  • Chronic phase is characterized by leukocytosis and hypercellular marrow
    • Peripheral blood leukocytosis
      • Granulocytes at all stages of maturation
        • Two peaks: segmented neutrophils and myelocytes
      • Basophilia
      • Eosinophilia (frequent)
      • Special forms may have prominent thrombocytosis, monocytosis, neutrophilia
    • Mild anemia
    • Hypercellular marrow
      • Myeloid:erythroid ratio >10:1
      • Granulocytes at all stages of maturation
      • Thickened peritrabecular cuff of immature myeloids
        • 5-7 cells thick vs 2-3 normal
        • Mature neutrophils in intertrabecular space
      • Blasts <10% and usually <2%
      • Small hypolobated megakaryocytes ("dwarf megakaryocytes")
      • Basophils and eosinophils elevated
      • Variable fibrosis
      • Pseudo-Gaucher histiocytes
  • Progression generally occurs to an accelerated phase and then to blast phase
    • Any one of the following indicates progression to accelerated phase
      • Cytogenetic evidence of clonal evolution
        • Change from initial karyotype
      • Persistent thrombocytopenia <100 x 103/μL
      • Lack of response to therapy
        • Persistent thrombocytosis >1000 x 103/μL OR
        • Persistent or increasing splenomegaly OR
        • Persistent or increasing leukocytosis >10 x 103/μL
      • Following criteria of accelerated phase are also associated with transition to blast phase
        • Blasts elevated to 10-19% in blood or marrow
        • Peripheral blood basophilia ≥20%
    • Blast phase may develop following accelerated phase or directly from chronic phase
      • Defined as either:
        • >20% blasts in marrow or blood, OR
        • Presence of an extramedullary blast proliferation
      • 2/3 of cases myeloid
      • 1/3 lymphoid
        • Improved survival
        • Mostly precursor B
        • Rarely T cell
  • BCR-ABL1 fusion gene results in the Philadelphia chromosome in 90-95% of cases (cytogenetic study)
    • Remaining cases appear to have variant or cryptic translocations detectable by RT-PCR or FISH
    • Rare BCR-ABL1 negative cases have been proposed
      • Must be tested by RT-PCR and/or FISH
      • Some may represent CMML or atypical CML
    • BCR-ABL1 is necessary but not sufficient for the diagnosis of CML
      • B lymphoblastic leukemia is BCR-ABL+ in 30% of adult cases
    • Rare p230 BCR-ABL1 isoform can present with thrombocytosis and /or neutrophilia

Dita Gratzinger MD PhD
Tracy I George MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting: 10/23/11

Supplemental Studies

Disorder Molecular or Cytogenetic Alteration Test Used
Chronic myelogenous leukemia BCR-ABL1 CG, FISH, PCR on PB or BM
Hematolymphoid neoplasms with eosinophilia and PDGFR/FGFR abnormalities

FIP1L1-PDGFRA (usually CEL)

ETV6-PDGFRB (usually CMML with eosinophilia)

FGFR1 (various)

PDGFRa/b (various)

Chronic eosinophilic leukemia NOS none specific, may have clonal CG abnormalities CG
Mastocytosis KIT D816V CG, PCR on BM, not PB
Acute myelogenous leukemia, even if <20% blasts inv or t(16)(p13.1q22); CBFB-MYH11 or t(8;21)(q22;q22) RUNX1-RUNX1T1 CG, FISH
PCR = polymerase chain reaction, PB = peripheral blood, CG = conventional cytogenetics, FISH = fluorescent in situ hybridization, BM = bone marrow, CEL = chronic eosinophilic leukemia, CMML = chronic myelomonocytic leukemia

Differential Diagnosis

Myeloproliferative and Mixed MDS/MPNs with Neutrophilia and/or Monocytosis
  CML-CP Atypical CML CMML-1 CNL
Ph Chromosome and/or BCR-ABL1 Translocation Almost 100% Absent Absent Absent


Left shifted neutrophilia* Left shifted neutrophilia Monocytosis, may have left shifted neutrophilia Neutrophilia
Blood basophils Increased Not increased Not increased Not increased
Blood monocytes Variable,** <1x103/μL Variable, <1x103/μL Always >1x103/μL <1x103/μL
Blood immature granulocytes >20% 10-20% Usually <10% <10%
Blood blasts Usually <2% >2% <5% <1%
Granulocytic dysplasia Absent ++ +/- Absent
*rare p230 BCR-ABL1 isoform may show mature neutrophilia, **rare p190 BCR-ABL1 isoform associated with monocytosis


Hematolymphoid Disorders with Thrombocytosis
  CML PV PMF, Cellular Phase ET RARS-T 5q-
Tyrosine kinase ABL p230 variant* JAK2 JAK2 or MPL 50% JAK2 or MPL 50% JAK2 50% JAK2 or MPL 10%
Blood ↑PMN, basophils, platelets Normo or hypochromatic anemia, may have ↑basophils, platelets Anemia, leukocytosis, ↑or nl platelets ↑platelets, often abnormal Dimorphic RBC, ↑platelets Macrocytic anemia, ↑or nl platelets
Marrow ↑↑Myeloids, ↑dwarf megas Panmyelosis, ±erythroid hyperplasia, atypical megas Panmyelosis, atypical tightly clustered megas ↑↑Megas Erythroid dysplasia, ring sideroblasts, ↑megas Erythroid hypoplasia, ↑small megas
Marrow Fibrosis Varies ↑ in spent phase ↑↑ in fibrotic phase Minimal Varies Minimal
Splenomegaly ++ ++ +++ ± ± Absent
Clinical/Other B symptoms Hypertension, thrombosis, pruritus, ↓EPO B symptoms, bleeding, gout Thrombosis, hemorrhage Anemia Anemia
EPO = erythropoietin, * rare p230 BCR-ABL1 isoform can present with thrombocytosis and /or neutrophilia



Common Myeloproliferative Neoplasms - Overview
Tyrosine kinase ABL JAK2 JAK2 or MPL JAK2 or MPL
Blood ↑WBC with IG, basophils Normo or hypochromatic anemia, may have ↑platelets & basophils Leukoerythroblastic with teardrops ↑Platelets, often abnormal
Marrow ↑↑Myeloids Panmyelosis, ± erythroid hyperplasia, atypical megas Panmyelosis, atypical megas ↑↑Megas
Marrow fibrosis Varies ↑In spent phase ↑↑In fibrotic phase Minimal
Splenomegaly ++ ++ +++ ±
Clinical Presentation /Other B symptoms Hypertension, thrombosis, pruritus,↓EPO B symptoms, bleeding, gout Thrombosis, hemorrhage
CML = chronic myeloid leukemia; PV = polycythemia vera; PMF = primary myelofibrosis; ET = essential thrombocythemia; IG = immature granulocytes; Megas = megakaryocytes; EPO = erythropoietin


  • Median age 60-65
    • Broad range 20-80 years
    • Rare in children
  • Onset frequently insidious
    • Headaches, weakness, weight loss, pruritis
    • Hemorrhage, thrombosis, hyperviscosity symptoms
    • Splenomegaly
  • CML is the prototype tyrosine kinase inhibitor (e.g. imatinib) responsive malignancy

Classification / Lists

WHO 2008 Classification of Myeloid Neoplasms

Myeloproliferative Neoplasms (MPN)

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

Myelodysplastic Syndromes (MDS)

Therapy Related Myeloid Neoplasms



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