Back to Homepage

Case 252 - Discussion

Hematopathology Case

 

Chronic Myelogenous Leukemia
 

CLINICAL FEATURES

  • Rare, 1-2 cases per 100,000 people

  • Age: rarely pediatric cases, median age ~ 65 years

  • Anemia, splenomegaly,  fatigue, left upper abdominal pain,  early satiety

  • 20%-40% of patients are asymptomatic at initial diagnosis

  • Bi- or triphasic: indolent chronic phase (CP), accelerated phase (AP), blast phase (BP)

PERIPHERAL BLOOD FINDINGS, CHRONIC PHASE

  • General: leukocytosis, median WBC counts 100 × 109/L
  • RBC: anemia common, mostly mild
  • WBC:
    • Different stages of maturation, mostly myelocytes (myelocyte bulge) and segmented neutrophils
    • Normal morphology, no significant dysplasia.
    • Blasts < 2%
    • Absolute basophilia
    • May have eosinophilia and absolute monocytosis
  • PLT:
    • Normal or elevated, >1000 × 109/L in10-15% cases
    • Thrombocytopenia uncommon
    • Unremarkable morphology, or occasional giant platelets
    • Abnormal platelet function studies common

BONE MARROW FINDINGS, CHRONIC PHASE

  • General:

    • Hypercellular and nearly devoid of fat cells
    • Elevated myeloid-to-erythroid ratio, sometimes greater than 20:1
  • Myeloid:
    • Prominently increased myelocytes (“myelocyte bulge”) and segmented neutrophils
    • Neutrophils no significant dysplasia
    • Blasts usually < 5%, and if > 10% or large clusters, indicates disease progression
  • Erythroid:
    • Erythroid islands reduced in size and number but show maturation.
    • Absent or minimal dyserythropoiesis
  • Megakaryocyte:

    • Megakaryocytes normal or increased
    • Small, “dwarf” cells with hypolobated nuclei
  • Other findings
    • Decreased or absent stainable storage iron in most patient
    • Moderate to marked reticulin fibrosis in up to 40% of patients
    • Gaucher cells or “sea-blue” histiocytes

Accelerated Phase

  • Persistent or increasing WBC count (>10 × 109/L), or persistent or increasing splenomegaly, unresponsive to therapy
  • Increased numbers of blasts, 10-19%
  • Sometimes granulocytic dysplasia.
  • Prominent basophilia, may > 20%
  • Occasional increased percentages of monocytes, in conjunction with dysplastic neutrophils, may resemble CMML
  • Persistent thrombocytosis (>1000 × 109/L) or thrombocytopenia (<100 × 109/L), uncontrolled by therapy
  • Bone marrow may show megakaryocytic proliferation in sheets or sizable clusters, marked reticulin or collagen fibrosis or severe granulocytic dysplasia
Blast Phase
  • Blasts account for 20% or more of WBCs in the blood or nucleated cells in the bone marrow or
  • Extramedullary blast proliferation (myeloid sarcoma)
  • Myeloid BP in most cases, may be neutrophilic, eosinophilic, basophilic, monocytic, megakaryocytic, erythroid, or any combination.
  • Some  resemble de novo AML with recurring cytogenetic abnormalities, such as inv(16)(p13.1q22) or t(16;16)(p13.2;q22), in the same cells with Ph chromosome.
  • In 20 - 30% of BP, the blasts are B- lymphoblasts

CYTOGENETICS AND GENETICS

  • t(9;22)(q34;q11.2), BCR-ABL1, also in 15 - 30% adults B-ALL and 5% of pediatric B-ALL

  • 90-95% detected by routine karyotyping,  FISH or RT-PCR more sensitive

  • p210, major breakpoint cluster region, 95% CML and ~ 30% Ph+ ALL

  • p190, minor breakpoint cluster region, 70% Ph+ ALL and in rare cases of CML (increased monocytes, resemble CMML; basophilia and “dwarf” megakaryocytes)

  • p230, mu-breakpoint cluster region, mainly segmented neutrophils with few immature forms in the blood, resembling CNL, or marked thrombocytosis, resembling ET

DIFFERENTIAL DIAGNOSES

  • Chronic Phase

    • Reactive leukocytosis or leukemoid reactions

      • Underlying infectious, inflammatory, or neoplastic process

      • Lack of basophilia and myelocyte bulge

      • May need molecular or FISH studies if questionable

    • CNL

      • BCR-ABL1–negative, but may resemble CML, particularly p230 CML

      • Sustained neutrophilia, hepatosplenomegaly, and bone marrow hypercellularity

      • Peripheral blood: mainly segmented neutrophils, often with toxic granulation; Lack the spectrum of immature and mature neutrophils typical of CML; Absent or minimal basophilia

      • Bone marrow: granulocytic proliferation, with a shift to mature forms;  no“dwarf” megakaryocytes

    • Eosinophilic disorders (myeloid neoplasms associated with abnormalities of PDGFRA, PDGFRB, and FGFR1; CEL, NOS; and hypereosinophilic syndrome)

      • Sustained eosinophil count, >1.5 × 109/L

      • Lack of  “dwarf” megakaryocytes typical of CML

      • If no apparent underlying inflammatory or nonmyeloid neoplastic disease, studies for BCR-ABL1 fusion and for rearrangements of PDGFRA, PDGFRB, and FGFR1 should be performed

    • CMML

      • Persistent monocytosis, > 1000/µL

      • >10%  monocytes in the peripheral blood

      • Dysplasia in one or more of the myeloid lineages

      • < 20% blasts in the blood or bone marrow

      • no Ph chromosome or BCR-ABL1 fusion gene

      • May resemble CML, particularly p190 CML with monocytosis

    • Atypical chronic myeloid leukemia

      • Not merely an atypical form of CML

      • No BCR-ABL1 fusion gene

      • Granulocytes with prominent dysplasia

      • No significant basophilia

      • Commonly thrombocytopenia is common

      • Bone marrow often shows dysplasia of granulocytic, erythroid and megakaryocytic lineages

      • Median survival times <2 years are reported

    • JMML

      • A disorder of children, > 90% diagnosed before the age of 4 years

      • Peripheral blood: leukocytosis, monocytosis >1000 × 109/L, variable numbers of immature granulocytes, nucleated RBCs

      • No Ph chromosome or BCR-ABL1 fusion gene

      • ~ 80% cases with mutated NRAS or KRAS, NF1, or PTNP11

      • 20-30% cases with monosomy 7

      •  is found in . The

  • Accelerated Phase or Blastic Phase

    • CML initially present in BP vs. de novo Ph+ ALL, Ph+ mixed phenotype acute leukemia, or Ph+ AML

    • BP-CML: likely blood shows blasts in a background of granulocytic proliferation with a left shift, a myelocyte bulge, and absolute basophilia, and there are “dwarf” megakaryocytes in the bone marrow

TREATMENT AND PROGNOSIS

  • Currently, the first line of therapy is the TKI imatinib
REFERENCES
  • Hematopathology, 2011. By Elaine Sarkin Jaffe, MD, Nancy Lee Harris, James Vardiman, MD, Elias Campo, MD and Daniel MD Arber, MD