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

• 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 senstive

• 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

• Hematopathology, 2011. By Elaine Sarkin Jaffe, MD, Nancy Lee Harris, James Vardiman, MD, Elias Campo, MD and Daniel MD Arber, MD