Bone marrow neoplastic
Bone marrow - neoplastic myeloid
Myeloproliferative neoplasms (MPN)
Chronic myeloid leukemia

Topic Completed: 1 August 2011

Minor changes: 19 June 2020

Copyright: 2002-2020,, Inc.

PubMed Search: Chronic myeloid leukemia [title] CML

Nikhil Sangle, M.D.
Page views in 2019: 17,566
Page views in 2020 to date: 9,015
Cite this page: Sangle N. Chronic myeloid leukemia. website. Accessed July 4th, 2020.
Clinical features
  • Most common chronic myeloproliferative neoplasm
  • Incidence of 10 - 20 cases per million annually
  • All ages affected; median age in 5th - 6th decade
  • Originates from pluripotent stem cell that gives rise to myeloid and lymphoid cells
  • Marrow has neoplastic and normal granulocyte precursors; BCR-ABL identified in all myeloid lineages and some lymphoid cells and endothelial cells but clinically only affects granulocytes
  • Insidious onset with anemia, fatigue, weight loss; may have dragging sensation due to splenomegaly; 20 – 40% are asymptomatic and diagnosed incidentally by WBC count
  • Extramedullary hematopoiesis may cause hepatosplenomegaly and lymphadenopathy; may have splenic infarcts

Disease course (without treatment):
  • Usually chronic phase for 3 - 4 years
  • 50% have accelerated phase (10 - 19% blasts in blood or marrow, > 20% basophils in blood, persistent platelet count < 100K or > 1000K, increasing splenomegaly or white blood cell count while on therapy, marked myelofibrosis, additional or clonal cytogenetic abnormalities with lack of response to treatment, then
  • blast transformation (phase) at mean 3 years after diagnosis (20% or more blasts in marrow or blood), often death shortly afterwards (median survival 3 years without treatment); 70% have myeloid blasts, 30% have lymphoid blasts resembling pre B cells (TdT+, CD19/CD20+); rarely erythroid blasts (Am J Surg Pathol 2004;28:1240); blasts may accumulate as tumor mass in soft tissue or lymph nodes (extramedullary blast proliferation); presumptive diagnosis of blast phase is warranted if blasts occupy significant portions of bone marrow (e.g. an entire intertrabecular area, Arch Pathol Lab Med 2001;125:1385)
Diagrams / tables

Images hosted on other servers:

Diagram of fusion proteins

  • Chronic myeloproliferative neoplasm with Philadelphia chromosome or BCR-ABL
  • Algorithm - if no Philadelphia chromosome but dwarf megakaryocytes, consider performing FISH to detect cryptic translocation of BCR-ABL
Prognosis and treatment
  • Evolution to myelofibrosis (loss of marrow volume to fibrosis, Hum Pathol 2003;34:391)
  • Failure to achieve a cytogenetic response to treatment
Case reports
  • Imatinib mesylate (Gleevec / STI571, J Clin Invest 2007;117:2036) an oral tyrosine kinase inhibitor, prevents phosphorylation of tyrosine residues by competing with ATP for binding to the BCR-ABL1 kinase domain
  • May reverse marrow fibrosis; 87% complete cytogenetic response rate with 96% estimated 3 year survival (Blood 2006;108:1835), peripheral blood normalizes before marrow, although BCR-ABL fusion gene may persist, drug resistance can develop due to point mutations preventing the binding of the inhibitor to the kinase domain of BCR-ABL1
  • Imatinib resistance can be circumvented by second generation protein kinase inhibitors (PTKI) such as nilotinib and dasatinib
  • Interferon produces a complete hematologic response in 80%, effective even in accelerated phase, but complete cytogenetic response rate of only 28% and estimated 3 year survival of only 81%
  • Hydroxyurea causes reduction in cellularity
  • Hematopoietic stem cell transplant remains the only curative approach
  • Note: may progress to blast transformation despite hematologic response to treatment, suggesting bone marrow follow up is critical (Arch Pathol Lab Med 2004;128:980)
Microscopic (histologic) description
  • Peripheral blood: > 100K white blood cells with neutrophilia, significant bulge in metamyelocytes and myelocytes, also basophilia and eosinophilia, monocytosis (but the monocyte fraction is < 3%), low LAP score
  • 50% have thrombocytosis

Leukocyte (neutrophil) alkaline phosphatase (LAP) score:
  • LAP is marker of terminally differentiated neutrophils (Br J Haematol 1999;105:163)
  • Blood film is stained and 100 neutrophils are scored from 0 to 4+ on the basis of the intensity of the precipitated blue dye in their cytoplasm
  • Values of the 100 cells are added and total score reported
  • Scoring: 0: no staining, 1+: weak cytoplasmic staining; 2+: blue staining but clear areas of cytoplasm and pink staining of nuclear lobes still present, 3+: intense cytoplasmic staining but nuclear lobes still visible, 4+: intense cytoplasmic staining obscures the nucleus; low score indicates abnormal neutrophil development, associated with CML, PNH (Blood 1989;73:1113)

Bone marrow:
  • Up to 100% cellular with increased granulocyte precursors, basophils, eosinophils and occasionally monocytes
  • Normal erythroid compartment, normal or increased megakaryocytes in clusters which are often smaller than usual
  • Variable pseudo Gaucher cells and sea blue histiocytes (storage histiocytes with wrinkled / sea blue cytoplasm, usually singly and more prominent near vessels); increased reticulin fibers but marrow fibrosis is rare at presentation; marrow fibrosis is associated with the number of CD61+ megakaryocytes
  • CD34 and / or terminal deoxynucleotidyl transferase (TdT) immunohistochemical stains may be required to identify blasts in fibrotic marrows

  • Diffuse infiltration of red pulp cords and sinuses by myeloid cells in all stages of differentiation
  • Obliteration of white pulp
  • No grossly visible nodules; splenic infarcts may appear
Microscopic (histologic) images

Scroll to see all images:

Bone marrow biopsy, contributed by Drs. K.V. Vinu Balraam and S. Venkatesan:



Bone marrow imprints

Special stains and IHC, contributed by Drs. K.V. Vinu Balraam and S. Venkatesan:

MPO stain on bone marrow imprint





Chronic phase - peripheral blood:

Immature to mature myeloid cells

Later chronic phase, WBC count of 18K

44 year old woman with WBC count of 425K

Early chronic phase, WBC count of 10K

WBC count of 147K and platelet count of 740K

Promyelocyte, myelocytes, neutrophils and 2 basophils

Chronic phase - bone marrow biopsy:

Hypercellular marrow with panmyeloid hyperplasia

Hypercellular marrow with increased megakaryocytes; myeloid cells are primarily neutrophils

PAS stain - left: perivascular accentuation of promyelocytes; right: promyelocytes and myelocytes adjacent to vascular structure

Chronic phase - bone marrow smear:

Pseudo-Gaucher cells

Accelerated phase - peripheral blood:

Pseudo-Pelger-Huët nucleus

47% basophils, 10% blasts, t(9;22) present

Mature neutrophils show prominent hyposegmentation

Accelerated phase - bone marrow biopsy:

Moderately hypercellular bone marrow biopsy with numerous megakaryocytes

Increased reticulin fibers (reticulin stain)

Marked hypercellularity

Myeloblastic transformation - bone marrow biopsy:

Increase in stromal and vascular structures

Marked increase in fibroblasts

Numerous blasts with dispersed chromatin and nucleoli

Marked increase in coarse reticulin fibers (reticulin stain)

Myeloblastic transformation - bone marrow smear:

Blasts and basophils

50% of WBCs are blasts

3 erythroid precursors

Auer rod and pseudo Pelger-Huet nucleus

Megakaryoblastic transformation - peripheral blood:

Left: EM showed platelet peroxidase in blasts; middle: high WBC count and high percentage of micromegakaryocytes; right: different patient; EM showed megakaryocyte differentiation

Lymphoblastic transformation - peripheral blood:

41% lymphoblasts

WBC count of 142K, 55% blasts

Lymphoblastic transformation - bone marrow biopsy:

Complete replacement by blasts

Lymphoblastic transformation - bone marrow smear:

Blasts (TdT+, myeloperoxidase-)

uniform population of blasts

Lymphoblasts resemble ALL-L3

Lymphoblastic transformation - lymph node biopsy:

Diffuse replacement by lymphoblasts

Uniform lymphoblasts, some with clefted nuclei

Erythroblastic transformation - bone marrow biopsy:

< 6% blasts, well circumscribed foci

Blasts have variable cytoplasm

Blasts are Hemoglobin A+

Focal blastic transformation:

22% blasts in marrow

Bone marrow biopsy

Bone marrow smear

Osteomyosclerosis (26 year old woman with 3 year history of CML) - bone marrow biopsies:

Widened trabeculae

Marked increase in coarse reticulin fibers (reticulin stain)

Posttransplant biopsy

5 months posttransplant biopsy

Posttreatment changes:

Bone marrow biopsy shows slightly hypercellular marrow with numerous megakaryocytes

Post interferon

Images hosted on other servers:

Chronic phase - peripheral blood:


Various images

Accelerated phase (general):

Various images

Myeloblastic transformation - bone marrow biopsy:

Post imatinib therapy

Lymphoblastic transformation - bone marrow biopsy:

Posthydroxyurea and postimatinib

Cytology images

Contributed by Drs. K.V. Vinu Balraam and S. Venkatesan

Peripheral blood smear

Flow cytometry images

Contributed by Drs. K.V. Vinu Balraam and S. Venkatesan

SSC vs CD45

CD34 vs CD19

CD10 vs CD19

CD3 vs MPO

Electron microscopy images
Lymphoblastic transformation:

Blasts were pre B phenotype and TdT+

Molecular / cytogenetics description
  • t(9;22)(q34;q11) Philadelphia chromosome (discovered in 1960 - J Natl Cancer Inst 1960;25:85) or ABL gene (#9q34) and BCR gene (#22q11) fusion transcript (Cell 1984;36:93) is requirement for diagnosis
  • Use FISH, RT-PCR or Southern blot techniques to detect cryptic translocations
  • Fusion gene produces 210 kd protein with tyrosine kinase activity that affects cell motility, deregulates the cell proliferation, reduces the capacity to adhere to bone marrow stroma or endothelial cells (BMC Cancer 2006;6:262)
  • No FLT3 mutations (Am J Clin Pathol 2006;126:530)
Molecular / cytogenetics images

Image hosted on PathOut server, contributed by Drs. K.V. Vinu Balraam and S. Venkatesan

FISH showing BCR-ABL1 fusion

Image hosted on PathOut server:


Images hosted on other servers:


Differential diagnosis
  • Leukemoid reaction, other chronic myeloproliferative neoplasms (increased LAP, negative for BCR-ABL), paroxysmal nocturnal hemoglobinuria (LAP negative/low, negative for BCR-ABL)
Additional references
Board review style question #1
Which of these features is true of adult patients with CML when compared with pediatric patients with CML?

A. Higher white blood cell count at initial presentation.
B. More likely to obtain deep molecular response with imatinib tyrosine kinase inhibitor therapy.
C. More likely to present in accelerated or blast phase.
D. More likely to have splenomegaly.
Board review answer #1
B. Adult patients with CML are more likely to achieve remission with imatinib therapy. Whether children may respond better to second generation tyrosine kinase inhibitors is under investigation. Pediatric patients presenting with CML tend to have a higher white blood cell count and are more likely to present in accelerated or blast phase than their adult counterparts. Both populations often present with splenomegaly, but it may be more noticeable in children.
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