Chronic Myelogenous Leukemia, BCR-ABL1+

Chronic Myelogenous Leukemia, BCR-ABL1+

Kaaren K. Reichard, MD

Peripheral blood shows leukocytosis with granulocytic left shift, basophilia image, and rare blasts image in the classic appearance of chronic phase chronic myelogenous leukemia, BCR-ABL1 positive.

GTW-banded chromosomes demonstrate the typical shortened chromosome 22, the Philadelphia chromosome image. This chromosome results in the BCR-ABL1 fusion at the molecular genetic level.



  • Chronic myelogenous leukemia (CML)


  • Chronic myeloid leukemia

  • Chronic granulocytic leukemia


  • Myeloproliferative neoplasm that derives from clonal hematopoietic stem cell

  • Diagnosis rests on identification of t(9;22)(q34;q11.2) (or variant) or BCR-ABL1 genetic fusion


Environmental Exposure

  • Radiation exposure implicated in some cases

  • Most predisposing factors unknown

  • Rare cases follow potent chemotherapy

BCR-ABL1 Fusion Protein

  • Using sensitive molecular techniques, very low levels of BCR-ABL1 fusion detected in healthy individuals

    • Individuals do not develop myeloid neoplasms

  • BCR-ABL1 fusion not specific for CML

    • Seen in some acute lymphoid and myeloid leukemias

    • Fusion transcript may be different


  • Chronic phase

    • Consequence of BCR-ABL1 fusion is protein constitutive tyrosine kinase activity

    • Acquisition of preleukemic genetic abnormalities

      • Leads to proliferation and survival advantage

      • Results in myeloproliferation

  • Transformation to blast phase

    • Increased BCR-ABL1 transcript levels

    • Differentiation arrest

      • Expression of transcription factors normally involved in maturation are lost (e.g., CEPBA)

    • Additional chromosomal abnormalities: +8, duplicate Philadelphia chromosome, i(17q), +17, +19

    • Inactivation of tumor suppressor genes (e.g, TP53) results in unchecked cell division

    • Gene expression profiling shows numerous other recurrent genetic abnormalities in CML progression

CML Stem Cell

  • BCR-ABL1 transforms cell that has inherent selfrenewal capabilities

    • Supports concept of clonal hematopoietic stem cell disorder

  • Quiescent BCR-ABL1-expressing leukemic stem cells resistant to chemotherapy, radiation, and targeted tyrosine kinase inhibitors

  • Targeted therapy (e.g., imatinib) theorized to eliminate differentiated cells

    • Leukemic stem cells remain, leading to persistent residual disease

  • Cells produced in bone marrow (even lymphocytes) contain the BCR-ABL1 fusion



  • Incidence

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

  • Age

    • Median at diagnosis is 50-70 years, but may occur at any age

  • Gender

    • Slight male predominance

  • Ethnicity

    • No reported ethnic predisposition


  • Splenomegaly

  • Weight loss

  • Fatigue

  • Night sweats

  • Abnormal CBC

  • Leukocytosis

  • Basophilia

  • 20-30% asymptomatic

    • Detected by routine CBC screening


  • Drugs

    • Historically, nontargeted therapies utilized

      • Radiation, busulfan, hydroxyurea, interferon alpha

      • Varying degrees of activity

    • Currently, targeted therapies (tyrosine kinase inhibitors, a.k.a. TKIs)

    • 1st generation TKI, imatinib mesylate (STI151)

      • Targets the abnormal BCR-ABL1 fusion kinase

      • Most data from the IRIS study (randomized clinical trial with > 5 years of follow-up)

      • Many patients respond to standard oral dose of imatinib (400 mg/day)

      • Some patients do not achieve adequate levels of response or discontinue therapy because of resistance; increasing dose of imatinib may help; response usually modest

      • Side effects of imatinib: Muscle cramps, edema, diarrhea, skin rash, myelosuppression

    • 2nd generation TKIs

      • Nilotinib (10-30 fold increased potency in imatinib-resistant patients)

      • Dasatinib inhibits all imatinib-resistant BCR-ABL1 mutations, except T315I

      • Both of these drugs are FDA-approved for use in patients with imatinib resistance/intolerance

      • Both also show decent activity in patients with relapsed chronic phase CML

  • Allogeneic stem cell transplantation

    • Only proven curative therapy

    • Associated with significant morbidity and mortality


  • Prior to TKI targeted therapies, median survival ranged from 3-6 years

  • With TKIs, prognosis determined by rate of hematologic, cytogenetic, and molecular response

    • Imatinib 5-year overall survival is 80-95% (chronic phase)

  • Mechanisms of relapse/resistance

    • BCR-ABL1 kinase domain mutations

      • 40-90% of patients resistant to imatinib have demonstrable mutation

    • Mutations that occur at contact point of imatinib and ABL1 kinase

      • Examples include T315I and F359V

      • T315I mutations are insensitive to 1st- and 2nd-line TKIs

    • Mutations that affect conformation of kinase; imatinib cannot bind

      • Mutations in P loop: M244V, E255K/V, etc.

      • Mutations in activation loop H396R/P

  • 3 classically defined phases of disease: Chronic, accelerated, and blast

    • Chronic: < 5% blasts

    • Accelerated and blast phases

      • Represent disease progression

      • Generally refractory to therapy

    • Blast phase (≥ 20% blasts); 75-80% myeloid lineage, 20-25% lymphoid lineage (predominantly B)

  • Moderate/marked reticulin fibrosis in chronic phase associated with worse prognosis

  • Minimal residual disease (MRD) monitoring

    • MRD monitored using quantitative PCR (Q-PCR) for BCR-ABL1 transcript levels

    • > 3 log reduction within 1st 12-18 months of imatinib therapy predictive of long-term disease remission status


Radiographic Findings

  • Splenomegaly


Predominant Pattern/Injury Type

  • Hyperplasia

Predominant Cell/Compartment Type

  • Hematopoietic, myeloid

Key Microscopic Features

Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Chronic Myelogenous Leukemia, BCR-ABL1+
Premium Wordpress Themes by UFO Themes
%d bloggers like this: