Chronic Myelogenous Leukemia, BCR-ABL1+



Chronic Myelogenous Leukemia, BCR-ABL1+


Kaaren K. Reichard, MD





Key Facts


Clinical Issues



  • Classically 3 phases of disease: Chronic, accelerated, and blast


Microscopic Pathology



  • Peripheral blood, chronic phase



    • Granulocytic leukocytosis with left shift and < 5% blasts


    • Basophilia


  • Bone marrow, chronic phase



    • Blasts < 5%


    • Granulocytic predominance with M:E ratio > 10


    • Small, monolobulated megakaryocytes


    • May see reticulin fibrosis


Ancillary Tests



  • Flow cytometry identifies blast lineage in accelerated and blast phases


  • Genetic studies required to confirm t(9;22) (q34;q11.2) or BCR-ABL1 fusion


  • Cytogenetic studies reveal clonal evolution portending disease progression


  • Molecular studies (BCR-ABL1 transcript levels) for minimal residual disease monitoring


Top Differential Diagnoses



  • Leukemoid reaction


  • BCR-ABL1(-) myeloproliferative neoplasm



    • Chronic neutrophilic leukemia


  • Myelodysplastic/myeloproliferative neoplasm



    • Atypical CML






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.


TERMINOLOGY


Abbreviations



  • Chronic myelogenous leukemia (CML)


Synonyms



  • Chronic myeloid leukemia


  • Chronic granulocytic leukemia


Definitions



  • 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


ETIOLOGY/PATHOGENESIS


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


BCR-ABL1



  • 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


CLINICAL ISSUES


Epidemiology



  • 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



Presentation



  • Splenomegaly


  • Weight loss


  • Fatigue


  • Night sweats


  • Abnormal CBC


  • Leukocytosis


  • Basophilia


  • 20-30% asymptomatic



    • Detected by routine CBC screening


Treatment



  • 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


Prognosis



  • 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



IMAGE FINDINGS


Radiographic Findings



  • Splenomegaly


MICROSCOPIC PATHOLOGY


Predominant Pattern/Injury Type



  • Hyperplasia


Predominant Cell/Compartment Type



  • Hematopoietic, myeloid


Key Microscopic Features

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Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Chronic Myelogenous Leukemia, BCR-ABL1+

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