Acute biphenotypic leukaemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Synonyms and Keywords: Biphenotypic Acute Leukaemia (BAL); BAL, Biphenotypic Acute Leukaemia

Overview

Leukemia was first described in 1827 by Alfred-Armand-Louis-Marie Velpeau, a french physician. In 1900 the myeloblast was first identified in the pathogenesis of acute myeloid leukemia. The pathogenesis of acute biphenotypic leukaemia can be de novo or secondary to previous cytotoxic therapy. Acute biphenotypic leukaemia is caused by t(9;22)(q34;q11) translocation. Acute biphenotypic leukaemia must be differentiated from other diseases that cause anemia and bruising such as acute myelocytic leukemia and acute lymphocytic leukemia. Common risk factors in the development of acute biphenotypic leukaemia are viral infection, hereditary factors, and radiation. Symptoms of acute biphenotypic leukaemia may include fever, asthma, dizziness, and persistent fever. Stem cell transplantation in conjunction with chemotherapy is the most common approach to the treatment of acute biphenotypic leukaemia.

Historical Perspective

  • In 1845, a series of patients who died with enlarged spleens and changes in the "colors and consistencies of their blood" was reported by the Edinburgh-based pathologist J.H. Bennett; he used the term "leucocythemia" to describe this pathological condition.[2]
  • The term "leukemia" was coined by Rudolf Virchow, the renowned German pathologist, in 1856. As a pioneer in the use of the light microscope in pathology, Virchow was the first to describe the abnormal excess of white blood cells in patients with the clinical syndrome described by Velpeau and Bennett. As Virchow was uncertain of the cause of the white blood cell excess, he used the purely descriptive term "leukemia" (Greek: "white blood") to refer to the condition.[3]
  • Finally, in 1900 the myeloblast, which is the malignant cell in acute myeloid leukemia, was characterized by Naegeli, who divided the leukemias into myeloid and lymphocytic.[6][7]

Pathophysiology

  • The pathogenesis of acute biphenotypic leukaemia can be de novo or secondary to previous cytotoxic therapy.
  • The t(9;22)(q34;q11) translocation and abnormalities of chromosome 11q23 have been associated with the development of acute biphenotypic leukaemia.[8]
  • The hybrid gene product BCR/ABL is an oncogene that could lead to several types of leukemia including acute biphenotypic leukaemia. BCR/ABL could activate several molecular pathways:
  • RAS signaling could be activated by BCR/ABL through the GRB2 adaptor protein, which interacts with Y177 of BCR.
  • PI3-K pathway could also be activated through AKT/PKB.
  • STAT5, 1, and 6 have been reported to participate in a major molecular signaling event after activation by BCR/ABL.
  • The focal adhesion complex PAXILLIN, FAK0 could be activated by BCR/ABL with adaptor molecule CRK-L.
  • BCR/ABL could inactivate negative regulatory molecules PTP1B and Abi-1. Their inactivation is related with progression into blast crisis.
  • BCR/ABL pathway could also activate PI64K/Akt/STAT5 pathway which has anti-apoptotic activity.
  • BCR/ABL induce cell adhesion and migratory abnormalities because the mutation will lead an abnormal response to chemokine SDF-1.
  • MLL gene encodes histone-lysine N-methyltransferase (HRX), which is a histone methyltransferase. It is a positive regulator for gene transcription. It has been shown to associate with host cell factor C1, CREB binding protein, WDR5, CTBP, MEN1, etc. The rearrangement of MLL is related to different kinds of aggressive acute leukemias. The majority of biphenotypic leukemia in children is due to the rearrangement of MLL.
  • Protein MLL PDB 2j2s
  • Additional gene abnormalities include:
    • t(8;21)
    • t(15;17)
    • del(6q)
    • del(12p)
    • t(x;12)
    • t(14;19)
  • Acute biphenotypic leukaemia patients are prone to bruising and spotting, which is due to megakaryocytes that could cause thrombocytopenia.

Philadelphia Chromosome Translocation. Structure of the MLL protein. Based on PyMOL rendering of PDB 2j2s.

  • On microscopic histopathological analysis, two blast populations are characteristic of acute biphenotypic leukaemia:
  1. One population resembling myeloid blasts
  2. One population with smaller lymphoid appearing blasts, azurophilic granules or Auer rods

Causes

  • Acute biphenotypic leukaemia may be caused by either virus, hereditary factors or radiation.
  • Acute biphenotypic leukaemia is caused by t(9;22)(q34;q11) translocation.

Differentiating Acute biphenotypic leukaemia from other Diseases

  • Acute biphenotypic leukaemia must be differentiated from other diseases that cause anemia and bruising such as:

Epidemiology and Demographics

  • The prevalence of acute biphenotypic leukaemia is unknown since it is an extremely rare disease.

Age

  • Acute biphenotypic leukaemia is more commonly observed among adults.

Risk Factors

Natural History, Complications and Prognosis

  • Early clinical features include anemia and bruising.
  • Common complications of acute biphenotypic leukaemia include pericardial effusion, pleural effusion, and septicemia.
  • Prognosis is generally poor, and the 4 year survival rate of patients with acute biphenotypic leukaemia is approximately 8%.

Diagnosis

Diagnostic Criteria

A diagnosis of acute biphenotypic leukaemia is made when at least 2 of the following criteria are met:

Points B lineage T lineage Myeloid lineage
2
CD79a
cyt IgM
cyt CD22
CD3 (cyt/m)
anti-TCR α/β
anti-TCR γ/δ
anti-MPO
(anti-lysozyme)
1
CD19
CD10
CD20
CD2
CD5
CD8
CD10
CD13
CD33
CDw65
CD117
0.5
TdT
CD24
TdT
CD7
CD1a
CD14
CD15
CD64

Abbreviations: cyt, cytoplasmic; m, monoclonal; MPO, myeloperoxidase; TCR, T-cell receptor; TdT, terminal deoxynucleotidyl transferase. More than 2 points are required to assign a lineage.[9]

Symptoms

  • Symptoms of acute biphenotypic leukaemia may include the following:

Physical Examination

  • Patients with acute biphenotypic leukaemia usually appear normal.
  • Physical examination may be remarkable for:

Laboratory Findings

  • Co-expression of myeloid and lymphoid markers is diagnostic of acute biphenotypic leukaemia.
  • An elevated concentration of serum CD79a, CD22, cytoplasmic immunoglobulin, CD3, anti-TCR, and myeloperoxidase are diagnostic of acute biphenotypic leukaemia.

Other Diagnostic Studies

  • Acute biphenotypic leukaemia may also be diagnosed using cytogenetics, molecular analysis, chromosomal analysis, ultrastructural MPO (EM-MPO), and monoclonal antibody panels

Treatment

Medical Therapy

  • The mainstay of therapy for acute biphenotypic leukaemia is induction chemotherapy.

Surgery

  • Stem cell transplantation in conjunction with chemotherapy is the most common approach to the treatment of acute biphenotypic leukaemia.

References

  1. Hoffman, Ronald; et al. (2005). Hematology: Basic Principles and Practice (4th. ed. ed.). St. Louis, Mo.: Elsevier Churchill Livingstone. pp. p. 1071. ISBN 0-443-06629-9. 
  2. Bennett JH. Two cases of hypertrophy of the spleen and liver, in which death took place from suppuration of blood. Edinburgh Med Surg J. (1845)64:413.
  3. Virchow R: Die Leukämie. In Virchow R (ed): Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt, Meidinger, 1856, p 190.
  4. Ebstein W. Ueber die acute Leukämie und Pseudoleukämie. Deutsch Arch Klin Med. (1889)44:343.
  5. Mosler F. Klinische Symptome und Therapie der medullären Leukämie. Berl Klin Wochenschr. (1876)13:702.
  6. Naegeli O. Über rothes Knochenmark und Myeloblasten. Deutsch Med Wochenschr. (1900) 26:287.
  7. Zhen-yi, Wang (2003). "Ham-Wasserman Lecture: Treatment of Acute Leukemia by Inducing Differentiation and Apoptosis". Hematology. PMID 14633774. 
  8. .Biphenotypic Acute Leukaemia (BAL) Atlasgeneticsoncology (2016). http://atlasgeneticsoncology.org/Anomalies/BiphenoALID1214.html Accessed on April 7, 2016
  9. Owaidah, T M; Beihany, A Al; Iqbal, M A; Elkum, N; Roberts, G T (2006). "Cytogenetics, molecular and ultrastructural characteristics of biphenotypic acute leukemia identified by the EGIL scoring system". Leukemia. 20 (4): 620–626. ISSN 0887-6924. doi:10.1038/sj.leu.2404128. 

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