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Acute promyelocytic leukaemia (aPML)

Subset of acute myeloid leukemia characterized by the fusion gene transcript PML-RAR-α and is now the most frequently curable acute leukemia in adults if promptly diagnosed and adequately treated.

Subset of acute myeloid leukemia characterized by the fusion gene transcript PML-RAR-α and is now the most frequently curable acute leukemia in adults if promptly diagnosed and adequately treated.

  • MEDICAL EMERGENCY (with very high pre-treatment mortality)
  • Most curable subtype of all the acute myeloid leukaemias (AML)
  • 7-8% of adult AML cases
  • Seen in middle-aged people with a median age of 47 years
Clinical and molecular characteristics of APL
Clinical and molecular characteristics of APL: 3 features of APL (A) a severe bleeding tendency due to fibrinogenopenia and disseminated intravascular coagulation, (B) accumulation of abnormal promyelocytes in bone marrow (top panel) and peripheral blood (bottom panel), and chromosomal translocation t(15;17)(q22;q21) (C) with the resultant fusion transcripts between PML and RARα (D). (C) t(15;17) detected by fluorescence in situ hybridization using PML-RARα dual-color, dual-fusion translocation probes (Vysis, Downers Grove, IL). (D) Schematics representing the formation of 15;17 reciprocal chromosomal translocations (top panel) and fusion transcripts (bottom panel). Stains were analyzed using an Olympus BX51 research microscope equipped with a 100×/1.30 numeric aperture (NA) oil objective (Olympus, Tokyo, Japan). Original magnification, ×1000. | He, L.-Z., Merghoub, T., & Pandolfi, P. P. (1999). In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications. Oncogene, 18, 5278. Retrieved from https://doi.org/10.1038/sj.onc.1203088

History

First described in 1957 in patients with severe bleeding tendencies with fibrinolysis, rapid deterioration of the clinical condition, and the presence of promyelocytes in peripheral blood and bone marrow.


Pathophysiology

Morphologically:

  • AML-M3 (French-American-British (FAB) classification)

Cytogenetically:

Balanced reciprocal translocation 
t (15:17) PML/RARα gene
(90% cases)
(Promyelocytic leukaemia gene (17) + Retinoic acid receptor α (RARα) gene (15))

PML/RARα protein heterodimerizes
with the retinoid X receptor (RXR)

PML/RARα-RXR complex
binds to
retinoic acid-responsive elements in target genes

Cessation of myeloid differentiation at promyelocytic stage

Procoagulant state

(excessive promyelocytes express tissue factor (TF) which forms a complex with factor VII and activates factor X and IX)
&
Immunosuppression
(immature promyelocytes also cannot build
defenses against infections)


Presentation

  • Generalized weakness & fatigue (anaemia)
  • Bleeding occurrence:
    • Gingival bleeding, petechiae or ecchymoses
    • Visual changes (secondary to retinal hemorrhages)
    • Epistaxis
    • Menorrhagia
  • Infections

Complications:

  • Disseminated intravascular coagulation (DIC) (life threatening)
  • Frank bleeding

Diagnosis

Coagulopathy workup:

  • Platelet count
  • Prothrombin time (PT), activated partial thromboplastin time (PTT)
  • d-dimer or fibrin split products
  • Fibrinogen

Peripheral blood smear (PBS):

  • Large atypical promyelocytes and other myeloid precursors (in various stages of development) (CHARACTERISTIC)
Abnormal promyelocytes with bilobate nuclei with conspicuous nucleoli are evident in aPML
Peripheral smear from a 22-year-old male with a white blood cell count (WBC) of 18.5 × 109/L. Abnormal promyelocytes with bilobate nuclei with conspicuous nucleoli are evident. Partial overlapping lobes are most evident in the cell at the top right. Numerous small azurophilic granules are present in the cytoplasm of the cell at the lower left. All of the cells stained strongly positive with myeloperoxidase and showed the t(15:17) translocation on fluorescent in situ hybridization (FISH) analysis. The WBC in the microgranular variant is typically increased as opposed to low or normal WBCs seen in hypergranular acute promyelocytic leukemia. | (2004). Acute promyelocytic leukemia, microgranular variant. Blood, 104(3), 605 LP-605. Retrieved from http://www.bloodjournal.org/content/104/3/605.abstract

Immunophenotyping (flow cytometry):

  • Unique immunophenotypic profile (CD34- CD117+ HLA-DR-) with characteristic CD11b and CD11c negativity

Gene testing:

  • Fluorescence in situ hybridization (FISH): Fusion of PML/RARA should be expedited for rapid diagnosis of this time-sensitive disease
  • Conventional karyotyping: Detects rare molecular subtypes of APL and other additional coexistent cytogenetic abnormalities
  • Reverse transcriptase polymerase chain reaction (RT-PCR) (for PML-RARA RNA): For confirming the diagnosis of APL and can also be used can for monitoring minimal residual disease
POSITIVE PML/RARA FISH with a translocation between PML (15q24) and RARA (17q21.1) in 84% of cells
POSITIVE PML/RARA FISH with a translocation between PML (15q24) and RARA (17q21.1) in 84% of cells. | Molecular Pathology Laboratory Network, Inc. (2018) Acute Promyelocytic Leukemia – Diagnosis, Prognosis, and Role of Ancillary Testing | Case Studies | News. Retrieved December 13, 2018, from http://www.mplnet.com/news/case-studies/acute-promyelocytic-leukemia-diagnosis-prognosis-and-role-of-ancillary-test

Risk stratification:

  • Low-risk (WBC ≤ 10,000/µl & platelets ≥ 40,000/µl)
  • Intermediate-risk (WBC ≤ 10,000/µl & platelets ≤ 40,000/µl)
  • High-risk (WBC > 10,000/microL)

Bone marrow biopsy:

  • Hypercellular bone marrow
  • APL promyelocytes: 30% myeloid cells (classic variant)
Bone marrow aspirate in aPML shows numerous abnormal promyelocytes with prominent cytoplasmic granules, characteristic of hypergranular acute promyelocytic leukemia
Bone marrow aspirate in aPML shows numerous abnormal promyelocytes with prominent cytoplasmic granules, characteristic of hypergranular acute promyelocytic leukemia: Some of these cells exhibit reniform or bilobed nuclei, and several cells contain multiple Auer rods. The blood smear from this patient showed a pancytopenia with rare abnormal promyelocytes. Wright-Giemsa stain. Device: Olympus BX51 microscope using a 100×/1.4 oil-objective lens. | He, L.-Z., Merghoub, T., & Pandolfi, P. P. (1999). In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications. Oncogene, 18, 5278. Retrieved from https://doi.org/10.1038/sj.onc.1203088

Management

All-trans retinoic acid (ATRA; tretinoin) therapy:

ATRA (acid form of vitamin A) does not directly kill the malignant cells but induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own.
Differentiation therapy in APL
Differentiation therapy in APL: APL is characterized by the clonal expansion of malignant myeloid cells blocked at the promyelocytic stage of hemopoietic differentiation. All-trans retinoic acid (RA) induces the malignant promyelocytes to terminally differentiate towards mature granulocytes. Occasionally, Auer rods (indicated by the yellow arrows), pathognomonic structures found in the cytoplasm of APL malignant promyelocytes, are still observed in the mature granulocytes upon RA treatment demonstrating that these mature cells originated from the neoplastic clone | He, L.-Z., Merghoub, T., & Pandolfi, P. P. (1999). In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications. Oncogene, 18, 5278. Retrieved from https://doi.org/10.1038/sj.onc.1203088
  • Initial therapy:
    • ATRA-ATO regimen: ATRA (45 mg⁄m2⁄ day orally for 45–90 days) + anthracycline chemotherapy (for induction)
  • Maintainance therapy:
    • Maintenance chemotherapy with methotrexate, mercaptopurine and ATRA (2 years)
  • Relapsed/refractory diseases:
    • Arsenic trioxide (As2O3)
  • Complications:
    • Differentiation syndrome “Retinoic acid syndrome”

Supportive treatment:

  • High suspicion for infections and appropriate management

Prognosis

Poor prognostic factors:

  • Older age
  • ↑ WBC
  • ↓ Platelets
  • CD56 expression

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