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: 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.
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)
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)
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. | 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
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
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: 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
