Paediatric Acute Promyelocytic Leukaemia: A Rare Case Report
Correspondence Address :
Dr. Siddhi Shringi,
Resident, Department of Pathology, Jawaharlal Nehru Medical College, DMIHER, Wardha-442001, Maharashtra, India.
E-mail: siddhishringi@ymail.com
Acute Myeloid Leukaemia (AML) is a malignant disorder of the bone marrow in which there is maturational arrest in blood cell progenitors, resulting in the failure of normal haematopoiesis. Acute Promyelocytic Leukaemia (APML) is a subtype of AML with a defined clinical course and a biology that is distinct from other forms of AML. Morphologically, the most common form of APML shows the presence of heavily granulated cells with folded and twisted nuclei in the bone marrow. Biologically, the cytogenetic changes define the syndrome, and molecular changes in the chromosomes play a critical role in leukaemogenesis. The occurrence of APML in the paediatric population is very rare, accounting for <5%. Here, a case is presented of a four-year-old child who with fever, one episode of non projectile vomiting, and two episodes of loose watery stools. Upon further investigation, the child had immature myeloid series cells in the peripheral blood smear, which on Bone Marrow Aspiration (BMA), flow cytometry, and Fluorescent In Situ Hybridisation (FISH) confirmed a case of APML. A major manifestation of this chimeric Promyelocytic Leukaemia (PML)-Retinoic Acid Receptor Alpha (RARA) protein is a maturation block at the promyelocyte stage of myeloid differentiation, leading to the accumulation of blasts and promyelocytes. Both Fluorescence In-Situ Hybridization (FISH) and Polymerase Chain Reaction (PCR) methods can detect the fusion gene, with PCR having the advantage of detecting the three major fusion transcripts and rare submicroscopic complex translocations. Additionally, quantitative PCR can be used to monitor minimal residual disease in APML following treatment. In this case, the patient survived her first episode of disease emergence, but during her relapse, she could not survive as she developed Disseminated Intravascular Coagulation (DIC), possibly due to chemotherapeutic agents. The patient might have developed differentiation syndrome, in which there is a large and rapid release of cytokines from leukaemic cells affected by chemotherapy agents. The challenge in treating such cases is to overcome differentiation syndrome and find a new therapy options.
Differentiation, Flow cytometry, Platelets, Promyelocytes
A four-year-old female presented with complaints of low-grade fever, breathlessness, and other constitutional symptoms such as upper respiratory tract infection and easy fatiguability since one week. Routine laboratory investigations revealed low haemoglobin, a high total leukocyte count, and severely reduced platelets (Table/Fig 1). Further peripheral smear examination showed an increased number of immature myeloid series cells, with the maximum being promyelocytes followed by myeloblasts (Table/Fig 2). Simultaneous clinical and radiological evaluation revealed splenomegaly in the patient. A Bone Marrow Aspiration (BMA) was performed and reported as (Table/Fig 3) with Myeloperoxidase positivity (Table/Fig 4). The patient was advised to undergo flow cytometric analysis (Table/Fig 5), as this analysis is an essential component in diagnosing APML. The flow cytometric charts are enclosed (Table/Fig 6).
The child received four cycles of chemotherapy along with all-trans retinoic acid, followed by which she entered the phase of remission, experiencing complete symptom-free survival for one year. After one year, the patient developed symptoms of anaemia. As a previously diagnosed case of APML-M3, she underwent further evaluation for laboratory investigations. The complete blood count (Table/Fig 7) revealed a raised total leukocyte count.
Further peripheral smear examination revealed increased immature myeloid series cells, with a higher number of promyelocytes and severely reduced platelet count (Table/Fig 8). Due to thrombocytopenia, the patient could not undergo a Bone Marrow Aspiration (BMA) procedure. Simultaneously, she was started on chemotherapy with all-trans retinoic acid based on the peripheral smear findings, laboratory investigations, clinical examination, and her previous disease course. She was considered to be in the relapse phase of APML. During the first cycle of chemotherapy in her relapse phase, the patient presented with sudden onset pulmonary haemorrhage, easy bruising, and multiple petechiae over her extremities and dependent parts of the body. Laboratory investigations showed a sudden fall in platelets. Despite being managed with repeated transfusions of random donor platelets and single donor platelets within acceptable limits for her age and body surface area, her condition worsened, leading to Disseminated Intravascular Coagulation (DIC). Unfortunately, she could not be saved. The clinical scenario was further correlated with her laboratory investigation results, showing serially declining platelets followed by a sudden fall (when she developed DIC), a deranged coagulation profile, and raised D-dimers levels. She could not withstand the chemotherapy due to bleeding manifestations and succumbed to death, which is one of the most dreaded complications in APML (Therapy-induced-a new challenge in treating paediatric cases of APML).
In this case, the rare finding was that APML was found in a four-year-old female, with the diagnosis confirmed through BMA, flow cytometry (Table/Fig 5), and FISH (Table/Fig 9).
AML-M3 (APML), for the first time in the literature, was identified as a distinct type of AML. With a declining course, it leads to severe bleeding. The incidence rate of APML is 5-10% in newly diagnosed AML cases, originating from a balanced translocation t(15;17)(q22.1;q12.21), accelerating the fusion process of the PML gene with the RARA gene, by clogging normal myeloid differentiation.
The resulting PML-RARA fusion oncoprotein induces leukaemia (1). Describing the myeloperoxidase-positive blast cells within the blast cytoplasm, there is a common presence of linear azurophilic granules and sometimes Auer rods, although this finding could be found in other AML subtypes (2). The level of PML-RARA transcript at the end of transcription therapy holds high predictive value for relapse (3). The laboratory features of APML are associated with a hyperfibrinolytic state leading to bleeding as the clinical manifestation, often resulting in DIC. DIC is more common in the hypergranular promyelocytic subtype, accounting for 60% to 100% of all APML cases in adults. Just 5-10% of paediatric APML cases are caused by translocation t(15;17)(q24.1;q21.2), with its incidence rising with advancing age (4). The coagulopathy in APML has a multifactorial cause; tissue factor is present in cytoplasmic granules of promyelocytes alongside leukocyte proteases and elastase, acting as procoagulants that stimulate clotting factor consumption and DIC development. Enhanced fibrinolysis results from increased promyelocyte expression of Annexin II, a receptor for plasminogen and tissue plasminogen activator, with malignant promyelocytes containing plasminogen activator. In some cases, acute fulminant DIC is triggered by the administration of thromboplastin contents from promyelocytes (5). Depletion of alpha-2 antiplasmin (which normally has three-fold function including plasmin proteolysis, inhibition of plasminogen binding to fibrin, and cross-linking fibrin) occurs during chemotherapy induction, a finding that is more predictive of bleeding complications due to unregulated fibrinolysis, leading to the destruction of functional haemostatic plugs and depletion of fibrinolysis. Immunophenotyping of APML cells demonstrates positivity for CD117, CD13, CD33, and myeloperoxidase with a high side scatter.
The balanced translocation t(15;17)(q24.1;q21.2) serves as the cytogenetic hallmark of APML and is the most common mutation driving APML development, described in 95% of APML cases (1). This translocation involves the fusion of the PML gene on chromosome 15 with the RARA gene on chromosome 17, leading to the PML-RARA fusion gene and the PML-RAR protein (6). The mechanism through which PML-RARA leads to APML development has been extensively described over several decades. PML-RAR retains the ability of RAR to bind retinoic acid-responsive elements and dimerise with the retinoid X receptor protein but inhibits the normal gene transcription regulated by these elements, ultimately leading to the suppression of RAR target genes and a blockage in differentiation at the promyelocyte stage (2). In this translocation, the PML gene on chromosome 15 joins with the RARA gene on chromosome 17, leading to formation of the PML-RAR alpha fusion gene and the development of the PML-RAR alpha protein.
This translocation blocks the differentiation of the myeloid series at the promyelocytic stage. By administering all-trans-retinoic acid in combination with chemotherapy, this differentiation is promoted towards the terminal stage of myeloid series cells.
APML typically occurs in individuals between the second and fifth decades of life, which translates to the age range of 22 to 44 years. This case presents a rare occurrence of a four-year-old who developed DIC during her relapse. As previously discussed, the pathogenesis of APML highlights that the balanced translocation t(15;17)(q24.1;q21.2) serves as the cytogenetic hallmark of APML. All Trans Retinoic Acid (ATRA) functions by relocating PML, restoring the normal structure of nuclear bodies, and degradation of PML-RAR alpha protein through caspase-mediated cleavage and proteasome degradation. Additionally, under therapeutic concentrations of ATRA, PML-RAR alpha is converted from a transcription corepressor to a transcription activator. In this particular case, the patient survived the initial emergence of the disease but unfortunately succumbed during the relapse, likely due to DIC. The proposed cause of DIC could be attributed to the chemotherapeutic agents administered to the patient. It is possible that the patient developed differentiation syndrome, in which there is large and rapid release of cytokines from leukaemic cells affected by chemotherapy agents. The challenge for the treatment of such cases is to overcome the differentiation syndrome and find a new therapy for these patients.
DOI: 10.7860/JCDR/2024/70197.19556
Date of Submission: Feb 24, 2024
Date of Peer Review: Mar 26, 2024
Date of Acceptance: May 14, 2024
Date of Publishing: Jun 01, 2024
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes
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ETYMOLOGY: Author Origin
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