APML Flashcards
What is Acute Promyelocytic Leukemia (APML)?
APML is a subtype of acute myeloid leukemia characterized by the accumulation of immature promyelocytes in the bone marrow, often associated with the t(15;17) translocation, leading to the fusion gene PML-RARA.
What is the genetic hallmark of APML?
The t(15;17)(q24;q21) translocation results in the fusion of the PML gene on chromosome 15 and the RARA gene on chromosome 17, forming the PML-RARA oncogene.
How does the PML-RARA fusion protein affect promyelocyte maturation?
The PML-RARA fusion protein blocks differentiation at the promyelocyte stage by interfering with retinoic acid receptor signaling.
How does the t(15;17) translocation contribute to leukemogenesis?
It produces the PML-RARA fusion protein, which acts as a dominant-negative inhibitor of retinoic acid receptor signaling, leading to a block in cell differentiation.
What are the common clinical features of APML?
Fatigue and pallor due to anemia
Bleeding (e.g., bruising, epistaxis, gum bleeding) due to coagulopathy
Fever and infections due to neutropenia
What specific bleeding manifestations are common in APML?
Bruising, petechiae, mucosal bleeding (e.g., gums), and in severe cases, intracranial or gastrointestinal hemorrhage.
Why is disseminated intravascular coagulation (DIC) commonly associated with APML?
Abnormal promyelocytes release procoagulant substances like tissue factor and annexin II, which activate clotting and fibrinolysis, leading to DIC.
What are the key diagnostic features of APML?
Peripheral blood smear: Promyelocytes with Auer rods
Bone marrow aspirate: Hypercellular marrow with promyelocytes
Cytogenetics/FISH: t(15;17) translocation
Molecular testing: Detection of PML-RARA fusion gene
What is the significance of Auer rods in the diagnosis of APML?
Auer rods, seen in promyelocytes, are a key morphological feature of APML and indicate the presence of myeloid differentiation.
What laboratory findings suggest DIC in APML?
Prolonged PT and aPTT, low fibrinogen levels, elevated D-dimer, and thrombocytopenia.
How does fibrinolysis contribute to bleeding in APML?
Excessive fibrinolysis due to plasmin activation leads to degradation of fibrin clots, exacerbating bleeding.
What is the first-line treatment for APML?
All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO)
ATRA promotes differentiation of promyelocytes into mature cells.
ATO targets the PML-RARA fusion protein.
What is the prognosis for patients with APML?
With modern treatment (ATRA + ATO), the cure rates are >90% in low-risk patients.
What supportive measures are critical in APML management?
Blood product support: Platelets and cryoprecipitate to manage coagulopathy.
Prophylactic antibiotics and antifungals during neutropenia.
What is the treatment for relapsed or refractory APML?
Repeat ATRA + ATO regimen if not previously used.
Hematopoietic stem cell transplantation (HSCT) may be considered in certain cases.
When is Hematopoietic Stem Cell Transplantation indicated in APML?
HSCT is reserved for relapsed or refractory cases or for patients who fail molecular remission after salvage therapy.
Why is chemotherapy often avoided as first-line treatment in APML?
Chemotherapy increases the risk of DIC during early treatment, making ATRA and ATO safer and more effective.
What is differentiation syndrome in APML, and how is it managed?
Definition: Life-threatening syndrome caused by rapid differentiation of leukemic cells.
Symptoms: Fever, dyspnea, weight gain, pleural/pericardial effusions, and hypotension.
Management: High-dose corticosteroids (e.g., dexamethasone) and supportive care.
What is the pathophysiology of differentiation syndrome?
Differentiation syndrome occurs due to cytokine release as leukemic cells mature rapidly, leading to capillary leak syndrome.
What preventive measures are used for differentiation syndrome?
Prophylactic corticosteroids (e.g., dexamethasone) may be given during induction therapy in high-risk patients.
What factors predict a better prognosis in APML?
Low WBC count at diagnosis, absence of FLT3 mutations, and early molecular remission are favorable prognostic factors.
What are poor prognostic factors in APML?
High WBC count (>10 x 10⁹/L), delay in initiating treatment, and severe coagulopathy.
What type of blood products are commonly used in APML?
Platelets and cryoprecipitate to correct thrombocytopenia and hypofibrinogenemia, respectively.
Why is antifibrinolytic therapy avoided in APML?
Antifibrinolytics may worsen thrombosis risk in the setting of coagulopathy.
