Acute Promyelocytic Leukemia (APL)

Overview of acute promyelocytic leukemia (APL):

• Comprises 10% of AML cases
• Symptoms: related to cytopenias (fatigue, infection, epistaxis, gingival bleeding, ecchymoses, menorrhagia)
• Most likely leukemia to present with fever (from cytokine release)
• Diagnosis:
• Smear with atypical promyelocytes: large cells with creased/folded/bilobed nuclei, containing many granules and Auer rods (can be absent in 25%)
• FISH for 15:17 translocation (PML gene to retinoic acid receptor alpha receptor gene)
• Pathogenesis: PML-RARa heterodimerizes to retinoid X receptor à this complex binds retinoic acid responsive elements, thus blocking retinoic acid induced myeloid differentiation
• Treatment: prompt initiation is critical, even if cytogenetic confirmation has not been obtained
• Induction:
• All-trans retinoic acid (ATRA): dissociates the PML-RARa/RXR complex from target genes, allowing for differentiation of promyelocytes into mature neutrophils
• Effective at inducing remissions, but these are short lived
• · More importantly, helps to shorten duration of coagulopathy secondary to DIC
• Addition of chemotherapy (anthracycline + cytarabine) helps control hyperleukocytosis from neutrophil differentiation
• Simultaneous therapy, as opposed to sequential therapy following ATRA-induced complete remission, results in longer remission
• Goal of therapy is molecular remission, as evidenced by absence of PML-RARa transcripts
• Prognosis:
• Median survival is one month without treatment
• With treatment, APL is the acute leukemia most likely to be cured, which underscores the importance of aggressive supportive therapy up front to prevent early mortality from complications such as DIC
• Lower WBC and higher platelet count at presentation are good prognostic signs

Complications of APL

• DIC: significant risk of fatal coagulopathy, which is most common cause of early mortality
• Can occur at presentation or after initiation of therapy
• Treatment: supportive transfusion of factor and platelets
• Differentiation syndrome:
• Occurs in 25% of patients undergoing induction
• Bimodal pattern (<1 week, 3-4 weeks after initiation of therapy)
• Risk increases with higher baseline WBC count
• Signs and symptoms: systemic inflammatory response, characterized by fever, pulmonary edema, DAH, hypotension, renal failure, serositis
• Index of suspicion must be high, as this mimics sepsis, which these patients are also predisposed to
• Pathogenesis: sudden increase in differentiated myelocytes and neutrophils à massive cytokine release à capillary leak
• Treatment: dexamethasone (without treatment, mortality 30%)
• Role of prophylactic steroids prior to ATRA induction unclear
• Hyperleukocytosis/leukostasis: from maturation of promyelocytes into neutrophils
• igns and symptoms: dyspnea, hypoxia (PaO2 can be falsely decreased from WBC consumption of O2, coined “leukocyte larceny” by Dr. C at the VA), neurologic changes, fever, ischemia
• Pathophysiology: microvascular dysfunction from WBC plugging
• Increased viscosity (blasts less deformable than mature WBCs)
• Local hypoxemia from increased metabolic demands of blasts à cytokine release and endothelial damage à migration of blasts into tissue
• Treatment: induction chemotherapy (leukapheresis can worsen coagulopathy)
• Cytoreduction: induction, hydroxyurea (decreases WBC by 50-80% within 1-2 days), ?total brain irradiation if persistent CNS deficits
• In APL, leukapheresis should not be performed, given that this can worsen the coagulopathy from DIC
• Supportive: if possible, hold PRBC transfusions, as this increases viscosity
• Idiopathic intracranial hypertension:
• Signs and symptoms: headache, papilledema, vision changes
• Diagnosis: increased opening pressure with normal CSF profile and imaging
• Tumor lysis: massive tumor cell lysis with release of potassium, phosphate, nucleic acids
• Definition: lab abnormalities (hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia), present within 3 days before or 7 days after initiation of chemotherapy
• Signs and symptoms: arrhythmia/SCD, AKI, tetany, seizure, cramping
• Pathophysiology:
• Metabolism of purines à uric acid, which is poorly water soluble
• Phosphorus in malignant cells is 4x normal cells à when Ca x Ph product greater than 60, it begins to precipitate
• Precipitation of uric acid and calcium phosphate in renal tubules → AKI
• Treatment:
• Prevention:
• Aggressive Hydration to prevent crystallization
• Allopurinol: prevents catabolism of hypoxanthine and xanthine into uric acid
• Does not reduce preexisting hyperuricemia
• Treatment of established TLS:
• Rasburicase: metabolizes uric acid into allantoin, which is water soluble
• Phosphate binders, kayexalate
• Hemodialysis

(Christopher Woo MD, 5/6/11)