A previously-healthy 72-year-old woman presented with two weeks of progressive fatigue. Laboratory testing revealed a white blood cell (WBC) count of 140×109/L, hemoglobin 8g/dL, platelets 30×109/L. Peripheral blood smear showed greater than 90% blasts and promyelocytes. Chest radiograph and transthoracic echocardiogram (TTE) were unremarkable. She was started on all-trans retinoic acid (ATRA), idarubicin (IDA), and dexamethasone. Molecular cytogenetics confirmed the diagnosis of acute promyelocytic leukemia (APL). WBC count decreased to 70×109/L by day three of treatment. However, she developed hypoxemic respiratory failure with extensive pulmonary consolidations on chest CT. She required invasive mechanical ventilation and bronchoscopy demonstrated airway inflammation with over 1500/mm3 blasts and promyelocytes in the bronchoalveolar lavage. Her hospital course was complicated by increasing oxygenation needs on mechanical ventilation, acute ischemic stroke of the left middle cerebral artery territory, and NSTEMI with new McConnell’s sign.
Discussion:
Patients with APL typically present with signs and symptoms of pancytopenia including fatigue and a bleeding diathesis. Our patient presented with a WBC count of 140×109/L that put her at high risk for developing differentiation syndrome (DS) and leukostasis. DS, a clinical diagnosis characterized by respiratory distress, fever, edema, hypotension, and renal failure, is a cytokine-mediated vasodilatory complication of ATRA that occurs in up to 25% of patients with APL. DS may occur as early as two days after initiation of therapy and has a mortality of 30%, primarily from respiratory failure or cerebral edema. Treatment improves mortality to 5% and includes corticosteroids and temporary discontinuation of ATRA. Prophylaxis is typically started for patients with WBC count greater than 10×109/L, though this recommendation has not been rigorously studied.
Leukostasis causes multiple end-organ damage by increased viscosity and plugging of microvasculature. Management involves rapid cytoreduction to prevent further end-organ damage. Leukapheresis is a treatment often used in hematologic malignancies but is not recommended in APL because cell lysis may release leukemic granules, worsen coagulopathy, and create a cytokine storm. Evidence for leukapheresis is conflicting and incomplete. One study showed fatal or near-fatal hemorrhage in a majority of APL patients who underwent leukapheresis. Another study showed that median overall survival and 3-year overall survival were not significantly affected in APL patients with WBC count greater than 50×109/L who underwent leukapheresis when compared to those who did not undergo leukapheresis. The preferred treatment for leukostasis in APL is induction therapy with ATRA or arsenic trioxide, but a case-by-case consideration of leukapheresis is warranted for those with severe leukostasis and multiple organ damage.
Conclusions:
Hyperleukocytosis is an uncommon and understudied presentation of APL that puts the patient at high risk for severe complications. Clinicians must be vigilant for development of DS and leukostasis, and initiate appropriate treatment quickly.