Serafim, L. Piccolo

Abstract Introduction: Differentiation syndrome (DS) is a life-threatening adverse drug reaction caused by differentiating agents, including all-trans retinoic acid, arsenic trioxide, inhibitors of mutant isocitrate dehydrogenase (e.g., enasidenib), and the FLT3 inhibitor gilteritinib. The proliferation of differentiated leukemic cells can alter cytokine balance, leading to tissue inflammation, but the pathogenesis remains incompletely understood. We present a case of severe DS in a patient with AML and multi-organ failure. Case: An 80-year-old female with a history of polycythemia vera and newly diagnosed AML, on decitabine, venetoclax, and enasidenib. She was admitted after her first treatment cycle with weakness, altered mental status, and neutropenic fever. Enasidenib was discontinued due to suspected DS, and she was treated with dexamethasone for five days. Three days after discontinuing steroids, her respiratory and mental status deteriorated, leading to a rapid response call and transfer to the ICU for acute hypoxemic respiratory failure. Point of care ultrasound revealed underfilled ventricles and collapsible IVC on inhalation. She became hypotensive and unresponsive, requiring intubation. Initial P/F was 72. PV tool with recruitment showed no low inflexion point but recruitable lung. Laboratory results revealed a WBC of 68.7 x 10⁹/L with 89% blasts which was increased from prior days and acute liver injury with hyperbilirubinemia. A CT scan revealed bilateral consolidations and pleural effusions with interlobular septal thickening. Despite initial oxygenation improvement with prone positioning, she remained hypotensive requiring norepinephrine, vasopressin, angiotensin II, and hydrocortisone. Methylene blue was administered with a favorable response. Leukocytosis worsened, and decitabine and hydroxyurea were initiated due to concern for uncontrolled acute leukemia. She was started on continuous renal replacement therapy (CRRT) for oliguric renal failure. After the fourth dose of decitabine, her shock resolved, urinary output improved, and leukocytosis decreased. However, in the following days, her oxygen requirements escalated, WBC again increased to 120 x 10⁹/L with 80% blasts, and she became hypotensive with signs of myocardial ischemia. She was ultimately transitioned to comfort care. Discussion: This case highlights severe DS following enasidenib administration, which progressed to multi-organ failure. Prompt initiation of systemic glucocorticoids is critical in the management of DS, and this condition should be considered in patients receiving active treatment for acute leukemia who require ICU-level care. Risk factors for DS development and the role of prophylaxis remain areas requiring further research in the context of acute leukemia treatment.