DIFFERENTIATION SYNDROME AFTER GILTERITINIB: A TRICKY MIMICKER OF SEPSIS

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Differentiation syndrome (DS) is a rare cause of acute hypoxic respiratory failure in patients undergoing treatment for acute myeloid and promyelocytic leukemia (AML, APL). CASE PRESENTATION: A 32 year-old female, recipient of hematopoietic stem cell transplantation for AML approximately 200 days prior to presentation, was hospitalized for acute hypoxic respiratory failure. She had been placed on gilteritinib for maintenance 2 months earlier.The patient became acutely breathless after smoking marijuana, which progressed over hours with associated dry cough. She denied vaping or dabbing. Hemoptysis was absent and no other symptoms were reported. On exam the patient was tachypneic, tachycardic and hypoxic requiring high flow oxygen. Laboratory testing was unremarkable. Chest imaging showed diffuse ground glass opacifications in all lung fields (Fig 1). A bronchoalveolar lavage yielded clear lavage fluid without hemorrhage. There was no evidence of any viral, bacterial or fungal infection by PCR, cytology or culture (Table 1). By excluding heart failure, active infection and alveolar hemorrhage, DS was diagnosed. Gilteritinib was then stopped and dexamethasone started. Oxygen requirement decreased and she was discharged on day 6 with 3lpm nasal cannula. DISCUSSION: DS, formerly known as retinoic acid syndrome, is a life-threatening reaction to differentiating agents used in the treatment of AML and APL. It occurs when rapid proliferation of maturing myeloid cells infiltrate different organs, release vasoactive cytokines and promote capillary leak. It is reported with the use of all-trans retinoic acid, arsenic trioxide and tyrosine kinase inhibitors (TKI) [1]. In the absence of a clear cause of acute respiratory failure, diagnosis requires at least two of the following: dyspnea, unexplained fever, >5kg weight gain, unexplained hypotension, acute renal failure, pulmonary infiltrates, and pleural or pericardial effusion [2].Gilteritinib is a TKI approved in 2018 for AML. The clinical trial supporting its use estimates DS rates of approximately 3% in 319 study participants, but reports since that time are lacking [3,4].Typically, DS occurs during induction, but can be seen in maintenance therapy, as was the case with our patient. When suspected, prompt treatment with corticosteroids is standard of care, despite the resemblance to sepsis. In fact, improvement after steroids can help confirm the diagnosis [5]. CONCLUSIONS: This case highlights the importance of recognizing differentiation syndrome, particularly given it's resemblance to many conditions, and demonstrates the efficacy of corticosteroids in DS. Last, it contributes to the scarce literature outside of clinical trials on the development of DS with gilteritinib therapy. REFERENCE #1: [1] Gasparovic L, Weiler S, Higi L, Burden AM. Incidence of Differentiation Syndrome Associated with Treatment Regimens in Acute Myeloid Leukemia: A Systematic Review of the Literature. J Clin Med. 2020 Oct 18; 9(10):3342. REFERENCE #2: [2] Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP. The "retinoic acid syndrome" in acute promyelocytic leukemia. Ann Intern Med. 1992; 117 (4): 292-296.[3] McMahon CM, Canaani J, Rea B, et al. Gilteritinib induces differentiation in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood Adv. 2019; 3 (10): 1581–1585. REFERENCE #3: [4] DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood. 2020; 135 (2): 85–96.[5] Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014; 123 (18): 2777-2782. DISCLOSURES: No relevant relationships by James Dugan, source=Web Response No relevant relationships by Rana Hejal, source=Web Response No relevant relationships by Claire Irons, source=Web Response No relevant relationships by Neha Jain, source=Web Response No relevant relationships by Soud Sediqe, source=Web Response No relevant relationships by Pallavi Sharma, source=Web Response