Possible CPX-351-associated drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome-like reaction during severe lymphopenia

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS), is a severe delayed drug reaction characterized by skin eruption, systemic inflammation, organ involvement, and human herpesvirus 6 (HHV-6) reactivation. CPX-351 is increasingly used for high-risk acute myeloid leukemia, and skin eruptions are common adverse events; however, CPX-351-associated DRESS/DIHS-like reactions have not been well described. We report a 62-year-old man with acute erythroid leukemia who developed a progressive eruption after CPX-351 therapy. An early intertriginous and truncal eruption was initially compatible with toxic erythema of chemotherapy (TEC), whereas subsequent recurrent fever, generalized erythema involving more than 90% of the body surface area, lymphadenopathy, atypical lymphocytes, liver enzyme elevation, and marked HHV-6 DNA elevation (1.2 × 10 6 copies/mL) supported the diagnosis of a DRESS/DIHS-like reaction. The reaction occurred despite severe lymphopenia, absence of peripheral eosinophilia, inconspicuous dermal eosinophils, and a normal serum thymus and activation-regulated chemokine level. Skin biopsy showed interface dermatitis with superficial perivascular lymphocytic infiltration. Systemic prednisolone led to rapid defervescence, improvement of appetite and skin lesions, disappearance of atypical lymphocytes, and clearance of HHV-6 DNA. The patient subsequently underwent conditioning and umbilical cord blood transplantation. CPX-351 was considered a possible culprit based on the temporal relationship, although TEC and concomitant medications represented important alternative considerations. This case suggests that a DRESS/DIHS-like reaction can develop in severely immunocompromised patients and that HHV-6 reactivation may help identify this condition when eosinophilia is absent.