Introduction

Acute promyelocytic leukemia (APL) is a biologically and clinically distinct subtype of acute myeloid leukemia defined by the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) fusion protein, which blocks myeloid differentiation. It represents a hematologic emergency because of its high risk of early mortality, primarily related to hemorrhagic complications from simultaneous activation of coagulation and fibrinolysis [1]. In this setting, immediate initiation of all-trans retinoic acid (ATRA) upon clinical, morphologic, or cytogenetic suspicion of APL is considered a cornerstone of initial management. Early administration of ATRA plays a fundamental role in the initial treatment of APL. Its ability to induce differentiation of leukemic promyelocytes contributes to the rapid correction of disease-associated coagulopathy and reduction of early mortality. Accordingly, major international guidelines recommend initiating ATRA at the earliest clinical suspicion of APL, even before definitive molecular confirmation [1].

Although ATRA has substantially changed the natural history of APL and remains an essential component of frontline therapy, differentiation therapy may trigger differentiation syndrome (DS), a potentially fatal complication characterized by fever, dyspnea, pulmonary infiltrates, hypotension, renal dysfunction, serous effusions, and weight gain [2,3]. The reported incidence of DS ranges from 2.5% to 37%, reflecting differences in diagnostic criteria, induction protocols, and concomitant chemotherapy use [3-5]. In contemporary practice, corticosteroid prophylaxis has been incorporated for high-risk patients; however, several studies have shown that this strategy reduces DS severity but does not completely prevent its occurrence, with reported rates ranging from 11% to 29% despite steroid prophylaxis [5,6]. The persistence of DS despite corticosteroid prophylaxis may be explained by mechanisms beyond leukocyte count control, including endothelial activation, cytokine release, capillary leak, and tissue migration of differentiating blasts [7].

From a regional perspective, APL is of particular epidemiologic relevance in Latin America, where its relative frequency among acute leukemias is consistently higher than that reported in North America and Europe, and early mortality remains elevated [8,9]. DS is commonly diagnosed on clinical grounds, based on the appearance of compatible manifestations such as fever, dyspnea, pulmonary infiltrates, hypoxemia, fluid retention, serous effusions, hypotension, or renal dysfunction after initiation of differentiation therapy. Its recognition may be delayed because there is no single confirmatory laboratory or imaging test, and its clinical features frequently overlap with sepsis, severe pneumonia, pulmonary leukostasis, transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and acute respiratory distress syndrome (ARDS). In complex cases, diagnostic attribution is often strengthened retrospectively by clinical improvement after corticosteroid therapy, once alternative causes have been reasonably evaluated. Concomitant infections and limited early access to specialized hematologic assessment may further complicate timely recognition.

We report the case of a patient with newly diagnosed APL who developed severe pulmonary DS despite dexamethasone prophylaxis, associated with progressive hyperleukocytosis and acute respiratory failure. The patient was managed with pulse methylprednisolone, high-flow nasal cannula (HFNC), and awake prone positioning, with subsequent clinical and oxygenation improvement, and invasive mechanical ventilation was avoided. This case highlights the diagnostic challenges of severe pulmonary DS in APL and suggests that advanced noninvasive respiratory support may be considered in carefully selected patients with close monitoring, particularly when hypoxemic respiratory failure is present but immediate standard indications for invasive mechanical ventilation are absent.