Discussion

DS is one of the most relevant and potentially fatal complications associated with the treatment of APL using differentiating agents such as ATRA and ATO. Since its initial description as “retinoic acid syndrome” in 1992, it has been recognized as a systemic inflammatory condition characterized by dyspnea, pulmonary infiltrates, unexplained fever, fluid retention, serosal effusions, hypotension, and renal dysfunction, with the potential to rapidly progress to multiorgan dysfunction if not promptly treated [3]. Despite the remarkable improvement in APL outcomes achieved with differentiation therapies, with cure rates exceeding 90% in modern protocols such as the ATRA/ATO regimen reported in the landmark trial by Lo-Coco et al. published in the New England Journal of Medicine, DS remains an important cause of early morbidity and mortality during induction therapy [2].

In the present case, the patient developed severe pulmonary-predominant DS despite dexamethasone prophylaxis, with progressive respiratory deterioration occurring within days of ATRA initiation. This temporal pattern is consistent with the classic time window for DS onset, which typically occurs within the first two weeks of exposure, as described in contemporary reviews and the European LeukemiaNet recommendations [1]. Weight gain exceeding 5 kg, progressive hypoxemia, and diffuse pulmonary infiltrates were consistent with severe DS according to the PETHEMA severity scoring system [10]. The subsequent requirement for advanced respiratory support with HFNC further reflected the severity of pulmonary involvement. The respiratory manifestations observed in this case represent one of the most challenging diagnostic scenarios in the intensive care unit because of their overlap with severe pneumonia, sepsis, pulmonary leukostasis, and noncardiogenic ARDS [6,7].

As detailed in the Case Presentation, opportunistic infection, diffuse alveolar hemorrhage, TRALI, TACO, drug-induced lung injury, and cardiogenic pulmonary edema were considered, and bronchoscopy with bronchoalveolar lavage was considered but not performed because of severe hypoxemia, marked thrombocytopenia, and a high hemorrhagic risk. Nevertheless, several findings supported DS as the predominant pathophysiologic mechanism, including the close temporal relationship with ATRA initiation, progressive hyperleukocytosis with a marked peak during induction, significant fluid retention, and the absence of evidence supporting cardiogenic failure as the primary explanation for respiratory deterioration. Recent studies have confirmed that both a rapid increase in leukocyte count and peak leukocyte levels during induction are independent predictors of DS, even among patients receiving steroid prophylaxis [11,12]. The decision to initiate hydroxyurea for cytoreduction in our patient is consistent with current recommendations for the management of differentiation-associated hyperleukocytosis, given its association with severe DS and pulmonary complications [13]. Current evidence suggests that the pathophysiology of DS extends beyond the leukocyte count itself and involves a complex inflammatory process mediated by cytokine release, endothelial injury, capillary leak syndrome, and tissue migration of differentiating blasts into target organs, particularly the lungs [7,8]. Sanz and Montesinos described DS as sharing pathophysiologic features with systemic inflammatory response syndrome, driven by the release of proinflammatory mediators, increased capillary permeability, and alterations in cellular adhesion induced by ATRA [5].

These mechanisms may help explain both the fulminant pulmonary presentation observed in our patient and the rapid clinical improvement following intensive anti-inflammatory treatment. The universally accepted cornerstone of DS management is the immediate administration of high-dose dexamethasone, with temporary discontinuation of ATRA and/or ATO generally reserved for patients with severe respiratory dysfunction or severe renal impairment [1,5]. However, evidence regarding optimal treatment intensification strategies in rapidly progressive severe DS remains limited. In our case, given the imminent risk of invasive mechanical ventilation, treatment was escalated to pulse methylprednisolone therapy (1 g/day for three days), followed by significant improvement in oxygenation and radiologic findings within the first 48 hours. Although pulse methylprednisolone therapy is not included in current standard recommendations and there are no randomized clinical trials specifically evaluating its use for DS, it may be considered only as an individualized rescue strategy in selected cases of severe DS with rapidly progressive respiratory deterioration and an imminent risk of invasive mechanical ventilation [6,7].

A distinctive aspect of this case was that respiratory failure was managed with advanced noninvasive respiratory support, a particularly relevant consideration in patients with APL, in whom invasive mechanical ventilation may be associated with hemorrhagic and infectious complications in the setting of profound thrombocytopenia and coagulopathy [6,7]. HFNC has been shown to improve oxygenation and reduce respiratory workload in immunocompromised patients with acute respiratory failure, representing a useful strategy to avoid invasive mechanical ventilation in selected patients [14]. Furthermore, studies involving patients with hematologic malignancies suggest that HFNC is safe and may be associated with improved outcomes through a reduced need for endotracheal intubation [15]. However, HFNC should not delay invasive mechanical ventilation when standard indications for intubation are present. In this case, as described in the Case Presentation, continued HFNC support was considered appropriate because the patient remained clinically stable and showed improvement in the ROX index from 4 to 8 after 48 hours. In this setting, rather than immediately discontinuing ATRA, early treatment intensification with pulse methylprednisolone was prioritized and combined with HFNC and intermittent awake prone positioning. This strategy was associated with rapid and sustained clinical, oxygenation, and radiologic improvement during the critical phase of the syndrome, supporting consideration of HFNC as a context-dependent option before escalation to invasive mechanical ventilation in carefully selected patients with APL and severe thrombocytopenia or coagulopathy.