To the Editor
The prognosis of acute promyelocytic leukemia (APL) has significantly improved due to the widespread use of all-trans retinoic acid (ATRA) and arsenic-based agents. However, differentiation syndrome (DS) remains a common and potentially fatal complication during initial induction therapy. Characterized by unexplained fever, dyspnea, and multi-organ dysfunction, DS occurs in 17% to 48% of APL patients, with a mortality rate of 7% to 11% [1–7].
Early recognition and prompt intervention are critical to reducing mortality. In recent years, early mortality from DS has markedly declined due to increased awareness of early detection and the use of newer agents, including ruxolitinib [8].
Invasive fungal infections (IFI) pose a serious threat to survival and are among the most common infections in patients with hematologic malignancies. However, studies specifically examining IFI in APL patients remain limited. Prospective data from the SEIFEM-D registry study across 33 Italian centers observed 8 cases of IFI during induction therapy among 106 APL patients [9].
Similarly, a real-world clinical study from India involving 98 newly diagnosed APL patients receiving dual induction with ATRA plus arsenic trioxide (ATO) reported 18 cases of IFI (18.3%) [10]. These findings underscore the importance of vigilance for IFI during induction therapy in APL. Identifying high-risk factors, implementing preventive strategies, and optimizing diagnostic and therapeutic approaches for IFI should be integrated into the comprehensive management strategy for newly diagnosed APL.
In clinical practice, we have observed that newly diagnosed APL patients, particularly those with high-risk disease, who develop DS during induction therapy with ATRA alone or in combination with ATO, exhibit a significantly increased likelihood of subsequently developing invasive pulmonary fungal infection (IPFI) requiring systemic antifungal treatment. However, no published literature currently establishes a correlation between DS and IPFI. We hypothesize that the occurrence of DS in APL patients may be a significant risk factor for IPFI.
In this study, we analyzed clinical data from 143 newly diagnosed APL patients to further investigate the correlation between DS and IPFI. We also examined the impact of their interplay on patient outcomes—including early mortality, relapse rates, and long-term survival. The findings aim to provide an evidence base for the early identification of IPFI in APL patients with DS and inform preventive strategies.
This retrospective study enrolled 143 consecutively hospitalized adult patients with newly diagnosed APL at our institution between January 1, 2017, and December 31, 2022. The cohort included 77 males (53.8%) and 66 females (46.2%), with a median age of 46 years (range: 18–80 years). All patients received ATRA (a daily divided oral dose of 25 ~ 45 mg/m2) + ATO (a daily intravenous dose of 0.16 mg/kg); Chemotherapy with idarubicin 8–12 mg/m2/day or daunorubicin 45–60 mg/m2/day for 3–4 days was added for high-risk patients, and for low-risk or intermediate-risk patients when necessary (especially for patients with WBC increasing more than 5 × 109/L).
Patients were stratified into two groups based on the occurrence of DS: the DS group (n = 39) and the non-DS group (n = 104) (Supplementary Table 1). The diagnosis of DS was established using the PETHEMA Group criteria [5]. No patients received prophylactic corticosteroid treatment for DS.
When a patient is highly suspected or confirmed to have DS, dexamethasone (10 mg twice daily) should be administered immediately, along with reducing the dosage or discontinuing ATRA until signs and symptoms resolve. Additionally, patients were categorized according to the development of IPFI: the IPFI group (n = 27) and the non-IPFI group (n = 116) (Supplementary Table 2). According to the 2020 EORTC/MSG criteria [11], proven IFI requires histopathologic identification of fungus or culture of a sterile specimen yielding a fungus; probable IFI requires the presence of host factors, specific clinical or radiological features, and mycological evidence (positive GM or PCR tests); possible IFI is defined by host factors and clinical features but a lack of mycological evidence.
The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of University of Science and Technology of China (approval number: 2025-RE-322) and was conducted in accordance with the Declaration of Helsinki; written informed consent was waived because of the retrospective nature of the review.
Among the 39 APL patients who developed DS during induction differentiation therapy, 35 cases (89.7%) were moderate and 4 cases (10.3%) were severe. Univariate analysis identified high white blood cell (WBC) count, elevated blood urea nitrogen (BUN) levels, and low albumin levels as significant risk factors for DS development (Supplementary Table 3). Multivariate analysis, however, revealed that only a high WBC count (≥ 8.99 × 10⁹/L) remained an independent risk factor for DS (p = 0.027) (Supplementary Table 3).
There was no statistically significant difference in the proportion of patients receiving prophylactic oral azole antifungals between the DS group and the non-DS group (46.2% vs. 32.7%, p = 0.136), however, the incidence of IPFI was significantly higher in the DS group compared to the non-DS group (41.0% vs. 10.6%, p < 0.001) (Supplementary Table 1).
Thirty-day early mortality was 15.4% (95% CI: 6.2%–28.3%) in the DS group versus 9.6% (95% CI: 4.9%–16.2%) in the non-DS group (p = 0.344) (Supplementary Fig. 1A); and the 5-year relapse rate was 10.3% (95% CI: 3.3%–22.0%) in the DS group versus 6.7% (95% CI: 3.0%–12.6%) in the non-DS group (p = 0.492) (Supplementary Fig. 1B).
The 5-year overall survival (OS) rate was 77.4% (95% CI: 59.0%–88.3%) in the DS group versus 88.2% (95% CI: 80.1%–93.1%) in the non-DS group (p = 0.19) (Supplementary Fig. 1C); and the 5-year disease-free survival (DFS) rate was 70.1% (95% CI: 50.3%–83.2%) in the DS group versus 81.2% (95% CI: 70.9%–88.1%) in the non-DS group (p = 0.215) (Supplementary Fig. 1D).
A total of 27 APL patients developed IPFI during induction differentiation therapy, including 1 proven case, 8 probable cases, and 18 possible cases. Among the 121 patients who received anthracycline-based chemotherapy during induction therapy, 26 developed IPFI (21.5%); of the 22 patients who did not receive anthracycline-based chemotherapy, 1 developed IPFI (4.5%). Univariate analysis identified the following features as significant risk factors for IPFI in newly diagnosed APL during induction: high WBC count, elevated alkaline phosphatase levels, elevated gamma-glutamyl transferase levels, elevated blood urea nitrogen levels, occurrence of DS, and male sex (Table 1).
Multivariate analysis revealed that occurrence of DS remained the only independent risk factor for IPFI development (Table 1). The 30-day cumulative incidence of IPFI was significantly higher in the DS group compared to the non-DS group [41.0% (95% CI: 25.7%–55.8%) vs. 7.7% (95% CI: 3.6%–13.8%); p < 0.001] (Fig.
1A); similarly, the 60-day cumulative incidence was significantly elevated in the DS group [41.0% (95% CI: 25.7%–55.8%) vs. 10.5% (95% CI: 5.6%–17.3%); p < 0.001] (Fig. 1B).
No statistically significant differences in outcomes were observed between the IPFI group and the non-IPFI group: 30-day early mortality was 11.1% (95% CI: 2.8%–25.9%) in the IPFI group versus 11.2% (95% CI: 6.3%–17.7%) in the non-IPFI group (p = 0.961) (Supplementary Fig. 2A); and 5-year relapse rates were 14.8% (95% CI: 4.7%–30.4%) vs. 6.0% (95% CI: 2.7%–11.4%) (p = 0.130) (Supplementary Fig.
2B), 5-year OS was 79.0% (95% CI: 55.5%–90.9%) vs. 86.8% (95% CI: 79.1%–91.8%) (p = 0.517) (Supplementary Fig. 2C), and 5-year DFS was 69.4% (95% CI: 45.2%–84.6%) vs.
80.9% (95% CI: 71.6%–87.4%) (p = 0.415) (Supplementary Fig. 2D).
Table 1Univariate and multivariate analysis of factors predicting the occurrence of IPFIFactors#Univariate analysisOR(95%CI)p valueMultivariate analysisOR(95%CI)p valueAge, ≥ 48years1.194(0.517–2.762)0.678Gender, Male2.957(1.162–7.530)0.0232.400(0.817–7.050)0.111WBC, ≥ 12.52×1093.087(1.304–7.308)0.0102.308(0.824–6.466)0.111RBC, < 2.33×10121.143(0.494–2.644)0.755Hemoglobin, < 74g/L1.143(0.609–3.278)0.421Platelet, < 16×109/L1.576(0.678–3.665)0.29Prothrombin time, ≥ 15.1second1.593(0.686–3.701)0.279Fibrinogen, ≥ 1.55g/L0.857(0.369–1.989)0.72Thrombin time, ≥ 16.9second1.077(0.466–2.49)0.862Alanine aminotransferase, ≥ 26IU/L1.828(0.786–4.251)0.161Aspartate aminotransferase, ≥ 23.6IU/L1.473(0.636–3.411)0.367Alkaline phosphatase, ≥ 78.6IU/L2.393(1.022–5.606)0.0451.591(0.549–4.606)0.392Gamma-glutamyl transferase, ≥ 39.5IU/L2.827(1.199–6.665)0.0182.092(0.758–5.773)0.154Total tilirubin,≥11.5umol/L1.077(0.466–2.49)0.862Albumin, < 40.3g/L1.699（0.729–3.956）0.219Creatinine, ≥ 68umol/L2.122(0.909–4.952)0.082Blood urea nitrogen, ≥ 6.3mmol/L3.929(1.646–9.378)0.0022.246(0.814–6.197)0.118Uric acid, ≥ 272.3umol/L0.875(0.378–2.025)0.755Sanz risk, Intermediate and high2.296(0.499–10.555)0.286Anthracycline-based chemotherapy5.747(0.738–44.755)0.0957.061(0.667–74.697)0.104DS5.881(2.408–14.367)< 0.0014.156(1.549–11.155)0.005Prophylactic oral antifungal agents*1.036(0.435–2.469)0.936Abbreviations: IPFI Invasive pulmonary fungal infection, WBC white blood cell, RBC Red blood cell, DS Differentiation syndrome#Data are derived from median values within the IPFI group (supplementary table 2)*Clinical criteria for antifungal prophylaxis including patients with persistent neutropenia lasting more than 7 days, development of severe oral mucositis, history of invasive fungal infection, and underlying conditions such as uncontrolled diabetes or chronic obstructive pulmonary disease.
This study is the first to report that the development of DS during initial induction therapy in newly diagnosed APL patients significantly increases the subsequent risk of IPFI, indicating that DS is a significant risk factor for IPFI in these patients. The characteristic pulmonary manifestations of DS, such as pulmonary infiltrates and pleural effusions, may disrupt the alveolo-capillary barrier, increasing the risk of fungal colonization (e.g., by Aspergillus or Candida species). The cytokine storm and multi-organ dysfunction (e.g., respiratory failure, renal failure, hepatic impairment) accompanying DS can further impair host defense mechanisms and disrupt immune homeostasis, promoting the development of IPFI.
Furthermore, patients with moderate and severe DS often require high-dose dexamethasone therapy or prolonged prednisone prophylaxis, which significantly impairs T-cell and macrophage function, thereby elevating IPFI risk, particularly during the myelosuppressive phase. Our findings imply that the inflammatory response associated with DS may mask early signs of IPFI; therefore, actively excluding infectious complications is crucial during DS management, such as application of bronchoalveolar lavage [12]. Symptoms such as fever, dyspnea, and hypotension necessitate differentiation from conditions like bacterial sepsis or fungal pneumonia; some DS patients may require concurrent empirical antibacterial and antifungal therapy, especially in high-risk individuals with neutropenia or prolonged steroid exposure.
For patients receiving ATRA plus anthracycline-based chemotherapy without arsenic trioxide, the significantly increased risk of febrile neutropenia warrants early surveillance for IFI [13].
This study is only a single-center retrospective analysis and does not investigate the causal relationship in the pathophysiological mechanisms between DS and IPFI. Future research should focus on developing risk prediction models for IPFI in DS patients (incorporating factors such as DS severity grade, cumulative corticosteroid dose, mucosal barrier integrity, and blood or bronchoalveolar lavage pathogen detection via next-generation sequencing) and identifying biomarkers that aid in early DS diagnosis and distinguish infectious complications, including IPFI.
Fig. 1The cumulative incidence of IPFI in the DS and non-DS groups. The 30-day cumulative incidence of IPFI was significantly higher in the DS group compared to the non-DS group [41.0% (95% CI: 25.7%–55.8%) vs.
7.7% (95% CI: 3.6%–13.8%); p < 0.001] (A); similarly, the 60-day cumulative incidence was significantly elevated in the DS group [41.0% (95% CI: 25.7%–55.8%) vs. 10.5% (95% CI: 5.6%–17.3%); p < 0.001] (B). IPFI, invasive pulmonary fungal infection; DS, differentiation syndrome
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary Material 1