Improved Prevention and Treatment Strategies for Differentiation Syndrome Contribute to Reducing Early Mortality in Patients With Acute Promyelocytic Leukemia
preprint
OA: closed
CC-BY-4.0
Abstract
Abstract In this report, we present an optimized prevention and treatment strategy for differentiation syndrome (DS). A total of 111 eligible patients with acute promyelocytic leukemia (APL) − 78 classified as low-risk and 33 as high-risk - received induction treatment consisting of all-trans retinoic acid (ATRA) in combination with an arsenic agent. Different doses of dexamethasone were administered based on the dynamics of white blood cell (WBC) counts to prevent DS. Ruxolitinib was used as a second-line therapy for DS. Among the patients, 41 (36.9%) experienced DS, with 16 having a severe form (14.4%) and 25 having a moderate form (22.5%). There was no significant difference in the incidence and severity of DS between the low-risk and high-risk patients (p = 0.057 and p = 0.056, respectively). The efficacy of ruxolitinib in cases of DS resistant to steroids was 67% without interruption of ATRA therapy. After discontinuing ATRA, the remaining DS cases were relieved through treatment with dexamethasone and ruxolitinib. The overall 30-day mortality rate was 1.8% (2/111), with two high-risk patients succumbing to intracranial hemorrhage. Complete remission (CR) was achieved in the remaining 109 patients. Our findings suggest that personalized prophylaxis against DS can mitigate the negative prognostic impact of hyperleukocytosis, and ruxolitinib is effective and well tolerated for refractory DS, ultimately decreasing early mortality in APL patients .(clinical trials.gov NCT04446806).
Full text
187,237 characters
· extracted from
preprint-html
· click to expand
Improved Prevention and Treatment Strategies for Differentiation Syndrome Contribute to Reducing Early Mortality in Patients With Acute Promyelocytic Leukemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Improved Prevention and Treatment Strategies for Differentiation Syndrome Contribute to Reducing Early Mortality in Patients With Acute Promyelocytic Leukemia Suning Chen, Qian Wu, Xiaofei Yang, Jing-Ren Zhang, Mengxing Xue, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4165353/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Jul, 2024 Read the published version in Blood Cancer Journal → Version 1 posted 11 You are reading this latest preprint version Abstract In this report, we present an optimized prevention and treatment strategy for differentiation syndrome (DS). A total of 111 eligible patients with acute promyelocytic leukemia (APL) − 78 classified as low-risk and 33 as high-risk - received induction treatment consisting of all-trans retinoic acid (ATRA) in combination with an arsenic agent. Different doses of dexamethasone were administered based on the dynamics of white blood cell (WBC) counts to prevent DS. Ruxolitinib was used as a second-line therapy for DS. Among the patients, 41 (36.9%) experienced DS, with 16 having a severe form (14.4%) and 25 having a moderate form (22.5%). There was no significant difference in the incidence and severity of DS between the low-risk and high-risk patients (p = 0.057 and p = 0.056, respectively). The efficacy of ruxolitinib in cases of DS resistant to steroids was 67% without interruption of ATRA therapy. After discontinuing ATRA, the remaining DS cases were relieved through treatment with dexamethasone and ruxolitinib. The overall 30-day mortality rate was 1.8% (2/111), with two high-risk patients succumbing to intracranial hemorrhage. Complete remission (CR) was achieved in the remaining 109 patients. Our findings suggest that personalized prophylaxis against DS can mitigate the negative prognostic impact of hyperleukocytosis, and ruxolitinib is effective and well tolerated for refractory DS, ultimately decreasing early mortality in APL patients .(clinical trials.gov NCT04446806). Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia Health sciences/Diseases/Immunological disorders acute promyelocytic leukemia differentiation syndrome prophylaxis strategy ruxolitinib steroid-resistance cytokine release syndrome Figures Figure 1 Figure 2 Figure 3 Introduction With the introduction of differentiating agents, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), the outcomes of patients with acute promyelocytic leukemia (APL) have significantly improved [ 1 – 3 ]. However, a higher rate of early deaths has been observed, especially among non-protocol patients and those at high risk [ 4 – 11 ]. In our analysis of 570 patients at our institution from 2005 to 2019, we reported a lower early death rate of 7.54% [ 12 ]. However, we still observed unexpected and preventable early deaths, mainly caused by steroid-unresponsive differentiation syndrome (DS) and catastrophic bleeding complications, many of which were associated with hesitation or early suspension of ATRA due to DS. While randomized controlled trials are lacking, prophylaxis against DS with steroids is commonly recommended, especially in patients with elevated white blood cell (WBC) counts (> 10 × 10 9 /L) [ 8 , 13 ]. However, the dosage and timing of steroids remain controversial. Patients with DS who do not respond to routine preemptive treatment with dexamethasone typically have a poor prognosis, underscoring the need for improved therapeutic strategies and early intervention in this area. In this report, we stratified patients based on WBC count during induction treatment to implement varying doses of dexamethasone as DS prophylaxis and explore the efficacy and safety of novel targeted therapy with ruxolitinib as a second-line treatment for refractory DS. This strategy is anticipated to significantly reduce early mortality and improve survival for patients with newly diagnosed APL treated with ATRA and arsenic agents. Methods Patients Previously untreated patients with a clinical diagnosis of APL were enrolled between June 1, 2019, and December 31, 2021, from 14 centers in China. Eligibility criteria included age of 18 to 75 years, a diagnosis of APL with t (15; 17) or PML/RAR rearrangement, Q-Tc interval less than 500 ms, absence of serious comorbidity, and an Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 4. Informed consent was obtained from all patients in accordance with the Declaration of Helsinki. The protocol was approved by the Research Ethics Board of each participating hospital. Study design In the prospective Phase 3 multicenter single-arm APL-01 trial, all patients diagnosed with APL, regardless of WBC counts, received induction treatment with ATRA in combination with either intravenous ATO or oral tetra-arsenic tetra-sulfide (As4S4) formula named the Realgar-Indigo naturalis formula (RIF) [ 14 ]. Treatment with ATRA at a dose of 25 mg/m 2 and blood product support was initiated upon suspicion of APL, depended on morphology, and/or coagulopathy as indicated by a positive disseminated intravascular coagulation screen. Once a positive result of a t (15; 17) translocation and/or PML-RARA rearrangement was confirmed [ 15 ], ATO (0.16 mg/kg capped at 10 mg)) or RIF (60 mg/kg) was administered until complete remission (CR) was achieved. Platelets and fresh frozen plasma were transfused to maintain the platelet count above 50 × 10 9 /L and the fibrinogen level above 1.5g/L during therapy. ATRA treatment was to be discontinued if the diagnosis was not supported by genetic or molecular data. The prevention regimen for DS was based on the WBC count at presentation and after the initiation of ATRA, which included cytoreductive agents and dexamethasone (Fig. 1 a ) . For patients with a WBC count between 5 and 10 × 10 9 /L, hydroxyurea (500 mg three times a day) and dexamethasone (5 mg/day) were administered. If the WBC count increased to greater than 10 × 10 9 /L, the dose of hydroxyurea was increased to 1000 mg three times a day, and dexamethasone was increased to 10 mg/day, in addition to 4–6 doses of idarubicin (2–5 mg/dose). These medications were then gradually tapered and discontinued once the WBC count dropped to less than 10 × 10 9 /L. When DS was suspected, prompt initiation of treatment with intravenous dexamethasone at a dose of 20 mg per day was recommended. If a favorable response was achieved, dexamethasone could be gradually tapered over a period of 1–2 weeks. However, in cases where no improvement was observed, ruxolitinib should be initiated within hours at a dose of 5–20 mg twice a day, with the dosage determined by the severity of DS, patient age, and general condition. Once significant relief was observed, the doses of dexamethasone and ruxolitinib could be alternately reduced. Additionally, ATRA/arsenic agent treatment should be discontinued if there was progression of the clinical features of DS (Fig. 1 b). End points and response criteria The primary study end point was the incidence of DS and severe DS, as well as early death. The diagnosis of DS was made on clinical grounds by the association of at least two of the following signs, in the absence of other causes [ 16 ]: dyspnea, unexplained fever, weight gain > 5 kg, unexplained hypotension, acute renal failure, pulmonary infiltrates or pleuropericardial effusion. The PETHEMA group defined the DS grading and classified patients into those with severe DS (> 3 signs or symptoms) or moderate DS (2–3 signs or symptoms) [ 17 ]. Whenever a diagnosis of APL DS was considered, it was vital to thoroughly exclude other conditions, such as infections or heart failure, which can mimic the manifestations of DS. Early death referred to any deaths occurring during the period from therapy initiation until the end of induction therapy, which sometimes extended for 30 days [ 18 ]. Secondary end points included CR rate, the assessment of toxic effects during induction, recurrence-free survival (RFS) and the probability of overall survival (OS). CR was defined as a patient having less than 5% blasts and atypical promyelocytes in an aspirate sample, an absolute neutrophil count of more than 10 9 /L, and a PLT count of more than 100 × 10 9 /L [ 19 ]. Toxic effects was graded according to Terminology Criteria for Adverse Events, version (CTCAE V5.0). OS and RFS were defined according to the NCI workshop definitions [ 19 ]. Statistical methods The distributions of continuous data were examined using the Kolmogorov-Smirnov test. Skewed data were presented as the median and range, and the differences were compared using the Mann-Whitney U test. Categorical data were presented as sample size and percentage, and the differences were compared using the chi-square test (or Fisher's exact test). Subsequently, multivariate analysis (automatic selection model) was performed for variables with a p-value less than 0.1 in the univariate analysis. The results of the multivariate regression were visualized using a forest plot. The Kaplan-Meier test was used to compare overall survival (OS) between the high-risk and low-risk patients, as well as between DS and Non-DS groups. All statistical analyses were conducted using SPSS 23.0 software (SPSS Inc., Chicago, IL, USA), with a p-value less than 0.05 considered statistically significant. Results Enrollment and Patient Characteristics A total of 111 patients diagnosed with APL were included in this trial. Of these, 33 were identified as high-risk patients (WBC count at diagnosis ≤ 10 × 10 9 /L) and 78 as low-risk patients (WBC count at diagnosis > 10 × 10 9 /L). The median WBC count before treatment in high-risk patients was 21.51 × 10 9 /L, with 10 patients having a count exceeding 50 × 10 9 /L. No patients withdrew from the study either due to treatment refusal or excessive toxicity. The demographic characteristics of the patients are outlined in Table 1 . Table 1 Characteristics of the patients at diagnosis and comparison of APL patients with and without DS, moderate DS and severe DS. Characteristic Total (n = 111, %) Non-DS (n = 70, %) DS (n = 41, %) P Moderate DS (n = 25, %) Severe DS (n = 16, %) P Age, y 40 38 (34) 4 (20) 24 (59) 11 (44) 13 (81) Sex 0.001 0.058 Male 48 (43) 22 (31) 26 (63) 13 (52) 13 (81) Female 63 (57) 48 (39) 15 (37) 12 (48) 3 (19) BMI 0.250 0.805 Underweight 1 (1) 1 (1) 0 (0) 0 0 Normal weight 52 (47) 28 (40) 24 (59) 14 (56) 10 (63) Overweight 40 (36) 28 (40) 12 (29) 7 (28) 5 (31) Obese 18 (16) 13 (19) 5 (12) 4 (16) 1 (6) ECOG 0.362 0.018 0–1 40 (36) 23 (33) 17 (41) 14 (56) 3 (19) ≥ 2 71 (64) 47 (67) 24 (59) 11 (44) 13 (81) WBC count, x 10 9 /L 0.025 0.009 ≤ 4 64 (58) 46 (66) 18 (44) 15 (60) 3 (19) > 4 47 (42) 24 (34) 23 (56) 10 (40) 13 (81) PLT count, x 10 9 /L 0.616 0.041 ≤ 10 13 (12) 7 (10) 6 (14) 1 (4) 5 (31) 10–40 57 (51) 35 (50) 22 (54) 14 (56) 8 (50) ≥ 40 41 (37) 28 (40) 13 (32) 10 (40) 3 (19) Hemoglobin, g/L 0.641 0.300 ≤ 10 70 (63) 43 (61) 27 (66) 18 (72) 9 (56) > 10 41 (37) 27 (39) 14 (34) 7 (28) 7 (44) Risk group † 0.101 0.249 Low-risk 78 (70) 53 (76) 25 (61) 17 (68) 8 (50) High-risk 33 (30) 17 (24) 16 (39) 8 (32) 8 (50) Fibrinogen, g/L 0.638 1.000 ≤ 1 27 (24) 16 (23) 11 (27) 7 (28) 4 (25) > 1 84 (76) 54 (77) 30 (73) 18 (72) 12 (75) D-dimer, mg/L 0.877 0.472 ≤ 20 83 (75) 52 (74) 31 (76) 20 (80) 11 (69) > 20 28 (25) 18 (26) 10 (24) 5 (20) 5 (31) LDH level, U/ L 0.395 1.000 ≤ 500 81 (73) 53 (76) 28 (68) 17 (68) 11 (69) > 500 30 (27) 17 (24) 13 (32) 8 (32) 5 (31) FLT3 mutation 0.974 6/17 5/11 0.701 Yes 25 (39) 14 (39) 11 (39) 6 (35) 5 (45) No 39 (61) 22 (61) 17 (61) 11 (65) 6 (55) Cr level, µmol/L 70.0 (57.6–82) 63.2 (54.9–72.7) 72.0 (58.5–83.0) 0.288 78.2 (59.1–86.0) 70.0 (54.2–79.9) 0.620 BM blast (%) 82.5 (20.8–97) 82.0 (29.2–118) 83.0 (20.8–97.0) 0.781 83.0 (53.0-93.8) 83.3 (20.8–97.0) 0.841 Abbreviations: BMI, Body mass index; BM, Bone marrow; Cr, Creatinine; DS, differentiation syndrome; ECOG, Eastern cooperative oncology group; LDH, lactate dehydrogenase; PLT, Platelet; WBC, White Blood Cell. † Patients were stratified into risk groups based on their presenting WBC count (≤ 10 × 10 9 /L for the low-risk APL cohort and > 10 × 10 9 /L for the high-risk APL cohort). Incidence and clinical characteristics of DS All high-risk patients and 57 out of 78 low-risk patients received dexamethasone (5–10 mg/day) for DS prophylaxis. Preemptive therapy with dexamethasone (10 mg every 12 hours) was administered to 40 out of 78 low-risk patients (51.3%) and 25 out of 33 high-risk patients (75.8%). Among the total 111 patients, 41 (36.9%) were ultimately diagnosed with DS, with 25 (22.5%) classified as moderate cases and 16 (14.4%) as severe cases (Table 1 ). The cumulative incidence of DS and severe DS in low-risk and high-risk patients was calculated. While the incidence of DS and severe DS was higher in high-risk patients compared to low-risk patients (48.5% vs. 32.1%, 24.2% vs. 10.3%), these differences were not statistically significant (p = 0.057, p = 0.056) (Fig. 2 ). Clinical manifestations and timing of DS The clinical features of DS are outlined in Table 2 . The most common symptoms observed among patients included weight gain (85%), pulmonary infiltrates (78%), and dyspnea (71%). Additionally, patients with severe DS showed a higher prevalence of dyspnea (Fisher's exact test, P = 0.013), pleuropericardial effusion (χ2 = 5.577, P = 0.018), and acute renal dysfunction (Fisher's exact test, P = 0.018) compared to those with moderate DS. Table 2 Clinical characteristics of APL patients with DS. Characteristic DS (n = 41, %) Moderate DS (n = 25, %) Severe DS (n = 16, %) χ2 P Dyspnea 29 (71) 14 (56) 15 (94) NA 0.013 Unexplained fever 14 (34) 6 (24) 8 (50) 2.933 0.087 Weight gain 35 (85) 20 (80) 15 (94) NA 0.376 Pulmonary infiltrates 32 (78) 18 (72) 14 (88) NA 0.441 Pleuropericardial effusion 24 (59) 11 (44) 13 (81) 5.577 0.018 Acute renal dysfunction 7 (17) 1 (4) 6 (38) NA 0.009 Unexplained hypotension 2 (5) 0 2 (13) NA 0.146 Abbreviations: DS, Differentiation syndrome; NA, Not available. DS occurred at a median of 8 days after the initiation of ATRA administration, with a range of 2–21 days. Within the initial week, 19 cases (46%) of DS occurred, followed by 20 cases (49%) in the second week. Only two cases (5%) occurred in the third week. Severe DS appeared at a median of 7 days, while moderate DS appeared at a median of 8 days. Outcomes of DS More than half of the patients with DS (23 out of 41) experienced a significant and rapid remission when they received dexamethasone treatment. The average duration of dexamethasone treatment for these patients was 10 days, with a range of 6 to 20 days. However, the condition of the remaining patients with severe DS (12 patients) and moderate DS (6 patients) worsened. All of these patients received ruxolitinib, with 12 responding well, while the other 6 required non-invasive mechanical ventilation and discontinued ATRA. Five of them recovered within 72 hours, and one patient was successfully weaned from the ventilator 10 days later. None of them developed ventilator dependency or required invasive mechanical ventilation. The median duration of DS resolution in patients receiving ruxolitinib was 5 days, with a range from 2 to 12 days, after the start of treatment. The median duration of ruxolitinib treatment was 13 days, ranging from 8 to 17 days (Table 3 ). All the patients who experienced DS achieved CR. Table 3 Effectiveness of the management of DS. Treatment Low-risk, n = 78 High-risk, n = 33 Total, n = 111 n % n % n % Prophylaxis for APL DS 57 73 33 100 90 81 Preemptive therapy (Dex 10mg q12h) 40 51 25 76 65 59 Definite diagnosis for APL DS 25 32 16 49 41 37 Moderate DS 17 22 8 24 25 23 Favorable response to Dex 13 6 19 No improvement: Ruxolitinib 4 2 6 Dramatic relief 4 2 6 Worsening: stop ATRA 0 0 0 Severe DS 8 10 8 24 16 14 Favorable response to Dex 3 1 4 No improvement: Ruxolitinib 5 7 12 Dramatic relief 3 3 6 Worsening: stop ATRA 2 4 6 Abbreviations: DS, Differentiation syndrome; Dex, dexamethasone; ATRA, all-trans retinoic acid. Predictive factors for DS and severe DS Upon univariate analysis of prognostic factors (Table 1 ), it was found that age older than 40 years (p < 0.001), male sex (p = 0.001) and WBC count exceeding 4 × 10 9 /L (p = 0.025) were associated with developing DS. Following multivariate analysis (Table 4 ), only a WBC count greater than 4 × 10 9 /L (p < 0.001) remained statistically significant. Table 4 Multivariate analysis of different risk and DS stages for APL patients. χ2 OR (95% CI) P DS vs. Non-DS Age (Reference category: ≤ 40) 2.311 0.958 (0.907–1.012) 0.128 Sex (Reference category: Male) 1.011 0.492 (0.123–1.963) 0.315 WBC (Reference category: < 4) 20.805 1.241 (1.131, 1.361) < 0.001 Severe DS vs. Moderate DS Age (Reference category: ≤ 40) 5.968 12.200 (1.640-90.772) 0.015 Sex (Reference category: Male) 1.163 0.342 (0.049–2.406) 0.281 ECOG (Reference category: ≤ 1) 0.396 1.374 (0.511–3.694) 0.529 WBC (Reference category: < 4) 2.891 2.019 (0.898–4.539) 0.089 PLT (Reference category: < 10) 1.351 0.426 (0.101–1.797) 0.245 Abbreviations: BM, Bone marrow; CI, confidence interval; DS, Differentiation syndrome; LDH, lactate dehydrogenase; OR, odds ratio; PLT, Platelet; WBC, White Blood Cell. In terms of severe DS, univariate analysis (Table 1 ) identified predictive factors such as age older than 40 years (p = 0.018), ECOG score ≥ 2 (p = 0.018), a WBC count exceeding 4 × 10 9/ L (p = 0.009), and PLT ( 40 years old)(p = 0.015) maintained its predictive value. Clinical outcomes The overall 30-day mortality rate was 1.8% (2/111), with two high-risk patients succumbing to intracranial hemorrhage, one on day 8 and the other on day 9 after initiation of ATRA. There were no deaths attributed to DS or infection. Of the 111 patients, the overall CR rate was 98.2%. Specifically, 100% (78/78) of the low-risk patients and 93.9% (31/33) of the high-risk patients achieved CR. The median time interval for achieving CR was 26 days (range: 18 to 71 days) in the overall analysis. Significant differences were observed in the median time to CR between high-risk patients and low-risk patients (29 days, range: 19 to 71 days vs. 26 days, range: 18 to 43 days; P = 0.001), as well as between the DS group and the Non-DS group (31 days, range: 20 to 71 days vs. 25 days, range: 18 to 41 days; P = 0.000). Our trial demonstrated a 100% negative rate for RQ-PCR among the remaining 109 evaluable patients at 3 months after diagnosis. All patients completed 7 cycles of consolidation therapy, with RIF administered at 60 mg/kg daily in a 4-week-on and 4-week-off regimen for 4 cycles, and ATRA 25 mg/m 2 daily in a 2-week-on and 2-week-off regimen for 7 cycles. However, patients with high-risk APL required 9 cycles of maintenance therapy with ATRA at 25 mg/m2 daily for 2 weeks every 4 weeks on cycles 1, 4, 7 and RIF at 60 mg/kg daily for 2 weeks every 4 weeks on cycles 2, 3, 5, 6, 8, 9). The present analysis was conducted in September 2023, with a median follow-up of 34 months. Four patients (3 low-risk and 1 high-risk) experienced relapse, with three having hematological relapse in the 11th, 16th, and 25th months, and one having central nervous system leukemia occur in the 17th month. Among these patients, one patient died of intracranial hemorrhage, while the remaining patients eventually achieved CR2 and survived. The 3-year OS and RFS rates did not show a significant difference between high-risk and low-risk patients, with rates of 93.9% versus 98.7% (p = 0.196; Fig. 3 a) and 90.9% versus 96.0%༈p = 0.265; Fig. 3 c), respectively. Additionally, there was no statistically significant difference in OS between the DS and Non-DS groups (Fig. 3 b), with a 3-year RFS rates in patients with and without DS were 97.6% and 92.7% ༈p = 0.322; Fig. 3 d). Treatment Toxicities During induction therapy, 51 patients (46%) developed grade 4 neutropenia, with eight patients (7.2%) experiencing agranulocytosis lasting more than 14 days; only two of them had received ruxolitinib. High-risk patients were more likely to develop grade 4 neutropenia compared to low-risk patients (22/33 vs. 29/78, P 0.05). Furthermore, 44 infectious events occurred in 42 patients (40%) during the induction period, including 25 cases of pneumonia, 6 cases of upper respiratory tract infection, 6 cases of intestinal infection, 2 cases of sepsis, 2 cases of gingivitis, 2 cases of soft tissue infection, and 1 case of cholecystitis. Severe bleeding was observed in 22 patients, including intracranial hemorrhage in 7 patients, hemoptysis in 5 patients, gastrointestinal bleeding in 4 patients, hematuria in 6 patients, retinal hemorrhage in 3 patients, and corpus luteum rupture in 1 patient. Additional details about these patients can be found in Table 5 . At the time of bleeding, only 27% and 40% of patients reached the target PLT count (50 × 10 9 /L) and fibrinogen level (1.5 g/L), respectively. One high-risk patient experienced cerebral infarction upon presentation. Three low-risk patients developed thrombosis, with one patient experiencing a pulmonary embolism on day 22, while two patients had catheter-related thrombosis on day 22 and day 25, respectively. Table 5 Details of patients who experienced severe hemorrhage during remission induction course. UPN Risk- group Onset of hemorrhage* DS Outcome Date* Site of bleeding WBC count (10 9 /L) PLT count (10 9 /L) D-dimer (mg/L) Fibrinogen (g/L) Date* Grading of severity 2 High Day10 Lung 49.4 60 15.52 1.88 Day 10 Severe Alive 6 High Day 8 Lung 71.81 47 34.42 1.29 Day 6 Severe Alive 7 High Day 22 Lung 2.68 15 5.4 0.88 Day 21 Severe Alive 9 High Day 10 Urinary system 83.31 17 > 20 0.94 Day 8 Severe Alive 10 High Day 5 Urinary system 136.22 47 > 20 0.99 Day 6 Moderate Alive 13 High Day 7 Gastrointestine, Urinary system 262.17 52 46.26 2.37 Day 6 Moderate Alive 16 High Day 7 Retina 46.31 54 ND 1.47 Day 6 Moderate Alive 18 High Day16 Retina 9.6 43 1.48 2.64 - - Alive 27 High Day 9 CNS, Urinary system, Retina 117.87 33 > 20 1.13 - - ED 31 High Day 8 CNS, Gastrointestine 243.83 62 6.05 1.35 - - ED 34 High Day 0 CNS 20.87 8 > 20 1.02 Day 5 Moderate Alive 40 Low Day 7 Lung 52.84 34 53.04 2.04 Day 4 Severe Alive 42 Low Day 18 Lung 1.53 28 > 20 0.78 Day 13 Severe Alive 43 Low Day 21 Gastrointestine 4.52 11 52.99 0.6 Day 14 Severe Alive 45 Low Day 0 Urinary system 1.2 102 1.12 11.8 Day 10 Severe Alive 47 Low Day 2 Urinary system 34.67 15 ND 1.71 Day 9 Moderate Alive 52 Low Day 0 Gastrointestine 7.6 49 > 20 0.96 Day 12 Moderate Alive 70 Low Day 0 CNS 1.05 23 > 20 0.97 - - Alive 100 Low Day 0 CNS 4.01 16 > 20 2.58 - - Alive 104 Low Day 0 Corpus luteum 2.17 37 10.9 2.02 - - Alive 107 Low Day 3 CNS 5.6 12 6.76 4.72 Day 5 Moderate Alive 110 Low Day 0 CNS 3.89 3 ND 0.99 Day 16 Moderate Alive Abbreviations: UPN, unique patient number; CNS, central nervous system; WBC, White Blood Cell; PLT, Platelet; ND, not done; ED, Early death. * Therapy with ATRA was started. Thirty-one (28%) patients experienced grade 3 or 4 hepatic toxic effects. In all cases, liver function abnormalities resolved upon temporary discontinuation of agents such as arsenic, triazole antifungals, and norethisterone. .No patients experienced grade 3 or 4 prolonged QTc intervals. Transient hyperglycemia (8.1%), likely due to dexamethasone treatment, occurred in nine patients without a history of diabetes. All of them successfully recovered with hypoglycemic therapy. Discussion In this trial, our improved therapy approach resulted in a significant decrease in induction mortality (1.8%), completely eliminating DS and infection-related early deaths. The use of selective steroid prophylaxis and the addition of ruxolitinib did not lead to an increase in myelosuppression and infections compared to previous studies [ 9 , 20 – 23 ]. High WBC counts have been widely recognized as an independent predictor of severe DS in various studies [ 16 , 17 , 20 , 24 – 26 ]. Early management of leukocytosis is essential in preventing DS and typically involves the use of cytoreductive agents and steroids. However, there is still uncertainty regarding the optimal treatment regimen [ 17 , 27 , 28 ]. APL can be cured without traditional chemotherapy currently, but aggressive chemotherapy or the addition of gemtuzumab ozogamicin (GO) is often recommended for high-risk patients and low-risk patients with leukocytosis, even with ATRA-ATO therapy. Due to GO is not yet commercially available in China, severe infections and life-threatening bleeding events [ 21 , 22 , 29 , 30 ] after intensive chemotherapy are a major issue. Moreover, the necessity of uniform steroid dosing throughout induction therapy is also a topic of debate. We developed a tailored treatment regimen based on individual WBC counts, utilizing varying dosages of dexamethasone in addition to minimal chemotherapy for comprehensive prophylaxis against DS. In our study, the maximum prophylactic dexamethasone dose was 10mg per day, half of the NCCN's recommended dosage [ 13 ]. However, this stratified approach proved effective in managing hyperleukocytosis in all cases except for two patients who succumbed to fatal bleeding. In several studies, 2%-41% of patients with APL have been reported to experience DS during induction therapy [ 9 , 17 , 21 , 22 ]. The wide variation in reported incidence can be attributed to differences in diagnostic criteria, use of prophylactic treatment, and various induction treatment regimens. In the current study, despite the implementation of DS prophylaxis, the incidence of DS at 36.9% was slightly higher than anticipated. This increase is likely due to improved recognition of the syndrome and the rigorous monitoring carried out throughout the entire induction period. Additionally, a contributing factor was that high-risk patients accounted for approximately 30% of the study population, a significantly higher proportion compared to previous studies [ 9 , 29 ]. The incidence of DS and severe DS in this study was lower than in our historical controls (36.9% vs. 52.2%; P < 0.05, 14.4% vs. 28.95%; P < 0.05) [ 12 ] who underwent the ATRA–ATO regimen without DS prophylaxis. This indicates that stratified prevention strategies helped reduce the incidence and severity of DS. Interestingly, unlike findings from multiple prospective and retrospective studies [ 17 , 24 , 25 ], our study did not show a statistically significant difference in the incidence of DS and severe DS (P = 0.101, P = 0.249) among patients with different risk profiles. We consider that high-risk patients may derive greater benefit from prophylactic measures. Two pretreatment variables, including a WBC count greater than 5 × 10 9 /L, elevated creatinine levels, and progressive hyperleukocytosis have been identified as increased risks for severe DS in patients receiving ATRA/chemotherapy regimens [ 10 , 17 , 26 ]. However, there is limited research on predictive factors for DS in patients undergoing treatment with ATRA plus ATO. Our study revealed that an increased WBC count at diagnosis, with a cutoff point of 4 × 10 9 /L, was the only independent predictive factor for DS. Additionally, we observed that being older than 40 years was statistically significantly associated with a severe form of the syndrome. Therefore, older patients with higher WBC counts should receive more attention within this therapeutic model. Several reports have indicated an increased relapse rate in patients who develop DS [ 10 , 17 , 18 , 25 ] treated with ATRA and chemotherapy. Contrary to these findings, our study showed that the 3-year RFS rates in the Non-DS group were even higher than those in the DS groups, although no significant difference was observed. In our study, we observed rapid resolution of symptoms in only 56% of DS patients who received preemptive dexamethasone with continuous ATRA therapy. The criteria for discontinuing ATRA have not been definitively established. The unique characteristics of promyelocyte maturation and tissue infiltration in DS may exacerbate the cell-mediated coagulopathy of APL, potentially explaining why DS patients are more susceptible to severe hemorrhagic complications [ 17 , 20 , 30 – 32 ]. Notably, patients who temporarily cease ATRA due to DS are typically experiencing a peak WBC count, which has been found to be a better predictor of early death than the initial diagnostic WBC count [ 10 ]. These individuals are at a high risk of fatal hemorrhagic events, particularly in the early stages of treatment when the procoagulant state has not yet been reversed by ATRA. However, the specific relationship between temporarily stopping the drug and subsequent hemorrhage occurrence has rarely been discussed. .In the PETHEMA study, 61% of DS patients discontinued ATRA, and 8% of them succumbing to hemorrhage [ 17 ]. In our previous study [ 12 ] involving 19 cases of early hemorrhagic deaths, 6 patients stopped ATRA due to DS, while 3 patients with hyperleukocytosis at presentation were receiving ATO and cytoductive therapy as a precaution against increased DS risks prior to starting ATRA. In our experience, even after discontinuing ATRA and administering high-dose steroids, patients with DS may still have a fulminant course. Hemoptysis is more likely to occur in these patients and may be considered a manifestation of pulmonary hemorrhage due to coagulation disorders. These patients often experience severe symptoms of DS simultaneously, such as respiratory distress, chest pain, hypoxemia, and respiratory failure. The association between hemoptysis and DS has been described in 1998 by Nicolls et al [ 33 ], who identified diffuse alveolar hemorrhage as a rare symptom of DS resulting from endothelial damage. Similarly, the JALSG APL97 study [ 31 ] revealed that 4 out of 6 patients who developed severe pulmonary bleeding also had DS, and 2 of them succumbed to early death. However, the temporal relationship was not further demonstrated. A retrospective analysis indicated that as 16 of the 35 early deaths in the study suffered from alveolar hemorrhage [ 10 ], the author suggested that some patients with severe DS might have been misdiagnosed with bleeding complication such as alveolar hemorrhage. In our study, four out of the five patients who exhibited hemoptysis (cases 2, 6, 7, and 40) were also developing DS at the same time. The details of the occurrences of hemoptysis and DS are outlined in Table 5 . Additionally, when compared with patients with intracranial hemorrhage, three patients showed improvement in coagulopathy, implying that hemoptysis was not solely related to coagulopathy. Despite treatment with high doses of steroids and sufficient transfusions, hemoptysis persisted until ruxolitinib was initiated. It is conceivable that hemoptysis may be a manifestation of DS stemming from lung injury caused by DS. Although the exact pathogenesis of DS is unknown, differentiation therapy may induce the production of chemokine in the lung and in APL cells, both of which trigger the migration of leukemic cells. Since dexamethasone does not efficiently decrease leukemic chemokine production, pulmonary infiltration of activated leukocytes may induce an uncontrollable systemic hyperinflammatory reaction known as cytokine release syndrome (CRS). CRS, combined with increased vascular permeability and endothelial damage, manifests as the main clinical presentations of DS [ 27 , 28 , 34 – 38 ], which can ultimately contribute to multi-organ failure. These hypothesis were consistent with the presence of diffuse alveolar damage and hemorrhage, accompanied by maturing myeloid cell infiltration in the lungs of postmortem patients with severe DS [ 16 ]. We implemented interventions aimed at modulating the immune response and suppressing exacerbating hyperinflammation by utilizing the selective JAK1/2 inhibitor, ruxolitinib. The efficacy of ruxolitinib for steroid-refractory DS was 67% when ATRA was maintained. The remaining six patients required non-invasive mechanical ventilation; however, after discontinuing ATRA therapy, all the clinical presentations dissipated with the simultaneous utilization of ruxolitinib and dexamethasone. All DS cases recovered, with none developing ventilator dependency or requiring invasive mechanical ventilation. In contrast, patients in other trials [ 17 , 25 , 39 ] required respiratory support more frequently, with rates of 20%-26% and DS-associated mortality of 8%-11%. The concurrent use of ruxolitinib and dexamethasone required special considerations regarding treatment toxicity. However, with progressive tapering of the doses within a brief course and minimal chemotherapy, the incidence of grade 4 neutropenia did not differ significantly between patients with or without DS. Infection occurred in 40% of all patients in this study, a lower rate compared to patients in the APL15 trial [ 23 ], using ATRA-ATO induction without chemotherapy (50%). It would be reasonable to recommend ruxolitinib as a second-line treatment for DS; the potential benefit of reducing fatal hemorrhage by continuing ATRA outweighs the minimal risk associated with a limited course of this drug. In conclusion, our data support the feasibility and benefits of the personalized strategies for managing DS in APL across all risk categories, resulting in a lower induction mortality rate of 1.8%. The lack of significant difference in DS incidence and severity between low-risk and high-risk patients suggests that tailored prophylaxis could help mitigate the negative prognostic impact of hyperleukocytosis. Misdiagnosing hemoptysis as a bleeding complication may be severely underestimated. Clinicians should confirm whether it is truly due to coagulopathy or simply a manifestation of severe DS. Ruxolitinib has shown clear advantages, and we recommend considering its use as targeted therapy routinely before discontinuing ATRA to minimize the risk of fatal bleeding. Declarations Acknowledgements The authors thank all the patients who participated in the current study. Funding This study was supported by grant from the National Natural Science Foundation of China (82170158,82200150). Consent to participate Informed consent was obtained from the individual described in this manuscript. Conflicts of interests The authors report no conflicts of interest. References Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–121. Ardeshir Ghavamzadeh, Kamran Alimoghaddam, Shahrbano Rostami, Seyed Hamidolah Ghaffari, Mohamad Jahani, Massoud Iravani, et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol. 2011;29:2753–7. Farhad Ravandi, Eli Estey, Dan Jones, Stefan Faderl, Susan O'Brien, Jackie Fiorentino, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27:504–10. S Lehmann, S Deneberg, P Antunovic, A Rangert-Derolf, H Garelius, V Lazarevic, et al. Early death rates remain high in high-risk APL: update from the Swedish Acute Leukemia Registry 1997-2013. Leukemia. 2017;31:1457–1459. Renata Abrahão, Raul C Ribeiro, Bruno C Medeiros, Ruth H Keogh, Theresa H M Keegan. Disparities in early death and survival in children, adolescents,and young adults with acute promyelocytic leukemia in California. Cancer. 2015;121:3990–3997. Jae H Park, Baozhen Qiao, Katherine S Panageas, Maria J Schymura, Joseph G Jurcic, Todd L Rosenblat, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118:1248–1254. S Lehmann, A Ravn, L Carlsson, P Antunovic, S Deneberg, L Möllgård, et al. Continuing high early death rate in acute promyelocytic leukemia: A population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011;25:1128–34. Sanz MA, Fenaux P, Tallman MS, Estey EH, Löwenberg B, Naoe T, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019;133:1630–1643. Alan K Burnett, Nigel H Russell, Robert K Hills, David Bowen, Jonathan Kell, Steve Knapper, et al. UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group: Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): Results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16:1295–305. Jae-Ho Yoon, Hee-Je Kim, Gi June Min, Sung-Soo Park, Young-Woo Jeon, Sung-Eun Lee, et al. Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acutepromyelocytic leukemia. Sci. Rep. 2019;9:11935. Jean Baptiste Micol, Emmanuel Raffoux, Nicolas Boissel, Etienne Lengliné, Emmanuel Canet, Marie Thérèse Daniel, et al. Management and treatment results in patients with acute promyelocytic leukaemia (APL) not enrolled in clinical trials. Eur J Cancer. 2014;50:1159–68. Ping Cai, Qian Wu, Yemin Wang, Xiaofei Yang, Xinyou Zhang, Suning Chen. An effective early death scoring system for predicting early death risk in de novo acute promyelocytic leukemia. Leuk Lymphoma. 2020;61:1989–1995. NCCN guidelines “Acute myeloid leukemia”, version 1.2024. Hong-Hu Zhu, De-Pei Wu, Jie Jin, Jian-Yong Li, Jun Ma, Jian-Xiang Wang, et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: A multicenter randomized controlled trial. J Clin Oncol. 2013;31:4215–4221. D Diverio, V Rossi, G Avvisati, S De Santis, A Pistilli, F Pane, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RAR alpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter “AIDA” trial. Blood. 1998;92:784–9. S R Frankel, A Eardley, G Lauwers, M Weiss, R P Warrell Jr. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med.1992;117:292–296. Pau Montesinos, Juan M Bergua, Edo Vellenga, Chelo Rayón, Ricardo Parody, Javier de la Serna, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113:775–83. Francesco Lo-Coco. ED in APL: tip of the iceberg? Blood. 2011;118:1188–1189. Bruce D Cheson, John M Bennett, Kenneth J Kopecky, Thomas Büchner, Cheryl L Willman, Elihu H Estey, et al. Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–4649. Javier de la Serna, Pau Montesinos, Edo Vellenga, Chelo Rayón, Ricardo Parody, Angel León, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111:3395–3402. Huyong Zheng, Hui Jiang, Shaoyan Hu, Ning Liao, Diying Shen, Xin Tian et al. Chinese Children's Leukemia GroupArsenic Combined With All-Trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia:Report From the CCLG-APL2016 Protocol Study. J Clin Oncol. 2021;39:3161–3170. Hong-Hu Zhu, Yan-Rong Liu, Jin-Song Jia, Ya-Zhen Qin, Xiao-Su Zhao, Yue-Yun Lai. Oral arsenic and all-trans retinoic acid for high-risk acute promyelocytic leukemia. Blood. 2018;131:2987–2989. Huai-Yu Wang, Sha Gong, Guo-Hui Li, Ya-Zhou Yao, Yin-Suo Zheng, Xiao-Hong Lu, et al. An effective and chemotherapy-free strategy of all-trans retinoic acid and arsenic trioxide for acute promyelocytic leukemia in all risk groups (APL15 trial). Blood Cancer J. 2022;12:158. J S Wiley, F C Firkin. Australian Leukaemia Study Group. Reduction of pulmonary toxicity by prednisolone prophylaxis during all-trans retinoic acid treatment of acute promyelocytic leukemia. Leukemia. 1995;9:774–778. S. De Botton, H. Dombret, M. Sanz, J. San Miguel, Incidence, clinical features, and outcome of all trans retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1998. 15;92:2712–8. Miguel A Sanz, Pau Montesinos, Chelo Rayón, Alexandra Holowiecka, Javier de la Serna, Gustavo Milone, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high risk patients: further improvements in treatment outcome. Blood. 2010;115:5137–5146. Miguel A Sanz, Pau Montesinos. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014;123:2777–2782. Maximilian Stahl, Martin S Tallman. Differentiation syndrome in acute promyelocytic leukaemia. Br J Haematol. 2019;187:157–162. Harry J Iland, Marnie Collins, Ken Bradstock, Shane G Supple, Alberto Catalano, Mark Hertzberg, et al. Australasian Leukaemia and Lymphoma GroupUse of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol. 2015;2:e357–66. Simon Mantha, Debra A Goldman, Sean M Devlin, Ju-Whei Lee, Diana Zannino, Marnie Collins, et al. Determinants of fatal bleeding during induction therapy for acute promye-locytic leukemia in the ATRA era. Blood. 2017;129:1763–7. Masamitsu Yanada, Tadashi Matsushita, Norio Asou, Yuji Kishimoto, Motohiro Tsuzuki, Yasuhiro Maeda, et al. Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome. Eur J Haematol. 2007;78 :213–219. Leonard Naymagon, Erin Moshier, Douglas Tremblay, John Mascarenhas. Predictors of early hemorrhage in acute promyelocytic leukemia. Leuk Lymphoma. 2019;60:2394–2403. M R Nicolls, L S Terada, R M Tuder, S A Prindiville, M I Schwarz. Diffuse alveolar hemorrhage with underlying pulmonary capillaritis in the retinoic acid syndrome. American Journal of Respiratory and Critical Care Medicine. Am J Respir Crit Care Med. 1998;158:1302–5. Maaike Luesink, Jeroen L A Pennings, Willemijn M Wissink, Peter C M Linssen, Petra Muus, Rolph Pfundt, et al. Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: Triggering the differentiation syndrome. Blood. 2009;114, 5512–5521. R S Larson, D C Brown, L A Sklar. Retinoic acid induces aggregation of the acute promyelocytic leukemia cell line NB-4 by utilization of LFA-1 and ICAM-2. Blood. 1997;90:2747–2756. Sunil Girish Iyer, Laila Elias, Michele Stanchina, Justin Watts. The treatment of acute promyelocytic leukemia in 2023: Paradigm, advances, and future directions. Front Oncol. 2023;18:12:1062524. C Dubois, M H Schlageter, A de Gentile, F Guidez, N Balitrand, M E Toubert, et al. Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells. Blood. 1994;83:3264–3270. M Marchetti, A Falanga, S Giovanelli, E Oldani, T Barbui. All-trans-retinoic acid increases adhesion to endothelium of the human promyelocytic leukaemia cell line NB4. Br J Haematol. 1996;93:360–366. Eduardo M Rego, Haesook T Kim, Guillermo J Ruiz-Argüelles, Maria Soledad Undurraga, Maria del Rosario Uriarte, Rafael H Jacomo, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121:1935–43. Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Published Journal Publication published 15 Jul, 2024 Read the published version in Blood Cancer Journal → Version 1 posted Editorial decision: revise 18 Apr, 2024 Review # 2 received at journal 15 Apr, 2024 Review # 1 received at journal 12 Apr, 2024 Review # 3 received at journal 08 Apr, 2024 Reviewer # 3 agreed at journal 03 Apr, 2024 Reviewer # 2 agreed at journal 03 Apr, 2024 Reviewer # 1 agreed at journal 02 Apr, 2024 Reviewers invited by journal 02 Apr, 2024 Editor assigned by journal 26 Mar, 2024 Submission checks completed at journal 26 Mar, 2024 First submitted to journal 25 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4165353","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":286855069,"identity":"752c00b8-9ad7-4ffb-9854-9c79a99f86b1","order_by":0,"name":"Suning Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYDACCQjFw8DAfIAhgUQtbAmkaQHpMiDOXfyzm489/Nl2R8acf83nDw932DHwt3fjt0zizrF0Y962ZzyWM95uk0g8k8wgcebsBrxaDCRyzKQZ2w7zGNw4u40hsY0ZKJJLSEv+N8mfYC1nHn9IbKsnRksOmwQvSMv5HgaJxLbDhLVI3Egzk+Y5B7KFzQyo5TgPQb/wz0h+Jvmj7LC9wfnDjz/+bKuW42/vxa8Fyb4EMMVDpHKwfQdIUDwKRsEoGAUjCgAAHvJHCV3kW9MAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-2967-3597","institution":"Jiangsu Institute of Hematology","correspondingAuthor":true,"prefix":"","firstName":"Suning","middleName":"","lastName":"Chen","suffix":""},{"id":286855070,"identity":"1afe01e2-aaf0-413e-8f67-580386d958d0","order_by":1,"name":"Qian Wu","email":"","orcid":"https://orcid.org/0009-0009-0254-7302","institution":"the First Affiliated Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Wu","suffix":""},{"id":286855071,"identity":"b8eb5ed8-4c21-4730-a035-cc9bd472cf3a","order_by":2,"name":"Xiaofei Yang","email":"","orcid":"","institution":"the First Affiliated Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Xiaofei","middleName":"","lastName":"Yang","suffix":""},{"id":286855072,"identity":"2dbec0ba-6190-461f-a1b2-f573a64337bc","order_by":3,"name":"Jing-Ren Zhang","email":"","orcid":"","institution":"National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Jing-Ren","middleName":"","lastName":"Zhang","suffix":""},{"id":286855073,"identity":"4375d4d8-31f7-462e-bcb8-1d602ee5c828","order_by":4,"name":"Mengxing Xue","email":"","orcid":"","institution":"[email protected]","correspondingAuthor":false,"prefix":"","firstName":"Mengxing","middleName":"","lastName":"Xue","suffix":""},{"id":286855074,"identity":"7241790b-f02d-4df8-9d08-4803ec8f0f33","order_by":5,"name":"Depei Wu","email":"","orcid":"https://orcid.org/0000-0002-6312-3863","institution":"The First Affiliated Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Depei","middleName":"","lastName":"Wu","suffix":""},{"id":286855075,"identity":"74beda93-35c5-43eb-8426-35b2aba0bbe1","order_by":6,"name":"Mengxing Xue","email":"","orcid":"","institution":"[email protected]","correspondingAuthor":false,"prefix":"","firstName":"Mengxing","middleName":"","lastName":"Xue","suffix":""},{"id":286855076,"identity":"f5c77f22-faa6-4882-91c4-fa710b108d28","order_by":7,"name":"Zheng Ge","email":"","orcid":"","institution":"Zhongda Hospital Southeast University","correspondingAuthor":false,"prefix":"","firstName":"Zheng","middleName":"","lastName":"Ge","suffix":""},{"id":286855077,"identity":"69a10293-f1a6-4d46-87d1-88093ad04e89","order_by":8,"name":"Yifei Chen","email":"","orcid":"","institution":"Jiangdu People's Hospital, The Affiliated Jiangdu People's Hospital of Yangzhou University","correspondingAuthor":false,"prefix":"","firstName":"Yifei","middleName":"","lastName":"Chen","suffix":""},{"id":286855078,"identity":"a5d1dd64-e4d9-4a82-ba62-fdf7be1efeb3","order_by":9,"name":"Weiying Gu","email":"","orcid":"https://orcid.org/0000-0003-4913-1610","institution":"The First People's Hospital of Changzhou, Third Affiliated Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Weiying","middleName":"","lastName":"Gu","suffix":""},{"id":286855079,"identity":"a44f7c71-028a-4c1e-a789-c756cd051e1d","order_by":10,"name":"Weimin Dong","email":"","orcid":"","institution":"The Firest People’s Hospital of Changzhou","correspondingAuthor":false,"prefix":"","firstName":"Weimin","middleName":"","lastName":"Dong","suffix":""},{"id":286855080,"identity":"058cabdc-df90-4ae7-bc9e-f673c6030914","order_by":11,"name":"Hongying Chao","email":"","orcid":"","institution":"3.\tDepartment of Hematology, Affiliated Changzhou Second Hospital of NanJing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hongying","middleName":"","lastName":"Chao","suffix":""},{"id":286855081,"identity":"dd152a15-628f-4263-89c4-35645cdfb77c","order_by":12,"name":"N Jiang","email":"","orcid":"","institution":"Changzhou No.2 People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"N","middleName":"","lastName":"Jiang","suffix":""},{"id":286855082,"identity":"2588c8b4-c777-4191-80e1-bc1f2774fc3c","order_by":13,"name":"Xuemei Sun","email":"","orcid":"","institution":"Jiangsu Province Hospital of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xuemei","middleName":"","lastName":"Sun","suffix":""},{"id":286855083,"identity":"72dec3bc-249e-4f0f-a67d-06c49e274c8f","order_by":14,"name":"Zefa Liu","email":"","orcid":"","institution":"Department of Hematology, Xinghua City People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zefa","middleName":"","lastName":"Liu","suffix":""},{"id":286855084,"identity":"93fc73d3-f7a6-4bf3-9e62-12be5d531366","order_by":15,"name":"Jin-Ning Shi","email":"","orcid":"","institution":"The Affiliated Jiangning Hospital with Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jin-Ning","middleName":"","lastName":"Shi","suffix":""},{"id":286855085,"identity":"7e228a13-b007-437d-8e52-99fc4ba34a5e","order_by":16,"name":"Hui Chen","email":"","orcid":"","institution":"Yancheng NO.1 People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Chen","suffix":""},{"id":286855086,"identity":"4e65db80-5049-469e-bde8-967d8368be72","order_by":17,"name":"Cixian Zhang","email":"","orcid":"","institution":"Xuzhou Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Cixian","middleName":"","lastName":"Zhang","suffix":""},{"id":286855087,"identity":"805b7ef7-28ce-4fc8-bee6-0298617375cc","order_by":18,"name":"Fengling Min","email":"","orcid":"","institution":"Department of Hematology, Affiliated Hospital of Yangzhou University","correspondingAuthor":false,"prefix":"","firstName":"Fengling","middleName":"","lastName":"Min","suffix":""},{"id":286855088,"identity":"2ab52984-6d65-404a-87d9-1c2d4b9b8813","order_by":19,"name":"Hongli Sun","email":"","orcid":"","institution":"Wuxi People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongli","middleName":"","lastName":"Sun","suffix":""},{"id":286855089,"identity":"7f2a573c-58fe-4308-8918-7e921a94a854","order_by":20,"name":"Xiaoli Qian","email":"","orcid":"","institution":"Taizhou Second People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaoli","middleName":"","lastName":"Qian","suffix":""},{"id":286855090,"identity":"195fc615-c835-4cb5-a0e8-19b1e66fddb8","order_by":21,"name":"Hongjian Yuan","email":"","orcid":"","institution":"Taizhou Second People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongjian","middleName":"","lastName":"Yuan","suffix":""},{"id":286855091,"identity":"1f30d92b-ffcf-43a4-8ff1-45585f3db634","order_by":22,"name":"Yuan Feng","email":"","orcid":"","institution":"Xuzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Feng","suffix":""}],"badges":[],"createdAt":"2024-03-25 19:26:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4165353/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4165353/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41408-024-01074-y","type":"published","date":"2024-07-15T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":54320717,"identity":"4e9cfe95-809a-4040-bb48-9ca2dd928130","added_by":"auto","created_at":"2024-04-08 19:18:10","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1192745,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4165353/v1/978c6a1920396ffc9f01b1b4.jpg"},{"id":54320719,"identity":"aa70f75c-8a51-4427-97f1-095e2671a7d8","added_by":"auto","created_at":"2024-04-08 19:18:10","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":491242,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4165353/v1/40bd0fedecd5079c05bf5745.jpg"},{"id":54320718,"identity":"296b286c-90d8-4355-afb8-b8bda511f79e","added_by":"auto","created_at":"2024-04-08 19:18:10","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":806758,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4165353/v1/a7167a16e541999a8e8f89b6.jpg"},{"id":60380254,"identity":"be3ce6f7-c729-45f0-b998-6da070c83eb5","added_by":"auto","created_at":"2024-07-16 07:08:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3617268,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4165353/v1/b8a77881-e590-4aed-91f4-671a55eadfac.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Improved Prevention and Treatment Strategies for Differentiation Syndrome Contribute to Reducing Early Mortality in Patients With Acute Promyelocytic Leukemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWith the introduction of differentiating agents, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), the outcomes of patients with acute promyelocytic leukemia (APL) have significantly improved [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, a higher rate of early deaths has been observed, especially among non-protocol patients and those at high risk [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9 CR10\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In our analysis of 570 patients at our institution from 2005 to 2019, we reported a lower early death rate of 7.54% [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, we still observed unexpected and preventable early deaths, mainly caused by steroid-unresponsive differentiation syndrome (DS) and catastrophic bleeding complications, many of which were associated with hesitation or early suspension of ATRA due to DS.\u003c/p\u003e \u003cp\u003eWhile randomized controlled trials are lacking, prophylaxis against DS with steroids is commonly recommended, especially in patients with elevated white blood cell (WBC) counts (\u0026gt; 10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, the dosage and timing of steroids remain controversial. Patients with DS who do not respond to routine preemptive treatment with dexamethasone typically have a poor prognosis, underscoring the need for improved therapeutic strategies and early intervention in this area.\u003c/p\u003e \u003cp\u003eIn this report, we stratified patients based on WBC count during induction treatment to implement varying doses of dexamethasone as DS prophylaxis and explore the efficacy and safety of novel targeted therapy with ruxolitinib as a second-line treatment for refractory DS. This strategy is anticipated to significantly reduce early mortality and improve survival for patients with newly diagnosed APL treated with ATRA and arsenic agents.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003ePreviously untreated patients with a clinical diagnosis of APL were enrolled between June 1, 2019, and December 31, 2021, from 14 centers in China. Eligibility criteria included age of 18 to 75 years, a diagnosis of APL with t (15; 17) or PML/RAR rearrangement, Q-Tc interval less than 500 ms, absence of serious comorbidity, and an Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 4. Informed consent was obtained from all patients in accordance with the Declaration of Helsinki. The protocol was approved by the Research Ethics Board of each participating hospital.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eIn the prospective Phase 3 multicenter single-arm APL-01 trial, all patients diagnosed with APL, regardless of WBC counts, received induction treatment with ATRA in combination with either intravenous ATO or oral tetra-arsenic tetra-sulfide (As4S4) formula named the Realgar-Indigo naturalis formula (RIF) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTreatment with ATRA at a dose of 25 mg/m\u003csup\u003e2\u003c/sup\u003e and blood product support was initiated upon suspicion of APL, depended on morphology, and/or coagulopathy as indicated by a positive disseminated intravascular coagulation screen. Once a positive result of a t (15; 17) translocation and/or PML-RARA rearrangement was confirmed [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], ATO (0.16 mg/kg capped at 10 mg)) or RIF (60 mg/kg) was administered until complete remission (CR) was achieved. Platelets and fresh frozen plasma were transfused to maintain the platelet count above 50 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L and the fibrinogen level above 1.5g/L during therapy. ATRA treatment was to be discontinued if the diagnosis was not supported by genetic or molecular data.\u003c/p\u003e \u003cp\u003eThe prevention regimen for DS was based on the WBC count at presentation and after the initiation of ATRA, which included cytoreductive agents and dexamethasone (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea\u003cb\u003e)\u003c/b\u003e. For patients with a WBC count between 5 and 10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, hydroxyurea (500 mg three times a day) and dexamethasone (5 mg/day) were administered. If the WBC count increased to greater than 10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, the dose of hydroxyurea was increased to 1000 mg three times a day, and dexamethasone was increased to 10 mg/day, in addition to 4\u0026ndash;6 doses of idarubicin (2\u0026ndash;5 mg/dose). These medications were then gradually tapered and discontinued once the WBC count dropped to less than 10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWhen DS was suspected, prompt initiation of treatment with intravenous dexamethasone at a dose of 20 mg per day was recommended. If a favorable response was achieved, dexamethasone could be gradually tapered over a period of 1\u0026ndash;2 weeks. However, in cases where no improvement was observed, ruxolitinib should be initiated within hours at a dose of 5\u0026ndash;20 mg twice a day, with the dosage determined by the severity of DS, patient age, and general condition. Once significant relief was observed, the doses of dexamethasone and ruxolitinib could be alternately reduced. Additionally, ATRA/arsenic agent treatment should be discontinued if there was progression of the clinical features of DS (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEnd points and response criteria\u003c/h2\u003e \u003cp\u003eThe primary study end point was the incidence of DS and severe DS, as well as early death. The diagnosis of DS was made on clinical grounds by the association of at least two of the following signs, in the absence of other causes [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]: dyspnea, unexplained fever, weight gain\u0026thinsp;\u0026gt;\u0026thinsp;5 kg, unexplained hypotension, acute renal failure, pulmonary infiltrates or pleuropericardial effusion. The PETHEMA group defined the DS grading and classified patients into those with severe DS (\u0026gt;\u0026thinsp;3 signs or symptoms) or moderate DS (2\u0026ndash;3 signs or symptoms) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Whenever a diagnosis of APL DS was considered, it was vital to thoroughly exclude other conditions, such as infections or heart failure, which can mimic the manifestations of DS. Early death referred to any deaths occurring during the period from therapy initiation until the end of induction therapy, which sometimes extended for 30 days [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSecondary end points included CR rate, the assessment of toxic effects during induction, recurrence-free survival (RFS) and the probability of overall survival (OS). CR was defined as a patient having less than 5% blasts and atypical promyelocytes in an aspirate sample, an absolute neutrophil count of more than 10\u003csup\u003e9\u003c/sup\u003e/L, and a PLT count of more than 100 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Toxic effects was graded according to Terminology Criteria for Adverse Events, version (CTCAE V5.0). OS and RFS were defined according to the NCI workshop definitions [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eThe distributions of continuous data were examined using the Kolmogorov-Smirnov test. Skewed data were presented as the median and range, and the differences were compared using the Mann-Whitney U test. Categorical data were presented as sample size and percentage, and the differences were compared using the chi-square test (or Fisher's exact test). Subsequently, multivariate analysis (automatic selection model) was performed for variables with a p-value less than 0.1 in the univariate analysis. The results of the multivariate regression were visualized using a forest plot. The Kaplan-Meier test was used to compare overall survival (OS) between the high-risk and low-risk patients, as well as between DS and Non-DS groups. All statistical analyses were conducted using SPSS 23.0 software (SPSS Inc., Chicago, IL, USA), with a p-value less than 0.05 considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eEnrollment and Patient Characteristics\u003c/h2\u003e\n\u003cp\u003eA total of 111 patients diagnosed with APL were included in this trial. Of these, 33 were identified as high-risk patients (WBC count at diagnosis\u0026thinsp;\u0026le;\u0026thinsp;10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L) and 78 as low-risk patients (WBC count at diagnosis\u0026thinsp;\u0026gt;\u0026thinsp;10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L). The median WBC count before treatment in high-risk patients was 21.51 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, with 10 patients having a count exceeding 50 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L. No patients withdrew from the study either due to treatment refusal or excessive toxicity. The demographic characteristics of the patients are outlined in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of the patients at diagnosis and comparison of APL patients with and without DS, moderate DS and severe DS.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;111, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNon-DS\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;70, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDS\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;41, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eModerate DS (n\u0026thinsp;=\u0026thinsp;25, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSevere DS (n\u0026thinsp;=\u0026thinsp;16, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge, y\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.018\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73 (66)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e56 (80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38 (34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.058\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (52)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63 (57)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (48)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.250\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.805\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnderweight\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNormal weight\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (47)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOverweight\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (29)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (28)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eObese\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eECOG\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.362\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.018\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u0026ndash;1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (33)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71 (64)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47 (67)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWBC count, x 10\u003c/strong\u003e\u003csup\u003e9\u003c/sup\u003e\u003cstrong\u003e/L\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.025\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64 (58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46 (66)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47 (42)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePLT count, x 10\u003c/strong\u003e\u003csup\u003e9\u003c/sup\u003e\u003cstrong\u003e/L\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.616\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.041\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u0026ndash;40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57 (51)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (54)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHemoglobin, g/L\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.641\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.300\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70 (63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43 (61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (66)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (72)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (28)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRisk group \u0026dagger;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.101\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.249\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow-risk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e78 (70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53 (76)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 (61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (68)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh-risk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFibrinogen, g/L\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.638\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (28)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e84 (76)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54 (77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (73)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (72)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eD-dimer, mg/L\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.877\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.472\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83 (75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (74)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31 (76)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (69)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (26)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLDH level, U/\u003c/strong\u003eL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.395\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;500\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e81 (73)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53 (76)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (68)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (68)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (69)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;500\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFLT3 mutation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.974\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6/17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5/11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.701\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (45)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39 (61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (55)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCr level, \u0026micro;mol/L\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70.0\u003c/p\u003e\n\u003cp\u003e(57.6\u0026ndash;82)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63.2\u003c/p\u003e\n\u003cp\u003e(54.9\u0026ndash;72.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72.0\u003c/p\u003e\n\u003cp\u003e(58.5\u0026ndash;83.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.288\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e78.2\u003c/p\u003e\n\u003cp\u003e(59.1\u0026ndash;86.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70.0\u003c/p\u003e\n\u003cp\u003e(54.2\u0026ndash;79.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.620\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBM blast (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e82.5\u003c/p\u003e\n\u003cp\u003e(20.8\u0026ndash;97)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e82.0\u003c/p\u003e\n\u003cp\u003e(29.2\u0026ndash;118)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83.0\u003c/p\u003e\n\u003cp\u003e(20.8\u0026ndash;97.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.781\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83.0\u003c/p\u003e\n\u003cp\u003e(53.0-93.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83.3\u003c/p\u003e\n\u003cp\u003e(20.8\u0026ndash;97.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.841\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eAbbreviations: BMI, Body mass index; BM, Bone marrow; Cr, Creatinine; DS, differentiation syndrome; ECOG, Eastern cooperative oncology group; LDH, lactate dehydrogenase; PLT, Platelet; WBC, White Blood Cell.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e\u003cstrong\u003e\u0026dagger;\u003c/strong\u003ePatients were stratified into risk groups based on their presenting WBC count (\u0026le;\u0026thinsp;10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L for the low-risk APL cohort and \u0026gt;\u0026thinsp;10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L for the high-risk APL cohort).\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eIncidence and clinical characteristics of DS\u003c/h2\u003e\n\u003cp\u003eAll high-risk patients and 57 out of 78 low-risk patients received dexamethasone (5\u0026ndash;10 mg/day) for DS prophylaxis. Preemptive therapy with dexamethasone (10 mg every 12 hours) was administered to 40 out of 78 low-risk patients (51.3%) and 25 out of 33 high-risk patients (75.8%). Among the total 111 patients, 41 (36.9%) were ultimately diagnosed with DS, with 25 (22.5%) classified as moderate cases and 16 (14.4%) as severe cases (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The cumulative incidence of DS and severe DS in low-risk and high-risk patients was calculated. While the incidence of DS and severe DS was higher in high-risk patients compared to low-risk patients (48.5% vs. 32.1%, 24.2% vs. 10.3%), these differences were not statistically significant (p\u0026thinsp;=\u0026thinsp;0.057, p\u0026thinsp;=\u0026thinsp;0.056) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eClinical manifestations and timing of DS\u003c/h2\u003e\n\u003cp\u003eThe clinical features of DS are outlined in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The most common symptoms observed among patients included weight gain (85%), pulmonary infiltrates (78%), and dyspnea (71%). Additionally, patients with severe DS showed a higher prevalence of dyspnea (Fisher's exact test, P\u0026thinsp;=\u0026thinsp;0.013), pleuropericardial effusion (\u0026chi;2\u0026thinsp;=\u0026thinsp;5.577, P\u0026thinsp;=\u0026thinsp;0.018), and acute renal dysfunction (Fisher's exact test, P\u0026thinsp;=\u0026thinsp;0.018) compared to those with moderate DS.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eClinical characteristics of APL patients with DS.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDS\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;41, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eModerate DS (n\u0026thinsp;=\u0026thinsp;25, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSevere DS (n\u0026thinsp;=\u0026thinsp;16, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u0026chi;2\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDyspnea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29 (71)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (94)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.013\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnexplained fever\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.933\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.087\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWeight gain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (85)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (94)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.376\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePulmonary infiltrates\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (78)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (72)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (88)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.441\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePleuropericardial effusion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.577\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.018\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAcute renal dysfunction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnexplained hypotension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.146\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003eAbbreviations: DS, Differentiation syndrome; NA, Not available.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eDS occurred at a median of 8 days after the initiation of ATRA administration, with a range of 2\u0026ndash;21 days. Within the initial week, 19 cases (46%) of DS occurred, followed by 20 cases (49%) in the second week. Only two cases (5%) occurred in the third week. Severe DS appeared at a median of 7 days, while moderate DS appeared at a median of 8 days.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eOutcomes of DS\u003c/h2\u003e\n\u003cp\u003eMore than half of the patients with DS (23 out of 41) experienced a significant and rapid remission when they received dexamethasone treatment. The average duration of dexamethasone treatment for these patients was 10 days, with a range of 6 to 20 days. However, the condition of the remaining patients with severe DS (12 patients) and moderate DS (6 patients) worsened. All of these patients received ruxolitinib, with 12 responding well, while the other 6 required non-invasive mechanical ventilation and discontinued ATRA. Five of them recovered within 72 hours, and one patient was successfully weaned from the ventilator 10 days later. None of them developed ventilator dependency or required invasive mechanical ventilation. The median duration of DS resolution in patients receiving ruxolitinib was 5 days, with a range from 2 to 12 days, after the start of treatment. The median duration of ruxolitinib treatment was 13 days, ranging from 8 to 17 days (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). All the patients who experienced DS achieved CR.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eEffectiveness of the management of DS.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"5\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eTreatment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eLow-risk, n\u0026thinsp;=\u0026thinsp;78\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eHigh-risk, n\u0026thinsp;=\u0026thinsp;33\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eTotal, n\u0026thinsp;=\u0026thinsp;111\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eProphylaxis for APL DS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003ePreemptive therapy (Dex 10mg q12h)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e59\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eDefinite diagnosis for APL DS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eModerate DS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eFavorable response to Dex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNo improvement: Ruxolitinib\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDramatic relief\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWorsening: stop ATRA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eSevere DS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eFavorable response to Dex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNo improvement: Ruxolitinib\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDramatic relief\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWorsening: stop ATRA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"11\"\u003eAbbreviations: DS, Differentiation syndrome; Dex, dexamethasone; ATRA, all-trans retinoic acid.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003ePredictive factors for DS and severe DS\u003c/h2\u003e\n\u003cp\u003eUpon univariate analysis of prognostic factors (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), it was found that age older than 40 years (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), male sex (p\u0026thinsp;=\u0026thinsp;0.001) and WBC count exceeding 4 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L (p\u0026thinsp;=\u0026thinsp;0.025) were associated with developing DS. Following multivariate analysis (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e), only a WBC count greater than 4 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) remained statistically significant.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMultivariate analysis of different risk and DS stages for APL patients.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u0026chi;2\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDS vs. Non-DS\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (Reference category: \u0026le; 40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.311\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.958 (0.907\u0026ndash;1.012)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.128\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex (Reference category: Male)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.011\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.492 (0.123\u0026ndash;1.963)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.315\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWBC (Reference category: \u0026lt; 4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e20.805\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.241 (1.131, 1.361)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSevere DS vs. Moderate DS\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (Reference category: \u0026le; 40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5.968\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12.200 (1.640-90.772)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.015\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex (Reference category: Male)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.163\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.342 (0.049\u0026ndash;2.406)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.281\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eECOG (Reference category: \u0026le; 1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.396\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.374 (0.511\u0026ndash;3.694)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.529\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWBC (Reference category: \u0026lt; 4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.891\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.019 (0.898\u0026ndash;4.539)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.089\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePLT (Reference category: \u0026lt; 10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.351\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.426 (0.101\u0026ndash;1.797)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.245\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eAbbreviations: BM, Bone marrow; CI, confidence interval; DS, Differentiation syndrome; LDH, lactate dehydrogenase; OR, odds ratio; PLT, Platelet; WBC, White Blood Cell.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIn terms of severe DS, univariate analysis (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) identified predictive factors such as age older than 40 years (p\u0026thinsp;=\u0026thinsp;0.018), ECOG score\u0026thinsp;\u0026ge;\u0026thinsp;2 (p\u0026thinsp;=\u0026thinsp;0.018), a WBC count exceeding 4 \u0026times; 10\u003csup\u003e9/\u003c/sup\u003eL (p\u0026thinsp;=\u0026thinsp;0.009), and PLT (\u0026lt; 10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L) (p\u0026thinsp;=\u0026thinsp;0.041). Male sex displayed a marginal significant difference between the two groups (P\u0026thinsp;=\u0026thinsp;0.058). However, following multivariate analysis (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e), only advanced age (\u0026gt; 40 years old)(p\u0026thinsp;=\u0026thinsp;0.015) maintained its predictive value.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eClinical outcomes\u003c/h2\u003e\n\u003cp\u003eThe overall 30-day mortality rate was 1.8% (2/111), with two high-risk patients succumbing to intracranial hemorrhage, one on day 8 and the other on day 9 after initiation of ATRA. There were no deaths attributed to DS or infection. Of the 111 patients, the overall CR rate was 98.2%. Specifically, 100% (78/78) of the low-risk patients and 93.9% (31/33) of the high-risk patients achieved CR. The median time interval for achieving CR was 26 days (range: 18 to 71 days) in the overall analysis. Significant differences were observed in the median time to CR between high-risk patients and low-risk patients (29 days, range: 19 to 71 days vs. 26 days, range: 18 to 43 days; P\u0026thinsp;=\u0026thinsp;0.001), as well as between the DS group and the Non-DS group (31 days, range: 20 to 71 days vs. 25 days, range: 18 to 41 days; P\u0026thinsp;=\u0026thinsp;0.000).\u003c/p\u003e\n\u003cp\u003eOur trial demonstrated a 100% negative rate for RQ-PCR among the remaining 109 evaluable patients at 3 months after diagnosis. All patients completed 7 cycles of consolidation therapy, with RIF administered at 60 mg/kg daily in a 4-week-on and 4-week-off regimen for 4 cycles, and ATRA 25 mg/m\u003csup\u003e2\u003c/sup\u003e daily in a 2-week-on and 2-week-off regimen for 7 cycles. However, patients with high-risk APL required 9 cycles of maintenance therapy with ATRA at 25 mg/m2 daily for 2 weeks every 4 weeks on cycles 1, 4, 7 and RIF at 60 mg/kg daily for 2 weeks every 4 weeks on cycles 2, 3, 5, 6, 8, 9).\u003c/p\u003e\n\u003cp\u003eThe present analysis was conducted in September 2023, with a median follow-up of 34 months. Four patients (3 low-risk and 1 high-risk) experienced relapse, with three having hematological relapse in the 11th, 16th, and 25th months, and one having central nervous system leukemia occur in the 17th month. Among these patients, one patient died of intracranial hemorrhage, while the remaining patients eventually achieved CR2 and survived.\u003c/p\u003e\n\u003cp\u003eThe 3-year OS and RFS rates did not show a significant difference between high-risk and low-risk patients, with rates of 93.9% versus 98.7% (p\u0026thinsp;=\u0026thinsp;0.196; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea) and 90.9% versus 96.0%༈p\u0026thinsp;=\u0026thinsp;0.265; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec), respectively. Additionally, there was no statistically significant difference in OS between the DS and Non-DS groups (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb), with a 3-year RFS rates in patients with and without DS were 97.6% and 92.7% ༈p\u0026thinsp;=\u0026thinsp;0.322; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ed).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eTreatment Toxicities\u003c/h2\u003e\n\u003cp\u003eDuring induction therapy, 51 patients (46%) developed grade 4 neutropenia, with eight patients (7.2%) experiencing agranulocytosis lasting more than 14 days; only two of them had received ruxolitinib. High-risk patients were more likely to develop grade 4 neutropenia compared to low-risk patients (22/33 vs. 29/78, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There was no significant difference between patients with DS and those without DS (23/41 vs. 28/70, P \u0026gt; 0.05).\u003c/p\u003e\n\u003cp\u003eFurthermore, 44 infectious events occurred in 42 patients (40%) during the induction period, including 25 cases of pneumonia, 6 cases of upper respiratory tract infection, 6 cases of intestinal infection, 2 cases of sepsis, 2 cases of gingivitis, 2 cases of soft tissue infection, and 1 case of cholecystitis. Severe bleeding was observed in 22 patients, including intracranial hemorrhage in 7 patients, hemoptysis in 5 patients, gastrointestinal bleeding in 4 patients, hematuria in 6 patients, retinal hemorrhage in 3 patients, and corpus luteum rupture in 1 patient. Additional details about these patients can be found in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e. At the time of bleeding, only 27% and 40% of patients reached the target PLT count (50 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L) and fibrinogen level (1.5 g/L), respectively. One high-risk patient experienced cerebral infarction upon presentation. Three low-risk patients developed thrombosis, with one patient experiencing a pulmonary embolism on day 22, while two patients had catheter-related thrombosis on day 22 and day 25, respectively.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab5\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDetails of patients who experienced severe hemorrhage during remission induction course.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eUPN\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eRisk-\u003c/p\u003e\n\u003cp\u003egroup\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"6\" align=\"left\"\u003e\n\u003cp\u003eOnset of hemorrhage*\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eDS\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOutcome\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDate*\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSite of bleeding\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWBC count (10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePLT count (10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eD-dimer\u003c/p\u003e\n\u003cp\u003e(mg/L)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFibrinogen (g/L)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDate*\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGrading of severity\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLung\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e49.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLung\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e71.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34.42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLung\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrinary system\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e83.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.94\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrinary system\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e136.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGastrointestine, Urinary system\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e262.17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e46.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eND\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRetina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCNS, Urinary system, Retina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e117.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eED\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCNS, Gastrointestine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e243.83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eED\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCNS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e20.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.02\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLung\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e52.84\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLung\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGastrointestine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrinary system\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e102\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e11.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrinary system\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e34.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eND\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGastrointestine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCNS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCNS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e104\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCorpus luteum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.02\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e107\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCNS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e110\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCNS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3.89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eND\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"11\"\u003eAbbreviations: UPN, unique patient number; CNS, central nervous system; WBC, White Blood Cell; PLT, Platelet; ND, not done; ED, Early death.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"11\"\u003e* Therapy with ATRA was started.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThirty-one (28%) patients experienced grade 3 or 4 hepatic toxic effects. In all cases, liver function abnormalities resolved upon temporary discontinuation of agents such as arsenic, triazole antifungals, and norethisterone. .No patients experienced grade 3 or 4 prolonged QTc intervals. Transient hyperglycemia (8.1%), likely due to dexamethasone treatment, occurred in nine patients without a history of diabetes. All of them successfully recovered with hypoglycemic therapy.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this trial, our improved therapy approach resulted in a significant decrease in induction mortality (1.8%), completely eliminating DS and infection-related early deaths. The use of selective steroid prophylaxis and the addition of ruxolitinib did not lead to an increase in myelosuppression and infections compared to previous studies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHigh WBC counts have been widely recognized as an independent predictor of severe DS in various studies [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Early management of leukocytosis is essential in preventing DS and typically involves the use of cytoreductive agents and steroids. However, there is still uncertainty regarding the optimal treatment regimen [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. APL can be cured without traditional chemotherapy currently, but aggressive chemotherapy or the addition of gemtuzumab ozogamicin (GO) is often recommended for high-risk patients and low-risk patients with leukocytosis, even with ATRA-ATO therapy. Due to GO is not yet commercially available in China, severe infections and life-threatening bleeding events [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] after intensive chemotherapy are a major issue. Moreover, the necessity of uniform steroid dosing throughout induction therapy is also a topic of debate. We developed a tailored treatment regimen based on individual WBC counts, utilizing varying dosages of dexamethasone in addition to minimal chemotherapy for comprehensive prophylaxis against DS. In our study, the maximum prophylactic dexamethasone dose was 10mg per day, half of the NCCN's recommended dosage [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, this stratified approach proved effective in managing hyperleukocytosis in all cases except for two patients who succumbed to fatal bleeding.\u003c/p\u003e \u003cp\u003eIn several studies, 2%-41% of patients with APL have been reported to experience DS during induction therapy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The wide variation in reported incidence can be attributed to differences in diagnostic criteria, use of prophylactic treatment, and various induction treatment regimens. In the current study, despite the implementation of DS prophylaxis, the incidence of DS at 36.9% was slightly higher than anticipated. This increase is likely due to improved recognition of the syndrome and the rigorous monitoring carried out throughout the entire induction period. Additionally, a contributing factor was that high-risk patients accounted for approximately 30% of the study population, a significantly higher proportion compared to previous studies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The incidence of DS and severe DS in this study was lower than in our historical controls (36.9% vs. 52.2%; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, 14.4% vs. 28.95%; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] who underwent the ATRA\u0026ndash;ATO regimen without DS prophylaxis. This indicates that stratified prevention strategies helped reduce the incidence and severity of DS. Interestingly, unlike findings from multiple prospective and retrospective studies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], our study did not show a statistically significant difference in the incidence of DS and severe DS (P\u0026thinsp;=\u0026thinsp;0.101, P\u0026thinsp;=\u0026thinsp;0.249) among patients with different risk profiles. We consider that high-risk patients may derive greater benefit from prophylactic measures.\u003c/p\u003e \u003cp\u003eTwo pretreatment variables, including a WBC count greater than 5 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, elevated creatinine levels, and progressive hyperleukocytosis have been identified as increased risks for severe DS in patients receiving ATRA/chemotherapy regimens [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. However, there is limited research on predictive factors for DS in patients undergoing treatment with ATRA plus ATO. Our study revealed that an increased WBC count at diagnosis, with a cutoff point of 4 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, was the only independent predictive factor for DS. Additionally, we observed that being older than 40 years was statistically significantly associated with a severe form of the syndrome. Therefore, older patients with higher WBC counts should receive more attention within this therapeutic model.\u003c/p\u003e \u003cp\u003eSeveral reports have indicated an increased relapse rate in patients who develop DS [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] treated with ATRA and chemotherapy. Contrary to these findings, our study showed that the 3-year RFS rates in the Non-DS group were even higher than those in the DS groups, although no significant difference was observed.\u003c/p\u003e \u003cp\u003eIn our study, we observed rapid resolution of symptoms in only 56% of DS patients who received preemptive dexamethasone with continuous ATRA therapy. The criteria for discontinuing ATRA have not been definitively established. The unique characteristics of promyelocyte maturation and tissue infiltration in DS may exacerbate the cell-mediated coagulopathy of APL, potentially explaining why DS patients are more susceptible to severe hemorrhagic complications [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Notably, patients who temporarily cease ATRA due to DS are typically experiencing a peak WBC count, which has been found to be a better predictor of early death than the initial diagnostic WBC count [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These individuals are at a high risk of fatal hemorrhagic events, particularly in the early stages of treatment when the procoagulant state has not yet been reversed by ATRA. However, the specific relationship between temporarily stopping the drug and subsequent hemorrhage occurrence has rarely been discussed. .In the PETHEMA study, 61% of DS patients discontinued ATRA, and 8% of them succumbing to hemorrhage [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In our previous study [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] involving 19 cases of early hemorrhagic deaths, 6 patients stopped ATRA due to DS, while 3 patients with hyperleukocytosis at presentation were receiving ATO and cytoductive therapy as a precaution against increased DS risks prior to starting ATRA.\u003c/p\u003e \u003cp\u003eIn our experience, even after discontinuing ATRA and administering high-dose steroids, patients with DS may still have a fulminant course. Hemoptysis is more likely to occur in these patients and may be considered a manifestation of pulmonary hemorrhage due to coagulation disorders. These patients often experience severe symptoms of DS simultaneously, such as respiratory distress, chest pain, hypoxemia, and respiratory failure. The association between hemoptysis and DS has been described in 1998 by Nicolls et al [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], who identified diffuse alveolar hemorrhage as a rare symptom of DS resulting from endothelial damage. Similarly, the JALSG APL97 study [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] revealed that 4 out of 6 patients who developed severe pulmonary bleeding also had DS, and 2 of them succumbed to early death. However, the temporal relationship was not further demonstrated. A retrospective analysis indicated that as 16 of the 35 early deaths in the study suffered from alveolar hemorrhage [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], the author suggested that some patients with severe DS might have been misdiagnosed with bleeding complication such as alveolar hemorrhage. In our study, four out of the five patients who exhibited hemoptysis (cases 2, 6, 7, and 40) were also developing DS at the same time. The details of the occurrences of hemoptysis and DS are outlined in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Additionally, when compared with patients with intracranial hemorrhage, three patients showed improvement in coagulopathy, implying that hemoptysis was not solely related to coagulopathy. Despite treatment with high doses of steroids and sufficient transfusions, hemoptysis persisted until ruxolitinib was initiated. It is conceivable that hemoptysis may be a manifestation of DS stemming from lung injury caused by DS.\u003c/p\u003e \u003cp\u003eAlthough the exact pathogenesis of DS is unknown, differentiation therapy may induce the production of chemokine in the lung and in APL cells, both of which trigger the migration of leukemic cells. Since dexamethasone does not efficiently decrease leukemic chemokine production, pulmonary infiltration of activated leukocytes may induce an uncontrollable systemic hyperinflammatory reaction known as cytokine release syndrome (CRS). CRS, combined with increased vascular permeability and endothelial damage, manifests as the main clinical presentations of DS [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan additionalcitationids=\"CR35 CR36 CR37\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], which can ultimately contribute to multi-organ failure. These hypothesis were consistent with the presence of diffuse alveolar damage and hemorrhage, accompanied by maturing myeloid cell infiltration in the lungs of postmortem patients with severe DS [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe implemented interventions aimed at modulating the immune response and suppressing exacerbating hyperinflammation by utilizing the selective JAK1/2 inhibitor, ruxolitinib. The efficacy of ruxolitinib for steroid-refractory DS was 67% when ATRA was maintained. The remaining six patients required non-invasive mechanical ventilation; however, after discontinuing ATRA therapy, all the clinical presentations dissipated with the simultaneous utilization of ruxolitinib and dexamethasone. All DS cases recovered, with none developing ventilator dependency or requiring invasive mechanical ventilation. In contrast, patients in other trials [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] required respiratory support more frequently, with rates of 20%-26% and DS-associated mortality of 8%-11%. The concurrent use of ruxolitinib and dexamethasone required special considerations regarding treatment toxicity. However, with progressive tapering of the doses within a brief course and minimal chemotherapy, the incidence of grade 4 neutropenia did not differ significantly between patients with or without DS. Infection occurred in 40% of all patients in this study, a lower rate compared to patients in the APL15 trial [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], using ATRA-ATO induction without chemotherapy (50%). It would be reasonable to recommend ruxolitinib as a second-line treatment for DS; the potential benefit of reducing fatal hemorrhage by continuing ATRA outweighs the minimal risk associated with a limited course of this drug.\u003c/p\u003e \u003cp\u003eIn conclusion, our data support the feasibility and benefits of the personalized strategies for managing DS in APL across all risk categories, resulting in a lower induction mortality rate of 1.8%. The lack of significant difference in DS incidence and severity between low-risk and high-risk patients suggests that tailored prophylaxis could help mitigate the negative prognostic impact of hyperleukocytosis. Misdiagnosing hemoptysis as a bleeding complication may be severely underestimated. Clinicians should confirm whether it is truly due to coagulopathy or simply a manifestation of severe DS. Ruxolitinib has shown clear advantages, and we recommend considering its use as targeted therapy routinely before discontinuing ATRA to minimize the risk of fatal bleeding.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all the patients who participated in the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by grant from the National Natural Science Foundation of China (82170158,82200150).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the individual described in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111\u0026ndash;121.\u003c/li\u003e\n\u003cli\u003eArdeshir Ghavamzadeh, Kamran Alimoghaddam, Shahrbano Rostami, Seyed Hamidolah Ghaffari, Mohamad Jahani, Massoud Iravani, et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol. 2011;29:2753\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eFarhad Ravandi, Eli Estey, Dan Jones, Stefan Faderl, Susan O\u0026apos;Brien, Jackie Fiorentino, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27:504\u0026ndash;10.\u003c/li\u003e\n\u003cli\u003eS Lehmann, S Deneberg, P Antunovic, A Rangert-Derolf, H Garelius, V Lazarevic, et al. Early death rates remain high in high-risk APL: update from the Swedish Acute Leukemia Registry 1997-2013. Leukemia. 2017;31:1457\u0026ndash;1459.\u003c/li\u003e\n\u003cli\u003eRenata Abrah\u0026atilde;o, Raul C Ribeiro, Bruno C Medeiros, Ruth H Keogh, Theresa H M Keegan. Disparities in early death and survival in children, adolescents,and young adults with acute promyelocytic leukemia in California. Cancer. 2015;121:3990\u0026ndash;3997.\u003c/li\u003e\n\u003cli\u003eJae H Park, Baozhen Qiao, Katherine S Panageas, Maria J Schymura, Joseph G Jurcic, Todd L Rosenblat, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118:1248\u0026ndash;1254.\u003c/li\u003e\n\u003cli\u003eS Lehmann, A Ravn, L Carlsson, P Antunovic, S Deneberg, L M\u0026ouml;llg\u0026aring;rd, et al. Continuing high early death rate in acute promyelocytic leukemia: A population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011;25:1128\u0026ndash;34.\u003c/li\u003e\n\u003cli\u003eSanz MA, Fenaux P, Tallman MS, Estey EH, L\u0026ouml;wenberg B, Naoe T, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019;133:1630\u0026ndash;1643.\u003c/li\u003e\n\u003cli\u003eAlan K Burnett, Nigel H Russell, Robert K Hills, David Bowen, Jonathan Kell, Steve Knapper, et al. UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group: Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): Results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16:1295\u0026ndash;305.\u003c/li\u003e\n\u003cli\u003eJae-Ho Yoon, Hee-Je Kim, Gi June Min, Sung-Soo Park, Young-Woo Jeon, Sung-Eun Lee, et al. Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acutepromyelocytic leukemia. Sci. Rep. 2019;9:11935.\u003c/li\u003e\n\u003cli\u003eJean Baptiste Micol, Emmanuel Raffoux, Nicolas Boissel, Etienne Lenglin\u0026eacute;, Emmanuel Canet, Marie Th\u0026eacute;r\u0026egrave;se Daniel, et al. Management and treatment results in patients with acute promyelocytic leukaemia (APL) not enrolled in clinical trials. Eur J Cancer. 2014;50:1159\u0026ndash;68.\u003c/li\u003e\n\u003cli\u003ePing Cai, Qian Wu, Yemin Wang, Xiaofei Yang, Xinyou Zhang, Suning Chen. An effective early death scoring system for predicting early death risk in de novo acute promyelocytic leukemia. Leuk Lymphoma. 2020;61:1989\u0026ndash;1995.\u003c/li\u003e\n\u003cli\u003eNCCN guidelines \u0026ldquo;Acute myeloid leukemia\u0026rdquo;, version 1.2024.\u003c/li\u003e\n\u003cli\u003eHong-Hu Zhu, De-Pei Wu, Jie Jin, Jian-Yong Li, Jun Ma, Jian-Xiang Wang, et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: A multicenter randomized controlled trial. J Clin Oncol. 2013;31:4215\u0026ndash;4221.\u003c/li\u003e\n\u003cli\u003eD Diverio, V Rossi, G Avvisati, S De Santis, A Pistilli, F Pane, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RAR alpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter \u0026ldquo;AIDA\u0026rdquo; trial. Blood. 1998;92:784\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eS R Frankel, A Eardley, G Lauwers, M Weiss, R P Warrell Jr. The \u0026ldquo;retinoic acid syndrome\u0026rdquo; in acute promyelocytic leukemia. Ann Intern Med.1992;117:292\u0026ndash;296.\u003c/li\u003e\n\u003cli\u003ePau Montesinos, Juan M Bergua, Edo Vellenga, Chelo Ray\u0026oacute;n, Ricardo Parody, Javier de la Serna, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113:775\u0026ndash;83.\u003c/li\u003e\n\u003cli\u003eFrancesco Lo-Coco. ED in APL: tip of the iceberg? Blood. 2011;118:1188\u0026ndash;1189.\u003c/li\u003e\n\u003cli\u003eBruce D Cheson, John M Bennett, Kenneth J Kopecky, Thomas B\u0026uuml;chner, Cheryl L Willman, Elihu H Estey, et al. Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642\u0026ndash;4649.\u003c/li\u003e\n\u003cli\u003eJavier de la Serna, Pau Montesinos, Edo Vellenga, Chelo Ray\u0026oacute;n, Ricardo Parody, Angel Le\u0026oacute;n, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111:3395\u0026ndash;3402.\u003c/li\u003e\n\u003cli\u003eHuyong Zheng, Hui Jiang, Shaoyan Hu, Ning Liao, Diying Shen, Xin Tian et al. Chinese Children\u0026apos;s Leukemia GroupArsenic Combined With All-Trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia:Report From the CCLG-APL2016 Protocol Study. J Clin Oncol. 2021;39:3161\u0026ndash;3170.\u003c/li\u003e\n\u003cli\u003eHong-Hu Zhu, Yan-Rong Liu, Jin-Song Jia, Ya-Zhen Qin, Xiao-Su Zhao, Yue-Yun Lai. Oral arsenic and all-trans retinoic acid for high-risk acute promyelocytic leukemia. Blood. 2018;131:2987\u0026ndash;2989.\u003c/li\u003e\n\u003cli\u003eHuai-Yu Wang, Sha Gong, Guo-Hui Li, Ya-Zhou Yao, Yin-Suo Zheng, Xiao-Hong Lu, et al. An effective and chemotherapy-free strategy of all-trans retinoic acid and arsenic trioxide for acute promyelocytic leukemia in all risk groups (APL15 trial). Blood Cancer J. 2022;12:158.\u003c/li\u003e\n\u003cli\u003eJ S Wiley, F C Firkin. Australian Leukaemia Study Group. Reduction of pulmonary toxicity by prednisolone prophylaxis during all-trans retinoic acid treatment of acute promyelocytic leukemia. Leukemia. 1995;9:774\u0026ndash;778.\u003c/li\u003e\n\u003cli\u003eS. De Botton, H. Dombret, M. Sanz, J. San Miguel, Incidence, clinical features, and outcome of all trans retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1998. 15;92:2712\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eMiguel A Sanz, Pau Montesinos, Chelo Ray\u0026oacute;n, Alexandra Holowiecka, Javier de la Serna, Gustavo Milone, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high risk patients: further improvements in treatment outcome. Blood. 2010;115:5137\u0026ndash;5146.\u003c/li\u003e\n\u003cli\u003eMiguel A Sanz, Pau Montesinos. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014;123:2777\u0026ndash;2782.\u003c/li\u003e\n\u003cli\u003eMaximilian Stahl, Martin S Tallman. Differentiation syndrome in acute promyelocytic leukaemia. Br J Haematol. 2019;187:157\u0026ndash;162.\u003c/li\u003e\n\u003cli\u003eHarry J Iland, Marnie Collins, Ken Bradstock, Shane G Supple, Alberto Catalano, Mark Hertzberg, et al. Australasian Leukaemia and Lymphoma GroupUse of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol. 2015;2:e357\u0026ndash;66.\u003c/li\u003e\n\u003cli\u003eSimon Mantha, Debra A Goldman, Sean M Devlin, Ju-Whei Lee, Diana Zannino, Marnie Collins, et al. Determinants of fatal bleeding during induction therapy for acute promye-locytic leukemia in the ATRA era. Blood. 2017;129:1763\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eMasamitsu Yanada, Tadashi Matsushita, Norio Asou, Yuji Kishimoto, Motohiro Tsuzuki, Yasuhiro Maeda, et al. Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome. Eur J Haematol. 2007;78 :213\u0026ndash;219.\u003c/li\u003e\n\u003cli\u003eLeonard Naymagon, Erin Moshier, Douglas Tremblay, John Mascarenhas. Predictors of early hemorrhage in acute promyelocytic leukemia. Leuk Lymphoma. 2019;60:2394\u0026ndash;2403.\u003c/li\u003e\n\u003cli\u003eM R Nicolls, L S Terada, R M Tuder, S A Prindiville, M I Schwarz. Diffuse alveolar hemorrhage with underlying pulmonary capillaritis in the retinoic acid syndrome. American Journal of Respiratory and Critical Care Medicine. Am J Respir Crit Care Med. 1998;158:1302\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eMaaike Luesink, Jeroen L A Pennings, Willemijn M Wissink, Peter C M Linssen, Petra Muus, Rolph Pfundt, et al. Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: Triggering the differentiation syndrome. Blood. 2009;114, 5512\u0026ndash;5521.\u003c/li\u003e\n\u003cli\u003eR S Larson, D C Brown, L A Sklar. Retinoic acid induces aggregation of the acute promyelocytic leukemia cell line NB-4 by utilization of LFA-1 and ICAM-2. Blood. 1997;90:2747\u0026ndash;2756.\u003c/li\u003e\n\u003cli\u003eSunil Girish Iyer, Laila Elias, Michele Stanchina, Justin Watts. The treatment of acute promyelocytic leukemia in 2023: Paradigm, advances, and future directions. Front Oncol. 2023;18:12:1062524.\u003c/li\u003e\n\u003cli\u003eC Dubois, M H Schlageter, A de Gentile, F Guidez, N Balitrand, M E Toubert, et al. Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells. Blood. 1994;83:3264\u0026ndash;3270.\u003c/li\u003e\n\u003cli\u003eM Marchetti, A Falanga, S Giovanelli, E Oldani, T Barbui. All-trans-retinoic acid increases adhesion to endothelium of the human promyelocytic leukaemia cell line NB4. Br J Haematol. 1996;93:360\u0026ndash;366.\u003c/li\u003e\n\u003cli\u003eEduardo M Rego, Haesook T Kim, Guillermo J Ruiz-Arg\u0026uuml;elles, Maria Soledad Undurraga, Maria del Rosario Uriarte, Rafael H Jacomo, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121:1935\u0026ndash;43.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"blood-cancer-journal","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bcj","sideBox":"Learn more about [Blood Cancer Journal](http://www.nature.com/bcj/)","snPcode":"41408","submissionUrl":"https://mts-bcj.nature.com/cgi-bin/main.plex","title":"Blood Cancer Journal","twitterHandle":"@bloodcancerjnl","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"acute promyelocytic leukemia, differentiation syndrome, prophylaxis strategy, ruxolitinib, steroid-resistance, cytokine release syndrome","lastPublishedDoi":"10.21203/rs.3.rs-4165353/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4165353/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn this report, we present an optimized prevention and treatment strategy for differentiation syndrome (DS). A total of 111 eligible patients with acute promyelocytic leukemia (APL) \u0026minus;\u0026thinsp;78 classified as low-risk and 33 as high-risk - received induction treatment consisting of all-trans retinoic acid (ATRA) in combination with an arsenic agent. Different doses of dexamethasone were administered based on the dynamics of white blood cell (WBC) counts to prevent DS. Ruxolitinib was used as a second-line therapy for DS. Among the patients, 41 (36.9%) experienced DS, with 16 having a severe form (14.4%) and 25 having a moderate form (22.5%). There was no significant difference in the incidence and severity of DS between the low-risk and high-risk patients (p\u0026thinsp;=\u0026thinsp;0.057 and p\u0026thinsp;=\u0026thinsp;0.056, respectively). The efficacy of ruxolitinib in cases of DS resistant to steroids was 67% without interruption of ATRA therapy. After discontinuing ATRA, the remaining DS cases were relieved through treatment with dexamethasone and ruxolitinib. The overall 30-day mortality rate was 1.8% (2/111), with two high-risk patients succumbing to intracranial hemorrhage. Complete remission (CR) was achieved in the remaining 109 patients. Our findings suggest that personalized prophylaxis against DS can mitigate the negative prognostic impact of hyperleukocytosis, and ruxolitinib is effective and well tolerated for refractory DS, ultimately decreasing early mortality in APL patients .(clinical trials.gov NCT04446806).\u003c/p\u003e","manuscriptTitle":"Improved Prevention and Treatment Strategies for Differentiation Syndrome Contribute to Reducing Early Mortality in Patients With Acute Promyelocytic Leukemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-08 19:18:05","doi":"10.21203/rs.3.rs-4165353/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-04-18T11:04:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-04-15T16:37:45+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-04-13T00:11:29+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-04-08T19:41:37+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-04-04T02:08:36+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-04-03T14:24:07+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-04-03T01:16:20+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-04-03T01:11:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-26T14:12:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-26T14:12:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Blood Cancer Journal","date":"2024-03-25T19:13:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"blood-cancer-journal","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bcj","sideBox":"Learn more about [Blood Cancer Journal](http://www.nature.com/bcj/)","snPcode":"41408","submissionUrl":"https://mts-bcj.nature.com/cgi-bin/main.plex","title":"Blood Cancer Journal","twitterHandle":"@bloodcancerjnl","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"de86ba58-4320-415c-9ee3-75a58e85d855","owner":[],"postedDate":"April 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":30194765,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia"},{"id":30194766,"name":"Health sciences/Diseases/Immunological disorders"}],"tags":[],"updatedAt":"2024-07-16T07:08:46+00:00","versionOfRecord":{"articleIdentity":"rs-4165353","link":"https://doi.org/10.1038/s41408-024-01074-y","journal":{"identity":"blood-cancer-journal","isVorOnly":false,"title":"Blood Cancer Journal"},"publishedOn":"2024-07-15 04:00:00","publishedOnDateReadable":"July 15th, 2024"},"versionCreatedAt":"2024-04-08 19:18:05","video":"","vorDoi":"10.1038/s41408-024-01074-y","vorDoiUrl":"https://doi.org/10.1038/s41408-024-01074-y","workflowStages":[]},"version":"v1","identity":"rs-4165353","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4165353","identity":"rs-4165353","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}
Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.
My notes (saved in your browser only)
Ask this paper
Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works
Citation neighborhood (no data yet)
We don't have any in-corpus citations linked to this paper yet. This is a recent paper (2024) — citers typically take a year or two to land, and the OpenAlex reference graph may still be filling in.
Source provenance
- europepmc
- last seen: 2026-05-20T01:45:00.602351+00:00
- unpaywall
- last seen: 2026-05-27T02:00:06.600101+00:00
License: CC-BY-4.0