Acute Promyelocytic Leukemia in Children Cancer Hospital Egypt

Acute Promyelocytic Leukemia in Children Cancer Hospital Egypt | 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 Research Article Acute Promyelocytic Leukemia in Children Cancer Hospital Egypt Samah Fathy Semary, Mahmoud Hammad, Dina Yassin, Nahla Elsharkawy, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3963955/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Jun, 2024 Read the published version in Discover Oncology → Version 1 posted 12 You are reading this latest preprint version Abstract Background: Paediatric acute promyelocytic leukemia (APL) accounts for 5% to 15% of all myelocytic leukemia. A retrospective study of pediatric patients diagnosed and treated with APL was done from July 2012 till the end of December 2019 at CCHE, aimed to, report the prevalence, clinical features, outcomes, and risk factors causing induction failure and early deaths. Result: Sixty-two patients were reported, age above 10, initial unsatisfactory coagulation profile, and total leukocyte count above 30 10 3 /mm affecting the 5 years (5y) overall (OS) and event-free survival (EFS), high promyelocyte count affecting the 5y EFS. Patients received protocol adopted from COG AAML1331 protocol. Prognostic factors causing early deaths during induction are high-risk patients with initial TLC >10x10 3 /mm and initial promyelocytic count above 30% with significant P-value. In the female gender, wild FLT3 increases the occurrence of differentiation syndrome (DS). Receiving steroids with all-trans retinoic acid (ATRA) in induction may minimize the frequency of DS. Relapse affecting the outcome, Bone marrow transplantation was done for 4 patients of the relapsed patients, with 5y OS 37%, with no significance. In the current study, forty-five patients are alive in complete remission with 5y OS of 72.5%, with 5y EFS of 69.4%, respectively. Conclusion: pediatric APL outcome is affected by age above 10, initial unsatisfactory coagulation profile and promyelocyte count above 10%. Early death is affected by an initial leukocyte count above 10 x10 3 /mm and, an initial promyelocytic count above 30%. Receiving steroids with ATRA may minimize the frequency of DS. acute myeloid leukemia acute promyelocytic leukemia translocation (15 17) all-trans retinoic acid differentiation syndrome Background Pediatric Acute promyelocytic leukemia (APL) accounts for 5%-15% of all myelocytic leukemia, having a low prevalence, better response to therapy, and survival outcome as compared to other acute myeloid leukemia (AML) subtypes [1-3]. The morphology corresponds to the M3 or M3v (hypo granular variant) subtype of the Franco-American-British (FAB) classification. Cytogenetically, translocation between chromosome 15 and 17 t (15; 17) (q22; q21) is common in about ninety-five percent of APL cases, and the fusion between the PML gene and the retinoic acid receptor alpha gene in chromosome 1, giving rise to the formation of the PML-RARa protein. This mutation blocks cell differentiation and causes more proliferation. The high incidence of deaths during induction chemotherapy needs further research to assess causes and prognostic factors. This study aims to report the prevalence, clinical features, outcomes, and risk factors causing induction failure and early deaths. Factors causing an increase in Differentiation Syndrome (DS) among patients with APL will be reported at Children Cancer Hospital Egypt from July 2012 till December 2019. Patients and methods It is a retrospective study reporting all pediatric patients less than 18 years old diagnosed and treated with acute promyelocytic leukemia (APL) from July 2012 till the end of December 2019 at Children Cancer Hospital Egypt, the study has IRB approval. All patients' guardians sign a declaration of consent before the start of chemotherapy protocol. The patient’s characteristics as age, gender, and obesity, laboratory data as initial peripheral blood total leukocyte count (TLC) which was above or below 10x10 3 /mm to classify the patient to standard or high risk, initial peripheral blood promyelocytic percent, the coagulation profile results, bone marrow aspirate (BMA) was done for morphologies, immunophenotyping for detection of CD13, CD33, CD117, CD56, CD2, and cytogenetic for t(15;17) (q24.1;q21.1) and PML-RARa, RAR breakpoint (bcr1,bcr2,bcr3), the presence of FLT3/ITD mutation or wild type, and cerebrospinal fluid (CSF) cytology were collected. Prognostic factors affecting and causing early induction deaths were evaluated as white blood cell count, the promyelocyte percent in peripheral blood, initial platelet count, coagulopathies, RAR breakpoint subtype, FLT3-ITD mutation, presence of all-trans retinoic acid (ATRA) syndrome (differentiation syndrome (DS)), its effect on the outcome of the patients, and whether giving prophylactic steroid will affect the incidence of ATRA syndrome. All patients started on the chemotherapy protocol adopted from COG AAML1331 protocol using ATRA without Arsenic Trioxide, which is unavailable in our center [4]. All patients started treatment with induction, ATRA (25mg/m2/day, Days 1-30, Per Oral (PO) twice a day (BID) had to be started once suspicion of presence of APL disease, IDA-rubicin (IDA): (12 mg/m2/dose) or (0.4 mg/kg/dose) IV Infusion /30 min, supplementary figure 1, and some patients received prophylaxis dexamethasone to prevent DS. If the count of white blood cells (WBC) initially was above 10,000/uL, hydroxyurea and steroid in the form of dexamethasone were given to control the leukocytosis, disseminated intravascular coagulopathy (DIC), and minimize the risk of DS symptoms. Bone marrow was done post induction to assess morphological response, then all patients proceeded to consolidation I (intrathecal (ITH) +ATRA+ high dose cytarabine (HD Ara-C) + mitoxantrone (MITOX)) and consolidation II (ITH+ATRA+IDA) [4], Supplementary Figure 1. The real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) of promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα) testing is a compassionate tool for the diagnosis of the common PML-RARα fusion gene transcript, which permits assessment of the response of the disease to treatment and allows for the detection of minimal residual disease (MRD), cytogenetic and molecular relapse. In standard-risk patients, PCR post consolidation II was done; if negative, they will proceed to maintenance, omitting consolidation III, and if positive result, they will proceed to consolidation III, while all high-risk patients receive consolidation III (ITH+ATRA+IDA+ HD Ara-C), and were evaluated by PCR post the cycle, Supplementary Figure 1. All patients proceed to maintenance 9 cycles of chemotherapy (each cycle lasts for 12 weeks - total of 108 weeks), ITH (ARA-C) given in Cycle one only, ATRA: 25 mg/m2/day, PO divided BID, 2 weeks daily, (every 3 months), Mercaptopurine (6-MP) daily, and Methotrexate (MTX) weekly, bone marrow aspirate for RQ-PCR analysis should be done at the end of each cycle of maintenance (every3 months) for all patients [4], Supplementary Figures 1. The date of the end of treatment was defined to calculate the type and time (early/late (pre or post 18 months from diagnosis)) of relapse if it occurred, type of relapse( bone marrow (BM), central nervous system (CNS), or combined relapse), line of treatment was given post relapse, response to chemotherapy cycles detected by RQ-PCR of PML-RARα testing, assess bone marrow transplantation (BMT) offered to relapsed patients, which type of BMT, autologous-BMT versus allogeneic-BMT, the state of life ( in complete remission, relapsed, palliative, death), finally the statistical analysis of survival (5 years overall and event-free survival), and the analysis of all prognostic factors affecting the overall and event-free survival, factors causing early deaths, and factors increasing the incidence of differentiation syndrome. Definitions: Risk stratification as standard risk: Patients who had an initial WBC less than 10,000/µL detected by complete blood count (CBC) at initial diagnosis are classified as standard risk [5]. Risk stratification as high risk: Patients with initial WBC greater than or equal to 10,000/µL detected by CBC at initial diagnosis are classified as high risk [5]. Early death: death occurred early within the first 30 days post-diagnosis, pre-end of induction evaluation. [6]. Complete remission (CR) was detected by the presence of blasts < 5%, the presence of less than 2% promyelocyte in bone marrow aspirate, no evidence of extra-medullary disease, transfusion independence, PCR negative, and CBC showing absolute neutrophil count more than 1000/ul with platelet count more than 100,000/µL [7]. Relapse disease: was diagnosed by the re-detection of more than 5% abnormal promyelocytes, which usually have abundant, often irregular-appearing primary azurophilic granules in the bone marrow aspirate [8]. Relapse (early/late), pre or post 18 months apart from diagnosis [8]. Differentiation syndrome (all-trans retinoic acid syndrome (ATRA syndrome)): This syndrome is manifested by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure [9]. Unsatisfactory coagulation: A complex coagulopathy associated with acute promyelocytic leukemia, reflects consumptive coagulation as well as primary or secondary fibrinolysis which can cause intracranial or pulmonary hemorrhage [10]. In the current study, for all patients with a suspected diagnosis of APL at the initial workup, a coagulation profile was done to assess the low platelet count, prolonged prothrombin time (PT), affecting the partial thromboplastin time (PTT), low prothrombin concentration (PC), and high international normalized ratio (INR) to diagnose bleeding disorder which commonly present with APL, and may be affected by the presence of the disease and leading to the increased incidence of bleeding. Body mass index: The Centers for Disease Control and Prevention (CDC) defined the Body mass index (BMI) as a person’s weight in kilograms divided by the square of height in meters. There are different methods to calculate the body mass index, in our center, the BMI-for-age percentile is based on CDC growth charts for children and teens ages 2 through 19 years. The calculator requires the child’s sex, age, height, and weight as inputs. Statistical analysis Overall survival (OS): Calculated from the date of first diagnosis to the date of death out of any cause or lost follow-up. Event-free survival: Calculated from the date of initial diagnosis to the date of diagnosis of relapse or death. The Kaplan-Meier method was used for survival analysis with 95% confidence intervals and values reported from the two–sided log-rank test. Chi-squared and Fisher’s exact tests were used to evaluate the association between categorical variables. The alpha error threshold (P-value) was set at 0.05. All statistical analyses were performed using IBM SPSS version 20. Results A total of 62 patients less than 18 years old diagnosed with APL out of 823 patients with AML (7.5%) were evaluated in Children Cancer Hospital Egypt, from July 2012 to December 2019, with a mean age of 9.2, with a median age of 9.9, range from 1.4 to 17.8, Supplementary Table 1. At diagnosis, thirty-one (50%) patients were more than 10 years old. The rest were less than 10 years with 5 years (5y) overall survival (OS) of 58.1%, and 87.1% respectively with significant P-values, 0.01, table 1, Supplementary Figure 2, and the 5y event-free survival (EFS) for them was 58.1%, 80.6% respectively, with significant P-value, 0.043, table 3, Supplementary Figure 12. Thirty-seven (59.7%) patients were males, with male to female ratio of 1.48:1, with 5y OS for males and females 81.1%, and 60.0%, respectively, with P-value 0.067, table 1, Supplementary Figure 3. Body mass index was calculated to assess the effect of obesity on the outcome of the patients; 15 patients were obese with no significant P-value, 0.5, table 1. Evaluation of initial peripheral blood total leukocyte count (TLC), which was below or above 10 x 10 3 /mm was done to classify the patient as standard or high risk; 35 (56.4%) patients had initial TLC 10 x 10 3 /mm and consider as high-risk patients with 5y OS 80%, 63% respectively with P-value 0.09, table 1, Supplementary Figure 5, but patient with initial TLC above 30 x10 3 /mm had 5y OS 55.6% with a significant P- value of 0.019, table 1, Supplementary Figure 5. Patients with high promyelocyte >10% presented initially in the peripheral blood count had 5y OS 66.7%, table 1, Supplementary Figure 6, and 5y EFS 61.9%, table 3, Supplementary Figure 14, in comparison with those who had a lower level of promyelocytes <10%, as 5y OS for them is 88.9%, table 1 and 5 y EFS 89.5%, table 3, Supplementary Figure 14, with a P-value of 0.059 for OS, table 1, and with a significant P-value of 0.035 for 5y EFS, table 3, Supplementary Figure 14. A coagulation profile was done for all patients initially. It was only satisfactory in 32% of patients. The rest of the patients (67.7%) had unsatisfactory coagulation profiles affecting the bleeding tendency and DIC at the time of diagnosis with 5y OS 95%, 61.9%, respectively, with significant P-value, 0.007, table 1, Supplementary Figure 7, and 5y EFS 95%, 57.1%, with significant P-value, 0.004, table 3, Supplementary Figure 15. Bone marrow aspirate was done for all patients for morphologies, and immunophenotyping for the presence of CD13, CD33, and CD117 for diagnosis. CD56 was detected in 7 (11%) patients with no significant P –value of 0.3, table 1. CD2 was positive in only 11 (17.7%) patients with no significant P –value of 0.3, table 1. Cytogenetic was done for detection of the presence of translocation (15; 17) (q24.1; q21.1) and PML-RARα for accurate diagnosis, RAR breakpoint (bcr1, bcr2, bcr3) was mapped by RT-PCR, bcr3 was diagnosed in 23 (37%) patients, bcr1was detected in 21(33.8%) with no significant P-value 0.52, table 1. FLT3/ITD mutation was diagnosed in 15 (24%) patients, with no significant P-value, 0.3, for survival outcome Table 1. Patients started on chemotherapy protocol adopted from COG AAML1331 chemotherapy protocol for APL using ATRA without using Arsenic Trioxide, which is not available in our center. All patients started induction treatment except one patient who died pre-treatment; ATRA started once suspicion of the presence of APL disease; the value of giving steroids with ATRA to minimize the incidence of ATRA syndrome (DS) was calculated as about 25 (40%) patients received steroid with ATRA initially, with P-value of 0.058, table 1, supplementary figure 8. Differentiation syndrome was detected throughout treatment in 31 (50%) patients, which affected the continuity of giving ATRA, followed by omitting or modification of ATRA dose, 5y OS for patients who did not suffer from ATRA syndrome was 74.2%, and for who complaining of recurrent ATRA syndrome was 71.0% with no significant P-value, 0.9, table 1, Supplementary Figure 9. DS had inconsistent diagnostic criteria such as fever, respiratory distress, weight gain, edema, pleural or pericardial effusions, and episodic hypotension. Diagnosis of DS depends on clinical symptoms, 44% of patients diagnosed with DS were manifested with dyspnea and tachypnea with or without fever. CT chest was done, and some had pulmonary infiltrations with or without unilateral or bilateral pleural effusion. 54% of patients manifested neurotoxicity symptoms such as headache, photophobia, blurring of vision, or convulsion. Pseudo-tumor cerebri was diagnosed by CT brain, and papilledema was diagnosed by fundus examination. Sixty-one patients received induction ATRA-IDArubicin, 50 (80%) patients received consolidation I but 11 (17.7%) patients died early within the first 30 days during induction and were considered as early death [6], Supplementary Table 2. Out of these 11 patients who died in induction, 8 of them died out of the presentation of intracranial hemorrhage, only one patient was presented with vaginal hemorrhage and considered as disease-related mortality, and the rest of 2 patients suffered from ATRA syndrome and died of respiratory distress and considered as treatment-related mortality. All of the patients in induction died early before day 10 of induction. Prognostic factors causing early deaths during induction were stated in Table 2 as follows, obesity did not affect early deaths in patients with APL in pediatric age as more deaths accrued in non-obese with a P-value of 0.02, table 2, but high-risk patients with initial TLC >10x 10 3 /mm suffered from early deaths than standard risk with significant P- value 0.01, initial promyelocytic count above 30% affecting the outcome of the APL patients and causing early death with significant P-value, 0.018, table 2, on the other hand, gender, low initial platelet count, unsatisfactory coagulation profile, presence of FLT3-ITD mutation, and initiating steroid with ATRA to minimize the incidence of DS were not considered as poor prognostic factors for causing early death, with no significant P-value, 0.5, 0.35, 0.35, 0.1, 0.69, respectively, table 2. Fifty (80.6%) patients received consolidation II (standard and high-risk patients); Table 3, RQ-PCR of PML-RARα testing was done only for 38 (76%) patients and was positive in 5 (13%) patients with no significant P-value for death or relapse, 0.38, 0.47 respectively, Supplementary Table 3,4. Nineteen (30.6%) patients received consolidation III (all high-risk patients and standard-risk patients who had positive RQ-PCR post consolidation II), RQ-PCR was done for 8 (42.1%) patients and was positive in 2(3%) patients, Supplementary Table 2. The main side effect of chemotherapy protocol which affects the continuity of the treatment and then affects the outcome of the disease is the DS. The prognostic factors cause recurrent ATRA syndrome through the treatment were reported, increased incidence of ATRA syndrome in females with a significant P-value, 0.01, table 4, and in patients with wild FLT3 with a significant P-value, 0.04, table 5, receiving steroids with ATRA decreasing the incidence of ATRA syndrome with a P-value of 0.058, table 4. On the other hand, age, obesity, initial promyelocytic count, receiving hydroxyurea, and risk stratification did not increase the incidence of ATRA syndrome, with no significant P-value, table 4-6. Six (9.7%) patients relapsed within the study duration with 5 y OS 33.3% with P-value, 0.07, table 1, Supplementary Figure 10. Early relapse was counted in one patient, and the rest had late relapses with a significant P-value of 0.025, table 1, Supplementary Figure 11. Relapsed patients received salvage therapy FLAG+- M+ATRA (fludarabine, high dose cytarabine with or without mitoxantrone). Bone marrow transplantation (BMT) was done for 4 patients out of the relapsing patients, autologous BMT was done for 2 patients, and allogeneic BMT for the other 2 patients, with 5y OS 50%, with no significant P-value, 0.45, table 1. Five years event-free Survival (EFS) they are not affected by obesity, gender, initial bone marrow cellularity, initial TLC, initial platelet count, risk stratification to standard or high risk, PML RARA transcript subtype, FLT3-ITD mutation, receiving steroid with ATRA, ATRA syndrome, with no significant P- value, table 3. In the current study, there are forty-five patients alive in complete remission with 5 years overall survival of 72.5% and 5 years event-free survival of 69.4%, Supplementary Table 2. Discussion Pediatric acute promyelocytic leukemia (APL) accounts for 5% - 15% of all myelocytic leukemia, having a low prevalence, better response to therapy, and survival outcome as compared to other acute myeloid leukemia (AML) subtypes [1-3]. A total of 62 pediatric patients with ages less than 18, had APL out of 823 patients of AML (7.5%) were evaluable for our study and treated at Children Cancer Hospital Egypt, from July 2012 till the end of December 2019. In FG Andrade · 2021, 163 (17.5%) patients who had APL were evaluated out of 931 AML cases [11]. The median age of pediatric APL cases is from 9 to 12 years [12,13] agreed with our result as the median age was 9.9 years old, Thirty-one (50%) patients were more than 10 years old. The rest were less than 10 years at diagnosis with 5 years (5y) overall survival (OS) of 58.1%, and 87.1% respectively with significant P-value, 0.01, and the 5y event-free survival (EFS) for them was 58.1%, 80.6%, with significant P-value, 0.043, concluding that older age suffered from poor outcome than young age, that agreed with Testi A.M et al. [13]. In pediatric age, females are predominant compared to adults age [14,15]; in the current study, male to female ratio is 1.48:1, with 5y OS for males and females 81.1%, and 60.0%, respectively, with P-value 0.067. Body mass index was calculated to assess the impact of obesity on the outcome of patients with APL; a total of 81% of analyzed APL patients were obese compared with 41.7% in the non-APL/ AML group (p 30 was detected in 57% of APL patients in comparison with 31% for the non-APL/AML group (p = 0.01). But neither obesity nor the chemotherapy calculated by dosing based on ideal body weight affected the survival outcome [16], which agreed with the current study as 15 (24%) patients were obese with no significant P-value, 0.5. On the other hand, the incidence of obesity is more in pediatric patients with APL compared to the general population. The presence of obesity affects the outcomes in patients who received AAML0631 treatment. These findings support the need for further research on the potential role of obesity in pediatric APL [17]. Evaluation of initial peripheral blood total leukocytic count (TLC), which was below or above 10x 10 3 /mm was done to classify the patient as standard or high risk; 35 (56.4%) patients had initial TLC 10 x10 3 /mm and consider as high-risk patients with 5y OS 80%, 63% respectively with P-value of 0.09, but patient with initial TLC above 30 x10 3 /mm had a lower 5y OS 55.6% with P-value of 0.019. That was shown by Sanz MA et al., who mentioned that the presence of white blood cells of more than 5,000/mm 3 or 10,000/mm 3 initially is one of the most important prognostic factors in patients with APL and causes a high incidence of relapse [18]. In the current study, the presence of promyelocytes >10% affected the 5 y EFS with a significant P-value, of 0.035. A coagulation profile was done for all patients initially. It was unsatisfactory in (67.7%), affecting the bleeding tendency, disseminated intravascular coagulopathy (DIC) at the time of diagnosis, and affecting the 5y OS to be 61.9%, with a significant P-value, of 0.007, and the 5y EFS to be 57.1%, with a significant P-value, 0.004. The presence of altered expression of numerous coagulation factors in the APL blasts may be the cause of coagulopathy initially at diagnosis. The blasts demonstrate an increased expression of tissue factors like tissue plasminogen activator, cysteine protease, Annexin 2, and urokinase-like plasminogen activator receptor, which cause both a hyper-coagulable condition and increased fibrinolysis [19, 20]. Bone marrow aspirate was done for all patients for morphologies and immunophenotyping diagnosis; CD56 is a unique marker found in 10% of APL cases and accompanied by poor prognosis, with a higher risk of relapse in adult patients [21]; in the current study, CD56 was detected only in 7 (11%) patients with no significant P –value 0.3. CD2 positive detection in APL was associated with high leukocytosis significantly (P = .004), shorter time to relapse and high incidence of relapse (P = .03), and lower overall survival (P = .07) than in patients with APL with negative detection of CD2 [22]. In the current study, CD2 was positive in only 11 (17.7%) with no significant P-value of 0.3, which can be explained by the small number of patients in each category in our study. Bone marrow aspirate was done for cytogenetic detection of presence of translocation (15; 17) (q24.1; q21.1) and PML-RARα for accurate diagnosis, RAR breakpoint (bcr1, bcr2, bcr3) was mapped by RT-PCR, bcr3 was diagnosed in 23 (37%) patients, bcr1was detected in 21(33.8%) with no significant P-value 0.52. As in [19], the long bcr-1, the variant bcr-2, and the short bcr-3. bcr-1 and bcr-3 are more frequently present in APL patients for about 95%, while the frequency of bCR-2 is only in 5% of APL patients. There was no association between different PML-RARA isoforms and the rest of the clinical and laboratory characteristics [23]. The detection of FLT3/ITD mutation in pediatric AML is commonly associated with poor prognosis [24], present initially with high WBC counts and worse prognosis than those who had AML without FLT3-ITD mutation [25]. In the current study, in pediatric APL, FLT3/ITD mutation was detected in 15 (24%) patients, with no significant P-value, 0.3, table 1. Kutny et al, mentions that FLT3 mutations account (43%) of pediatric patients with APL. The COG AAML0631 study failed to show an association of FLT3 mutations with bleeding/clotting events causing early induction death. Still, the relapse rate following Arsenic Trioxide (ATO) consolidation was significantly higher in FLT3 mutant patients [26]. Patients started on chemotherapy protocol adopted from COG AAML1331 chemotherapy protocol for APL using ATRA without using Arsenic Trioxide. In the COG AAML 1331 trial, all patients received ATRA and arsenic trioxide during induction and 4 consolidation cycles, and no maintenance therapy was administered. Only patients with high-risk APL received 4 doses of idarubicin during induction. Patients with standard risk had a 2-year EFS rate of 98.0% and an OS rate of 99.0%. Patients with high risk had a 2-year EFS rate of 96.4% and an OS rate of 100% [4]. Two main centers are treating pediatric oncology in our country, our canter the Children Cancer Hospital (CCHE) Egypt, and the National Cancer Institute (NCI), Egypt. Both are using the same protocol adopted from COG AAML 1331 using ATRA without using Arsenic Trioxide which is not available in our country. But did not have data about the outcome of pediatric patients with APL treated in NCI, as the only published data for NCI is for adult patients with APL treated from 2007 till 2011 [27]. ATRA started once suspicion of APL diagnosis, complaining of unexplained fever, dyspnea, water retention causing weight gain > 5 kg, laboratory findings showing elevated WBC, acute renal insufficiency, and radiological diagnosis as pleural or pericardial effusion detected by chest x-ray are the most common manifestations of DS [28]. In the current study, the most common symptoms for diagnosis of DS were fever, dyspnea, tachypnea, and neurotoxicity symptoms such as headache, photophobia, blurring of vision, or convulsion. CT chest confirms the diagnosis of DS with the presence of pulmonary infiltrations or pleural effusion. Pseudo-tumor cerebri was diagnosed by CT brain, and papilledema was diagnosed by fundus examination. Early evaluation, recognition, and treatment of corticosteroids are lifesaving in the management of the life-threatening condition of DS [28]. In the current study, 21(46.6%) patients out of 45 patients who received prophylactic steroids initially had a DS. In comparison, 9 (56.2%)patients out of 16 patients who did not receive prophylactic steroids had DS, the comparison between both groups, prophylactic steroids may decrease DS with a P-value 0.058, table 4. Differentiation syndrome was detected severally throughout treatment, which affected the continuity of giving ATRA, followed by omitting or modification of ATRA dose, which may affect the outcome of the APL patient. 5y OS for patients who did not suffer from ATRA syndrome was 74.2%, and for those who complained of recurrent ATRA syndrome was 71.0% with no significant P-value of 0.9, that finding was also mentioned by [29]. On the other hand, age, obesity, initial promyelocytic count, receiving hydroxyurea, and risk stratification did not increase the prevalence of ATRA syndrome. In [30], an analysis indicated that a WBC counts more than 5 x 10(9)/L and a higher serum creatinine level correlated with an increased incidence of occurrence of severe DS. Still, patients receiving steroids in prophylaxis base decreasing the incidence of severe, and recurrent DS. Severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003) Despite therapeutic advances and proper supportive care, early death (ED) in induction remains a most inferior factor affecting the survival outcome of APL [31]. Factors significantly associated with ED included male gender (P = .01); initial white leukocyte counts higher than or equal to 10 × 10 9 /L (P = .03); level of fibrinogen <1.5 g/L (P = .02); and delayed ATRA administration more than 24 hours after diagnosis and hospital admission (P < .001) [32]. In the current study, ED occurred in 17.7% of the study patients, and the prognostic factors causing early deaths during induction were evaluated; obesity did not affect early deaths in pediatric patients with APL with P-value 0.02, but high-risk patients with initial TLC >10 x10 3 /mm suffered from early deaths than the standard risk with significant P- value 0.01, initial promyelocytic count above 30% affecting the outcome of the APL patients and causing early death with significant P-value, 0.018, these findings are with [32]. On the other hand, gender, low initial platelet count, unsatisfactory coagulation profile, presence of FLT3-ITD mutation, and initiating steroid with ATRA to minimize the incidence of DS are not considered as poor prognostic factors for causing early death. Treatment of APL in pediatric age with ATRA in combination with chemotherapy causes complete response rates >90 % and long-term overall survival of more than 80 %. Testi M et al, who stratified the patients into standard-risk (SR) and high-risk (HR) groups according to initial WBC counts, received ATRA-dependent protocol, without ATO, the cumulative dose of anthracyclines in SR and HR patients was lower than that of other studies (355 mg/m 2 and 405 mg/m 2 , respectively). Five-year overall and event-free survival for the whole cohort was 94.6% and 79.9%, respectively. These data demonstrate that extended use of ATRA coupled with limited anthracycline exposure achieves high cure rates in childhood APL [3]. In the current study, there are forty-five patients alive in complete remission with 5 years of overall survival 72.5%, and 5 years of event-free survival 69.4%, which may be described by a high rate of induction deaths 17.7% and a high incidence of relapse 9.6%. Conclusion The outcome of pediatric APL affected by age above 10, initial unsatisfactory coagulation profile affecting the 5 years (5y) overall (OS) and event-free survival (EFS), promyelocyte count above 10% affecting the 5y EFS. Patients started on a protocol adapted from the COG AAML1331 chemotherapy protocol. Prognostic factors causing early deaths during induction of patients stratified as high-risk patients with initial total leukocyte count above 10 103/cm, and initial promyelocytic count above 30% with a significant P- P-value of 0.01, and 0.018 respectively. Female gender, wild FLT3 increases the incidence of differentiation syndrome with significant P-values, 0.01, and 0.04, respectively. Receiving steroids with ATRA may minimize the frequency of ATRA syndrome with a P-value of 0.058. Relapse affects the outcome. Bone marrow transplantation was done for 4 patients of the relapsed patients, with 5y OS 37%, with no significant P-value, 0.45. In the current study, forty-five patients are alive in complete remission with 5y OS at 72.5% with 5y EFS at 69.4%, respectively, due to a high incidence of induction deaths at 17.7% and a high rate of relapse of 9.6%. Abbreviations APL acute promyelocytic leukemia TLC total leukocyte count OS Overall Survival EFS event-free survival COG Children’s Cancer Group AML Acute myeloid leukemia ATRA All trans-retinoic acid FAB Franco-American-British t translocation PML-RARa Promyelocytic leukemia protein-retinoic acid receptor alpha FLT3/ITD FLT3/Internal tandem duplication CSF cerebro-spinal fluid PO Per oral BID Twice a day WBC White blood cells IDA IDArubicin ITH intrathecal HD High dose Ara-C cytarabine MITOX mitoxantrone RQ-PCR Real-time quantitative reverse transcriptase polymerase chain reaction PCR reverse transcriptase polymerase chain reaction MRD Minimal residual disease 6-MP Mercaptopurine MTX Methotrexate BMA Bone marrow aspirate CNS Central nervous system BMT Bone Marrow Transplantation Auto-BMT Autogenic Bone Marrow Transplantation Allo-BMT Allogenic Bone Marrow Transplantation CBC Complete blood count CR Complete remission BMI Body mass index CDC Centers for Disease Control and Prevention IBM SPSS International Business Machines- Statistical Package for the Social Sciences FLAG-ATRA (fludarabine, high dose cytarabine with All trans retinoic acid DIC Disseminated intravascular coagulation DS Differentiation Syndrome ED early death Declarations Ethics approval and consent to participate: All authors confirm that we obtained approval from an ethical committee ) the Council of Ethics for Scientific Research which is an organization accredited by Joint Commission International ) on 16/3/2023, it is a retrospective research article to report the clinical characteristics, outcome, and the incidence of induction failure due to early deaths and risk factors associated with it among pediatric patients with acute promyelocytic leukemia at Children Cancer Hospital Egypt from July 2012 till December 2019. We collected statistical data from the files of the patients who had written consent to follow the chemotherapy protocol for the treatment of acute promyelocytic leukemia at Children Cancer Hospital Egypt. we confirm that all experiments on humans and/or the use of human tissue samples were performed according to relevant guidelines and regulations. Consent for publication We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, concerning intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We understand that the Corresponding Author is the sole contact for the Editorial process (including the Editorial Manager and direct communications with the office). She is responsible for communicating with the other authors about progress, submissions of revisions, and final approval of proofs. We confirm that we have provided a current, correct email address accessible by the Corresponding Author. Availability of data and material: All authors agree to make the raw data and materials described in our manuscript freely available to any scientist wishing to use them for non-commercial purposes, as long as this does not breach participant confidentiality. Competing interests All authors have approved that there are no known conflicts of interest associated with this publication Funding there has been no significant financial support for this work that could have influenced its outcome. Acknowledgments I gratefully acknowledge my colleagues in the acute myeloid leukemia study team and my patients at Children Cancer Hospital Egypt (CCHE) . References De Albuquerque-Antunes A, Monteiro-Breviglieri CN, Martins-Celeste D, et al. Prevalence and outcomes of thrombotic and hemorrhagic complications in pediatric acute promyelocytic leukemia in a tertiary Brazilian center. Hematol Transfus Cell Ther. 2021;43(3):309–12. Pardo-Gonzalez CA, Lagos-Ibarra CA, Ballesteros-Linares JJ. Results of the implementation of the PETHEMA LPA 99 for treating children with acute promyelocytic leukemia in Bogotá, Colombia. Rev Fac Med. 2021;69(2):e202. Testi AM, Pession A, Diverio D et al. 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Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, Naoe T, Lengfelder E, Bücher T, Döhner H, Burnett AK, Lo-Coco F. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875–91. Richard S, Larson S, Tallman. Retinoic acid syndrome: manifestations, pathogenesis, and treatment. Best Pract Res Clin Haematol. 2003;16(3):453–61. Miguel A, Sanz P, Fenaux MS, Tallman, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019;133(15):1630–43. Francianne G, Andrade SVM, Feliciano I, Sardou-Cezar et al. Pediatric Acute Promyelocytic Leukemia: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome. Fonc 2021. 642744. Creutzig U, Zimmermann M, Reinhardt D, Rasche M, von Neuhoff C, Alpermann T, Dworzak M, Perglerová K, Zemanova Z, Tchinda J, et al. 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High Prevalence of Obesity in Acute Promyelocytic Leukemia (APL): Implications for Differentiating Agents in APL and Metabolic Syndrome. PubMed. 2011;2(3):141–5. Kathryn L, Laurie P, Lee A, Rademaker et al. 3,. Obesity in children with acute promyelocytic leukemia: What is its prevalence and prognostic significance? Pediatr Blood Cancer. 2022;69(6): e29613. Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayon C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96:1247–53. Breen KA, Grimwade D, Hunt BJ. The pathogenesis and management of the coagulopathy of acute promyelocytic leukemia. Br J Haematol. 2012;156:24–36. 10.1111/j.1365-2141.2011.08922.x . Menell JS, Cesarman GM, Jacovina AT, McLaughlin MA, Lev EA, Hajjar KA. Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med. 1999;340:994–1004. 10.1056/NEJM199904013401303 . Testa U, Lo-Coco F. Prognostic factors in acute promyelocytic leukemia: Strategies to define high-risk patients. Ann Hematol. 2016;95:673–80. 10.1007/s00277-016-2622-1 . Pei Lin S 1, Hao LJ, Medeiros, et al. Expression of CD2 in acute promyelocytic leukemia correlates with the short form of PML-RARalpha transcripts and poorer prognosis. Am J Clin Pathol. 2004;121(3):402–7. Iaccarino L, Divona M, Ottone T et al. Identification and monitoring of atypical PML/RARA fusion transcripts in acute promyelocytic leukemia Genes Chromosomes Cancer, 58 (2019), pp. 60–5. Samah, Semary et al. Outcome of Childhood Acute Myeloid Leukemia With FLT3-ITD Mutation: The Experience of Children's Cancer Hospital Egypt, 2007-17.clin lymphoma myeloma leuk, 2020;20(8):e529–41. Gledson L, Picharski, Diancarlos P, Andrade, et al. The Impact of Flt3 Gene Mutations in Acute Promyelocytic Leukemia: A Meta-Analysis. Cancers (Basel). 2019;11(9):1311. Matthew A, Kutny MD, Todd A, Alonzo, PhD R, Gerbing BS, et al. FLT3 Mutations in Pediatric Acute Promyelocytic Leukemia; A Report from the Children's Oncology Group AAML0631 Trial. Blood. 2016;128(22):2884. Ola Khorshid1, Amira Diaa1, Mohamed Abd El Moaty1. Clinical Features and Treatment Outcome of Acute Promyelocytic Leukemia Patients Treated at Cairo National Cancer Institute in Egypt. Mediterr J Hematol Infect Dis. 2011;3(1):e2011060. Jakia, Sultana. 1 Jui Dutta,Role of Prophylactic Steroids in Differentiation Syndrome.Cureus 2022; 14(9): e29531. Alessandro, Molinaro, et al. Challenging Management of Severe Differentiation Syndrome in Pediatric Acute Promyelocytic Leukemia Treated with ATRA/ATO. Mediterr J Hematol Infect Dis. 2022;14(1):e2022027. Pau, Montesinos 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-2008-07-168617. Epub 2008 Oct 22. Harinder, Gill, et al. Characteristics and predictors of early hospital deaths in newly diagnosed APL: a 13-year population-wide study. Blood adv. 2021;5(14):2829–38. Ugo, Testa. Francesco Lo-Coco. Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients. Annals Hematol April. 2016. 10.1007/s00277-016-2622-1 . Tables Table 1 to 6 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SUPPLE1.doc Tables.docx Cite Share Download PDF Status: Published Journal Publication published 11 Jun, 2024 Read the published version in Discover Oncology → Version 1 posted Editorial decision: Revision requested 23 Apr, 2024 Reviews received at journal 19 Apr, 2024 Reviews received at journal 15 Apr, 2024 Reviews received at journal 15 Apr, 2024 Reviewers agreed at journal 12 Apr, 2024 Reviewers agreed at journal 09 Apr, 2024 Reviewers agreed at journal 08 Apr, 2024 Reviewers agreed at journal 08 Apr, 2024 Reviewers invited by journal 24 Mar, 2024 Editor assigned by journal 20 Mar, 2024 Submission checks completed at journal 20 Mar, 2024 First submitted to journal 17 Feb, 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. 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07:48:37","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":46459,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-3963955/v1/9d087ff47efd5df77cf69486.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Acute Promyelocytic Leukemia in Children Cancer Hospital Egypt","fulltext":[{"header":"Background","content":"\u003cp\u003ePediatric Acute promyelocytic leukemia (APL) accounts for 5%-15% of all myelocytic leukemia, having a low prevalence, better response to therapy, and survival outcome as compared to other acute myeloid leukemia (AML) subtypes [1-3]. The morphology corresponds to the M3 or M3v (hypo granular variant) subtype of the Franco-American-British (FAB) classification. Cytogenetically, translocation between chromosome 15 and 17 t (15; 17) (q22; q21) is common in about ninety-five percent of APL cases, and the fusion between the PML gene and the retinoic acid receptor alpha gene in chromosome 1, giving rise to the formation of the PML-RARa protein. This mutation blocks cell differentiation and causes more proliferation. The high incidence of deaths during induction chemotherapy needs further research to assess causes and prognostic factors. This study aims to report the prevalence, clinical features, outcomes, and risk factors causing induction failure and early deaths. Factors causing an increase in Differentiation Syndrome (DS) among patients with APL will be reported at Children Cancer Hospital Egypt from July 2012 till December 2019.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003eIt is a retrospective study reporting all pediatric patients less than 18 years old diagnosed and treated with acute promyelocytic leukemia (APL) from July 2012 till the end of December 2019 at Children Cancer Hospital Egypt, the study has IRB approval. All patients\u0026apos; guardians sign a declaration of consent before the start of chemotherapy protocol.\u003c/p\u003e\n\u003cp\u003eThe patient\u0026rsquo;s characteristics as age, gender, and obesity, laboratory data as initial peripheral blood total leukocyte count (TLC) which was above or below 10x10\u003csup\u003e3\u003c/sup\u003e/mm to classify the patient to standard or high risk, initial peripheral blood promyelocytic percent, the coagulation profile results, bone marrow aspirate (BMA) was done for morphologies, immunophenotyping for detection of CD13, CD33, CD117, CD56, CD2, and cytogenetic for t(15;17) (q24.1;q21.1) and PML-RARa, RAR breakpoint (bcr1,bcr2,bcr3), the presence of FLT3/ITD mutation or wild type, and cerebrospinal fluid (CSF) cytology were collected.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrognostic factors affecting and causing early induction deaths were evaluated as white blood cell count, the promyelocyte percent in peripheral blood, initial platelet count, coagulopathies, RAR breakpoint subtype, FLT3-ITD mutation, presence of all-trans retinoic acid (ATRA) syndrome (differentiation syndrome (DS)), its effect on the outcome of the patients, and whether giving prophylactic steroid will affect the incidence of ATRA syndrome.\u003c/p\u003e\n\u003cp\u003eAll patients started on the chemotherapy protocol adopted from COG AAML1331 protocol using ATRA without Arsenic Trioxide, which is unavailable in our center [4].\u003c/p\u003e\n\u003cp\u003eAll patients started treatment with induction, ATRA (25mg/m2/day, Days 1-30, Per Oral (PO) twice a day (BID) had to be started once suspicion of presence of APL disease, IDA-rubicin (IDA): (12 mg/m2/dose) or (0.4 mg/kg/dose) IV Infusion /30 min, supplementary figure 1, and some patients received prophylaxis dexamethasone to prevent DS. If the count of white blood cells (WBC) initially was above 10,000/uL, hydroxyurea and steroid in the form of dexamethasone were given to control the leukocytosis, disseminated intravascular coagulopathy (DIC), and minimize the risk of DS symptoms.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBone marrow was done post induction to assess morphological response, then all patients proceeded to consolidation I (intrathecal (ITH) +ATRA+ high dose cytarabine (HD Ara-C) + mitoxantrone (MITOX)) and consolidation II (ITH+ATRA+IDA) [4], Supplementary Figure 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) of promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RAR\u0026alpha;) testing is a compassionate tool for the diagnosis of the common PML-RAR\u0026alpha; fusion gene transcript, which permits assessment of the response of the disease to treatment and allows for the detection of minimal residual disease (MRD), cytogenetic and molecular relapse. In standard-risk patients, PCR post consolidation II was done; if negative, they will proceed to maintenance, omitting consolidation III, and if positive result, they will proceed to consolidation III, while all high-risk patients receive consolidation III (ITH+ATRA+IDA+ HD Ara-C), and were evaluated by PCR post the cycle, Supplementary Figure 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients proceed to maintenance 9 cycles of chemotherapy (each cycle lasts for 12 weeks - total of 108 weeks), ITH (ARA-C) given in Cycle one only, ATRA: 25 mg/m2/day, PO divided BID, 2 weeks daily, (every 3 months), Mercaptopurine (6-MP) daily, and Methotrexate (MTX) weekly, bone marrow aspirate for RQ-PCR analysis should be done at the end of each cycle of maintenance (every3 months) for all patients [4], Supplementary Figures 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe date of the end of treatment was defined to calculate the type and time (early/late (pre or post 18 months from diagnosis)) of relapse if it occurred, type of relapse( bone marrow (BM), central nervous system (CNS), or combined relapse), line of treatment was given post relapse, response to chemotherapy cycles detected by RQ-PCR of PML-RAR\u0026alpha; testing, assess bone marrow transplantation (BMT) offered to relapsed patients, which type of BMT, autologous-BMT versus allogeneic-BMT, the state of life ( in complete remission, relapsed, palliative, death), finally the statistical analysis of survival (5 years overall and event-free survival), and the analysis of all prognostic factors affecting the overall and event-free survival, \u0026nbsp; factors causing early deaths, and factors increasing the incidence of differentiation syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDefinitions:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRisk stratification as standard risk: Patients who had an initial WBC less than 10,000/\u0026micro;L detected by complete blood count (CBC) at initial diagnosis are classified as standard risk [5].\u003c/p\u003e\n\u003cp\u003eRisk stratification as high risk: Patients with initial WBC greater than or equal to 10,000/\u0026micro;L detected by CBC at initial diagnosis are classified as high risk [5].\u003c/p\u003e\n\u003cp\u003eEarly death: death occurred early within the first 30 days post-diagnosis, pre-end of induction evaluation. [6].\u003c/p\u003e\n\u003cp\u003eComplete remission (CR) was detected by the presence of blasts \u0026lt; 5%, the presence of less than 2% promyelocyte in bone marrow aspirate, no evidence of extra-medullary disease, transfusion independence, PCR negative, and CBC showing absolute neutrophil count more than 1000/ul with platelet count more than 100,000/\u0026micro;L [7].\u003c/p\u003e\n\u003cp\u003eRelapse disease: was diagnosed by the re-detection of more than 5% abnormal promyelocytes,\u0026nbsp;which usually have abundant, often irregular-appearing primary azurophilic granules in the bone marrow aspirate [8].\u003c/p\u003e\n\u003cp\u003eRelapse (early/late), pre or post 18 months apart from diagnosis [8].\u003c/p\u003e\n\u003cp\u003eDifferentiation syndrome (all-trans retinoic acid syndrome (ATRA syndrome)): This syndrome is manifested by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure [9].\u003c/p\u003e\n\u003cp\u003eUnsatisfactory coagulation: A complex coagulopathy associated with acute promyelocytic leukemia, reflects consumptive coagulation as well as primary or secondary fibrinolysis which can cause intracranial or pulmonary hemorrhage [10]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the current study,\u0026nbsp;for all patients with a suspected diagnosis of APL at the initial workup, a coagulation profile was done to assess the low platelet count, prolonged prothrombin time (PT), affecting the partial thromboplastin time (PTT), low prothrombin concentration (PC), and high international normalized ratio (INR) to diagnose bleeding disorder which commonly present with APL, and may be affected by the presence of the disease and leading to the increased incidence of bleeding. \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBody mass index: The Centers for Disease Control and Prevention (CDC) defined the Body mass index (BMI) as a person\u0026rsquo;s weight in kilograms divided by the square of height in meters.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are different methods to calculate the body mass index, in our center, the BMI-for-age percentile is based on CDC growth charts for children and teens ages 2 through 19 years. The calculator requires the child\u0026rsquo;s sex, age, height, and weight as inputs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Overall survival (OS): Calculated from the date of first diagnosis to the date of death out of any cause or lost follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEvent-free survival: Calculated from the date of initial diagnosis to the date of diagnosis of relapse or death.\u003c/p\u003e\n\u003cp\u003eThe Kaplan-Meier method was used for survival analysis with 95% confidence intervals and values reported from the two\u0026ndash;sided log-rank test.\u003c/p\u003e\n\u003cp\u003eChi-squared and Fisher\u0026rsquo;s exact tests were used to evaluate the association between categorical variables.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The alpha error threshold (P-value) was set at 0.05. All statistical analyses were performed using IBM SPSS version 20.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 62 patients less than 18 years old diagnosed with APL out of 823 patients with AML (7.5%) were evaluated in Children Cancer Hospital Egypt, from July 2012 to December 2019, with a mean age of 9.2, with a median age of 9.9, range from 1.4 to 17.8, Supplementary Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;At diagnosis, thirty-one (50%) patients were more than 10 years old. The rest were less than 10 years with 5 years (5y) overall survival (OS) of 58.1%, and 87.1% respectively with significant P-values, 0.01, table 1, Supplementary Figure 2, and the 5y event-free survival (EFS) for them was 58.1%, 80.6% respectively, with significant P-value, 0.043, table 3, Supplementary Figure 12.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThirty-seven (59.7%) patients were males, with male to female ratio of 1.48:1, with 5y OS for males and females 81.1%, and 60.0%, respectively, with P-value 0.067, table 1, Supplementary Figure 3. Body mass index was calculated to assess the effect of obesity on the outcome of the patients; 15 patients were obese with no significant P-value, 0.5, table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEvaluation of initial peripheral blood total leukocyte count (TLC), which was below or above 10 x 10\u003csup\u003e3\u003c/sup\u003e/mm was done to classify the patient as standard or high risk; 35 (56.4%) patients had initial TLC \u0026lt; 10 x10\u003csup\u003e3\u003c/sup\u003e/mm and considered as standard risk patients, and 27 (43.5%) patients had initial TLC \u0026gt; 10 x 10\u003csup\u003e3\u003c/sup\u003e/mm and consider as high-risk patients with 5y OS 80%, 63% respectively with P-value 0.09, table 1, Supplementary Figure 5, but patient with initial TLC above 30 x10\u003csup\u003e3\u003c/sup\u003e/mm had \u0026nbsp;5y OS 55.6% with a significant P- value of 0.019, table 1, Supplementary Figure 5. Patients with high promyelocyte \u0026gt;10% presented initially in the peripheral blood count had 5y OS 66.7%, table 1, Supplementary Figure 6, and 5y EFS 61.9%, table 3, Supplementary Figure 14, in comparison with those who had a lower level of promyelocytes \u0026lt;10%, as 5y OS for them is 88.9%, table 1 and 5 y EFS 89.5%, table 3, Supplementary Figure 14, with a P-value of 0.059 for OS, table 1, and with a significant P-value of 0.035 for 5y EFS, table 3, Supplementary Figure 14.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA coagulation profile was done for all patients initially. It was only satisfactory in 32% of patients. The rest of the patients (67.7%) had unsatisfactory coagulation profiles affecting the bleeding tendency and DIC at the time of diagnosis with 5y OS 95%, 61.9%, respectively, with significant P-value, 0.007, table 1, Supplementary Figure 7, and 5y EFS 95%, 57.1%, with significant P-value, 0.004, table 3, Supplementary Figure 15.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBone marrow aspirate was done for all patients for morphologies, and immunophenotyping for the presence of CD13, CD33, and CD117 for diagnosis. CD56 was detected in 7 (11%) patients with no significant P \u0026ndash;value of 0.3, table 1. CD2 was positive in only 11 (17.7%) patients with no significant P \u0026ndash;value of 0.3, table 1. Cytogenetic was done for detection of the presence of translocation (15; 17) (q24.1; q21.1) and PML-RAR\u0026alpha; for accurate diagnosis, RAR breakpoint (bcr1, bcr2, bcr3) was mapped by RT-PCR, bcr3 was diagnosed in 23 (37%) patients, bcr1was detected in 21(33.8%) with no significant P-value 0.52, table 1. FLT3/ITD mutation was diagnosed in 15 (24%) patients, with no significant P-value, 0.3, for survival outcome Table 1.\u003c/p\u003e\n\u003cp\u003ePatients started on chemotherapy protocol adopted from COG AAML1331 chemotherapy protocol for APL using ATRA without using Arsenic Trioxide, which is not available in our center.\u003c/p\u003e\n\u003cp\u003eAll patients started induction treatment except one patient who died pre-treatment; ATRA started once suspicion of the presence of APL disease; the value of giving steroids with ATRA to minimize the incidence of ATRA syndrome (DS) was calculated as about 25 (40%) patients received steroid with ATRA initially, with P-value of 0.058, table 1, supplementary figure 8. Differentiation syndrome was detected throughout treatment in 31 (50%) patients, which affected the continuity of giving ATRA, followed by omitting or modification of ATRA dose, 5y OS for patients who did not suffer from ATRA syndrome was 74.2%, and for who complaining of recurrent ATRA syndrome was 71.0% with no significant P-value, 0.9, table 1, Supplementary Figure 9.\u003c/p\u003e\n\u003cp\u003eDS had inconsistent diagnostic criteria such as fever, respiratory distress, weight gain, edema, pleural or pericardial effusions, and episodic hypotension.\u003c/p\u003e\n\u003cp\u003eDiagnosis of DS depends on clinical symptoms, 44% of patients diagnosed with DS were manifested with dyspnea and tachypnea with or without fever.\u0026nbsp;\u0026nbsp;CT chest was done, and some had pulmonary infiltrations with or without unilateral or bilateral pleural effusion. 54% of patients manifested neurotoxicity symptoms such as headache, photophobia, blurring of vision, or convulsion. Pseudo-tumor cerebri was diagnosed by CT brain, and papilledema was diagnosed by fundus examination.\u003c/p\u003e\n\u003cp\u003eSixty-one patients received induction ATRA-IDArubicin, 50 (80%) patients received consolidation I but 11 (17.7%) patients died early within the first 30 days during induction and were considered as early death [6], Supplementary Table 2. Out of these 11 patients who died in induction, 8 of them died out of the presentation of intracranial hemorrhage, only one patient was presented with vaginal hemorrhage and considered as disease-related mortality, and the rest of 2 patients suffered from ATRA syndrome and died of respiratory distress and considered as treatment-related mortality. All of the patients in induction died early before day 10 of induction. Prognostic factors causing early deaths during induction were stated in Table 2 as follows, obesity did not affect early deaths in patients with APL in pediatric age as more deaths accrued in non-obese with a P-value of 0.02, table 2, but high-risk patients with initial TLC \u0026gt;10x 10\u003csup\u003e3\u003c/sup\u003e/mm suffered from early deaths than standard risk with significant P- value 0.01, initial promyelocytic count above 30% affecting the outcome of the APL patients and causing early death with significant P-value, 0.018, table 2, on the other hand, gender, low initial platelet count, unsatisfactory coagulation profile, presence of FLT3-ITD mutation, and initiating steroid with ATRA to minimize the incidence of DS were not considered as poor prognostic factors for causing early death, with no significant P-value, 0.5, 0.35, 0.35, 0.1, 0.69, respectively, table 2.\u003c/p\u003e\n\u003cp\u003eFifty (80.6%) patients received consolidation II (standard and high-risk patients); Table 3, RQ-PCR of PML-RAR\u0026alpha; testing was done only for 38 (76%) patients and was positive in 5 (13%) patients with no significant P-value for death or relapse, 0.38, 0.47 respectively, Supplementary Table 3,4.\u003c/p\u003e\n\u003cp\u003eNineteen (30.6%) patients received consolidation III (all high-risk patients and standard-risk patients who had positive RQ-PCR post consolidation II), RQ-PCR was done for 8 (42.1%) patients and was positive in 2(3%) patients, Supplementary Table 2.\u003c/p\u003e\n\u003cp\u003eThe main side effect of chemotherapy protocol which affects the continuity of the treatment and then affects the outcome of the disease is the DS. The prognostic factors cause recurrent ATRA syndrome through the treatment were reported, increased incidence of ATRA syndrome in females with a significant P-value, 0.01, table 4, and in patients with wild FLT3 with a significant P-value, 0.04, table 5, receiving steroids with ATRA decreasing the incidence of ATRA syndrome with a P-value of 0.058, table 4. On the other hand, age, obesity, initial promyelocytic count, receiving hydroxyurea, and risk stratification did not increase the incidence of ATRA syndrome, with no significant P-value, table 4-6.\u003c/p\u003e\n\u003cp\u003eSix (9.7%) patients relapsed within the study duration with 5 y OS 33.3% with P-value, 0.07, table 1, Supplementary Figure 10. Early relapse was counted in one patient, and the rest had late relapses with a significant P-value of 0.025, table 1, Supplementary Figure 11. Relapsed patients received salvage therapy FLAG+- M+ATRA (fludarabine, high dose cytarabine with or without mitoxantrone). Bone marrow transplantation (BMT) was done for 4 patients out of the relapsing patients, autologous BMT was done for 2 patients, and allogeneic BMT for the other 2 patients, with 5y OS 50%, with no significant P-value, 0.45, table 1. \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFive years event-free Survival (EFS) they are not affected by obesity, gender, initial bone marrow cellularity, initial TLC, initial platelet count, risk stratification to standard or high risk, PML RARA transcript subtype, FLT3-ITD mutation, receiving steroid with ATRA, ATRA syndrome, with no significant P- value, table 3.\u003c/p\u003e\n\u003cp\u003eIn the current study, there are forty-five patients alive in complete remission with 5 years overall survival of 72.5% and 5 years event-free survival of 69.4%, Supplementary Table 2.\u003c/p\u003e\n"},{"header":"Discussion","content":"\u003cp\u003ePediatric acute promyelocytic leukemia (APL) accounts for 5% - 15% of all myelocytic leukemia, having a low prevalence, better response to therapy, and survival outcome as compared to other acute myeloid leukemia (AML) subtypes [1-3]. A total of 62 pediatric patients with ages less than 18, had APL out of 823 patients of AML (7.5%) were evaluable for our study and treated at Children Cancer Hospital Egypt, from July 2012 till the end of December 2019. In FG Andrade \u0026middot; 2021, 163 (17.5%) patients who had APL were evaluated out of 931 AML cases [11]. The median age of pediatric APL cases is from 9 to 12 years [12,13] agreed with our result as the median age was 9.9 years old, Thirty-one (50%) patients were more than 10 years old. The rest were less than 10 years at diagnosis with 5 years (5y) overall survival (OS) of 58.1%, and 87.1% respectively with significant P-value, 0.01, and the 5y event-free survival (EFS) for them was 58.1%, 80.6%, with significant P-value, 0.043, concluding that older age suffered from poor outcome than young age, that agreed with Testi A.M et al. [13]. In pediatric age, females are predominant compared to adults age [14,15]; in the current study, male to female ratio is 1.48:1, with 5y OS for males and females 81.1%, and 60.0%, respectively, with P-value 0.067. Body mass index was calculated to assess the impact of obesity on the outcome of patients with APL; a total of 81% of analyzed APL patients were obese compared with 41.7% in the non-APL/ AML group (p \u0026lt; 0.001). \u0026nbsp;High body mass index (BMI) \u0026gt;30 was detected in 57% of APL patients in comparison with 31% for the non-APL/AML group (p = 0.01). But neither obesity nor the chemotherapy calculated by dosing based on ideal body weight affected the survival outcome [16], which agreed with the current study as 15 (24%) patients were obese with no significant P-value, 0.5. On the other hand, the incidence of obesity is more in pediatric patients with APL compared to the general population. The presence of obesity affects the outcomes in patients who received AAML0631 treatment. These findings support the need for further research on the potential role of obesity in pediatric APL [17].\u003c/p\u003e\n\u003cp\u003eEvaluation of initial peripheral blood total leukocytic count (TLC), which was below or above 10x 10\u003csup\u003e3\u003c/sup\u003e/mm was done to classify the patient as standard or high risk; 35 (56.4%) patients had initial TLC \u0026lt; 10 x10\u003csup\u003e3\u003c/sup\u003e/mm and considered as standard risk patients, and 27 (43.5%) patients had initial TLC \u0026gt; 10 x10\u003csup\u003e3\u003c/sup\u003e/mm and consider as high-risk patients with 5y OS 80%, 63% respectively with P-value of 0.09, but patient with initial TLC above 30 x10\u003csup\u003e3\u003c/sup\u003e/mm had a lower 5y OS 55.6% with P-value of 0.019. That was shown by Sanz MA et al., who mentioned that the presence of white blood cells of more than 5,000/mm\u003csup\u003e3\u003c/sup\u003e or 10,000/mm\u003csup\u003e3\u003c/sup\u003e initially is one of the most important prognostic factors in patients with APL and causes a high incidence of relapse [18].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the current study, the presence of promyelocytes \u0026gt;10% affected the 5 y EFS with a significant P-value, of 0.035. A coagulation profile was done for all patients initially. It was unsatisfactory in (67.7%), affecting the bleeding tendency, disseminated intravascular coagulopathy (DIC) at the time of diagnosis, and affecting the 5y OS to be 61.9%, with a significant P-value, of 0.007, and the 5y EFS to be 57.1%, with a significant P-value, 0.004. The presence of altered expression of numerous coagulation factors in the APL blasts may be the cause of coagulopathy initially at diagnosis. The blasts demonstrate an increased expression of tissue factors like tissue plasminogen activator, cysteine protease, Annexin 2, and urokinase-like plasminogen activator receptor, which cause both a hyper-coagulable condition and increased fibrinolysis [19, 20].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBone marrow aspirate was done for all patients for morphologies and immunophenotyping diagnosis; CD56 is a unique marker found in 10% of APL cases and accompanied by poor prognosis, with a higher risk of relapse in adult patients [21]; in the current study, CD56 was detected only in 7 (11%) patients with no significant P \u0026ndash;value 0.3. CD2 positive detection in APL was associated with high leukocytosis significantly (P = .004), shorter time to relapse and high incidence of relapse (P = .03), and lower overall survival (P = .07) than in patients with APL with negative detection of CD2 [22]. In the current study, CD2 was positive in only 11 (17.7%) with no significant P-value of 0.3, which can be explained by the small number of patients in each category in our study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Bone marrow aspirate was done for cytogenetic detection of presence of translocation (15; 17) (q24.1; q21.1) and PML-RAR\u0026alpha; for accurate diagnosis, RAR breakpoint (bcr1, bcr2, bcr3) was mapped by RT-PCR, bcr3 was diagnosed in 23 (37%) patients, bcr1was detected in 21(33.8%) with no significant P-value 0.52. As in [19], the long bcr-1, the variant bcr-2, and the short bcr-3. bcr-1 and bcr-3 are more frequently present in APL patients for about 95%, while the frequency of bCR-2 is only in 5% of APL patients. There was no association between different PML-RARA isoforms and the rest of the clinical and laboratory characteristics [23].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe detection of FLT3/ITD mutation in pediatric AML is commonly associated with poor prognosis [24], present initially with high WBC counts and worse prognosis than those who had AML without FLT3-ITD mutation [25]. In the current study, in pediatric APL, FLT3/ITD mutation was detected in 15 (24%) patients, with no significant P-value, 0.3, table 1. Kutny et al, mentions that\u0026nbsp;\u003cem\u003eFLT3\u003c/em\u003e mutations account (43%) of pediatric patients with APL. The COG AAML0631 study failed to show an association of \u003cem\u003eFLT3\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003emutations with bleeding/clotting events causing early induction death. Still, the relapse rate following\u0026nbsp;Arsenic Trioxide\u0026nbsp;(ATO) consolidation was significantly higher in \u003cem\u003eFLT3\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003emutant patients [26].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients started on chemotherapy protocol adopted from COG AAML1331 chemotherapy protocol for APL using ATRA without using Arsenic Trioxide. In the\u0026nbsp;COG AAML 1331 trial, all patients received ATRA and arsenic trioxide during induction and 4 consolidation cycles, and no maintenance therapy was administered. Only patients with high-risk APL received 4 doses of idarubicin during induction. Patients with standard risk had a 2-year EFS rate of 98.0% and an OS rate of 99.0%. Patients with high risk had a 2-year EFS rate of 96.4% and an OS rate of 100% [4].\u003c/p\u003e\n\u003cp\u003eTwo main centers are treating pediatric oncology in our country, our canter the Children Cancer Hospital (CCHE) Egypt, and the National Cancer Institute (NCI), Egypt. Both are using the same protocol adopted from COG AAML 1331 using ATRA without using Arsenic Trioxide which is not available in our country. But did not have data about the outcome of pediatric patients with APL treated in NCI, as the only published data for NCI is for adult patients with APL treated from 2007 till 2011 [27].\u003c/p\u003e\n\u003cp\u003eATRA started once suspicion of APL diagnosis, complaining of unexplained fever, dyspnea, water retention causing weight gain \u0026gt; 5 kg, laboratory findings showing elevated WBC, acute renal insufficiency, and radiological diagnosis as pleural or pericardial effusion detected by chest x-ray are the most common manifestations of DS [28]. In the current study, the most common symptoms for diagnosis of DS were fever,\u0026nbsp;dyspnea, tachypnea, and\u0026nbsp;neurotoxicity symptoms such as headache, photophobia, blurring of vision, or convulsion.\u0026nbsp;\u0026nbsp;CT chest confirms the diagnosis of DS with the presence of\u0026nbsp;pulmonary infiltrations or pleural effusion. Pseudo-tumor cerebri was diagnosed by CT brain, and papilledema was diagnosed by fundus examination.\u003c/p\u003e\n\u003cp\u003eEarly evaluation, recognition, and treatment of corticosteroids are lifesaving in the management of the life-threatening condition of DS [28]. In the current study, 21(46.6%) patients out of 45 patients who received prophylactic steroids initially had a DS. In comparison, 9 (56.2%)patients out of 16 patients who did not receive prophylactic steroids had DS, the comparison between both groups, prophylactic steroids may decrease DS with a P-value 0.058, table 4. Differentiation syndrome was detected severally throughout treatment, which affected the continuity of giving ATRA, followed by omitting or modification of ATRA dose, which may affect the outcome of the APL patient. 5y OS for patients who did not suffer from ATRA syndrome was 74.2%, and for those who complained of recurrent ATRA syndrome was 71.0% with no significant P-value of 0.9, that finding was also mentioned by [29]. On the other hand, age, obesity, initial promyelocytic count, receiving hydroxyurea, and risk stratification did not increase the prevalence of ATRA syndrome. In [30], an analysis indicated that a WBC counts more than 5 x 10(9)/L and a higher serum creatinine level correlated with an increased incidence of occurrence of severe DS. Still, patients receiving steroids in prophylaxis base decreasing the incidence of severe, and recurrent DS. Severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003)\u003c/p\u003e\n\u003cp\u003eDespite therapeutic advances and proper supportive care, early death (ED) in induction remains a most inferior factor affecting the survival outcome of APL [31]. Factors significantly associated with ED included male gender (P = .01); initial white leukocyte counts higher than or equal to 10 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L (P = .03); level of fibrinogen \u0026lt;1.5 g/L (P = .02); and delayed ATRA administration more than 24 hours after diagnosis and hospital admission (P \u0026lt; .001) [32]. \u0026nbsp;In the current study, ED occurred in 17.7% of the study patients, and the prognostic factors causing early deaths during induction were evaluated; obesity did not affect early deaths in pediatric patients with APL with P-value 0.02, but high-risk patients with initial TLC \u0026gt;10 x10\u003csup\u003e3\u003c/sup\u003e/mm suffered from early deaths than the standard risk with significant P- value 0.01, initial promyelocytic count above 30% affecting the outcome of the APL patients and causing early death with significant P-value, 0.018, these findings are with [32]. On the other hand, gender, low initial platelet count, unsatisfactory coagulation profile, presence of FLT3-ITD mutation, and initiating steroid with ATRA to minimize the incidence of DS are not considered as poor prognostic factors for causing early death.\u003c/p\u003e\n\u003cp\u003eTreatment of APL in pediatric age with ATRA in combination with chemotherapy causes complete response rates \u0026gt;90 % and long-term overall survival of more than 80 %. Testi M et al, who stratified the patients into standard-risk (SR) and high-risk (HR) groups according to initial WBC counts, received ATRA-dependent protocol, without ATO, the cumulative dose of anthracyclines in SR and HR patients was lower than that of other studies (355 mg/m\u003csup\u003e2\u003c/sup\u003e and 405 mg/m\u003csup\u003e2\u003c/sup\u003e, respectively). Five-year overall and event-free survival for the whole cohort was 94.6% and 79.9%, respectively. These data demonstrate that extended use of ATRA coupled with limited anthracycline exposure achieves high cure rates in childhood APL [3]. In the current study, there are forty-five patients alive in complete remission with 5 years of overall survival 72.5%, and 5 years of event-free survival 69.4%, which may be described by a high rate of induction deaths 17.7% and a high incidence of relapse 9.6%.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe outcome of pediatric APL affected by age above 10, initial unsatisfactory coagulation profile affecting the 5 years (5y) overall (OS) and event-free survival (EFS), promyelocyte count above 10% affecting the 5y EFS. Patients started on a protocol adapted from the COG AAML1331 chemotherapy protocol. Prognostic factors causing early deaths during induction of patients stratified as high-risk patients with initial total leukocyte count above 10 103/cm, and initial promyelocytic count above 30% with a significant P- P-value of 0.01, and 0.018 respectively. Female gender, wild FLT3 increases the incidence of differentiation syndrome with significant P-values, 0.01, and 0.04, respectively. Receiving steroids with ATRA may minimize the frequency of ATRA syndrome with a P-value of 0.058. Relapse affects the outcome. Bone marrow transplantation was done for 4 patients of the relapsed patients, with 5y OS 37%, with no significant P-value, 0.45. In the current study, forty-five patients are alive in complete remission with 5y OS at 72.5% with 5y EFS at 69.4%, respectively, due to a high incidence of induction deaths at 17.7% and a high rate of relapse of 9.6%.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAPL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eacute promyelocytic leukemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eTLC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003etotal leukocyte count\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eOverall Survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eEFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eevent-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCOG\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eChildren\u0026rsquo;s Cancer Group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAML\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAcute myeloid leukemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eATRA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAll trans-retinoic acid\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eFAB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eFranco-American-British\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003et\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003etranslocation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePML-RARa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePromyelocytic leukemia protein-retinoic acid receptor alpha\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eFLT3/ITD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eFLT3/Internal tandem duplication\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCSF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ecerebro-spinal fluid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePer oral\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eBID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eTwice a day\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eWBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eWhite blood cells\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eIDA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eIDArubicin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eITH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eintrathecal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eHigh dose\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAra-C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ecytarabine\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eMITOX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003emitoxantrone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eRQ-PCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eReal-time quantitative reverse transcriptase polymerase chain reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ereverse transcriptase polymerase chain reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eMRD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eMinimal residual disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e6-MP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eMercaptopurine\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eMTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eMethotrexate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eBMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eBone marrow aspirate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCentral nervous system\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eBMT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eBone Marrow Transplantation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAuto-BMT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAutogenic Bone Marrow Transplantation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAllo-BMT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAllogenic Bone Marrow Transplantation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eComplete blood count\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eComplete remission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eBody mass index\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCDC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCenters for Disease Control and Prevention\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eIBM SPSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eInternational Business Machines- Statistical Package for the Social Sciences\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eFLAG-ATRA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e(fludarabine, high dose cytarabine with All trans retinoic acid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eDIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eDisseminated intravascular coagulation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eDifferentiation Syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eED\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eearly death\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors confirm that we obtained approval from an ethical committee \u003cspan dir=\"RTL\"\u003e\u0026nbsp;)\u003c/span\u003e the Council of Ethics for Scientific Research which is an organization accredited by Joint Commission International ) on 16/3/2023, it is a retrospective research article to report the clinical characteristics, outcome, and the incidence of induction failure due to early deaths and risk factors associated with it among pediatric patients with acute promyelocytic leukemia at Children Cancer Hospital Egypt from July 2012 till December 2019.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe collected statistical data from the files of the patients who had written consent to follow the chemotherapy protocol for the treatment of acute promyelocytic leukemia at Children Cancer Hospital Egypt.\u003c/p\u003e\n\u003cp\u003ewe confirm that all experiments on humans and/or the use of human tissue samples were performed according to relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, concerning intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe understand that the Corresponding Author is the sole contact for the Editorial process (including the Editorial Manager and direct communications with the office). She is responsible for communicating with the other authors about progress, submissions of revisions, and final approval of proofs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe confirm that we have provided a current, correct email address accessible by the Corresponding Author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors agree to make the raw data and materials described in our manuscript freely available to any scientist wishing to use them for non-commercial purposes, as long as this does not breach participant confidentiality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eAll authors have approved that there are no known conflicts of interest associated with this publication\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003ethere has been no significant financial support for this work that could have influenced its outcome.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgments\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI gratefully acknowledge my colleagues in the acute myeloid leukemia study team and my patients at Children Cancer Hospital Egypt (CCHE)\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDe Albuquerque-Antunes A, Monteiro-Breviglieri CN, Martins-Celeste D, et al. Prevalence and outcomes of thrombotic and hemorrhagic complications in pediatric acute promyelocytic leukemia in a tertiary Brazilian center. Hematol Transfus Cell Ther. 2021;43(3):309\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePardo-Gonzalez CA, Lagos-Ibarra CA, Ballesteros-Linares JJ. Results of the implementation of the PETHEMA LPA 99 for treating children with acute promyelocytic leukemia in Bogot\u0026aacute;, Colombia. Rev Fac Med. 2021;69(2):e202.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTesti AM, Pession A, Diverio D et al. Risk-adapted treatment of acute promyelocytic leukemia: results from the International Consortium for Childhood APL. 2018;132(4):405\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatthew A, Kutny MD, Todd A, Alonzo, PhD2, Oussama Abla MD, et al. Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia. A Report From the Children\u0026rsquo;s Oncology Group AAML1331 Trial. JAMA Oncol. 2022;8(1):79\u0026ndash;87. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamaoncol.2021.5206\u003c/span\u003e\u003cspan address=\"10.1001/jamaoncol.2021.5206\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. (Supplemental Content 1 \u0026ndash; Trial Protocol).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTesti AM, Biondi A, Lo Coco F, et al. GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood. 2005;106:447\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLehmann S. Early death in APL.71\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheson BD, et al. Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. 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Blood. 2019;133(15):1630\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrancianne G, Andrade SVM, Feliciano I, Sardou-Cezar et al. Pediatric Acute Promyelocytic Leukemia: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome. Fonc 2021. 642744.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCreutzig U, Zimmermann M, Reinhardt D, Rasche M, von Neuhoff C, Alpermann T, Dworzak M, Perglerov\u0026aacute; K, Zemanova Z, Tchinda J, et al. Changes in cytogenetics and molecular genetics in acute myeloid leukemia from childhood to adult age groups. 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Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. blood-2008-07-168617. Epub 2008 Oct 22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarinder, Gill, et al. Characteristics and predictors of early hospital deaths in newly diagnosed APL: a 13-year population-wide study. Blood adv. 2021;5(14):2829\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUgo, Testa. Francesco Lo-Coco. Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients. Annals Hematol April. 2016. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00277-016-2622-1\u003c/span\u003e\u003cspan address=\"10.1007/s00277-016-2622-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 6 are available in the Supplementary Files section.\u003c/p\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":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"acute myeloid leukemia; acute promyelocytic leukemia; translocation (15, 17); all-trans retinoic acid; differentiation syndrome","lastPublishedDoi":"10.21203/rs.3.rs-3963955/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3963955/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground:\u003cstrong\u003e \u003c/strong\u003ePaediatric acute promyelocytic leukemia (APL) accounts for 5% to 15% of all myelocytic leukemia. A retrospective study of pediatric patients diagnosed and treated with APL was done from July 2012 till the end of December 2019 at CCHE, aimed to, report the prevalence, clinical features, outcomes, and risk factors causing induction failure and early deaths.\u003c/p\u003e\n\u003cp\u003eResult: Sixty-two patients were reported, age above 10, initial unsatisfactory coagulation profile, and total leukocyte count above 30 10\u003csup\u003e3\u003c/sup\u003e/mm affecting the 5 years (5y) overall (OS) and event-free survival (EFS), high promyelocyte count affecting the 5y EFS. Patients received protocol adopted from COG AAML1331 protocol. Prognostic factors causing early deaths during induction are high-risk patients with initial TLC \u0026gt;10x10\u003csup\u003e3\u003c/sup\u003e/mm and initial promyelocytic count above 30% with significant P-value. In the female gender, wild FLT3 increases the occurrence of differentiation syndrome (DS). Receiving steroids with all-trans retinoic acid (ATRA) in induction may minimize the frequency of DS. Relapse affecting the outcome, Bone marrow transplantation was done for 4 patients of the relapsed patients, with 5y OS 37%, with no significance. In the current study, forty-five patients are alive in complete remission with 5y OS of 72.5%, with 5y EFS of 69.4%, respectively.\u003c/p\u003e\n\u003cp\u003eConclusion: pediatric APL outcome is affected by age above 10, initial unsatisfactory coagulation profile and promyelocyte count above 10%. Early death is affected by an initial leukocyte count above 10 x10\u003csup\u003e3\u003c/sup\u003e/mm and, an initial promyelocytic count above 30%. Receiving steroids with ATRA may minimize the frequency of DS.\u003c/p\u003e","manuscriptTitle":"Acute Promyelocytic Leukemia in Children Cancer Hospital Egypt","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-22 07:48:32","doi":"10.21203/rs.3.rs-3963955/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-23T05:43:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-19T21:06:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-15T12:05:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-15T11:55:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"d6ea1122-3559-4f00-97ed-efc9844614bf","date":"2024-04-12T07:37:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6b3c4eb0-8858-4308-a5b2-e5694fb7f671","date":"2024-04-09T07:46:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6f1857bf-6a67-4b79-8e8c-6a59a0bedcb9","date":"2024-04-08T17:40:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"f5fed39d-ae02-4ddd-bd5f-15e41d6079aa","date":"2024-04-08T05:26:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-25T01:51:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-20T10:15:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-20T10:13:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Oncology","date":"2024-02-17T11:37:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"210a01cf-2907-4d14-b660-7f1ef94b9f69","owner":[],"postedDate":"March 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-06-21T14:52:43+00:00","versionOfRecord":{"articleIdentity":"rs-3963955","link":"https://doi.org/10.1007/s12672-024-01037-6","journal":{"identity":"discover-oncology","isVorOnly":false,"title":"Discover Oncology"},"publishedOn":"2024-06-11 14:52:43","publishedOnDateReadable":"June 11th, 2024"},"versionCreatedAt":"2024-03-22 07:48:32","video":"","vorDoi":"10.1007/s12672-024-01037-6","vorDoiUrl":"https://doi.org/10.1007/s12672-024-01037-6","workflowStages":[]},"version":"v1","identity":"rs-3963955","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3963955","identity":"rs-3963955","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}