Clinical Profile and Treatment Outcomes in Paediatric and Adult Acute Promyelocytic Leukemia: Experience from a Tertiary Care Centre in Northern India

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However, early mortality due to hemorrhage, differentiation syndrome (DS), and infections remains a significant challenge, particularly in resource-limited settings. There is a paucity of real-world data from India, where delayed diagnosis and high infection rates may impact outcomes. Methods: This retrospective cohort study included APL patients diagnosed at SGPGIMS, Lucknow, between July 2014 and June 2024. Diagnosis was confirmed via morphology, flow cytometry, and RT-PCR. Patients received risk-adapted induction therapy with ATRA and ATO ± anthracycline. Kaplan-Meier and multivariate Cox regression analyses were performed. Results: Of 102 patients (median age 33 years; 17.6% pediatric), 47% were high-risk. Fever and mucocutaneous bleeding were common presentations; 18.6% had life-threatening hemorrhages, mainly intracranial. Median diagnosis delay was 18 days. DS occurred in 56% of adults and 33% of pediatric patients. Pseudotumor cerebri and hepatotoxicity occurred in 7.8% and 37.6%, respectively. CR was achieved in 76.4% (87% low-risk vs. 64.6% high-risk). Induction mortality (24.5%) was mainly due to bleeding and infections. At a median follow-up of 28 months, 2-year OS was 75.9% (low-risk: 90.4%; high-risk: 65.9%), and DFS was 94.9%. High-risk status, age >50 with comorbidities, low hemoglobin, and poor performance status independently predicted mortality. Conclusions: Early mortality in APL remains high due to delayed diagnosis and bleeding complications. Region-specific challenges necessitate timely intervention and tailored supportive care to improve outcomes in Indian APL patients, especially in pediatric and high-risk groups. Leukemia Promyelocytic Arsenic trioxide anthracyclines tretinoin Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Acute promyelocytic leukemia (APL) is a distinct and rare subtype of acute myeloid leukemia, accounting for approximately 7–8% of all AML cases. 1 Historically, APL was highly lethal, but the introduction of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed it into one of the most curable hematological malignancies. The 2-year disease-free survival rates in APL is now reported at 90-97%. 2 Despite the major milestones achieved in the management of APL, early death in APL is still significant enough to impact the treatment outcomes. While death during the induction phase from causes like catastrophic haemorrhage, differentiation syndrome (DS) and infection poses a significant challenge in early treatment, resistance to therapy is an uncommon cause of induction failure. 3–5 While western literature shows outstanding outcomes in APL patients, there is a paucity of real-world data from the developing countries on management strategies, complications and outcomes, particularly from India. A majority of Indian population reside in rural areas with a very high infection rate and limited healthcare access leading to poorer induction outcomes. Given the risk of early death due to fatal bleeding, APL is considered a hematologic emergency requiring rapid diagnosis and prompt treatment initiation at the slightest suspicion, often before confirmatory cytogenetic or molecular results are available. 6 To address the knowledge gap in the Indian context, we conducted a retrospective study on the clinical characteristics, complications and induction outcomes, including mortality and morbidity in order to delineate the challenges faced in curing APL at our tertiary care centre. Aims and Objectives: To study the clinical profile, complications and induction outcomes in paediatric and adult APL patients. To assess the overall survival and disease-free survival in these patients. To assess the risk factors associated with adverse induction outcomes. Materials and Methods This was a single-center, retrospective cohort study conducted at SGPGIMS, Lucknow, enrolling all consecutively diagnosed APL cases between July 2014 and June 2024. The study protocol was approved by the institutional ethics committee and written informed consent was obtained from all patients/ their legal guardians. A presumptive diagnosis of APL was made based on morphology - presence of abnormal promyelocytes in peripheral blood (PB) or bone marrow (BM) and strong MPO positivity on cytochemical staining. Flow cytometry was done in selected suspicious cases. Abnormal promyelocytes were identified by their high forward scatter and side scatter in hypergranular type, absent expression of CD34 and HLA-DR, positivity for cytoplasmic MPO, CD13, CD33, CD117. In microgranular type, abnormal promyelocytes exhibited low side scatter and were located in the blast gate on the CD45 versus side scatter plot, phenotype similar to that of hypergranular APL. RT-PCR for PML-RARα fusion gene detection and transcript typing confirmed the diagnosis. Rq-PCR was used for quantitation of PML-RARα transcripts, while fragment analysis to detect FLT3-ITD mutation in APL patients. Cases negative for PML-RARα fusion gene on RT-PCR were subjected to flow cytometry and molecular studies to confirm a diagnosis of non-promyelocytic AML. Cases diagnosed elsewhere were reviewed and confirmed at our centre. The following information was collected for each patient using a standardised data collection form: Demographics, clinical presentation, baseline laboratory parameters including complete blood count, PB and BM morphological findings, coagulation profile, serum lactate dehydrogenase (LDH), liver function test, renal function test, serum procalcitonin and blood culture reports, molecular findings (PML-RARA transcript type, FLT3-ITD), treatment details, complications and outcomes. Missing data were explicitly noted and excluded from relevant analyses. Patients were stratified as low- and high-risk groups as per NCCN guidelines. Low risk patients received ATRA + ATO induction; high risk patients received ATRA + ATO + Anthracycline (APL0406 protocol). Pediatric patients ( 18 years of age) received 45 mg/m 2 in 2 divided doses. ATO was dosed at 0.15mg/kg in all patients. Idarubicin was the preferred anthracycline used during induction at a dose of 12 mg/m 2 (age 1–60 years), 9 mg/m 2 (age 61–70 years) and 6 mg/m 2 (age > 70 years). If idarubicin was not available, daunorubicin was used at an equivalent dose. Appropriate transfusion thresholds included: platelet count < 30 × 10 9 /L, haemoglobin < 8 g/dL, fibrinogen level was < 150 mg/dL. Fresh frozen plasma was administered if prothrombin time and activated partial thromboplastin time were 1.5 times of their respective upper limits of normal. Neutropenic patients received empiric broad-spectrum antibiotics as per the hospital’s protocol. Overall survival (OS) was defined from the date of initial diagnosis to the date of death or last follow up. Disease free survival (DFS) was defined from the date of first documented remission (CR) to date of first relapse, death or date of last follow up. Data were analysed using the SPSS software version 26. Categorical variables were compared using chi-square or Fisher’s exact test. Survival curves were generated using Kaplan-Meier analysis; differences assessed by log-rank test. Multivariate Cox regression identified independent predictors of adverse outcomes. Missing data were handled by case-wise exclusion. Results Of 116 suspected APL cases, 11 were excluded (non-promyelocytic AML) and 5 patients died before any confirmatory testing. Thus, a total of 102 patients were analyzed in the study. The median age at diagnosis was 33 years (IQR 23.5 - 45). There were 62 (60.7%) males. Of the 102 patients, 18 (17.64%) were children. The baseline demographic and clinical characteristics of our study cohort have been summarised in Table 1. The most common comorbidities were diabetes (n=19, 18.6%) and hypertension (n=14, 13.7%) followed by hypothyroidism (n=5, 5%). One patient was diagnosed with low-risk APL during 2 nd trimester of pregnancy. Two patients had rheumatoid arthritis and were on DMARDs. Two patients were incidentally detected to be HBsAg positive. The most common clinical presentation was fever (n=54, 52.9%) followed by mucocutaneous non-life-threatening bleeds (n=40, 39%). Four patients presented with bilateral vitreous hemorrhage. Life threatening bleeds were reported in 19 patients (18.6%) most of which belonged to the high-risk category (n=15, 31%)- commonly encountered were intracranial bleeds (n=10, 10%) followed by major GI bleeds (n=2, 2%). Two patients developed diffuse alveolar haemorrhage while on induction therapy. Two patients presented with unilateral massive pleural effusions which were reported as malignant exudates on cytological examination. The laboratory parameters at presentation in our study cohort are summarised in Table 2. Missing data acknowledged- FLT3-ITD status available in 21.6% (22/102 cases); end of induction bone marrow cellularity missing in 40.2%. On multivariate analysis, it was found that high risk APL group had a significant correlation with the BCR-3 transcript of PML-RARA on RTPCR (p=0.03) and FLT3-ITD positivity (p=0.021). Details of induction therapy regimens administered in our APL cohort and complications reported during induction are shown in Table 3. TLC: Total leucocyte count; LDH: Lactate dehydrogenase; PB: Peripheral blood; BCR: Breakpoint cluster region; FLT3-ITD: FMS-like tyrosine kinase internal tandem duplication. Median time duration from onset of first symptom to confirmatory diagnosis was 18 days (IQR 9-31); from provisional diagnosis to initiation of ATRA was 2 days (IQR 0-4). Median time to differentiation was 13 days (IQR 9-18 days). Median duration between initiation of therapy and CR1 was 38 days. Median duration of administration of ATRA and ATO during induction were 33 days and 25 days respectively. Hydroxyurea was used for cytoreduction in 83% (40/48) high-risk patients. The incidence of infection at presentation was significantly higher in high-risk in comparison to low-risk groups (62.1% vs 35.1%, p=0.03). Most inductions were complicated by bacterial sepsis and fungal pneumonias. On multivariate analysis, development of infection during induction was a significant predictor of death or relapse (p=0.02, HR:0.3; 95% CI 0.12-0.84). The most frequent clinical manifestations of severe DS were dyspnea (95%), pulmonary infiltrates (81%), unexplained fever (60%), weight gain >5 kg (56%), pleural effusion (22%), and renal failure (16%). The frequencies of these symptoms were considerably lower in moderate than in severe DS. DS occurred at a median of 11 days after starting ATRA treatment (range 4-26 days). Severe DS occurred comparatively early, at a median of 8 days, while moderate DS appeared after a median of 15 days. A bimodal time distribution of the peak incidence of DS was observed in severe DS, the first peak occurring during the first week of ATRA treatment in 9% of patients, and the second peak in the third week (2%). Most common therapy related adverse events reported were headache followed by transaminitis. 7.8% patients developed pseudotumor cerebri. All of them were treated with acetazolamide, 4 patients' symptoms persisted despite acetazolamide and the dose of ATRA was lowered to 25 mg/m 2 . Eight patients developed thrombosis, 3 had cortical sinus thrombosis at presentation and 3 patients developed central line related thrombosis during therapy. One patient who developed bowel gangrene secondary to superior mesenteric artery thrombosis during induction, underwent bowel resection and colostomy. One patient had a left MCA infarct at presentation. Incidence of thrombotic complications were higher in patients infected with Covid-19. Approximately, 37.6% patients developed hepatotoxicity of which 3 had an underlying chronic liver disease. Baseline characteristics and complications reported in pediatric subset (n=18) Median age was 13 years and 8/18 (44%) were males. 9/18 (50%) were in the high-risk group. Two patients presented with an intracranial bleed, 1 patient with a massive upper GI bleed and 1 patient with a lower GI bleed from ileal ulcer. One patient had a diffuse alveolar haemorrhage. 8/18 (44%) patients had an ECOG >2 at presentation. None had comorbidities. 8/18 patients had baseline infections. 6/18 (33%) had DS during induction. One patient had severe DS who eventually succumbed. Most common treatment toxicity was transaminitis followed by febrile neutropenia . 2 patients developed pseudo-tumour cerebri . Treatment outcomes in patients post induction chemotherapy are shown in Table 4. 76.4% patients attained complete remission after induction. 7 patients died from infection, 16 from bleeding and 1 from severe DS. At a median follow up of 28 months, 4 high-risk patients and 1 low-risk patient had relapsed. They received reinduction with ATRA, ATO and anthracycline; one succumbed to pancreatitis during induction, the others attained CR2 and are on maintenance therapy. One patient had a CNS and molecular relapse who underwent cranial radiotherapy followed by autologous HSCT and is currently in remission post maintenance therapy. In the pediatric subset, two patients succumbed due to intracranial bleed and 2 died as a result of massive gastro-intestinal bleed with sepsis; one patient succumbed to severe DS. Survival estimates The 2-year OS in our study cohort was 75.9%. Patients in low-risk group had a better 2-year OS (90.4% vs 65.9%, p=0.002) as compared to patients in the high-risk group. The 2-year DFS was 94.9%. Patients in the low-risk group had a better 2-year DFS (91.8% vs 78.6%, p=0.042) as compared to patients in the high-risk group. Kaplan–Meier estimates of OS and DFS in the APL cohort and in patients with low- vs high risk APL are depicted in Figures 1 and 2. Patients in low-risk group had a better 2-year OS (100% vs 50%, p=0.105) as compared to patients in the high-risk group in the paediatric population. Kaplan–Meier estimates of OS in the pediatric subset with low- vs high risk APL is depicted in Figure 3. Kaplan Meier plots comparing OS and DFS in different BCR transcripts of PML-RARA are depicted in figure 4. The 2 Year OS was 78.3% (BCR-1) v/s 67.9 % (BCR-3) (p= 0.36). Similarly, 2 Year DFS was 90.5 % (BCR-1) v/s 86.5 %(BCR-3) (p= 0.759). On multivariate analysis,it was found that presence of comorbidities in elderly patients >50 years, a lower hemoglobin at presentation (2) independently predicted higher induction mortality. Other parameters such as gender, age, platelet count, plasma fibrinogen level, d-dimer, serum LDH levels, PML-RARA transcript type and FLT3-ITD mutational status did not show any predictive significance. The causes of mortality in low- and high-risk APL patients in our study cohort have been summarised in Table 5. Majority of the deaths occurred due to a major life-threatening bleed. most common being an intracranial bleed- 3 patients in high-risk group presented with a spontaneous subdural hematoma and 5 patients with intra-parenchymal bleed. 60% (6/10) IC bleeds occurred at presentation or within 7 days of admission. One patient amongst the low-risk group died due to disease progression. He was unresponsive to initial induction therapy and was refractory to anthracycline. One patient in the high-risk group died in 1 st relapse due to chemotherapy refractory disease. Discussion APL which was previously considered as one of the most fatal subtypes of AML due to the bleeding diathesis has now become the most curable form of AML. 7 This retrospective study elucidates the clinical presentation and provides critical insights into the management and outcomes of APL in a resource-constrained tertiary care setting in Northern India. The lower survival rates in our cohort reflect the unique challenges of delivering complex hematologic care in a region with high baseline infection rates, delayed presentations, and limited access to rapid molecular diagnostics. We contextualize our findings within the global APL literature while highlighting region-specific barriers. The demographic profile of our cohort- median age 33 years and male predominance - aligns with Indian epidemiologic data. 8 – 10 But this is much lower than that in the Western populations, where APL peaks at around 45 years. 11 Notably, 17.6% of patients were pediatric, a higher proportion than the 5–10% reported in European studies, possibly reflecting India’s younger population structure. 12 The proportion of high-risk patients in our study was 47%, which is much higher than that reported by other studies. 8 – 10 The difference may stem from delayed diagnosis, as evidenced by a median 18-day lag between symptom onset and diagnosis, possibly due to financial constrains or a difficult access to healthcare facilities. High-risk patients exhibited distinct biologic features- a higher prevalence of BCR-3 transcripts and FLT3-ITD mutations. A number of clinical trials have shown a CR rate of 90–95% of patients with APL receiving ATRA + anthracycline. 7,13,14 The CR rate in our study, 76.4% (87% low-risk vs. 64.6% high-risk) was comparatively lower than others who reported a higher CR rate. 8 – 10 , 15 In multicentre clinical trials, the CR rates are close to 90%. 2,16 While low-risk children achieved 100% CR, high-risk pediatric mortality reached 55.5%, highlighting the vulnerability of this subgroup. The median time to CR is 38 days which is similar to other studies. 10 , 17 Despite the advancements, induction failure due to early induction deaths remain a major challenge especially in developing countries. The mortality reported during induction was 23.5% which was slightly higher in comparison to other studies. 8 – 10 The common causes of induction deaths include haemorrhage, infection and DS. 17 Majority of deaths in our study occurred due to a major hemorrhage unlike other studies where infection was the leading cause. 8 , 9 This probably is a reflection of a higher proportion of high-risk patients in our study due to delay in seeking treatment and the need for more intensive support during induction to prevent deaths due to hemorrhage. Life-threatening hemorrhages occurred in 18.6% of patients, with intracranial bleeds (10%) being the most common. This exceeds the 5–10% incidence in contemporary series, likely due to prolonged coagulopathy before ATRA initiation (median 2-day delay post-diagnosis). 18 Pediatric patients faced particularly severe bleeding complications: 27.7% mortality, primarily from intracranial/GI hemorrhages. This contrasts with Western pediatric cohorts, where early death rates are < 10%. 19 48.1% presented with active infections (62.1% in high-risk), far higher than the 15–20% in European studies. 20 Gram-negative sepsis (67%) dominated, reflecting endemic antimicrobial resistance patterns. Infections correlated with prolonged hospitalization and higher induction mortality. 36.2% developed neutropenic sepsis. Fungal infections (10.8%)-mostly pulmonary aspergillosis-were linked to prolonged neutropenia (median 28 days). The incidence of DS reported in our study (40.2%) was higher in comparison to that reported in clinical trials (PETHEMA LPA96 and LPA99). 21 The GIMEMA group which used the AIDA regimen, reported a lower incidence of DS of 2.5% (6 of 240 patients). 22 Bimodal peaks of DS occurrence in our cohort (days 4–7 and 21–26) suggest dual mechanisms: early cytokine release and late ATRA-mediated differentiation. Dexamethasone resolved 78% of cases, but 22% required ATRA interruption. No mortality was directly attributed to DS in our study cohort. On multivariate analysis, previously reported prognostic factors for severe DS, such as high TLC at presentation, abnormal serum creatinine, FLT3-ITD mutations, BCR-3 variant and male sex were not significant in our study. 21 Key contributors of high induction mortality rate in our cohort include: (1) delayed ATRA initiation: median 2-day delay vs. <24 hours in high-income settings, (2) transfusion limitations: despite protocol-guided transfusions, 34% of patients received suboptimal platelet/cryoprecipitate support due to shortages, (3) antimicrobial resistance: 48% of bacterial isolates were carbapenem-resistant, complicating sepsis management. 7.8% experienced thrombotic events, including cerebral venous sinus thrombosis (3.9%). This paradox of APL-balancing hemorrhage and thrombosis-requires vigilant monitoring, especially with concurrent infections like COVID-19. Our study showed a higher incidence of pseudo-tumor cerebri compared to the 1.7% reported in another study. 23 Hepatotoxicity during induction therapy occurred in 37.6% of cases in our study, lower than reported in another study. 24 Multivariate analysis performed in our study showed that elderly patients with comorbidities, Hb 2) had a higher induction mortality. There was also a significant correlation between high-risk group and FLT3-ITD positivity as well as presence of BCR-3 transcript of PML-RARA. Other factors like male sex, raised serum creatinine and serum fibrinogen levels, BCR-3 transcript which showed higher induction mortality in other studies did not show a significant correlation in our study. 4 , 25 The 2-year OS in patients expressing BCR-3 transcript was lower in comparison to other BCR transcripts as reported in another study. 26 The 4.9% relapse rate aligns with modern outcomes, but all relapses occurred in high-risk patients. 27 Notably, one case involved isolated CNS relapse-a rarity in the ATRA/ATO era-emphasizing the need for CNS prophylaxis in high-risk subsets. This study presents valuable real-world data from one of the largest APL cohorts in South Asia, offering insights into treatment challenges often not captured in controlled clinical trials. A notable strength is its focus on pediatric patients, providing rare and important data on APL outcomes in Indian children—a group frequently underrepresented in existing literature. The study also employs comprehensive risk stratification, incorporating molecular markers such as FLT3-ITD and BCR-3 expression, thereby extending beyond conventional Sanz risk scores. However, the retrospective design introduces limitations, including missing data, restricting the scope of multivariate analyses. Additionally, treatment heterogeneity, particularly in anthracycline use based on drug availability, may have introduced confounding variables that affect outcome comparisons. Conclusion While APL is highly curable, this study highlights persistent challenges in resource-limited settings, including higher rates of DS, infections, hepatotoxicity, and early death—particularly among high-risk and pediatric patients. ATRA, ATO and anthracycline combination is the preferred protocol for treating high-risk patients. Incorporating molecular risk markers, optimizing blood transfusions and supportive care during induction therapy, and adapting treatment protocols to local realities are critical steps toward improving outcomes. To close the survival gap with high-income countries, strategic protocol modifications, system-level interventions, and focused research are urgently needed. Declarations Conflict of Interest: No conflict of interest to disclose. Funding: No external funding. Ethics: Ethical clearence has been taken as per the Institutional ethics policy. Data availability statement: Data cannot be shared openly but are available on request from authors. Author Contribution HM framed the study design and wrote the original manuscript.NG helped framing tables and figures and edited the manuscript.SY ,RK, RG and KR reviewed and edited the manuscript. DC, MS and MV reviewed the manuscript. References Stanley M, McKenna RW, Ellinger G, Brunning RD. 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Supplementary Files Tables.docx Cite Share Download PDF Status: Published Journal Publication published 07 Oct, 2025 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 26 Jun, 2025 Reviews received at journal 18 Jun, 2025 Reviews received at journal 15 Jun, 2025 Reviewers agreed at journal 09 Jun, 2025 Reviewers agreed at journal 09 Jun, 2025 Reviewers invited by journal 06 Jun, 2025 Editor assigned by journal 03 Jun, 2025 Submission checks completed at journal 03 Jun, 2025 First submitted to journal 01 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6794583","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":467542122,"identity":"1b93230c-7593-4811-a1b8-275b6865a668","order_by":0,"name":"Harshal Mamlekar","email":"data:image/png;base64,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","orcid":"","institution":"Sanjay Gandhi Post Graduate Institute of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Harshal","middleName":"","lastName":"Mamlekar","suffix":""},{"id":467542123,"identity":"342010ed-7b22-4752-943e-5eda659579a0","order_by":1,"name":"Nandhini Gangadaran","email":"","orcid":"","institution":"Sanjay Gandhi Post Graduate Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nandhini","middleName":"","lastName":"Gangadaran","suffix":""},{"id":467542125,"identity":"e8f49dec-b4cf-4dba-b2df-63dd9743e7ce","order_by":2,"name":"Sanjeev Yadav","email":"","orcid":"","institution":"Sanjay Gandhi Post Graduate Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Sanjeev","middleName":"","lastName":"Yadav","suffix":""},{"id":467542126,"identity":"a9f99114-048f-44b2-ac32-78f1a44d70e6","order_by":3,"name":"Rajesh Kashyap","email":"","orcid":"","institution":"Sanjay Gandhi Post Graduate Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Rajesh","middleName":"","lastName":"Kashyap","suffix":""},{"id":467542128,"identity":"09ba27fe-5158-4f48-a8b0-6cc8bd07b208","order_by":4,"name":"Khaliqur Rahman","email":"","orcid":"","institution":"Sanjay Gandhi Post Graduate Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Khaliqur","middleName":"","lastName":"Rahman","suffix":""},{"id":467542130,"identity":"37473e03-1100-46e1-9608-717852124c48","order_by":5,"name":"Ruchi Gupta","email":"","orcid":"","institution":"Sanjay Gandhi Post Graduate Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ruchi","middleName":"","lastName":"Gupta","suffix":""},{"id":467542132,"identity":"39cbd480-9c7e-4ce5-bb87-d42c3d6d23fb","order_by":6,"name":"Manish Singh","email":"","orcid":"","institution":"Sanjay Gandhi Post Graduate Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Manish","middleName":"","lastName":"Singh","suffix":""},{"id":467542133,"identity":"20807cff-a14a-4aa0-8ae0-43618df487cf","order_by":7,"name":"Dinesh Chandra","email":"","orcid":"","institution":"Sanjay Gandhi Post Graduate Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Dinesh","middleName":"","lastName":"Chandra","suffix":""},{"id":467542134,"identity":"6df0f745-8230-4e5a-8133-5d636413d482","order_by":8,"name":"Mona Vijayaran","email":"","orcid":"","institution":"Sanjay Gandhi Post Graduate Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mona","middleName":"","lastName":"Vijayaran","suffix":""}],"badges":[],"createdAt":"2025-06-01 08:23:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6794583/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6794583/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-025-06646-x","type":"published","date":"2025-10-07T15:56:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84340808,"identity":"5f57d0b4-a449-4491-9f0e-9f933cf12f13","added_by":"auto","created_at":"2025-06-10 18:26:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":96486,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA) Kaplan–Meier plot demonstrating overall survival (OS) in the APL study cohort (n = 102), B) Kaplan–Meier analysis of OS in low-risk versus high-risk patients with APL (low risk, n = 54; high risk, n = 48).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6794583/v1/dfbcb4c60dffb319abc26f9a.jpg"},{"id":84341359,"identity":"2ac3279a-e73f-4913-8c0b-bd30aed8c943","added_by":"auto","created_at":"2025-06-10 18:34:46","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":111043,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA) Kaplan–Meier plot showing disease-free survival (DFS) among patients with APL who achieved complete remission (CR) (n = 78), B) Kaplan–Meier analysis of DFS stratified in low-risk versus high-risk patients with APL who achieved CR post-induction.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6794583/v1/ef55c7defd5909f48b01ed0d.jpg"},{"id":84341361,"identity":"2b45ac5e-0f95-4396-8353-cf4a5246e751","added_by":"auto","created_at":"2025-06-10 18:34:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":59372,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier plot demonstrating OS of low-risk versus high-risk patients in the pediatric subset of our study cohort with APL\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6794583/v1/d731d6959419307e5122992a.jpg"},{"id":84341366,"identity":"5c7ef8f3-a8ce-42b9-adef-d7253ca95e51","added_by":"auto","created_at":"2025-06-10 18:34:46","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":115442,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA) Kaplan–Meier plot comparing OS of patients with different BCR transcripts of PML-RARA, B) Kaplan–Meier plot comparing OS of patients with different BCR transcripts of PML-RARA\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6794583/v1/fb860dd68054a1b7269a36ee.jpg"},{"id":93419452,"identity":"3b995c46-9acf-46dd-852c-605b73c3103e","added_by":"auto","created_at":"2025-10-13 16:00:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1170835,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6794583/v1/6944ce91-bbf3-4e6e-9a4c-5ee5e75f1e4b.pdf"},{"id":84340809,"identity":"703d899e-bfe6-4fa5-9b72-08538bd6902e","added_by":"auto","created_at":"2025-06-10 18:26:45","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24611,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6794583/v1/c1d5c1f2f9dbd01ce0eedf47.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eClinical Profile and Treatment Outcomes in Paediatric and Adult Acute Promyelocytic Leukemia: Experience from a Tertiary Care Centre in Northern India\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute promyelocytic leukemia (APL) is a distinct and rare subtype of acute myeloid leukemia, accounting for approximately 7–8% of all AML cases.\u003csup\u003e1\u003c/sup\u003e Historically, APL was highly lethal, but the introduction of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed it into one of the most curable hematological malignancies. The 2-year disease-free survival rates in APL is now reported at 90-97%.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eDespite the major milestones achieved in the management of APL, early death in APL is still significant enough to impact the treatment outcomes. While death during the induction phase from causes like catastrophic haemorrhage, differentiation syndrome (DS) and infection poses a significant challenge in early treatment, resistance to therapy is an uncommon cause of induction failure.\u003csup\u003e3–5\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eWhile western literature shows outstanding outcomes in APL patients, there is a paucity of real-world data from the developing countries on management strategies, complications and outcomes, particularly from India. A majority of Indian population reside in rural areas with a very high infection rate and limited healthcare access leading to poorer induction outcomes. Given the risk of early death due to fatal bleeding, APL is considered a hematologic emergency requiring rapid diagnosis and prompt treatment initiation at the slightest suspicion, often before confirmatory cytogenetic or molecular results are available.\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eTo address the knowledge gap in the Indian context, we conducted a retrospective study on the clinical characteristics, complications and induction outcomes, including mortality and morbidity in order to delineate the challenges faced in curing APL at our tertiary care centre.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAims and Objectives:\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eTo study the clinical profile, complications and induction outcomes in paediatric and adult APL patients.\u003c/li\u003e\n\u003cli\u003eTo assess the overall survival and disease-free survival in these patients. \u003c/li\u003e\n\u003cli\u003eTo assess the risk factors associated with adverse induction outcomes.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis was a single-center, retrospective cohort study conducted at SGPGIMS, Lucknow, enrolling all consecutively diagnosed APL cases between July 2014 and June 2024. The study protocol was approved by the institutional ethics committee and written informed consent was obtained from all patients/ their legal guardians.\u003c/p\u003e \u003cp\u003eA presumptive diagnosis of APL was made based on morphology - presence of abnormal promyelocytes in peripheral blood (PB) or bone marrow (BM) and strong MPO positivity on cytochemical staining. Flow cytometry was done in selected suspicious cases. Abnormal promyelocytes were identified by their high forward scatter and side scatter in hypergranular type, absent expression of CD34 and HLA-DR, positivity for cytoplasmic MPO, CD13, CD33, CD117. In microgranular type, abnormal promyelocytes exhibited low side scatter and were located in the blast gate on the CD45 versus side scatter plot, phenotype similar to that of hypergranular APL. RT-PCR for PML-RARα fusion gene detection and transcript typing confirmed the diagnosis. Rq-PCR was used for quantitation of PML-RARα transcripts, while fragment analysis to detect FLT3-ITD mutation in APL patients. Cases negative for PML-RARα fusion gene on RT-PCR were subjected to flow cytometry and molecular studies to confirm a diagnosis of non-promyelocytic AML. Cases diagnosed elsewhere were reviewed and confirmed at our centre.\u003c/p\u003e \u003cp\u003eThe following information was collected for each patient using a standardised data collection form: Demographics, clinical presentation, baseline laboratory parameters including complete blood count, PB and BM morphological findings, coagulation profile, serum lactate dehydrogenase (LDH), liver function test, renal function test, serum procalcitonin and blood culture reports, molecular findings (PML-RARA transcript type, FLT3-ITD), treatment details, complications and outcomes. Missing data were explicitly noted and excluded from relevant analyses.\u003c/p\u003e \u003cp\u003ePatients were stratified as low- and high-risk groups as per NCCN guidelines. Low risk patients received ATRA\u0026thinsp;+\u0026thinsp;ATO induction; high risk patients received ATRA\u0026thinsp;+\u0026thinsp;ATO\u0026thinsp;+\u0026thinsp;Anthracycline (APL0406 protocol). Pediatric patients (\u0026lt;\u0026thinsp;18 years of age) received 25 mg/m\u003csup\u003e2\u003c/sup\u003e of ATRA in 2 divided doses, while adults (\u0026gt;\u0026thinsp;18 years of age) received 45 mg/m\u003csup\u003e2\u003c/sup\u003e in 2 divided doses. ATO was dosed at 0.15mg/kg in all patients. Idarubicin was the preferred anthracycline used during induction at a dose of 12 mg/m\u003csup\u003e2\u003c/sup\u003e (age 1\u0026ndash;60 years), 9 mg/m\u003csup\u003e2\u003c/sup\u003e (age 61\u0026ndash;70 years) and 6 mg/m\u003csup\u003e2\u003c/sup\u003e (age\u0026thinsp;\u0026gt;\u0026thinsp;70 years). If idarubicin was not available, daunorubicin was used at an equivalent dose. Appropriate transfusion thresholds included: platelet count\u0026thinsp;\u0026lt;\u0026thinsp;30 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, haemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;8 g/dL, fibrinogen level was \u0026lt;\u0026thinsp;150 mg/dL. Fresh frozen plasma was administered if prothrombin time and activated partial thromboplastin time were 1.5 times of their respective upper limits of normal. Neutropenic patients received empiric broad-spectrum antibiotics as per the hospital\u0026rsquo;s protocol.\u003c/p\u003e \u003cp\u003eOverall survival (OS) was defined from the date of initial diagnosis to the date of death or last follow up. Disease free survival (DFS) was defined from the date of first documented remission (CR) to date of first relapse, death or date of last follow up.\u003c/p\u003e \u003cp\u003eData were analysed using the SPSS software version 26. Categorical variables were compared using chi-square or Fisher\u0026rsquo;s exact test. Survival curves were generated using Kaplan-Meier analysis; differences assessed by log-rank test. Multivariate Cox regression identified independent predictors of adverse outcomes. Missing data were handled by case-wise exclusion.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOf 116 suspected APL cases, 11 were excluded (non-promyelocytic AML) and 5 patients died before any confirmatory testing. Thus, a total of 102 patients were analyzed in the study. The median age at diagnosis was 33 years (IQR 23.5 - 45). There were 62 (60.7%) males. Of the 102 patients, 18 (17.64%) were children. The baseline demographic and clinical characteristics of our study cohort have been summarised in Table 1.\u003c/p\u003e\n\u003cp\u003eThe most common comorbidities were diabetes (n=19, 18.6%) and hypertension (n=14, 13.7%) followed by hypothyroidism (n=5, 5%). One patient was diagnosed with low-risk APL during 2\u003csup\u003end\u003c/sup\u003e trimester of pregnancy. Two patients had rheumatoid arthritis and were on DMARDs. Two patients were incidentally detected to be HBsAg positive. The most common clinical presentation was fever (n=54, 52.9%) followed by mucocutaneous non-life-threatening bleeds (n=40, 39%). Four patients presented with bilateral vitreous hemorrhage. Life threatening bleeds were reported in 19 patients (18.6%) most of which belonged to the high-risk category (n=15, 31%)- commonly encountered were intracranial bleeds (n=10, 10%) followed by major GI bleeds (n=2, 2%). Two patients developed diffuse alveolar haemorrhage while on induction therapy. Two patients presented with unilateral massive pleural effusions which were reported as malignant exudates on cytological examination. \u003c/p\u003e\n\u003cp\u003eThe laboratory parameters at presentation in our study cohort are summarised in Table 2. \u003c/p\u003e\n\u003cp\u003eMissing data acknowledged- FLT3-ITD status available in 21.6% (22/102 cases); end of induction bone marrow cellularity missing in 40.2%. \u003c/p\u003e\n\u003cp\u003eOn multivariate analysis, it was found that high risk APL group had a significant correlation with the BCR-3 transcript of PML-RARA on RTPCR (p=0.03) and FLT3-ITD positivity (p=0.021). \u003c/p\u003e\n\u003cp\u003eDetails of induction therapy regimens administered in our APL cohort and complications reported during induction are shown in Table 3. \u003c/p\u003e\n\u003cp\u003eTLC: Total leucocyte count; LDH: Lactate dehydrogenase; PB: Peripheral blood; BCR: Breakpoint cluster region; FLT3-ITD: FMS-like tyrosine kinase internal tandem duplication. \u003c/p\u003e\n\u003cp\u003eMedian time duration from onset of first symptom to confirmatory diagnosis was 18 days (IQR 9-31); from provisional diagnosis to initiation of ATRA was 2 days (IQR 0-4). Median time to differentiation was 13 days (IQR 9-18 days). Median duration between initiation of therapy and CR1 was 38 days. Median duration of administration of ATRA and ATO during induction were 33 days and 25 days respectively. Hydroxyurea was used for cytoreduction in 83% (40/48) high-risk patients. \u003c/p\u003e\n\u003cp\u003eThe incidence of infection at presentation was significantly higher in high-risk in comparison to low-risk groups (62.1% vs 35.1%, p=0.03). Most inductions were complicated by bacterial sepsis and fungal pneumonias. On multivariate analysis, development of infection during induction was a significant predictor of death or relapse (p=0.02, HR:0.3; 95% CI 0.12-0.84). The most frequent clinical manifestations of severe DS were dyspnea (95%), pulmonary infiltrates (81%), unexplained fever (60%), weight gain \u0026gt;5 kg (56%), pleural effusion (22%), and renal failure (16%). The frequencies of these symptoms were considerably lower in moderate than in severe DS. DS occurred at a median of 11 days after starting ATRA treatment (range 4-26 days). Severe DS occurred comparatively early, at a median of 8 days, while moderate DS appeared after a median of 15 days. A bimodal time distribution of the peak incidence of DS was observed in severe DS, the first peak occurring during the first week of ATRA treatment in 9% of patients, and the second peak in the third week (2%). \u003c/p\u003e\n\u003cp\u003eMost common therapy related adverse events reported were headache followed by transaminitis. 7.8% patients developed pseudotumor cerebri. All of them were treated with acetazolamide, 4 patients\u0026apos; symptoms persisted despite acetazolamide and the dose of ATRA was lowered to 25 mg/m\u003csup\u003e2\u003c/sup\u003e. Eight patients developed thrombosis, 3 had cortical sinus thrombosis at presentation and 3 patients developed central line related thrombosis during therapy. One patient who developed bowel gangrene secondary to superior mesenteric artery thrombosis during induction, underwent bowel resection and colostomy. One patient had a left MCA infarct at presentation. Incidence of thrombotic complications were higher in patients infected with Covid-19. Approximately, 37.6% patients developed hepatotoxicity of which 3 had an underlying chronic liver disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline characteristics and complications reported in pediatric subset (n=18)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedian age was 13 years and 8/18 (44%) were males. 9/18 (50%) were in the high-risk group. Two patients presented with an intracranial bleed, 1 patient with a massive upper GI bleed and 1 patient with a lower GI bleed from ileal ulcer. One patient had a diffuse alveolar haemorrhage. 8/18 (44%) patients had an ECOG \u0026gt;2 at presentation. None had comorbidities. \u003c/p\u003e\n\u003cp\u003e8/18 patients had baseline infections. 6/18 (33%) had DS during induction. One patient had severe DS who eventually succumbed. Most common treatment toxicity was transaminitis followed by febrile neutropenia\u003cstrong\u003e. \u003c/strong\u003e2 patients developed pseudo-tumour cerebri\u003cstrong\u003e. \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTreatment outcomes in patients post induction chemotherapy are shown in Table 4.\u003c/p\u003e\n\u003cp\u003e76.4% patients attained complete remission after induction. 7 patients died from infection, 16 from bleeding and 1 from severe DS. At a median follow up of 28 months, 4 high-risk patients and 1 low-risk patient had relapsed. They received reinduction with ATRA, ATO and anthracycline; one succumbed to pancreatitis during induction, the others attained CR2 and are on maintenance therapy. One patient had a CNS and molecular relapse who underwent cranial radiotherapy followed by autologous HSCT and is currently in remission post maintenance therapy.\u003c/p\u003e\n\u003cp\u003eIn the pediatric subset, two patients succumbed due to intracranial bleed and 2 died as a result of massive gastro-intestinal bleed with sepsis; one patient succumbed to severe DS. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival estimates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 2-year OS in our study cohort was 75.9%. Patients in low-risk group had a better 2-year OS (90.4% vs 65.9%, p=0.002) as compared to patients in the high-risk group. The 2-year DFS was 94.9%. Patients in the low-risk group had a better 2-year DFS (91.8% vs 78.6%, p=0.042) as compared to patients in the high-risk group. Kaplan\u0026ndash;Meier estimates of OS and DFS in the APL cohort and in patients with low- vs high risk APL are depicted in Figures 1 and 2. \u003c/p\u003e\n\u003cp\u003ePatients in low-risk group had a better 2-year OS (100% vs 50%, p=0.105) as compared to patients in the high-risk group in the paediatric population. Kaplan\u0026ndash;Meier estimates of OS in the pediatric subset with low- vs high risk APL is depicted in Figure 3.\u003c/p\u003e\n\u003cp\u003eKaplan Meier plots comparing OS and DFS in different BCR transcripts of PML-RARA are depicted in figure 4.\u003c/p\u003e\n\u003cp\u003eThe 2 Year OS was 78.3% (BCR-1) v/s 67.9 % (BCR-3) (p= 0.36). Similarly, 2 Year DFS was 90.5 % (BCR-1) v/s 86.5 %(BCR-3) (p= 0.759).\u003c/p\u003e\n\u003cp\u003eOn multivariate analysis,it was found that presence of comorbidities in elderly patients \u0026gt;50 years, a lower hemoglobin at presentation (\u0026lt;8 g%), high-risk APL and poorer ECOG at presentation (\u0026gt;2) independently predicted higher induction mortality. Other parameters such as gender, age, platelet count, plasma fibrinogen level, d-dimer, serum LDH levels, PML-RARA transcript type and FLT3-ITD mutational status did not show any predictive significance.\u003c/p\u003e\n\u003cp\u003eThe causes of mortality in low- and high-risk APL patients in our study cohort have been summarised in Table 5. \u003c/p\u003e\n\u003cp\u003eMajority of the deaths occurred due to a major life-threatening bleed. most common being an intracranial bleed- 3 patients in high-risk group presented with a spontaneous subdural hematoma and 5 patients with intra-parenchymal bleed. 60% (6/10) IC bleeds occurred at presentation or within 7 days of admission. One patient amongst the low-risk group died due to disease progression. He was unresponsive to initial induction therapy and was refractory to anthracycline. One patient in the high-risk group died in 1\u003csup\u003est\u003c/sup\u003e relapse due to chemotherapy refractory disease. \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAPL which was previously considered as one of the most fatal subtypes of AML due to the bleeding diathesis has now become the most curable form of AML.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e This retrospective study elucidates the clinical presentation and provides critical insights into the management and outcomes of APL in a resource-constrained tertiary care setting in Northern India. The lower survival rates in our cohort reflect the unique challenges of delivering complex hematologic care in a region with high baseline infection rates, delayed presentations, and limited access to rapid molecular diagnostics. We contextualize our findings within the global APL literature while highlighting region-specific barriers.\u003c/p\u003e \u003cp\u003eThe demographic profile of our cohort- median age 33 years and male predominance - aligns with Indian epidemiologic data.\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e But this is much lower than that in the Western populations, where APL peaks at around 45 years.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Notably, 17.6% of patients were pediatric, a higher proportion than the 5\u0026ndash;10% reported in European studies, possibly reflecting India\u0026rsquo;s younger population structure.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe proportion of high-risk patients in our study was 47%, which is much higher than that reported by other studies.\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e The difference may stem from delayed diagnosis, as evidenced by a median 18-day lag between symptom onset and diagnosis, possibly due to financial constrains or a difficult access to healthcare facilities. High-risk patients exhibited distinct biologic features- a higher prevalence of \u003cem\u003eBCR-3\u003c/em\u003e transcripts and \u003cem\u003eFLT3-ITD\u003c/em\u003e mutations.\u003c/p\u003e \u003cp\u003eA number of clinical trials have shown a CR rate of 90\u0026ndash;95% of patients with APL receiving ATRA\u0026thinsp;+\u0026thinsp;anthracycline.\u003csup\u003e7,13,14\u003c/sup\u003e The CR rate in our study, 76.4% (87% low-risk vs. 64.6% high-risk) was comparatively lower than others who reported a higher CR rate.\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e In multicentre clinical trials, the CR rates are close to 90%.\u003csup\u003e2,16\u003c/sup\u003e While low-risk children achieved 100% CR, high-risk pediatric mortality reached 55.5%, highlighting the vulnerability of this subgroup. The median time to CR is 38 days which is similar to other studies.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDespite the advancements, induction failure due to early induction deaths remain a major challenge especially in developing countries. The mortality reported during induction was 23.5% which was slightly higher in comparison to other studies.\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e The common causes of induction deaths include haemorrhage, infection and DS.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Majority of deaths in our study occurred due to a major hemorrhage unlike other studies where infection was the leading cause.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e This probably is a reflection of a higher proportion of high-risk patients in our study due to delay in seeking treatment and the need for more intensive support during induction to prevent deaths due to hemorrhage.\u003c/p\u003e \u003cp\u003eLife-threatening hemorrhages occurred in 18.6% of patients, with intracranial bleeds (10%) being the most common. This exceeds the 5\u0026ndash;10% incidence in contemporary series, likely due to prolonged coagulopathy before ATRA initiation (median 2-day delay post-diagnosis).\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Pediatric patients faced particularly severe bleeding complications: 27.7% mortality, primarily from intracranial/GI hemorrhages. This contrasts with Western pediatric cohorts, where early death rates are \u0026lt;\u0026thinsp;10%.\u003csup\u003e19\u003c/sup\u003e 48.1% presented with active infections (62.1% in high-risk), far higher than the 15\u0026ndash;20% in European studies.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Gram-negative sepsis (67%) dominated, reflecting endemic antimicrobial resistance patterns. Infections correlated with prolonged hospitalization and higher induction mortality. 36.2% developed neutropenic sepsis. Fungal infections (10.8%)-mostly pulmonary aspergillosis-were linked to prolonged neutropenia (median 28 days).\u003c/p\u003e \u003cp\u003eThe incidence of DS reported in our study (40.2%) was higher in comparison to that reported in clinical trials (PETHEMA LPA96 and LPA99).\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e The GIMEMA group which used the AIDA regimen, reported a lower incidence of DS of 2.5% (6 of 240 patients).\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Bimodal peaks of DS occurrence in our cohort (days 4\u0026ndash;7 and 21\u0026ndash;26) suggest dual mechanisms: early cytokine release and late ATRA-mediated differentiation. Dexamethasone resolved 78% of cases, but 22% required ATRA interruption. No mortality was directly attributed to DS in our study cohort. On multivariate analysis, previously reported prognostic factors for severe DS, such as high TLC at presentation, abnormal serum creatinine, FLT3-ITD mutations, BCR-3 variant and male sex were not significant in our study.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eKey contributors of high induction mortality rate in our cohort include: (1) delayed ATRA initiation: median 2-day delay vs. \u0026lt;24 hours in high-income settings, (2) transfusion limitations: despite protocol-guided transfusions, 34% of patients received suboptimal platelet/cryoprecipitate support due to shortages, (3) antimicrobial resistance: 48% of bacterial isolates were carbapenem-resistant, complicating sepsis management.\u003c/p\u003e \u003cp\u003e7.8% experienced thrombotic events, including cerebral venous sinus thrombosis (3.9%). This paradox of APL-balancing hemorrhage and thrombosis-requires vigilant monitoring, especially with concurrent infections like COVID-19. Our study showed a higher incidence of pseudo-tumor cerebri compared to the 1.7% reported in another study.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Hepatotoxicity during induction therapy occurred in 37.6% of cases in our study, lower than reported in another study.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMultivariate analysis performed in our study showed that elderly patients with comorbidities, Hb\u0026thinsp;\u0026lt;\u0026thinsp;8g% at presentation, high-risk APL and poor performance status (ECOG status\u0026thinsp;\u0026gt;\u0026thinsp;2) had a higher induction mortality. There was also a significant correlation between high-risk group and FLT3-ITD positivity as well as presence of BCR-3 transcript of PML-RARA. Other factors like male sex, raised serum creatinine and serum fibrinogen levels, BCR-3 transcript which showed higher induction mortality in other studies did not show a significant correlation in our study.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e The 2-year OS in patients expressing BCR-3 transcript was lower in comparison to other BCR transcripts as reported in another study.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe 4.9% relapse rate aligns with modern outcomes, but all relapses occurred in high-risk patients.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Notably, one case involved isolated CNS relapse-a rarity in the ATRA/ATO era-emphasizing the need for CNS prophylaxis in high-risk subsets.\u003c/p\u003e \u003cp\u003eThis study presents valuable real-world data from one of the largest APL cohorts in South Asia, offering insights into treatment challenges often not captured in controlled clinical trials. A notable strength is its focus on pediatric patients, providing rare and important data on APL outcomes in Indian children\u0026mdash;a group frequently underrepresented in existing literature. The study also employs comprehensive risk stratification, incorporating molecular markers such as FLT3-ITD and BCR-3 expression, thereby extending beyond conventional Sanz risk scores. However, the retrospective design introduces limitations, including missing data, restricting the scope of multivariate analyses. Additionally, treatment heterogeneity, particularly in anthracycline use based on drug availability, may have introduced confounding variables that affect outcome comparisons.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWhile APL is highly curable, this study highlights persistent challenges in resource-limited settings, including higher rates of DS, infections, hepatotoxicity, and early death\u0026mdash;particularly among high-risk and pediatric patients. ATRA, ATO and anthracycline combination is the preferred protocol for treating high-risk patients. Incorporating molecular risk markers, optimizing blood transfusions and supportive care during induction therapy, and adapting treatment protocols to local realities are critical steps toward improving outcomes. To close the survival gap with high-income countries, strategic protocol modifications, system-level interventions, and focused research are urgently needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u003c/strong\u003e No conflict of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics:\u003c/strong\u003e Ethical clearence has been taken as per the Institutional ethics policy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e Data cannot be shared openly but are available on request from authors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eHM framed the study design and wrote the original manuscript.NG helped framing tables and figures and edited the manuscript.SY ,RK, RG and KR reviewed and edited the manuscript. DC, MS and MV reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eStanley M, McKenna RW, Ellinger G, Brunning RD. Classification of 358 Cases of Acute Myeloid Leukemia by FAB Criteria: Analysis of Clinical and Morphologic Features. In: Bloomfield CD, editor. Chronic and Acute Leukemias in Adults [Internet]. Boston, MA: Springer US; 1985 [cited 2025 May 3]. p. 147\u0026ndash;74. (McGuire WL, editor. Cancer Treatment and Research; vol. 26). Available from: http://link.springer.com/10.1007/978-1-4613-2581-9_5\u003c/li\u003e\n\u003cli\u003eLo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010;116:3171\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eTallman MS, Brenner B, Serna JDL, Dombret H, Falanga A, Kwaan HC, et al. Meeting report. Leukemia Research. 2005;29:347\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eDe La Serna J, Montesinos P, Vellenga E, Ray\u0026oacute;n C, Parody R, Le\u0026oacute;n A, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111:3395\u0026ndash;402. \u003c/li\u003e\n\u003cli\u003eHillestad LK. Acute promyelocytic leukemia. Acta Med Scand. 1957;159:189\u0026ndash;94. \u003c/li\u003e\n\u003cli\u003eKarim F, Shaikh U, Adil SN, Khurshid M. Clinical characteristics, outcome and early induction deaths in patients with acute promyelocytic leukaemia: a five-year experience at a tertiary care centre. Singapore Med J. 2014;55:443\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eWang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111:2505\u0026ndash;15. \u003c/li\u003e\n\u003cli\u003eBajpai J, Sharma A, Kumar L, Dabkara D, Raina V, Kochupillai V, et al. Acute promyelocytic leukemia: An experience from a tertiary care centre in north India. Indian J Cancer. 2011;48:316. \u003c/li\u003e\n\u003cli\u003eDayama A, Dass J, Seth T, Mahapatra M, Mishra P, Saxena R. Clinico-hematological profile and outcome of acute promyelocytic leukemia patients at a tertiary care center in North India. Indian J Cancer. 2015;52:309. \u003c/li\u003e\n\u003cli\u003eYedla RP, Bala SC, Pydi VR, Kuruva SP, Chennamaneni R, Konatam ML, et al. Outcomes in Adult Acute Promyelocytic Leukemia: A Decade Experience. Clinical Lymphoma Myeloma and Leukemia. 2020;20:e158\u0026ndash;64. \u003c/li\u003e\n\u003cli\u003eAd\u0026egrave;s L, Thomas X, Bresler AG, Raffoux E, Spertini O, Vey N, et al. Arsenic trioxide is required in the treatment of newly diagnosed acute promyelocytic leukemia. Analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group. Haematologica. 2018;103:2033\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eZhang L, Samad A, Pombo-de-Oliveira MS, Scelo G, Smith MT, Feusner J, et al. Global characteristics of childhood acute promyelocytic leukemia. Blood Reviews. 2015;29:101\u0026ndash;25. \u003c/li\u003e\n\u003cli\u003eTallman MS. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002;100:4298\u0026ndash;302. \u003c/li\u003e\n\u003cli\u003eJacomo RH, Melo RAM, Souto FR, De Mattos ER, De Oliveira CT, Fagundes EM, et al. Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines. Haematologica. 2007;92:1431\u0026ndash;2. \u003c/li\u003e\n\u003cli\u003eMathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, et al. Single-Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: Long-Term Follow-Up Data. JCO. 2010;28:3866\u0026ndash;71. \u003c/li\u003e\n\u003cli\u003ePowell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116:3751\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eSherin P Mathew. Clinical Profile and Induction Outcome in Adult and Pediatric Acute Promyelocytic Leukemia. \u003c/li\u003e\n\u003cli\u003eSerefhanoglu S, Buyukasik Y, Goker H, Sayinalp N, Haznedaroglu IC, Aksu S, et al. Clinical features and outcomes of 49 Turkish patients with acute promyelocytic leukemia who received ATRA and anthracyclines (PETHEMA protocol) therapy. Leukemia Research. 2010;34:e317\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eConneely S, Stevens A. Advances in Pediatric Acute Promyelocytic Leukemia. Children. 2020;7:11. \u003c/li\u003e\n\u003cli\u003eGirmenia C, Lo Coco F, Breccia M, Latagliata R, Spadea A, D\u0026rsquo;Andrea M, et al. Infectious complications in patients with acute promyelocytic leukaemia treated with the AIDA regimen. Leukemia. 2003;17:925\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eMontesinos P, Bergua JM, Vellenga E, Ray\u0026oacute;n C, Parody R, De La Serna J, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113:775\u0026ndash;83. \u003c/li\u003e\n\u003cli\u003eMandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, et al. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell\u0026rsquo;Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood. 1997;90:1014\u0026ndash;21. \u003c/li\u003e\n\u003cli\u003eCoombs CC, DeAngelis LM, Feusner JH, Rowe JM, Tallman MS. Pseudotumor Cerebri in Acute Promyelocytic Leukemia Patients on Intergroup Protocol 0129: Clinical Description and Recommendations for New Diagnostic Criteria. Clin Lymphoma Myeloma Leuk. 2016;16:146\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eZhang Z, Zhang S, Zhang F, Zhang Q, Wei H, Xiu R, et al. Clinical Indicators of Hepatotoxicity in Newly Diagnosed Acute Promyelocytic Leukemia Patients Undergoing Arsenic Trioxide Treatment. Biol Trace Elem Res. 2024;202:122\u0026ndash;32. \u003c/li\u003e\n\u003cli\u003eSanz MA, Montesinos P, Vellenga E, Ray\u0026oacute;n C, De La Serna J, Parody R, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood. 2008;112:3130\u0026ndash;4. \u003c/li\u003e\n\u003cli\u003eBaba SM, Shah ZA, Pandith AA, Dil-Afroze null, Jan A, Mir KA, et al. Influence of bcr-3 PML-RAR\u0026alpha; transcript on outcome in Acute Promyelocytic Leukemia patients of Kashmir treated with all-trans retinoic acid and/or arsenic tri-oxide. Cancer Genet. 2019;231\u0026ndash;232:14\u0026ndash;21. \u003c/li\u003e\n\u003cli\u003eIyer SG, Elias L, Stanchina M, Watts J. The treatment of acute promyelocytic leukemia in 2023: Paradigm, advances, and future directions. Front Oncol. 2023;12:1062524.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 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":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Leukemia, Promyelocytic, Arsenic trioxide, anthracyclines, tretinoin","lastPublishedDoi":"10.21203/rs.3.rs-6794583/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6794583/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e\u003cbr\u003e\nAcute promyelocytic leukemia (APL) is a distinct and highly curable subtype of acute myeloid leukemia. However, early mortality due to hemorrhage, differentiation syndrome (DS), and infections remains a significant challenge, particularly in resource-limited settings. There is a paucity of real-world data from India, where delayed diagnosis and high infection rates may impact outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003cbr\u003e\n\u003c/strong\u003eThis retrospective cohort study included APL patients diagnosed at SGPGIMS, Lucknow, between July 2014 and June 2024. Diagnosis was confirmed via morphology, flow cytometry, and RT-PCR. Patients received risk-adapted induction therapy with ATRA and ATO ± anthracycline. Kaplan-Meier and multivariate Cox regression analyses were performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003cbr\u003e\n\u003c/strong\u003eOf 102 patients (median age 33 years; 17.6% pediatric), 47% were high-risk. Fever and mucocutaneous bleeding were common presentations; 18.6% had life-threatening hemorrhages, mainly intracranial. Median diagnosis delay was 18 days. DS occurred in 56% of adults and 33% of pediatric patients. Pseudotumor cerebri and hepatotoxicity occurred in 7.8% and 37.6%, respectively. CR was achieved in 76.4% (87% low-risk vs. 64.6% high-risk). Induction mortality (24.5%) was mainly due to bleeding and infections. At a median follow-up of 28 months, 2-year OS was 75.9% (low-risk: 90.4%; high-risk: 65.9%), and DFS was 94.9%. High-risk status, age \u0026gt;50 with comorbidities, low hemoglobin, and poor performance status independently predicted mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003cbr\u003e\n\u003c/strong\u003eEarly mortality in APL remains high due to delayed diagnosis and bleeding complications. Region-specific challenges necessitate timely intervention and tailored supportive care to improve outcomes in Indian APL patients, especially in pediatric and high-risk groups.\u003c/p\u003e","manuscriptTitle":"Clinical Profile and Treatment Outcomes in Paediatric and Adult Acute Promyelocytic Leukemia: Experience from a Tertiary Care Centre in Northern India","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-10 18:26:41","doi":"10.21203/rs.3.rs-6794583/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-26T09:08:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-18T15:36:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-15T20:21:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"114945701664186207100413344567867042310","date":"2025-06-09T14:29:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"138270254216125032620456339952011151385","date":"2025-06-09T13:28:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-06T12:04:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-03T16:51:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-03T16:48:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-06-01T08:20:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8399210d-4070-44e2-b502-02101ca0e34d","owner":[],"postedDate":"June 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T15:58:45+00:00","versionOfRecord":{"articleIdentity":"rs-6794583","link":"https://doi.org/10.1007/s00277-025-06646-x","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2025-10-07 15:56:53","publishedOnDateReadable":"October 7th, 2025"},"versionCreatedAt":"2025-06-10 18:26:41","video":"","vorDoi":"10.1007/s00277-025-06646-x","vorDoiUrl":"https://doi.org/10.1007/s00277-025-06646-x","workflowStages":[]},"version":"v1","identity":"rs-6794583","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6794583","identity":"rs-6794583","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}