Clinical characteristics and treatment outcomes of adult acute promyelocytic leukemia in the West Bank of Palestine: a single-center retrospective study

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The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed APL into a highly curable disease, with survival rates approaching 90% despite its historically poor prognosis. Data on APL outcomes in Palestine are rare. This study aimed to describe the clinical characteristics, treatment-related complications, and mortality in adult APL patients treated at a tertiary cancer center in Palestine, and to explore factors associated with early death and poor prognosis. Methods: We conducted a retrospective cohort study of 30 adult patients (≥18 years) diagnosed with APL between January 2016 and June 2024 at An-Najah National University Hospital (NNUH), West Bank, Palestine. Low-risk patients received ATRA plus ATO, whereas high-risk patients received ATRA in combination with anthracycline-based chemotherapy. Demographic, clinical, and laboratory data, treatment details, complications, and outcomes were abstracted from medical records. Early death was defined as death within 30 days of diagnosis. Continuous variables were summarized as medians with interquartile ranges (IQRs), and categorical variables as frequencies and percentages. Group comparisons used the Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Results: Thirty patients (15 males, 15 females) with a median age of 37 years (range, 18–79) were included. According to the Sanz risk score, 9 (30.0%) were low-risk, 13 (43.3%) intermediate-risk and 8 (26.7%) high-risk. Most patients presented with preserved performance status (ECOG 0–1). Median baseline values at diagnosis were: hemoglobin 9 g/dL, white blood cell (WBC) count 4.8×10⁹/L, platelet count 18.1×10⁹/L, absolute neutrophil count 0.95×10⁹/L, prothrombin time (PT) 17.2 seconds, fibrinogen 142.5 mg/dL and D-dimer 30.9. The early death rate (EDR) was 13.3% (4/30): one patient died before induction and three died during induction; all early deaths were due to hemorrhage related to DIC. Among the 26 patients who survived beyond 30 days and completed induction, all achieved complete remission (CR); approximately two-thirds achieved CR after the first induction cycle and the remainder after a second cycle. The median time to hematologic remission was 35 days. During consolidation and maintenance, one patient died during consolidation and one died after completing maintenance from a non-leukemia-related cause. No relapses were observed, and no patient required hematopoietic stem cell transplantation by the end of follow-up. Higher WBC (p = 0.038) and prolonged PT at diagnosis (p = 0.033) were significantly associated with early death; hemoglobin, ANC, platelets, fibrinogen, and D-dimer were not. Conclusions: In this single-center Palestinian cohort, APL outcomes with ATRA-based protocols were comparable to those reported from high-resource settings, with high remission rates and no observed relapse during follow-up. Early mortality, driven by hemorrhagic complications, remained the main obstacle to cure and was associated with higher leukocyte counts and more pronounced coagulopathy at diagnosis. These findings highlight the importance of timely diagnosis, immediate initiation of ATRA, and intensive supportive care in resource-limited settings, and support the need for larger multicenter studies in the region. Acute promyelocytic leukemia induction therapy early mortality complete remission arsenic trioxide Palestine Background Acute promyelocytic leukemia (APL) is a specific variant of acute myeloid leukemia (AML), characterized by the balanced chromosomal translocation t(15;17)(q22;q12), which results in the promyelocytic leukemia–retinoic acid receptor-α (PML–RARA) fusion gene ( 1 – 3 ). Before the advent of modern differentiation therapy, APL was one of the most lethal AML subtypes, with a median survival of less than one month in the absence of effective treatment( 4 ). The introduction of all-trans retinoic acid (ATRA) revolutionized APL management by inducing differentiation of malignant promyelocytes. Subsequent combinations of ATRA with anthracycline-based chemotherapy have improved outcomes, achieving complete remission (CR) rates exceeding 90% and long-term survival rates of 70–80% ( 5 ). More recently, chemotherapy-free regimens combining ATRA and arsenic trioxide (ATO) have become standard of care for low- and intermediate-risk APL and are associated with further improvements in efficacy and tolerability ( 6 ). In high-income countries, APL now has the best survival outcomes among leukemias, with CR rates approaching 95% and two-year disease-free survival (DFS) exceeding 90% ( 7 ). However, outcomes in low- and middle-income countries are less favorable, mainly due to higher rates of early death, frequently driven by hemorrhagic complications in the setting of disseminated intravascular coagulation (DIC) ( 8 ). In Palestine, cancer is the second leading cause of death, and hematologic malignancies such as APL face unique challenges related to fragmented cancer care, delays in diagnosis and referral, restricted access to intensive supportive care (including blood products and intensive care beds), and occasional constraints in the availability of ATRA and ATO ( 9 , 10 ). An-Najah National University Hospital (NNUH) has emerged as a major referral center for hematologic cancers, including APL, and receives patients both from the West Bank and from the Gaza Strip. Despite the remarkable advances in APL treatment worldwide, data describing the clinical profile, treatment patterns, and outcomes of Palestinian patients are lacking. Generating specific evidence about APL is essential to adapt international guidelines to local constraints, identify modifiable determinants of early death, and inform national strategies for leukemia care. This study is particularly important because it provides, to our knowledge, the first detailed description of adult APL in the West Bank of Palestine. By characterizing clinical presentation, early complications, and outcomes, we aim to inform clinicians and policymakers and to highlight both the strengths and gaps within the current system of care. We hypothesized that, despite the resource limitations and fragmented cancer care in Palestine, implementation of modern ATRA-based protocols at a tertiary center would yield remission and early death rates comparable to those reported internationally, and that baseline disease burden and coagulation parameters would be associated with early mortality. Accordingly, the objectives of this study were: ( 1 ) to describe the clinical characteristics and presentation of adult APL patients treated at NNUH; ( 2 ) to evaluate treatment outcomes, including early mortality, CR, and relapse; and ( 3 ) to explore baseline factors associated with early death and poor prognosis in this cohort. Methods Study design and setting This was a retrospective cohort study conducted at An-Najah National University Hospital (NNUH), a tertiary care cancer center in Nablus, West Bank, Palestine. We reviewed the electronic medical records of adult patients (aged ≥ 18 years) diagnosed with APL between January 2016 and June 2024 and treated with curative intent. Data were collected on demographics, clinical and laboratory characteristics at diagnosis, bone marrow histopathology, cytogenetic and molecular findings, treatment regimens, treatment-related complications, remission status, relapse, and survival. Study population and sample size All consecutive adult patients with a confirmed diagnosis of APL who were treated at NNUH during the study period were eligible. A total of 30 patients met the inclusion criteria and were included in the analysis. The sample size reflects the rarity of APL and was determined by the number of eligible cases treated at our center between January 2016 and June 2024. Inclusion and exclusion criteria Inclusion criteria were: - Age ≥ 18 years at the time of diagnosis; - Diagnosis of APL confirmed by bone marrow morphology, immunophenotyping and cytogenetic studies (conventional karyotyping and fluorescence in situ hybridization [FISH] for PML–RARA); - If FISH was negative, confirmation of PML–RARA by reverse transcriptase polymerase chain reaction (RT-PCR); - Initiation of APL-directed therapy at NNUH. Patients referred from other centers were included if pathology reports and confirmatory cytogenetic or molecular testing were available or repeated at NNUH. Patients with incomplete diagnostic data, or insufficient follow-up information to determine early death and remission status were excluded. Diagnosis of APL was based on the World Health Organization (WHO) classification. DIC was defined according to the International Society for Thrombosis and Haemostasis (ISTH) scoring system, with a score ≥ 5 indicating overt DIC ( 11 ). Coagulopathy was defined as prolonged prothrombin time (PT) and/or activated partial thromboplastin time (aPTT) and/or decreased fibrinogen levels, even if full ISTH criteria for DIC were not met. Minimal residual disease (MRD) monitoring by RT-PCR was not consistently available for all patients and was therefore not systematically analyzed. Treatment protocols All patients received risk-adapted induction therapy according to institutional protocols aligned with contemporary international guidelines. - Low-risk APL (WBC ≤ 10,000/µL): ATRA 45 mg/m²/day plus ATO 0.15 mg/kg/day. - High-risk APL (WBC > 10,000/µL): ATRA in combination with anthracycline-based chemotherapy (e.g. daunorubicin or idarubicin), with the optional addition of cytarabine or mitoxantrone at the treating physician’s discretion. ATRA 45 mg/m²/day was initiated immediately when APL was clinically suspected (based on characteristic morphology on peripheral smear and/or bleeding manifestations), without waiting for confirmatory cytogenetic or molecular testing. Once the diagnosis was confirmed, patients were managed in protective isolation until complete hematologic remission. Supportive care included prophylactic platelet transfusions to maintain platelet counts above 30,000–50,000/µL and administration of cryoprecipitate or fresh frozen plasma when fibrinogen levels were < 100 mg/dL. Differentiation syndrome was managed with dexamethasone and temporary interruption of ATRA and/or ATO when indicated. Prophylactic corticosteroids for differentiation syndrome were not used consistently at the beginning of the study period but were adopted more routinely later in the cohort. All patients were intended to receive a uniform consolidation regimen consisting of ATRA plus ATO for four cycles. Maintenance therapy comprised intermittent ATRA in combination with 6-mercaptopurine (6-MP) and methotrexate (MTX) for two years in patients remaining in remission. Data collection Data were extracted from electronic medical records using a standardized data collection form. Early death was defined as death from any cause occurring within 30 days from the date of APL diagnosis. Variables collected included: - Demographics and clinical presentation: age, sex, place of residence (West Bank vs Gaza Strip), Eastern Cooperative Oncology Group (ECOG) performance status, main presenting symptoms (bleeding, fever, fatigue), and Sanz risk classification (low, intermediate, high). - Baseline laboratory parameters: WBC count, hemoglobin (Hb), absolute neutrophil count (ANC), platelet count, PT, fibrinogen, D-dimer, and ISTH DIC score. - Treatment data: use of cytoreductive therapy (hydroxyurea) before induction, type of induction regimen (ATRA + ATO vs ATRA + chemotherapy), number of induction cycles, type and number of consolidation cycles, and receipt of maintenance therapy. - Complications: occurrence of sepsis, DIC, alveolar hemorrhage, differentiation syndrome, and other clinically significant events during induction and consolidation. - Outcomes: achievement of hematologic CR, time to hematologic remission, achievement of molecular remission when assessed, early death, death during consolidation or maintenance, relapse, and need for hematopoietic stem cell transplantation. Hematologic CR was defined as ANC ≥ 1.5×10⁹/L, platelet count > 100×10⁹/L, normocellular bone marrow with < 5% blasts plus promyelocytes, and absence of clinical evidence of APL. Patients were followed from diagnosis until death, last documented contact or 30 June 2024, whichever occurred first. Some variables were missing for a minority of patients due to incomplete documentation; analyses were performed on a variable-by-variable basis. Ethics This study received ethical approval from the Ethics Committee of An-Najah National University Hospital, Nablus, Palestine, in 2023, in accordance with national regulations and the principles of the Declaration of Helsinki (1964) and its subsequent amendments. Given the retrospective design and use of anonymized data, the requirement for informed consent was waived. Statistical analysis Statistical analyses were performed using SPSS version 21 (IBM Corp., Armonk, NY, USA). The distribution of continuous variables was assessed using the Kolmogorov–Smirnov test and was found to be non-normal. Continuous variables are therefore presented as medians with interquartile ranges (IQRs), and categorical variables as frequencies and percentages. For exploratory analyses of factors associated with early mortality (≤ 30 days from diagnosis), patients were categorized into early-death and survivor groups. Comparisons of continuous variables between groups (e.g. baseline WBC, Hb, platelet count, PT, fibrinogen, D-dimer) were performed using the Mann–Whitney U test. Associations between categorical variables (e.g. Sanz risk category, presence of DIC, induction regimen, use of cytoreductive therapy, occurrence of differentiation syndrome) and early mortality were evaluated using the chi-square test or Fisher’s exact test, as appropriate. Because only four early death events occurred, multivariable regression analyses were not undertaken, as they would be statistically unreliable. Two-sided p-values < 0.05 were considered statistically significant. Results Clinical presentation and baseline characteristics Thirty adult patients with newly diagnosed APL were included. The cohort comprised 15 males (50.0%) and 15 females (50.0%), with a median age at diagnosis of 37 years (range, 18–79 years). Approximately one-third of patients (33.3%) were residents of the Gaza Strip, and the remainder were primarily from the northern West Bank. Most patients presented with good performance status: 20 (66.7%) had an ECOG performance status of 0, 8 (26.7%) had ECOG 1, and only 2 (6.7%) had ECOG 2. According to the Sanz risk classification, 9 patients (30.0%) were low-risk, 13 (43.3%) intermediate-risk, and 8 (26.7%) high-risk. Median baseline laboratory parameters at admission were: WBC 4.8×10⁹/L (IQR, 1.3–17.3×10⁹/L), Hb 9.0 g/dL (IQR, 7.3–9.5 g/dL), ANC 0.95×10⁹/L (IQR, 0.32–5.0×10⁹/L), platelet count 18.1×10⁹/L (IQR, 11.6–36.0×10⁹/L), PT 17.2 seconds (IQR, 15.0–18.9), fibrinogen 142.5 mg/dL (IQR, 103.5–245.0), and D-dimer 30.9 (IQR, 21.0–51.0). Overt DIC (ISTH score ≥ 5) was recorded in approximately one-quarter of patients. Table 1 Baseline Characteristics Variable Value Age (median, range) 37 (18–79) Sex 15 Male / 15 Female Residence 33% Gaza, 67% West Bank ECOG 0–1 28 (93.3%) Sanz risk categories Low 30%, Intermediate 43.3%, High 26.7% WBC 4.8×10⁹/L Hemoglobin 9 g/dL Platelets 18.1×10⁹/L PT 17.2 sec Fibrinogen 142.5 mg/dL D-dimer 30.9 Overt DIC 26.7% At presentation, bleeding manifestations were documented in 30.0% of patients, fever in 10.0%, and fatigue in 7.0%; several patients had more than one symptom. Table 2 Presenting Symptoms Symptom n (%) Bleeding 9 (30%) Fever 3 (10%) Fatigue 2 (6.7%) Induction therapy, complications, and early mortality ATRA 45 mg/m²/day was initiated promptly when APL was clinically suspected. Risk-adapted induction therapy included ATRA plus ATO for low-risk patients and ATRA plus anthracycline-based chemotherapy (± cytarabine or mitoxantrone) for high-risk patients. One patient (3.3%) died of fulminant hemorrhage before induction therapy could be started. Of the remaining 29 patients, 16 (46.7%) received cytoreductive chemotherapy with hydroxyurea before initiation of definitive induction. The most commonly used induction regimen was ATRA plus ATO (60.0%). The median time to hematologic response was 35 days (IQR, 30–42 days). Complications during induction occurred in 13 patients (43.3%). Sepsis was the most frequent complication, followed by DIC and alveolar hemorrhage. Differentiation syndrome occurred in 13.3% of patients and was successfully managed with dexamethasone and temporary interruption of ATRA/ATO. Overall, four patients (13.3%) experienced early death (≤ 30 days from diagnosis): one before starting induction and three during induction. All early deaths were due to severe hemorrhagic events in the context of DIC. Table 3 Induction Therapy and Complications Variable Value Hydroxyurea use 53.3% ATRA + ATO 60% ATRA + chemotherapy 40% Patients with ≥ 1 complication 43.3% Sepsis 40% DIC 26.7% Alveolar bleeding 20% Differentiation syndrome 13.3% Consolidation, maintenance therapy, and outcomes Of the 30 patients, 26 (86.7%) survived the induction phase and proceeded to consolidation therapy. Most received consolidation with ATRA plus ATO, while a minority continued consolidation at another center. At the end of consolidation, all evaluable patients achieved molecular complete remission. During consolidation, one patient died, and one additional patient died after completing maintenance therapy from a cause unrelated to APL. No hematologic or molecular relapses were detected during follow-up, and none of the patients underwent hematopoietic stem cell transplantation. Overall, 24 patients (80.0%) were alive in continuous remission at last follow-up. Table 4 Consolidation and Maintenance Outcomes Variable Value Started consolidation 26 (86.7%) ATRA + ATO consolidation 76.7% Molecular CR 100% Death during consolidation 1 (3.3%) Death post-maintenance 1 (3.3%) Table 6 Factors Associated with Early Mortality Variable p-value Interpretation WBC 0.038 Higher in early-death group PT 0.033 Prolonged in early-death group Hemoglobin 0.938 NS ANC 0.162 NS Platelets 0.254 NS Fibrinogen 0.378 NS D-dimer 0.419 NS Factors associated with early mortality In univariable analyses, higher baseline WBC count at diagnosis was significantly associated with early death (p = 0.038). Prolonged PT at diagnosis was also significantly associated with early mortality (p = 0.033). Other baseline laboratory parameters, including hemoglobin, ANC, platelet count, fibrinogen, and D-dimer, were not significantly different between patients who died early and those who survived beyond 30 days. Table 5 Survival and Remission Summary Outcome Value Early deaths 4 (13.3%) CR after induction 100% of survivors Molecular CR 100% Relapse 0 Hematopoietic stem cell transplant 0 Alive at last follow-up 24 (80%) Discussion In this eight-year retrospective cohort of adult APL patients treated at a single tertiary center in Palestine, we found that risk-adapted ATRA-based therapy resulted in high rates of hematologic and molecular remission and an absence of documented relapse during the follow-up period. The early death rate of 13.3%, almost entirely due to hemorrhagic complications in the setting of DIC, is comparable to early mortality rates reported in population-based series from other countries, including Brazil, the United States and Denmark, where early death rates of 12–19% have been described despite access to modern treatment ( 12 – 14 ) Our findings confirm that, when contemporary APL protocols are implemented, outcomes in a resource-constrained environment can approach those seen in high-income settings. All evaluable patients in our cohort achieved molecular CR following consolidation, and no relapses were observed during follow-up. While the limited sample size and heterogeneous follow-up duration mean that late relapses cannot be excluded, these results are broadly consistent with international data demonstrating the high curability of APL with differentiation therapy, particularly ATRA combined with ATO, compared with classical chemotherapy-based regimens ( 15 – 17 ) The median age of 37 years and balanced sex distribution in our cohort are consistent with reports from several other regions but younger than some Western series, such as a large U.S. study in which the median age was 53 years ( 18 ) ( 19 ). This supports the notion that APL in many low- and middle-income settings tends to affect relatively younger adults compared with other AML subtypes, whose incidence peaks later in life ( 20 ). Most of our patients presented with good performance status (ECOG 0–1), which is in line with previous studies indicating that the majority of APL patients fall between ECOG 0 and 2 at diagnosis ( 21 – 23 ) Bleeding was the most common presenting symptom, and overt DIC was documented in approximately one-quarter of patients at diagnosis, mirroring the classic hemostatic phenotype of APL and prior reports in which bleeding is present in the vast majority of patients ( 24 , 25 ). The pronounced hemorrhagic diathesis in APL is driven by a complex interplay of DIC, hyperfibrinolysis and severe thrombocytopenia. Leukemic promyelocytes express procoagulant molecules such as tissue factor and annexin II, which activate coagulation and fibrinolytic pathways, leading to consumption of clotting factors and increased fibrin degradation ( 26 , 27 ). Our observation that prolonged PT and higher WBC at diagnosis were significantly associated with early death lessens the central role of coagulopathy and disease burden in determining short-term outcomes. Differentiation syndrome occurred in a minority of patients in our cohort, entirely in the absence of prophylactic corticosteroids, and at elevated WBC counts. All cases were successfully managed with dexamethasone and temporary interruption of ATRA/ATO, with subsequent rechallenge. The observed incidence falls within the wide range reported in the literature (2.5–63%), which reflects differences in diagnostic criteria, induction regimens, leukocyte thresholds and use of steroid prophylaxis ( 28 , 29 ). Our experience supports the use of close clinical monitoring, early recognition, and standardized management protocols for differentiation syndrome in routine practice. An interesting feature of our cohort is the relatively high proportion of high-risk APL (26.7%) compared with some international series, where high-risk disease often accounts for around 10–15% of cases ( 30 , 31 ). This may be related to delayed presentation, referral bias toward more complex or unstable cases at a tertiary center, or differences in diagnostic and referral pathways. Although high-risk classification appeared to correlate with early mortality, this association did not reach statistical significance in our small sample. From a health-systems perspective, our findings highlight several key messages. First, early death in APL remains a major barrier to cure and is concentrated in the first weeks after diagnosis. Strategies to reduce early mortality in Palestine should focus on shortening the interval between first contact and initiation of ATRA, improving early recognition of suspected APL in peripheral hospitals, and ensuring immediate availability of ATRA and blood products. Second, our results demonstrate that, once patients reach a specialized center and receive standardized ATRA-based therapy and supportive care, long-term outcomes can be excellent. This supports investment in regional referral pathways, training for non-hematology clinicians on APL as a hematologic emergency, and national adoption of risk-adapted APL protocols. Strengths and limitations This study has several limitations. Its retrospective design and single-center setting limit the generalizability of the findings and introduce a risk of selection and information bias. The sample size is small, with only four early death events, which restricts statistical power and precludes robust multivariable analysis of prognostic factors. Some laboratory and complication data were missing due to incomplete documentation, and MRD monitoring was not consistently performed for all patients. Follow-up duration, although sufficient to capture early outcomes, may not fully reflect late relapses. Nonetheless, the study also has important strengths. To our knowledge, it represents the first systematic description of adult APL in Palestine and provides real-world data on presentation, treatment and outcomes from the main national referral center. The cohort includes all consecutive adult cases treated over an eight-year period, and detailed data on complications and supportive care are available. Importantly, the results show that, with timely diagnosis and implementation of ATRA-based protocols, outcomes in a resource-limited setting can approximate those in high-income countries. Conclusions APL is a hematologic emergency that requires rapid recognition and immediate initiation of appropriate therapy to prevent fatal hemorrhagic complications. In this single-center Palestinian cohort, modern ATRA-based treatment regimens resulted in high rates of hematologic and molecular remission, with no observed relapses during follow-up. Early mortality remained a major challenge and was driven by hemorrhagic events in the context of DIC, particularly in patients with higher WBC and prolonged PT at diagnosis. Our findings support the view that newly diagnosed APL is a highly curable disease when guideline-concordant differentiation therapy and intensive supportive care are available, even in resource-limited environments. Strengthening early diagnostic pathways, ensuring rapid access to ATRA and blood products, and standardizing supportive care protocols may further reduce early deaths in Palestine. Larger multicenter studies and national registries are needed to validate these observations, refine prognostic stratification and optimize APL management across the region. Abbreviations APL: acute promyelocytic leukemia AML: acute myeloid leukemia ANC: absolute neutrophil count ATRA: all-trans retinoic acid ATO: arsenic trioxide CR: complete remission DIC: disseminated intravascular coagulation DFS: disease-free survival ECOG: Eastern Cooperative Oncology Group FISH: fluorescence in situ hybridization ISTH: International Society for Thrombosis and Haemostasis IQR: interquartile range MRD: minimal residual disease MTX: methotrexate NNUH: An-Najah National University Hospital PT: prothrombin time RT-PCR: reverse transcriptase polymerase chain reaction WBC: white blood cell count 6-MP: 6-mercaptopurine Declarations Ethics approval and consent to participate This study received ethical approval from the Ethics Committee of An-Najah National University Hospital, Nablus, Palestine, in 2023, in accordance with national regulations and the principles of the Declaration of Helsinki (1964) and its subsequent amendments. Owing to the retrospective design and use of anonymized data, the requirement for informed consent was waived. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors’ contributions R.T. collected the data together with M.I. and M.K. A. R.T. analyzed the data, wrote the manuscript and revised it. R.A. critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript. 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Br J Haematol. 2011;156:24–36. Kwaan H, Weiss I, Tallman M. The Role of Abnormal Hemostasis and Fibrinolysis in Morbidity and Mortality of Acute Promyelocytic Leukemia. Semin Thromb Hemost. 2019;45. Montesinos P, Sanz M. The Differentiation Syndrome in Patients with Acute Promyelocytic Leukemia: Experience of the Pethema Group and Review of the Literature. Mediterranean J Hematol Infect Dis. 2011;3:e2011059. Nayak AR, Aggarwal M, Naranje P, Dass J, Kumar P. An Untimely Occurrence of Differentiation Syndrome in APL- Better be Suspicious. Indian J Hematol Blood Transfus. 2025. Jimenez JJ, Chale RS, Abad AC, Schally AV. Acute promyelocytic leukemia (APL): a review of the literature. Oncotarget. 2020;11(11):992–1003. Chin K-K, Tallman M. Curative strategies for high-risk acute promyelocytic leukemia. Curr Opin Oncol. 2025;37. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 20 Apr, 2026 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 11 Feb, 2026 Reviews received at journal 05 Feb, 2026 Reviews received at journal 04 Feb, 2026 Reviews received at journal 03 Feb, 2026 Reviews received at journal 02 Feb, 2026 Reviewers agreed at journal 01 Feb, 2026 Reviewers agreed at journal 30 Jan, 2026 Reviewers agreed at journal 26 Jan, 2026 Reviewers agreed at journal 25 Jan, 2026 Reviewers agreed at journal 24 Jan, 2026 Reviewers agreed at journal 23 Jan, 2026 Reviewers agreed at journal 23 Jan, 2026 Reviewers invited by journal 23 Jan, 2026 Editor invited by journal 05 Jan, 2026 Editor assigned by journal 05 Jan, 2026 Submission checks completed at journal 05 Jan, 2026 First submitted to journal 26 Dec, 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. 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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-8456765","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":580488470,"identity":"4f1731a1-c9ec-41ca-8172-95522c2a0580","order_by":0,"name":"Raghad Tanbour¹","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYHACNjBiYOABETYIQUJaJKBa0kjXcpiwFvP249ce/ChjqOOf3XvwMe+e8/L8M3IPMHwoO4xTi8yZnHLDnnMMEhJ3ziUb8zy7bTjjRl4C44xzuLVIMOSkSfC2AekbOWbSPAduMzbcyDFg5m3Do4X/TZrkX6AWeYiWc/bzQVr+4tMikX5MGmSLAUTLgcQNIC2MeLW8YZOWOSchufFGXrLhnAPJyRvPvEs42HMuHY/D0p9Jvimz4Ze7kXvwwZsDdrbzjgMZP8qscWoBRocBOBSQRRgO4FEPBOwPMAzBr2EUjIJRMApGHAAAWsdUSyUJaIUAAAAASUVORK5CYII=","orcid":"","institution":"Arab American University","correspondingAuthor":true,"prefix":"","firstName":"Raghad","middleName":"","lastName":"Tanbour¹","suffix":""},{"id":580488471,"identity":"3099def9-d8bd-4f30-981c-58cab9cd39ee","order_by":1,"name":"Manal Ishtayeh²","email":"","orcid":"","institution":"An-Najah National university Hospital","correspondingAuthor":false,"prefix":"","firstName":"Manal","middleName":"","lastName":"Ishtayeh²","suffix":""},{"id":580488472,"identity":"592eaeb8-9d86-4c6a-9586-d32ce904cad6","order_by":2,"name":"Mohammad Khaled Alhindi²","email":"","orcid":"","institution":"An-Najah National university Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Khaled","lastName":"Alhindi²","suffix":""},{"id":580488473,"identity":"38db22a5-f4f6-45d3-b8ef-d034e8bac1fd","order_by":3,"name":"Riad Amer³","email":"","orcid":"","institution":"An-Najah National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Riad","middleName":"","lastName":"Amer³","suffix":""}],"badges":[],"createdAt":"2025-12-26 16:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8456765/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8456765/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-026-16031-0","type":"published","date":"2026-04-20T15:57:39+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":107927686,"identity":"76371cba-b882-4a42-9ca0-1cccbabe6033","added_by":"auto","created_at":"2026-04-27 16:01:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":262143,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8456765/v1/6b60f8cd-62cc-4db6-b8e1-62f50f9f2278.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical characteristics and treatment outcomes of adult acute promyelocytic leukemia in the West Bank of Palestine: a single-center retrospective study","fulltext":[{"header":"Background","content":"\u003cp\u003eAcute promyelocytic leukemia (APL) is a specific variant of acute myeloid leukemia (AML), characterized by the balanced chromosomal translocation t(15;17)(q22;q12), which results in the promyelocytic leukemia–retinoic acid receptor-α (PML–RARA) fusion gene (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Before the advent of modern differentiation therapy, APL was one of the most lethal AML subtypes, with a median survival of less than one month in the absence of effective treatment(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe introduction of all-trans retinoic acid (ATRA) revolutionized APL management by inducing differentiation of malignant promyelocytes. Subsequent combinations of ATRA with anthracycline-based chemotherapy have improved outcomes, achieving complete remission (CR) rates exceeding 90% and long-term survival rates of 70–80% (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). More recently, chemotherapy-free regimens combining ATRA and arsenic trioxide (ATO) have become standard of care for low- and intermediate-risk APL and are associated with further improvements in efficacy and tolerability (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn high-income countries, APL now has the best survival outcomes among leukemias, with CR rates approaching 95% and two-year disease-free survival (DFS) exceeding 90% (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). However, outcomes in low- and middle-income countries are less favorable, mainly due to higher rates of early death, frequently driven by hemorrhagic complications in the setting of disseminated intravascular coagulation (DIC) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn Palestine, cancer is the second leading cause of death, and hematologic malignancies such as APL face unique challenges related to fragmented cancer care, delays in diagnosis and referral, restricted access to intensive supportive care (including blood products and intensive care beds), and occasional constraints in the availability of ATRA and ATO (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). An-Najah National University Hospital (NNUH) has emerged as a major referral center for hematologic cancers, including APL, and receives patients both from the West Bank and from the Gaza Strip.\u003c/p\u003e \u003cp\u003eDespite the remarkable advances in APL treatment worldwide, data describing the clinical profile, treatment patterns, and outcomes of Palestinian patients are lacking. Generating specific evidence about APL is essential to adapt international guidelines to local constraints, identify modifiable determinants of early death, and inform national strategies for leukemia care. This study is particularly important because it provides, to our knowledge, the first detailed description of adult APL in the West Bank of Palestine. By characterizing clinical presentation, early complications, and outcomes, we aim to inform clinicians and policymakers and to highlight both the strengths and gaps within the current system of care.\u003c/p\u003e \u003cp\u003eWe hypothesized that, despite the resource limitations and fragmented cancer care in Palestine, implementation of modern ATRA-based protocols at a tertiary center would yield remission and early death rates comparable to those reported internationally, and that baseline disease burden and coagulation parameters would be associated with early mortality. Accordingly, the objectives of this study were: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) to describe the clinical characteristics and presentation of adult APL patients treated at NNUH; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) to evaluate treatment outcomes, including early mortality, CR, and relapse; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) to explore baseline factors associated with early death and poor prognosis in this cohort.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eStudy design and setting\u003c/p\u003e\n\u003cp\u003eThis was a retrospective cohort study conducted at An-Najah National University Hospital (NNUH), a tertiary care cancer center in Nablus, West Bank, Palestine. We reviewed the electronic medical records of adult patients (aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years) diagnosed with APL between January 2016 and June 2024 and treated with curative intent. Data were collected on demographics, clinical and laboratory characteristics at diagnosis, bone marrow histopathology, cytogenetic and molecular findings, treatment regimens, treatment-related complications, remission status, relapse, and survival.\u003c/p\u003e\n\u003cp\u003eStudy population and sample size\u003c/p\u003e\n\u003cp\u003eAll consecutive adult patients with a confirmed diagnosis of APL who were treated at NNUH during the study period were eligible. A total of 30 patients met the inclusion criteria and were included in the analysis. The sample size reflects the rarity of APL and was determined by the number of eligible cases treated at our center between January 2016 and June 2024.\u003c/p\u003e\n\u003cp\u003eInclusion and exclusion criteria\u003c/p\u003e\n\u003cp\u003eInclusion criteria were:\u003c/p\u003e\n\u003cp\u003e- Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years at the time of diagnosis;\u003c/p\u003e\n\u003cp\u003e- Diagnosis of APL confirmed by bone marrow morphology, immunophenotyping and cytogenetic studies (conventional karyotyping and fluorescence in situ hybridization [FISH] for PML\u0026ndash;RARA);\u003c/p\u003e\n\u003cp\u003e- If FISH was negative, confirmation of PML\u0026ndash;RARA by reverse transcriptase polymerase chain reaction (RT-PCR);\u003c/p\u003e\n\u003cp\u003e- Initiation of APL-directed therapy at NNUH.\u003c/p\u003e\n\u003cp\u003ePatients referred from other centers were included if pathology reports and confirmatory cytogenetic or molecular testing were available or repeated at NNUH. Patients with incomplete diagnostic data, or insufficient follow-up information to determine early death and remission status were excluded.\u003c/p\u003e\n\u003cp\u003eDiagnosis of APL was based on the World Health Organization (WHO) classification. DIC was defined according to the International Society for Thrombosis and Haemostasis (ISTH) scoring system, with a score\u0026thinsp;\u0026ge;\u0026thinsp;5 indicating overt DIC (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e). Coagulopathy was defined as prolonged prothrombin time (PT) and/or activated partial thromboplastin time (aPTT) and/or decreased fibrinogen levels, even if full ISTH criteria for DIC were not met. Minimal residual disease (MRD) monitoring by RT-PCR was not consistently available for all patients and was therefore not systematically analyzed.\u003c/p\u003e\n\u003cp\u003eTreatment protocols\u003c/p\u003e\n\u003cp\u003eAll patients received risk-adapted induction therapy according to institutional protocols aligned with contemporary international guidelines.\u003c/p\u003e\n\u003cp\u003e- Low-risk APL (WBC\u0026thinsp;\u0026le;\u0026thinsp;10,000/\u0026micro;L): ATRA 45 mg/m\u0026sup2;/day plus ATO 0.15 mg/kg/day.\u003c/p\u003e\n\u003cp\u003e- High-risk APL (WBC\u0026thinsp;\u0026gt;\u0026thinsp;10,000/\u0026micro;L): ATRA in combination with anthracycline-based chemotherapy (e.g. daunorubicin or idarubicin), with the optional addition of cytarabine or mitoxantrone at the treating physician\u0026rsquo;s discretion.\u003c/p\u003e\n\u003cp\u003eATRA 45 mg/m\u0026sup2;/day was initiated immediately when APL was clinically suspected (based on characteristic morphology on peripheral smear and/or bleeding manifestations), without waiting for confirmatory cytogenetic or molecular testing. Once the diagnosis was confirmed, patients were managed in protective isolation until complete hematologic remission.\u003c/p\u003e\n\u003cp\u003eSupportive care included prophylactic platelet transfusions to maintain platelet counts above 30,000\u0026ndash;50,000/\u0026micro;L and administration of cryoprecipitate or fresh frozen plasma when fibrinogen levels were \u0026lt;\u0026thinsp;100 mg/dL. Differentiation syndrome was managed with dexamethasone and temporary interruption of ATRA and/or ATO when indicated. Prophylactic corticosteroids for differentiation syndrome were not used consistently at the beginning of the study period but were adopted more routinely later in the cohort.\u003c/p\u003e\n\u003cp\u003eAll patients were intended to receive a uniform consolidation regimen consisting of ATRA plus ATO for four cycles. Maintenance therapy comprised intermittent ATRA in combination with 6-mercaptopurine (6-MP) and methotrexate (MTX) for two years in patients remaining in remission.\u003c/p\u003e\n\u003cp\u003eData collection\u003c/p\u003e\n\u003cp\u003eData were extracted from electronic medical records using a standardized data collection form. Early death was defined as death from any cause occurring within 30 days from the date of APL diagnosis.\u003c/p\u003e\n\u003cp\u003eVariables collected included:\u003c/p\u003e\n\u003cp\u003e- Demographics and clinical presentation: age, sex, place of residence (West Bank vs Gaza Strip), Eastern Cooperative Oncology Group (ECOG) performance status, main presenting symptoms (bleeding, fever, fatigue), and Sanz risk classification (low, intermediate, high).\u003c/p\u003e\n\u003cp\u003e- Baseline laboratory parameters: WBC count, hemoglobin (Hb), absolute neutrophil count (ANC), platelet count, PT, fibrinogen, D-dimer, and ISTH DIC score.\u003c/p\u003e\n\u003cp\u003e- Treatment data: use of cytoreductive therapy (hydroxyurea) before induction, type of induction regimen (ATRA\u0026thinsp;+\u0026thinsp;ATO vs ATRA\u0026thinsp;+\u0026thinsp;chemotherapy), number of induction cycles, type and number of consolidation cycles, and receipt of maintenance therapy.\u003c/p\u003e\n\u003cp\u003e- Complications: occurrence of sepsis, DIC, alveolar hemorrhage, differentiation syndrome, and other clinically significant events during induction and consolidation.\u003c/p\u003e\n\u003cp\u003e- Outcomes: achievement of hematologic CR, time to hematologic remission, achievement of molecular remission when assessed, early death, death during consolidation or maintenance, relapse, and need for hematopoietic stem cell transplantation.\u003c/p\u003e\n\u003cp\u003eHematologic CR was defined as ANC\u0026thinsp;\u0026ge;\u0026thinsp;1.5\u0026times;10⁹/L, platelet count\u0026thinsp;\u0026gt;\u0026thinsp;100\u0026times;10⁹/L, normocellular bone marrow with \u0026lt;\u0026thinsp;5% blasts plus promyelocytes, and absence of clinical evidence of APL.\u003c/p\u003e\n\u003cp\u003ePatients were followed from diagnosis until death, last documented contact or 30 June 2024, whichever occurred first. Some variables were missing for a minority of patients due to incomplete documentation; analyses were performed on a variable-by-variable basis.\u003c/p\u003e\n\u003cp\u003eEthics\u003c/p\u003e\n\u003cp\u003eThis study received ethical approval from the Ethics Committee of An-Najah National University Hospital, Nablus, Palestine, in 2023, in accordance with national regulations and the principles of the Declaration of Helsinki (1964) and its subsequent amendments. Given the retrospective design and use of anonymized data, the requirement for informed consent was waived.\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eStatistical analyses were performed using SPSS version 21 (IBM Corp., Armonk, NY, USA). The distribution of continuous variables was assessed using the Kolmogorov\u0026ndash;Smirnov test and was found to be non-normal. Continuous variables are therefore presented as medians with interquartile ranges (IQRs), and categorical variables as frequencies and percentages.\u003c/p\u003e\n\u003cp\u003eFor exploratory analyses of factors associated with early mortality (\u0026le;\u0026thinsp;30 days from diagnosis), patients were categorized into early-death and survivor groups. Comparisons of continuous variables between groups (e.g. baseline WBC, Hb, platelet count, PT, fibrinogen, D-dimer) were performed using the Mann\u0026ndash;Whitney U test. Associations between categorical variables (e.g. Sanz risk category, presence of DIC, induction regimen, use of cytoreductive therapy, occurrence of differentiation syndrome) and early mortality were evaluated using the chi-square test or Fisher\u0026rsquo;s exact test, as appropriate. Because only four early death events occurred, multivariable regression analyses were not undertaken, as they would be statistically unreliable. Two-sided p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eClinical presentation and baseline characteristics\u003c/h2\u003e \u003cp\u003eThirty adult patients with newly diagnosed APL were included. The cohort comprised 15 males (50.0%) and 15 females (50.0%), with a median age at diagnosis of 37 years (range, 18\u0026ndash;79 years). Approximately one-third of patients (33.3%) were residents of the Gaza Strip, and the remainder were primarily from the northern West Bank.\u003c/p\u003e \u003cp\u003eMost patients presented with good performance status: 20 (66.7%) had an ECOG performance status of 0, 8 (26.7%) had ECOG 1, and only 2 (6.7%) had ECOG 2. According to the Sanz risk classification, 9 patients (30.0%) were low-risk, 13 (43.3%) intermediate-risk, and 8 (26.7%) high-risk.\u003c/p\u003e \u003cp\u003eMedian baseline laboratory parameters at admission were: WBC 4.8\u0026times;10⁹/L (IQR, 1.3\u0026ndash;17.3\u0026times;10⁹/L), Hb 9.0 g/dL (IQR, 7.3\u0026ndash;9.5 g/dL), ANC 0.95\u0026times;10⁹/L (IQR, 0.32\u0026ndash;5.0\u0026times;10⁹/L), platelet count 18.1\u0026times;10⁹/L (IQR, 11.6\u0026ndash;36.0\u0026times;10⁹/L), PT 17.2 seconds (IQR, 15.0\u0026ndash;18.9), fibrinogen 142.5 mg/dL (IQR, 103.5\u0026ndash;245.0), and D-dimer 30.9 (IQR, 21.0\u0026ndash;51.0). Overt DIC (ISTH score\u0026thinsp;\u0026ge;\u0026thinsp;5) was recorded in approximately one-quarter of patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (18\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 Male / 15 Female\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResidence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33% Gaza, 67% West Bank\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG 0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (93.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSanz risk categories\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow 30%, Intermediate 43.3%, High 26.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.8\u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 g/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.1\u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.2 sec\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrinogen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e142.5 mg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-dimer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvert DIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAt presentation, bleeding manifestations were documented in 30.0% of patients, fever in 10.0%, and fatigue in 7.0%; several patients had more than one symptom.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePresenting Symptoms\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptom\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (30%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInduction therapy, complications, and early mortality\u003c/h3\u003e\n\u003cp\u003eATRA 45 mg/m\u0026sup2;/day was initiated promptly when APL was clinically suspected. Risk-adapted induction therapy included ATRA plus ATO for low-risk patients and ATRA plus anthracycline-based chemotherapy (\u0026plusmn;\u0026thinsp;cytarabine or mitoxantrone) for high-risk patients.\u003c/p\u003e \u003cp\u003eOne patient (3.3%) died of fulminant hemorrhage before induction therapy could be started. Of the remaining 29 patients, 16 (46.7%) received cytoreductive chemotherapy with hydroxyurea before initiation of definitive induction. The most commonly used induction regimen was ATRA plus ATO (60.0%). The median time to hematologic response was 35 days (IQR, 30\u0026ndash;42 days).\u003c/p\u003e \u003cp\u003eComplications during induction occurred in 13 patients (43.3%). Sepsis was the most frequent complication, followed by DIC and alveolar hemorrhage. Differentiation syndrome occurred in 13.3% of patients and was successfully managed with dexamethasone and temporary interruption of ATRA/ATO.\u003c/p\u003e \u003cp\u003eOverall, four patients (13.3%) experienced early death (\u0026le;\u0026thinsp;30 days from diagnosis): one before starting induction and three during induction. All early deaths were due to severe hemorrhagic events in the context of DIC.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInduction Therapy and Complications\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydroxyurea use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATRA\u0026thinsp;+\u0026thinsp;ATO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATRA\u0026thinsp;+\u0026thinsp;chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with \u0026ge;\u0026thinsp;1 complication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlveolar bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDifferentiation syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eConsolidation, maintenance therapy, and outcomes\u003c/h3\u003e\n\u003cp\u003eOf the 30 patients, 26 (86.7%) survived the induction phase and proceeded to consolidation therapy. Most received consolidation with ATRA plus ATO, while a minority continued consolidation at another center.\u003c/p\u003e \u003cp\u003eAt the end of consolidation, all evaluable patients achieved molecular complete remission. During consolidation, one patient died, and one additional patient died after completing maintenance therapy from a cause unrelated to APL. No hematologic or molecular relapses were detected during follow-up, and none of the patients underwent hematopoietic stem cell transplantation. Overall, 24 patients (80.0%) were alive in continuous remission at last follow-up.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eConsolidation and Maintenance Outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStarted consolidation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (86.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATRA\u0026thinsp;+\u0026thinsp;ATO consolidation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular CR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath during consolidation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath post-maintenance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFactors Associated with Early Mortality\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHigher in early-death group\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eProlonged in early-death group\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.938\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eANC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrinogen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.378\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-dimer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eFactors associated with early mortality\u003c/h3\u003e\n\u003cp\u003eIn univariable analyses, higher baseline WBC count at diagnosis was significantly associated with early death (p\u0026thinsp;=\u0026thinsp;0.038). Prolonged PT at diagnosis was also significantly associated with early mortality (p\u0026thinsp;=\u0026thinsp;0.033). Other baseline laboratory parameters, including hemoglobin, ANC, platelet count, fibrinogen, and D-dimer, were not significantly different between patients who died early and those who survived beyond 30 days.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurvival and Remission Summary\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly deaths\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (13.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR after induction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100% of survivors\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular CR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematopoietic stem cell transplant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlive at last follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (80%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this eight-year retrospective cohort of adult APL patients treated at a single tertiary center in Palestine, we found that risk-adapted ATRA-based therapy resulted in high rates of hematologic and molecular remission and an absence of documented relapse during the follow-up period. The early death rate of 13.3%, almost entirely due to hemorrhagic complications in the setting of DIC, is comparable to early mortality rates reported in population-based series from other countries, including Brazil, the United States and Denmark, where early death rates of 12\u0026ndash;19% have been described despite access to modern treatment (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eOur findings confirm that, when contemporary APL protocols are implemented, outcomes in a resource-constrained environment can approach those seen in high-income settings. All evaluable patients in our cohort achieved molecular CR following consolidation, and no relapses were observed during follow-up. While the limited sample size and heterogeneous follow-up duration mean that late relapses cannot be excluded, these results are broadly consistent with international data demonstrating the high curability of APL with differentiation therapy, particularly ATRA combined with ATO, compared with classical chemotherapy-based regimens (\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe median age of 37 years and balanced sex distribution in our cohort are consistent with reports from several other regions but younger than some Western series, such as a large U.S. study in which the median age was 53 years (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). This supports the notion that APL in many low- and middle-income settings tends to affect relatively younger adults compared with other AML subtypes, whose incidence peaks later in life (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Most of our patients presented with good performance status (ECOG 0\u0026ndash;1), which is in line with previous studies indicating that the majority of APL patients fall between ECOG 0 and 2 at diagnosis (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eBleeding was the most common presenting symptom, and overt DIC was documented in approximately one-quarter of patients at diagnosis, mirroring the classic hemostatic phenotype of APL and prior reports in which bleeding is present in the vast majority of patients (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The pronounced hemorrhagic diathesis in APL is driven by a complex interplay of DIC, hyperfibrinolysis and severe thrombocytopenia. Leukemic promyelocytes express procoagulant molecules such as tissue factor and annexin II, which activate coagulation and fibrinolytic pathways, leading to consumption of clotting factors and increased fibrin degradation (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Our observation that prolonged PT and higher WBC at diagnosis were significantly associated with early death lessens the central role of coagulopathy and disease burden in determining short-term outcomes.\u003c/p\u003e \u003cp\u003eDifferentiation syndrome occurred in a minority of patients in our cohort, entirely in the absence of prophylactic corticosteroids, and at elevated WBC counts. All cases were successfully managed with dexamethasone and temporary interruption of ATRA/ATO, with subsequent rechallenge. The observed incidence falls within the wide range reported in the literature (2.5\u0026ndash;63%), which reflects differences in diagnostic criteria, induction regimens, leukocyte thresholds and use of steroid prophylaxis (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Our experience supports the use of close clinical monitoring, early recognition, and standardized management protocols for differentiation syndrome in routine practice.\u003c/p\u003e \u003cp\u003eAn interesting feature of our cohort is the relatively high proportion of high-risk APL (26.7%) compared with some international series, where high-risk disease often accounts for around 10\u0026ndash;15% of cases (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). This may be related to delayed presentation, referral bias toward more complex or unstable cases at a tertiary center, or differences in diagnostic and referral pathways. Although high-risk classification appeared to correlate with early mortality, this association did not reach statistical significance in our small sample.\u003c/p\u003e \u003cp\u003eFrom a health-systems perspective, our findings highlight several key messages. First, early death in APL remains a major barrier to cure and is concentrated in the first weeks after diagnosis. Strategies to reduce early mortality in Palestine should focus on shortening the interval between first contact and initiation of ATRA, improving early recognition of suspected APL in peripheral hospitals, and ensuring immediate availability of ATRA and blood products. Second, our results demonstrate that, once patients reach a specialized center and receive standardized ATRA-based therapy and supportive care, long-term outcomes can be excellent. This supports investment in regional referral pathways, training for non-hematology clinicians on APL as a hematologic emergency, and national adoption of risk-adapted APL protocols.\u003c/p\u003e \u003cp\u003eStrengths and limitations\u003c/p\u003e \u003cp\u003eThis study has several limitations. Its retrospective design and single-center setting limit the generalizability of the findings and introduce a risk of selection and information bias. The sample size is small, with only four early death events, which restricts statistical power and precludes robust multivariable analysis of prognostic factors. Some laboratory and complication data were missing due to incomplete documentation, and MRD monitoring was not consistently performed for all patients. Follow-up duration, although sufficient to capture early outcomes, may not fully reflect late relapses.\u003c/p\u003e \u003cp\u003eNonetheless, the study also has important strengths. To our knowledge, it represents the first systematic description of adult APL in Palestine and provides real-world data on presentation, treatment and outcomes from the main national referral center. The cohort includes all consecutive adult cases treated over an eight-year period, and detailed data on complications and supportive care are available. Importantly, the results show that, with timely diagnosis and implementation of ATRA-based protocols, outcomes in a resource-limited setting can approximate those in high-income countries.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAPL is a hematologic emergency that requires rapid recognition and immediate initiation of appropriate therapy to prevent fatal hemorrhagic complications. In this single-center Palestinian cohort, modern ATRA-based treatment regimens resulted in high rates of hematologic and molecular remission, with no observed relapses during follow-up. Early mortality remained a major challenge and was driven by hemorrhagic events in the context of DIC, particularly in patients with higher WBC and prolonged PT at diagnosis.\u003c/p\u003e \u003cp\u003e Our findings support the view that newly diagnosed APL is a highly curable disease when guideline-concordant differentiation therapy and intensive supportive care are available, even in resource-limited environments. Strengthening early diagnostic pathways, ensuring rapid access to ATRA and blood products, and standardizing supportive care protocols may further reduce early deaths in Palestine. Larger multicenter studies and national registries are needed to validate these observations, refine prognostic stratification and optimize APL management across the region.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAPL: acute promyelocytic leukemia\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;AML: acute myeloid leukemia\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ANC: absolute neutrophil count\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ATRA: all-trans retinoic acid\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ATO: arsenic trioxide\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CR: complete remission\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;DIC: disseminated intravascular coagulation\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;DFS: disease-free survival\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ECOG: Eastern Cooperative Oncology Group\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;FISH: fluorescence in situ hybridization\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ISTH: International Society for Thrombosis and Haemostasis\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IQR: interquartile range\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MRD: minimal residual disease\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MTX: methotrexate\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;NNUH: An-Najah National University Hospital\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PT: prothrombin time\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;RT-PCR: reverse transcriptase polymerase chain reaction\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;WBC: white blood cell count\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;6-MP: 6-mercaptopurine\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study received ethical approval from the Ethics Committee of An-Najah National University Hospital, Nablus, Palestine, in 2023, in accordance with national regulations and the principles of the Declaration of Helsinki (1964) and its subsequent amendments. Owing to the retrospective design and use of anonymized data, the requirement for informed consent was waived.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions\u003c/p\u003e\n\u003cp\u003eR.T. collected the data together with M.I. and M.K. A. R.T. analyzed the data, wrote the manuscript and revised it. R.A. critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the medical, nursing and administrative staff of the Hematology and Oncology Department at An-Najah National University Hospital for their support in patient care and assistance with data retrieval.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGrignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M, et al. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell. 1993;74(3):423\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the acute leukaemias. 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The evaluation of risk factors leading to early deaths in patients with acute promyelocytic leukemia: a retrospective study. Ann Hematol. 2022;101(5):1049\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChin KK, Tallman MS. Curative strategies for high-risk acute promyelocytic leukemia. Curr Opin Oncol. 2025;37(6):633\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZapata-Canto N, Aguilar M, Arana L, Montano E, Ramos-Penafiel C, De la Pena JA, et al. Acute Promyelocytic Leukemia: A Long-Term Retrospective Study in Mexico. J Hematol. 2021;10(2):53\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGill H, Raghupathy R, Lee CYY, Yung Y, Chu HT, Ni MY, et al. Acute promyelocytic leukaemia: population-based study of epidemiology and outcome with ATRA and oral-ATO from 1991 to 2021. BMC Cancer. 2023;23(1):141.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMunroe M, Chamba C, Yonazi M, Mahfudh S, Mawalla W, Mbelekwa K et al. Low survival in younger adults with Acute Myeloid Leukemia (AML) in Tanzania linked to high disease burden and socioeconomic factors. PLoS ONE. 2025;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParas G, Othus M, Schonhoff K, Shaw C, Sorror M, Halpern AB, et al. Effect of ECOG performance status on outcomes in patients with acute myeloid leukemia and other high-grade myeloid neoplasms. Leukemia. 2023;37(1):231\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29(33):4417\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSorror ML, Storer BE, Fathi AT, Gerds AT, Medeiros BC, Shami P, et al. Development and Validation of a Novel Acute Myeloid Leukemia-Composite Model to Estimate Risks of Mortality. JAMA Oncol. 2017;3(12):1675\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel R, Patel D, Patel M, Ohemeng-Dapaah J, Onyechi A, Patel Z, et al. Disseminated Intravascular Coagulation in Acute Promyelocytic Leukemia Patients: A Retrospective Analysis of Outcomes and Healthcare Burden in US Hospitals. Turk J Haematol. 2024;41(1):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHermsen J, Hambley B. The Coagulopathy of Acute Promyelocytic Leukemia: An Updated Review of Pathophysiology, Risk Stratification, and Clinical Management. Cancers. 2023;15(13):3477.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBreen K, Grimwade D, Hunt B. The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia. Br J Haematol. 2011;156:24\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwaan H, Weiss I, Tallman M. The Role of Abnormal Hemostasis and Fibrinolysis in Morbidity and Mortality of Acute Promyelocytic Leukemia. Semin Thromb Hemost. 2019;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMontesinos P, Sanz M. The Differentiation Syndrome in Patients with Acute Promyelocytic Leukemia: Experience of the Pethema Group and Review of the Literature. Mediterranean J Hematol Infect Dis. 2011;3:e2011059.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNayak AR, Aggarwal M, Naranje P, Dass J, Kumar P. An Untimely Occurrence of Differentiation Syndrome in APL- Better be Suspicious. Indian J Hematol Blood Transfus. 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJimenez JJ, Chale RS, Abad AC, Schally AV. Acute promyelocytic leukemia (APL): a review of the literature. Oncotarget. 2020;11(11):992\u0026ndash;1003.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChin K-K, Tallman M. Curative strategies for high-risk acute promyelocytic leukemia. Curr Opin Oncol. 2025;37.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Acute promyelocytic leukemia, induction therapy, early mortality, complete remission, arsenic trioxide, Palestine","lastPublishedDoi":"10.21203/rs.3.rs-8456765/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8456765/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), accounting for 5–20% of AML cases and characterized by a high risk of early mortality, most commonly due to hemorrhage secondary to disseminated intravascular coagulation (DIC). The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed APL into a highly curable disease, with survival rates approaching 90% despite its historically poor prognosis. Data on APL outcomes in Palestine are rare. This study aimed to describe the clinical characteristics, treatment-related complications, and mortality in adult APL patients treated at a tertiary cancer center in Palestine, and to explore factors associated with early death and poor prognosis.\u003c/p\u003e\n\u003cp\u003eMethods: We conducted a retrospective cohort study of 30 adult patients (≥18 years) diagnosed with APL between January 2016 and June 2024 at An-Najah National University Hospital (NNUH), West Bank, Palestine. Low-risk patients received ATRA plus ATO, whereas high-risk patients received ATRA in combination with anthracycline-based chemotherapy. Demographic, clinical, and laboratory data, treatment details, complications, and outcomes were abstracted from medical records. Early death was defined as death within 30 days of diagnosis. Continuous variables were summarized as medians with interquartile ranges (IQRs), and categorical variables as frequencies and percentages. Group comparisons used the Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables.\u003c/p\u003e\n\u003cp\u003eResults: Thirty patients (15 males, 15 females) with a median age of 37 years (range, 18–79) were included. According to the Sanz risk score, 9 (30.0%) were low-risk, 13 (43.3%) intermediate-risk and 8 (26.7%) high-risk. Most patients presented with preserved performance status (ECOG 0–1). Median baseline values at diagnosis were: hemoglobin 9 g/dL, white blood cell (WBC) count 4.8×10⁹/L, platelet count 18.1×10⁹/L, absolute neutrophil count 0.95×10⁹/L, prothrombin time (PT) 17.2 seconds, fibrinogen 142.5 mg/dL and D-dimer 30.9. The early death rate (EDR) was 13.3% (4/30): one patient died before induction and three died during induction; all early deaths were due to hemorrhage related to DIC. Among the 26 patients who survived beyond 30 days and completed induction, all achieved complete remission (CR); approximately two-thirds achieved CR after the first induction cycle and the remainder after a second cycle. The median time to hematologic remission was 35 days. During consolidation and maintenance, one patient died during consolidation and one died after completing maintenance from a non-leukemia-related cause. No relapses were observed, and no patient required hematopoietic stem cell transplantation by the end of follow-up. Higher WBC (p = 0.038) and prolonged PT at diagnosis (p = 0.033) were significantly associated with early death; hemoglobin, ANC, platelets, fibrinogen, and D-dimer were not.\u003c/p\u003e\n\u003cp\u003eConclusions: In this single-center Palestinian cohort, APL outcomes with ATRA-based protocols were comparable to those reported from high-resource settings, with high remission rates and no observed relapse during follow-up. Early mortality, driven by hemorrhagic complications, remained the main obstacle to cure and was associated with higher leukocyte counts and more pronounced coagulopathy at diagnosis. These findings highlight the importance of timely diagnosis, immediate initiation of ATRA, and intensive supportive care in resource-limited settings, and support the need for larger multicenter studies in the region.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics and treatment outcomes of adult acute promyelocytic leukemia in the West Bank of Palestine: a single-center retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-28 11:56:30","doi":"10.21203/rs.3.rs-8456765/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-11T17:17:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-05T16:10:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-04T13:13:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-03T17:13:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-02T21:08:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2905674596290939008638881684941130576","date":"2026-02-01T15:27:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"110727674306992136597899397323037808533","date":"2026-01-31T02:18:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194026292122107155724862672836858870072","date":"2026-01-26T11:28:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"67129225525971739506447287755203969849","date":"2026-01-25T16:03:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"215564520758300961573854030187431624937","date":"2026-01-24T08:41:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"273759988765245236909955859568953762782","date":"2026-01-23T16:28:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"103955353552301121303515147730077406625","date":"2026-01-23T16:23:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-23T15:26:30+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-05T14:57:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-05T07:42:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-05T07:39:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-12-26T16:38:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c154222a-1490-41a5-b309-8681dc61767e","owner":[],"postedDate":"January 28th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T16:00:57+00:00","versionOfRecord":{"articleIdentity":"rs-8456765","link":"https://doi.org/10.1186/s12885-026-16031-0","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2026-04-20 15:57:39","publishedOnDateReadable":"April 20th, 2026"},"versionCreatedAt":"2026-01-28 11:56:30","video":"","vorDoi":"10.1186/s12885-026-16031-0","vorDoiUrl":"https://doi.org/10.1186/s12885-026-16031-0","workflowStages":[]},"version":"v1","identity":"rs-8456765","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8456765","identity":"rs-8456765","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}