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Abstract: The introduction of all-trans retinoic acid combined with anthracyclines has significantly improved the outcomes for patients diagnosed with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries in which arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly because of high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the International Consortium on Acute Promyelocytic Leukemia study involving 806 patients with APL recruited from 2005 to 2020 in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has notably decreased to 14.6% compared with the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age of ≥40 years, Eastern Cooperative Oncology Group performance status score of 3, high-risk status based on the Programa Español de Tratamiento en Hematologia/Gruppo Italiano Malattie EMatologiche dell'Adulto classification, albumin level of ≤3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival rate is 81%, the 4-year disease-free survival rate is 80%, and the 4-year cumulative incidence of relapse rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia (AML) that was previously one of the most fatal forms of acute leukemia. With advances in diagnosis and treatment, APL has become one of the most curable myeloid leukemias. The major reason for treatment failure in APL is early death after initiation of treatment. We performed a retrospective cross-sectional analysis of the Healthcare Cost and Utilization Project 2016 and 2019 Kids' Inpatient Database, with the diagnosis of APL or AML not in remission as defined by ICD-10-CM codes. We compared complications and outcomes associated with APL and AML (exclusive of APL) in hospitalized children in the U.S. and described yearly national incidence. The national incidence of APL was 2.2 cases per million children per year. Children with APL were more likely to have cardiopulmonary complications (OR 1.79; CI 1.20-2.67; p  = 0.004), coagulation abnormalities or DIC (OR 7.75; CI 5.81-10.34; p  < 0.001), pulmonary hemorrhage (OR 2.18; CI 1.49-3.17; p  < 0.001), and intracranial hemorrhage (OR 10.82; CI 5.90-19.85; p  < 0.001) and less likely to have infectious complications (OR 0.48; CI 0.34-0.67; p  < 0.001) compared to children with AML. In-hospital mortality rates were similar in children with APL and AML (4.2% vs 2.6%; OR 1.62; CI 0.86-3.06; p  = 0.13), while the median length of stay for children who died from APL was shorter compared to AML (2 (IQR: 1-7) versus 25 (IQR: 5-66) days; p  < 0.05). Hemorrhagic complications occur more often, and infectious complications occur less often in hospitalized children with APL compared to AML.

Introduction: In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the clinical significance of CD117 antigen in acute promyelocytic leukemia (APL). The aim of this study was to retrospectively analyze the clinical features and prognostic significance of CD117 in APL., Methods: In this study, we retrospectively investigated the clinicopathological characteristics, outcome, and prognostic impact of negative CD117 expression (CD117 - ) in 169 APL patients treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) containing regimen., Results: The median follow-up period was 63.0 months. CD117 - was detected in 13 APL patients (7.7%). No significant differences were found in baseline characteristics between CD117+ and CD117 - subgroups. However, compared to CD117+ APL, the incidence of early death (ED) was significantly higher in CD117 - APL (p = 0.023). By multivariate analysis, CD117- was an independent adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) (p = 0.022 and p = 0.014, respectively)., Conclusions: To sum up, CD117 - is associated with greater risk of ED and has the statistical power to predict inferior OS and PFS, this marker may be considered to build prognostic scores for risk-adapted therapeutic strategies in APL management., (© 2024 The Author(s). International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

This study was conducted to identify the characteristics and risk factors for early death in critically ill acute promyelocytic leukaemia (APL) patients in the Hemato-oncology ICU (HICU). A total of 44 APL patients from 2017 to 2023 were included. The mortality among APL patients in the HICU was high (27/44, 61.36%). Compared with patients who survived, nonsurvivors had a longer prothrombin time (P = 0.002), lower fibrinogen (P = 0.022), higher white blood cell count (P = 0.004) and higher creatinine (P = 0.037) on hosipital admission. Severe bleeding was the most frequent complication (34 cases, 77.27%), which occurred either preinduction or on Day 5 (IQR 3-7.5 days) of induction. Cerebral bleeding associated with consciousness disturbance was the main reason for HICU admission (18 cases, 40.9%). The leading cause of death was fatal haemorrhage (18/34, 52.94%), which occurred either preinduction or on Day 4 (IQR 3-7 days) of induction. Another common cause of death was sepsis (8/18, 44.44%), which occurred on Day 12 (IQR 9.5-24.75 days) during induction. In conclusion, the main cause of death in APL patients treated in the HICU was primary being attributed to fatal bleeding, followed by sepsis., (© 2024. The Author(s).)

Objective: To describe the prognostic variables and course of paediatric acute promyelocytic leukaemia (APL) in Pakistan., Study Design: Cohort study. Place and Duration of the Study: Department of Paediatric Oncology, Combined Military Hospital, Rawalpindi, Pakistan, from January 2012 to December 2022., Methodology: Patients aged 1-15 years, clinically confirmed APL with promyelocytic leukaemia- retinoic acid receptor alpha (PML-RARA) were enrolled. Initial admission included a thorough examination, recording demographic and clinical data, reporting time, prior treatment, and socioeconomic status. Statistical analysis used SPSS 25.0, with significance at p <0.05., Results: This study included 50 cases of APL. Out of which, 32 (64%) were males and 18 (34%) were females. The mean age at diagnosis was 7.02 ± 3.86 years. Pallor (96%) and fever (88%) were common presentations. The average white blood cell count was 28.70 ± 35.39 x109/L. Treatment protocols include 48% International Consortium for Childhood (ICC)-APL, and 52% arsenic trioxide (ATO). High-risk cases were 54%. Neutropenic fever and differentiation syndrome were common induction complications. Delays over one month increased induction deaths (6.7 to 35%, p = 0.011), reducing disease-free survival (DFS), (76.7 to 35%, p = 0.001), and overall survival (OS), (80 to 45%, p = 0.007). After 40.90 ± 45.19 months' follow-up, 10-year OS and DFS were 66.0% and 60.0%, respectively. The best OS and DFS, at 80%, were observed in standard-risk cases treated with ATO., Conclusion: Neutropenic fever and bleeding were the primary causes of mortality in paediatric APL induction. Treatment delay was a key prognostic factor. ATO-based therapy offered safer, improved DFS, and OS suitable for primary healthcare settings., Key Words: Acute promyelocytic leukaemia, Chemotherapy, Neutropenic fever.

There is an urgent need for an oral, efficient and safe regimen for high-risk APL under the pandemic of COVID-19. We retrospectively analysed 60 high-risk APL patients. For induction therapy (IT), in addition to all-trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650-1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8-44) versus 35 days (32-42; p = 0.75) and 3 months (0.8-3.5) versus 3.3 months (2.4-3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2-year estimated overall survival and event-free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The outcome of patients with acute promyelocytic leukemia (APL) has improved significantly since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as APL therapies. The optimal therapy for APL relapse is believed to require autologous or allogeneic stem cell transplantation (SCT) based on historical experience., Study Aims: To evaluate the outcome of patients with relapsed APL before and after the era of ATRA-ATO., Patients and Methods: We reviewed 61 patients with relapsed APL treated from November 1991 to June 2023; 31 patients (51%) received modern therapy with the combination of ATRA and ATO with and without idarubicin and gemtuzumab ozogamicin (GO)., Results: Overall, 56 patients (92%) achieved CR after the first salvage therapy; 20 patients received SCT (10 autologous SCT;10 allogeneic SCT). With a median follow-up time of 138 months, the median survival durations were 32 months and 164 months with historical therapy vs. modern (ATRA-ATO) therapy (P = .035); the 5-year survival rates were 44% vs. 71%. With a 10-month landmark analysis, the median survival durations were 102 months vs. not reached, and the 5-year survival rates were 57% and 70% without SCT vs. with SCT (P = .193). The survival benefit with SCT was more prominent in the historical therapy era. However, patients who received the modern combination therapy of ATRA-ATO with and without idarubicin and GO had similar outcomes without vs. with SCT (P = .848)., Conclusion: The combination of ATRA-ATO (+/- GO and idarubicin) is a highly effective salvage therapy in relapsed APL. The use of SCT may not be needed after first relapse-second remission but may be considered in subsequent relapses., Competing Interests: Disclosure Koji Sasaki reports personal fees from Otsuka and Pfizer, outside the submitted work; research funding from Novartis; advisory boards from Novartis. Farhad Ravandi reports research funding from Amgen, Cyclacel LTD, Macrogenix, Menarini Ricerche, Selvita, and Xencor; and personal fees from Amgen, Macrogenix, and Xencor, all outside the submitted work. Guillermo Garcia-Manero reports grants or research support from Amphivena, Helsinn, Novartis, AbbVie, Bristol-Myers Squibb, Astex, Onconova, H3 Biomedicine, Merck, Curis, Janssen, Genentech, Forty Seven, and Aprea; and personal fees from Bristol-Myers Squibb, Astex, Helsinn, and Genentech outside the submitted work. Tapan Kadia reports research Funding from AbbVie, Amgen, BioLine Rx, Bristol‐Myers Squibb, Celgene, Jazz, and Pfizer; and personal fees from AbbVie, Amgen, Genentech, Jazz, Pfizer, Pharmacyclics, and Takeda, all outside the submitted work. Courtney DiNardo reports personal fees and honoraria from AbbVie, Agios, Celgene, Daiichi Sankyo, Jazz, Medimmune, and Syros, all outside the submitted work. Musa Yilmaz reports research funding from Pfizer and Daiichi-Sankyo. Nicholas Short reports research funding from Takeda Oncology; and personal fees from Amgen, AstraZeneca, and Takeda Oncology, all outside the submitted work. Gautam Borthakur reports research funding from AbbVie, Agensys, Arvinas, AstraZeneca, Bayer Healthcare AG, BioLine Rx, Bristol‐Myers Squibb, Cantargia AB, Cyclacel, Eli Lilly and Company, Esai, GlaxoSmithKline, Incyte, Merck, Novartix, Oncoceutics, Polaris, Tetralogic Pharmaceuticals, and XBiotech USA; and personal fees from Argenx, BioLine Rx, BioTheryX, FTC Therapeutics, NKarta, Strategia Therapeutics, and TPC Therapeutics, all outside the submitted work. Hagop Kantarjian reports research grants and honoraria from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis, Pfizer and Sanofi; honoraria from Actinium (Advisory Board), Adaptive Biotechnologies, Aptitude Health, BioAscend, Delta Fly, Janssen Global, Oxford Biomedical and Takeda Oncology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acute promyelocytic leukemia (APL) stands out as a distinctive form of acute leukemia, exhibiting a higher occurrence of thrombotic events when contrasted with other leukemia subtypes. Since thrombosis is a relatively rare but unfavorable condition with poor prognostic implications, it is crucial to determine the risk factors for thrombotic events in APL(thrombosis in large venous or arterial from onset to differentiation therapy in 30d). We performed a retrospective study involving 950 APL patients between January 2000 and October 2022, from which 123 were excluded by younger than 16 years of age, 95 were excluded by incomplete data, and 6 were excluded by thrombosis related to CVC or PICC. A total of 23 APL patients with thrombosis for inclusion in our analysis were performed a 1:5 ratio matching based on sex (perfect match) and age (within 5 years) to patients without thrombosis. These patients were continuously monitored in the outpatient department over a period of 5 years. We meticulously examined clinical and laboratory data to pinpoint the risk factors related to thrombotic events in APL. Our primary clinical endpoints were all-cause mortality and achieving complete remission, while secondary clinical outcomes included APL relapse. Thrombotic events were observed in 2.4% (23/950) of APL patients. Compared to patients without thrombosis, patients with thrombosis had higher lactate dehydrogenase (LDH) [313 (223, 486) vs. 233 (188, 367) U/L, p = 0.020], higher indirect bilirubin [11.2 (7.4, 18.6) vs.8.3 (6.0, 10.7) umol/L, p = 0.004], higher creatinine [72 (62, 85) vs. 63 (54, 74) umol/L, p = 0.026], higher CD2 expression (65.2 vs. 15.2%, p < 0.001), higher CD15 expression (60.9 vs. 24.3%, p = 0.001), and PML/RARαisoforms (p < 0.001). Multivariate-logistic-regression analysis revealed several factors that were markedly related to thrombosis, including LDH (OR≈1.003, CIs≈1.000-1.006, p = 0.021), indirect bilirubin (OR≈1.084, CIs≈1.000-1.188, p = 0.043), CD2 expression positive (OR≈16.629, CIs≈4.001-62.832, p < 0.001), and CD15 expression positive (OR≈7.747, CIs≈2.005-29.941, p = 0.003). The S-type (OR≈0.012, CIs≈0.000-0.310, p = 0.008) and L-type (OR≈0.033, CIs≈0.002-0.609, p = 0.022) PML/RARα isoforms were negatively associated with thrombosis. Kaplan-Meier curves indicated that the survival rates were remarkably varied between APL patients with and without thrombosis (HR:21.34, p < 0.001). LDH and indirect bilirubin are variables significantly associated with thrombosis in APL, S-type and L-type PML/RARαisoforms exhibit a negative association with thrombotic events. The thrombotic events of APL can predict the subsequent survival of thrombosis. The findings of our study have the potential to facilitate early detection of thrombosis and enhance the prognosis for individuals with APL who develop thrombosis. Further validation of our findings will be essential through future prospective or multicenter studies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Outcomes of childhood acute promyelocytic leukemia (APL) have exceeded 90% in the era of differentiating agents. In resource-limited settings, early mortality secondary to coagulopathy remains a significant challenge. Differentiation syndrome is a unique complication of APL therapy that requires a high degree of suspicion for timely initiation of therapy., Methods: A retrospective study of children ≤15 y of age with APL diagnosed between January-2013 and June-2019 treated at a tertiary cancer centre was conducted. Patients with a total leukocyte count ≥10,000/µL were risk stratified as high-risk. Treatment included differentiating agents, all-trans retinoic acid and arsenic trioxide along with chemotherapy. Baseline demographics, clinical complications and outcomes were analysed., Results: Out of 90 patients treated, 48 (53%) had high-risk APL and 25 (28%) presented with significant bleeding manifestations. Response to therapy was excellent with 96% of evaluable patients achieving molecular remission by the end of consolidation phase. Differentiation syndrome occurred in 23 (25%) patients of which two expired. Early mortality rate was 5.5% and was due to severe hemorrhage most often at the time of presentation. The 3-y overall survival of the entire cohort was 91% (95% CI: 85-97%). Two of 4 patients with relapse of disease could be salvaged with only differentiating agents followed by autologous transplantation., Conclusions: Long-term outcomes of Indian children with APL are excellent. Timely management of coagulopathy and prompt initiation of differentiating agents along with appropriate cytoreductive measures is critical. Efforts to build academic-community partnerships to ensure timely diagnosis and emergency care in order to reduce early mortality are needed., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Despite therapeutic advances for acute promyelocytic leukemia (APL) with the emergence of all-trans retinoic acid, arsenic trioxide, and gemtuzumab-ozogamycin, approximately 10% of patients still experience disease relapse, typically occurring within 24 to 36 months following completion of front-line treatment. Traditionally, both allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) have been considered reasonable treatment options for relapsed APL; however, no randomized controlled studies have been conducted comparing allo-HCT and auto-HCT in patients with relapsed APL. We performed a systematic review/meta-analysis to assess the totality of evidence pertaining to allo-HCT or auto-HCT in relapsed APL. Our search identified 1158 references, of which 23 met our inclusion criteria. While acknowledging the limitations of comparing these 2 treatment modalities indirectly, based on results from separate meta-analyses, it appears that pooled rates of event-free survival (71% versus 54%), progression-free survival (63% versus 43%), and overall survival (82% versus 58%) are higher after auto-HCT. This difference can be explained in part by the higher risk of pooled nonrelapse mortality (NRM) in patients undergoing allo-HCT (29% versus 5%), owing to inherent risks associated with this modality. In the absence of a randomized prospective clinical trial comparing allo-HCT and auto-HCT, our results show that both modalities are acceptable in patients with relapsed APL. The higher pooled NRM rate with allo-HCT is an important consideration when choosing this option. Additionally, the comparable pooled relapse rate for auto-HCT and allo-HCT (24% versus 23%) provides a rationale for evaluating post-HCT consolidative strategies to mitigate this risk., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

In order to explore the risk factors of relapse and potential optimized therapeutic regimen of low-risk acute promyelocytic leukaemia (APL), here we retrospectively analysed 282 patients who were diagnosed between February 2014 and September 2021. The median follow-up was 59 (9-102) months. The 5-year overall survival and cumulative relapse incidence were 97.9% and 5.9%, respectively. In terms of different cytoreductive therapies, 86 patients were administered with hydroxycarbamide (30.5%), 113 with anthracyclines or cytarabine (40.1%), 31 with etoposide (11.0%) and 52 with no cytoreductive therapy (18.4%) during the induction therapy. The hydroxycarbamide treatment group did not decrease the relapse rate compared to the no cytoreduction group (11.4% vs. 5.9%, p = 0.289). Compared with the hydroxycarbamide group, the anthracyclines/cytarabine treatment group showed improved 5-year RFS (88.145% vs. 98.113%, p = 0.008). Multivariate Cox regression analysis revealed that myeloblasts in bone marrow at diagnosis, and PML-RARA transcript level of 6.5% or more after induction therapy were associated with a subsequent risk of relapse. The only factor positively reducing the relapse rate was anthracyclines/cytarabine cytoreductive treatment. In conclusion, cytoreductive chemotherapy in induction therapy plays a potential key role in the prognosis of low-risk APL., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Introduction: γδ T cells recognize and exert cytotoxicity against tumor cells. They are also considered potential immune cells for immunotherapy. Our previous study revealed that the altered expression of immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on γδ T cells may result in immunosuppression and is possibly associated with a poor overall survival in acute myeloid leukemia (AML). However, whether γδ T-cell memory subsets are predominantly involved and whether they have a relationship with clinical outcomes in patients with AML under the age of 65 remain unclear., Methods: In this study, we developed a multicolor flow cytometry-based assay to monitor the frequency and distribution of γδ T-cell subsets, including central memory γδ T cells (T CM γδ), effector memory γδ T cells (T EM γδ), and T EM expressing CD45RA (T EMRA γδ), in peripheral blood from 30 young (≤65 years old) patients with newly diagnosed non-acute promyelocytic leukemia (also known as M3) AML (AMLy-DN), 14 young patients with AML in complete remission (AMLy-CR), and 30 healthy individuals (HIs)., Results: Compared with HIs, patients with AMLy-DN exhibited a significantly higher differentiation of γδ T cells, which was characterized by decreased T CM γδ cells and increased T EMRA γδ cells. A generally higher TIGIT expression was observed in γδ T cells and relative subsets in patients with AMLy-DN, which was partially recovered in patients with AMLy-CR. Furthermore, 17 paired bone marrow from patients with AMLy-DN contained higher percentages of γδ and TIGIT+ γδ T cells and a lower percentage of T CM γδ T cells. Multivariate logistic regression analyses revealed the association of high percentage of TIGIT+ T CM γδ T cells with an increased risk of poor induction chemotherapy response., Conclusions: In this study, we investigated the distribution of γδ T cells and their memory subsets in patients with non-M3 AML and suggested TIGIT+ T CM γδ T cells as potential predictive markers of induction chemotherapy response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hou, Wang, Kong, Chen, Yao, Luo, Li, Jin and Wu.)

There is a lack of contemporary population-based data on the epidemiology of acute promyelocytic leukemia (APL) in the United States. In this study, we aim to elucidate the demographics and early mortality patterns of APL hospitalizations utilizing the National Inpatient Sample database from 2016-2019. APL's annual age-adjusted incidence rate was 0.28/100,000, and the incidence increased with age, with the peak incidence in the 75-79 age group at 0.62/100,000. Whites constituted the majority of admissions at 67.7%, followed by Hispanics at 15.3%, the youngest racial group with a median age of 40 years. The median length of stay was 31 days for patients age < 60 years and 25 days for age ≥ 60 years (p < 0.001). After adjusting for confounders, the mean length of stay was 7 days higher in teaching hospitals compared to non-teaching hospitals (p 0.001). Overall mortality was 12.1% (22.2% for age ≥ 60 and 6.4% for < 60 years {p < 0.001}), and 56.5% of deaths happened before 7 days, with the median time to death being 6 days. The proportion of early deaths (< 7 days) in non-teaching hospitals was higher than late deaths (≥ 7 days) (19.2% vs. 5%; p 0.03), and admission to a teaching hospital was associated with lower mortality (adjusted odds ratio 0.27; p 0.01). Therefore, optimal treatment strategies need to be explored to mitigate this significant early mortality, especially in non-teaching hospitals., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

For many cancers, adolescents and young adults (AYAs) have a poorer prognosis than pediatric patients. Our study evaluates survival outcomes of children (0-17 years) and AYAs (18-39 years) diagnosed with acute myeloid leukemia (AML) in the Netherlands between 1990 and 2015 (N = 2058) utilizing the population-based Netherlands Cancer Registry, which includes information on therapy and site of primary treatment. Five- and 10-year relative (disease-specific) survival were estimated for all patients, children and AYAs. Multivariable analyses were performed using generalized linear models (excess mortality) and logistic regression (early mortality). AYAs with AML had a substantially lower 5- and 10-year relative survival than children (5-year: 43% vs 58%; 10-year: 37% vs 51%). The gap in 5-year relative survival was largest (nearly 20 percent-points) in 2010 to 2015, despite survival improvements over time across all ages. The multivariable-adjusted excess risk of dying was 60% higher in AYAs (95% CI: 37%-86%). Early mortality (death within 30 days of diagnosis) declined over time, and did not differ between children and AYAs. In conclusion, AYAs diagnosed with AML in the Netherlands had a worse prognosis than pediatric patients. The survival gap seemed most pronounced in recent years, suggesting that improvements in care resulting in better outcome for children have not led to equal benefits for AYAs., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: Acute promyelocytic leukemia (APL) is a rare disease in children and there are some different characteristics between children and adult. We aimed to evaluate incidence, clinical characteristics and treatment outcomes of pediatric APL in Korea., Materials and Methods: Seventy-nine pediatric APL patients diagnosed from January 2009 to December 2016 in 16 tertiary medical centers in Korea were reviewed retrospectively., Results: Of 801 acute myeloid leukemia children, 79 (9.9%) were diagnosed with APL. The median age at diagnosis was 10.6 years (range, 1.3 to 18.0). Male and female ratio was 1:0.93. Thirty patients (38.0%) had white blood cell (WBC) count greater than 10×109/L at diagnosis. All patients received induction therapy consisting of all-trans retinoic acid and chemotherapy. Five patients (6.6%) died during induction chemotherapy and 66 patients (86.8%) achieved complete remission (CR) after induction chemotherapy. The causes of death were three intracranial hemorrhage, one cerebral infarction, and one sepsis. Five patients (7.1%) suffered a relapse during or after maintenance chemotherapy. The estimated 4-year event-free survival and overall survival (OS) rates were 82.1%±4.4%, 89.7%±5.1%, respectively. The 4-year OS was significantly higher in patients with initial WBC < 10×109/L than in those with initial WBC ≥ 10×109/L (p=0.020)., Conclusion: This study showed that the CR rates and survival outcomes in Korean pediatric APL patients were relatively good. The initial WBC count was the most important prognostic factor and most causes of death were related to serious bleeding in the early stage of treatment.

Background: Whether the characteristics and outcome of secondary acute promyelocytic leukemia (s-APL) are similar to de no APL (dn-APL) remains unknown., Patients and Methods: Using the SEER database, we identified 3877 patients with APL diagnosed from 2000 to 2014, including 465 s-APL and 3412 dn-APL., Results: Compared with dn-APL, s-APL werecharacterized by older median age, and a higher early mortality rate. Multivariate Cox model showed s-APL, older age, earlier year of diagnosis, and male gender were independently associated with worse survival. Notably, s-APL had a significantly inferior survival regardless of gender, race, marital status, and year of diagnosis. However, the difference between the 2 cohorts was only evident in younger patients (≤ 65 years) but was lost in older patients (> 65 years). Additionally, the majority of index cancer type was breast and prostate in female and male s-APL, respectively. Latency < 3 years was associated with superior survival in s-APL with breast index cancer., Conclusions: Inferior survival of s-APL points to the need for treatment improvement., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to evaluate the efficacy and safety of different doses of anthracyclines combined with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) for induction in newly diagnosed acute promyelocytic leukemia (APL)., Methods: One hundred and forty patients were included between January 2011 and December 2017. Seventy patients received low dose anthracycline, ATO and ATRA for induction chemotherapy; and other seventy patients received standard dose anthracycline, ATO and ATRA for induction chemotherapy., Results: The outcomes of both groups were similar: low dose group versus standard dose group: early mortality 5.7% vs. 10.0% ( P = 0.532), disease-free survival (DFS), probabilities of overall-survival (OS) at 2 years 94.6% vs. 95.1% ( P = 0.657), 92.8% vs. 88.2% ( P = 0.951), respectively. However, the standard-dose group was associated with a longer duration of neutropenia ( p < 0.001) and thrombocytopenia ( p < 0.001), more volumes of platelets ( p = 0.037) and red blood cell transfusions ( p < 0.001), and a higher rate of infections ( p = 0.042)., Conclusion: Low-dose group achieves outcomes similar to those of standard dose group for APL patients, but the low-dose group may be even safer than standard-dose group. So the low-dose anthracycline may be a better choice for newly diagnosed APL patients.

Purpose: Arsenic combined with all-trans retinoic acid (ATRA) is the standard of care for adult acute promyelocytic leukemia (APL). However, the safety and effectiveness of this treatment in pediatric patients with APL have not been reported on the basis of larger sample sizes., Methods: We conducted a multicenter trial at 38 hospitals in China. Patients with newly diagnosed APL were stratified into two risk groups according to baseline WBC count and FLT3-ITD mutation. ATRA plus arsenic trioxide or oral arsenic without chemotherapy were administered to the standard-risk group, whereas ATRA, arsenic trioxide, or oral arsenic plus reduced-dose anthracycline were administered to the high-risk group. Primary end points were event-free survival and overall survival at 2 years., Results: We enrolled 193 patients with APL. After a median follow-up of 28.9 months, the 2-year overall survival rate was 99% (95% CI, 97 to 100) in the standard-risk group and 95% (95% CI, 90 to 100) in the high-risk group ( P = .088). The 2-year event-free survival was 97% (95% CI, 93 to 100) in the standard-risk group and 90% (95% CI, 83 to 96) in the high-risk group ( P = .252). The plasma levels of arsenic were significantly elevated after treatment, with a stable effective level ranging from 42.9 to 63.2 ng/mL during treatment. In addition, plasma, urine, hair, and nail arsenic levels rapidly decreased to normal 6 months after the end of treatment., Conclusion: Arsenic combined with ATRA is effective and safe in pediatric patients with APL, although long-term follow-up is still needed.

To prevent early death, management of coagulopathy is important in patients with untreated acute promyelocytic leukemia (APL). This study aimed to clarify factors associated with in-hospital death in patients with coagulopathy during induction therapy for APL. We retrospectively identified patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) and developed coagulopathy, using a nationwide inpatient database in Japan. Of 1115 eligible patients, 175 (15%) died at a median of 13 days (interquartile range, 7-30) after admission. In the multivariable analysis, compared with younger patients (aged < 40 years), the occurrence of in-hospital death was significantly more common among older patients (aged ≥ 40 and < 60 years: odds ratio = 2.58 [95% confidence interval: 1.29-5.19]; aged ≥ 60 and < 80 years: 7.66 [3.89-15.10]; aged ≥ 80 years: 16.83 [7.41-38.21]). Delayed initiation of ATRA and no conventional chemotherapy were significantly associated with in-hospital death (1.79 [1.16-2.76] and 2.40 [1.47-3.92], respectively). A total of 699 patients (63%) received anticoagulant therapies, but none of these was significantly associated with lower mortality. Although the present study was constrained by a lack of laboratory findings because of database limitations, the results showed that untreated patients with APL, especially the elderly, had a poor prognosis. Immediate administration of ATRA may reduce in-hospital mortality., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: APL patients have recurrent alterations in FLT3, WT1, NRAS and KRAS. Gene mutations have a strong potential for involvement in pathogenesis and may have potential effects on the clinical manifestations. Gene mutations may even be associated with early death (ED) in APL patients. However, there is little published information on mutations in APL patients and whether they are attributed to early death., Methods: In this study, we retrospectively analyzed the clinical data and gene mutations of 134 de novo APL patients. We detected the gene mutations by next-generation sequencing (NGS) to investigate the genetic predictors of early death in APL patients. According to the number of gene mutations per patient, the 134 APL patients were divided into three groups. All patients received arsenic trioxide (ATO) alone as induction therapy. The clinical data and gene mutations were compared and analyzed., Results: A total of 134 APL patients were involved in the study. The clinical data of sex, WBC, PT, and DD, UA, and LDH level were significantly different between the three groups (P = 0.000, P = 0.000, P = 0.009, P = 0.020, P = 0.030, P = 0.001 and P = 0.014, respectively). Meanwhile, among them, the Sanz risk stratification and early death rate were significantly different (P = 0.001). The early death rate was 10.4%, and the median time to early death was 6.6 days (range 2-15 days). For the next-generation sequencing, a mean of 1.28 ± 1.06 mutations per patient was detected (range: 0-5). The univariate and the multivariate regression analysis showed that age > 50[HR = 1.666, CI (1.027-2.702), P = 0.039], high WBC count [HR = 4.702, CI (1.026-21.543), P = 0.046] and low ALB levels [HR = 4.547, CI (1.088-18.995), P = 0.038] were independent risk factors for early death in APL patients. Furthermore, Kaplan-Meier survival analysis, univariate analysis, and the multivariate regression analysis showed that patients with multiple gene mutations [HR = 2.258, CI (1.115-4.571), P = 0.024], KRAS [HR = 5.136, CI (1.356-19.455), P = 0.016] and/or GATA2 [HR = 4.070, CI (1.287-12.877), P = 0.017] have a significantly higher early death rate., Conclusion: The results of this investigation show that both molecular markers and clinical variables should be used as potential predictors for early death in APL patients. Our results suggested that age > 50, high WBC count, low ALB levels, and the presence of multiple gene mutations, KRAS and/or GATA2 at the time of diagnosis were independent risk factors for early death in APL patients. For these patients, clinicians should be more cautious during the course of induction treatment., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

Background: Acute myeloid leukemia (AML) is a common, challenging hematologic malignancy worldwide. Thai data on its characteristics and outcomes have never been systematically reported, to our knowledge. The objective of this study was to determine the clinical features and outcomes of Thai patients with AML., Patients and Methods: This was a prospective observational study of nine academic hospitals. Patients with newly diagnosed AML were invited to register online., Results: A total of 679 patients with AML were included. The presence of circulating peripheral blood blasts was correlated with a high white blood cell count. Acute promyelocytic leukemia (APL) had predominantly lower white blood cell counts and higher proportions without peripheral blood blasts compared with non-APL AML. Disseminated intravascular coagulation was commonly presented in APL (37.7%). Splenomegaly and normal platelet count were more frequently seen in patients with Philadelphia chromosome-positive AML. The median follow-up time for those who survived more than 1 year was 28.0 months. One-year overall survival rates for non-APL AML and APL were 31.9% and 88.2%, respectively; 2-year overall survival rates were 29.6% and 88.2%, respectively. Hematopoietic stem cell transplantation could improve survival in non-APL AML., Conclusion: APL should be considered despite absence of peripheral blood blast. This study demonstrates poor outcome of Thai AML and more research to improve outcomes are underway. Expanding access to hematopoietic stem cell transplantation should be considered in Thailand., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: The current stratification system for acute promyelocytic leukemia (APL) is based on the white blood cell (WBC) and the platelet counts (i.e., Sanz score) over the past two decades. However, the borderlines among different risk groups are sometimes ambiguous, and for some patients, early death and relapse remained challenges. Besides, with the evolving of the treatment strategy from all-trans-retinoic acid (ATRA) and chemotherapy to ATRA-arsenic trioxide-based synergistic targeted therapy, the precise risk stratification with molecular markers is needed., Experimental Design: This study performed a systematic analysis of APL genomics and transcriptomics to identify genetic abnormalities in 348 patients mainly from the APL2012 trial (NCT01987297) to illustrate the potential molecular background of Sanz score and further optimize it. The least absolute shrinkage and selection operator algorithm was used to analyze the gene expression in 323 cases to establish a scoring system (i.e., APL9 score)., Results: Through combining NRAS mutations, APL9 score, and WBC, 321 cases can be stratified into two groups with significantly different outcomes. The estimated 5-year overall ( P = 0.00031), event-free ( P < 0.0001), and disease-free ( P = 0.001) survival rates in the revised standard-risk group (95.6%, 93.8%, and 98.1%, respectively) were significantly better than those in the revised high-risk group (82.9%, 77.4%, and 88.4%, respectively), which could be validated using The Cancer Genome Atlas dataset., Conclusions: We have proposed a two-category system for improving prognosis in patients with APL. Molecular markers identified in this study may also provide genomic insights into the disease mechanism for improved therapy., (©2021 American Association for Cancer Research.)

The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML., (© 2021 American Cancer Society.)

Background: The Texas/Chihuahua (US/Mexico) border is a medically underserved region with many reported barriers for health care access. Although Hispanic ethnicity is associated with health disparities for many different diseases, the population-based estimates of incidence and survival for patients with blood cancer along the border are unknown. The authors hypothesized that Hispanic ethnicity and border proximity is associated with poor blood cancer outcomes., Methods: Data from the Texas Cancer Registry (1995-2016) were used to investigate the primary exposures of patient ethnicity (Hispanic vs non-Hispanic) and geographic location (border vs non-border). Other confounders and covariates included sex, age, year of diagnosis, rurality, insurance status, poverty indicators, and comorbidities. The Mantel-Haenszel method and Cox regression analyses were used to determine adjusted effects of ethnicity and border proximity on the relative risk (RR) and survival of patients with different blood cancer types., Results: Hispanic patients were diagnosed at a younger age than non-Hispanic patients and presented with increased comorbidities. Whereas non-Hispanics had a higher incidence of developing blood cancer compared with Hispanics overall, Hispanics demonstrated a higher incidence of acute lymphoblastic leukemia (RR, 1.92; 95% CI, 1.79-2.08; P < .001) with worse outcomes. Hispanics from the Texas/Chihuahua border demonstrated a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) compared with Hispanics living elsewhere in Texas., Conclusions: Hispanic ethnicity and border proximity were associated with a poor presentation and an adverse prognosis despite the younger age of diagnosis. Future studies should explore differences in disease biology and treatment strategies that could drive these regional disparities., (© 2020 American Cancer Society.)

Background: The characteristics and outcomes of patients with acute promyelocytic leukemia (APL) from sub-Saharan Africa have not been published., Patients and Methods: We report retrospectively on consecutively diagnosed APL patients treated in Cape Town, South Africa, during 1998-2019. A total of 69 patients were treated, of whom 27 (39%) were classified as having high risk APL., Results: Early death rates at 7 and 30 days were 7% and 13%, respectively, including 4 patients who died before any treatment could be administered. Overall survival at 3 years was 76.5% (95% confidence interval, 63.9-85.2) for the entire cohort, and 82.5% (95% confidence interval, 69.7-90.2) if patients who died within 7 days of diagnosis were excluded. For 13 patients (18.8%), there was a delay of 5 or more days from time of initial presentation at a peripheral hospital until arrival at the leukemia center and administration of all-trans retinoic acid; only 1 of these patients died within 30 days., Conclusion: Despite the challenges faced in the public healthcare system of a developing country, outcomes of APL patients treated at our center are similar to outcomes from developed countries., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Significant advancements have been achieved with regard to the outcomes of acute promyelocytic leukemia (APL) patients through the introduction of all-trans retinoic acid; however, early hemorrhagic death and differentiation syndrome remain the major causes of remission induction failure in patients with APL. To investigate early death, serious hemorrhage, and differentiation syndrome during remission induction therapy in terms of incidence, risk factors, influence on outcomes, and prophylactic effects of several new anticoagulants, the results of 344 patients enrolled in the Acute Promyelocytic Leukemia 204 study conducted by the Japan Adult Leukemia Study Group were analyzed. Early death was observed in 16 patients (4.7%), of whom 14 had serious hemorrhage and 2 had differentiation syndrome. Serious hemorrhage and differentiation syndrome of grade 2 or higher were observed in 21 and 54 patients, respectively. Patients who achieved complete remission had a 7-year disease-free survival of 84.8% if they did not experience serious hemorrhage and 40.0% if they experienced serious hemorrhage during remission induction therapy (P = 0.001). Risk factor analyses showed that higher white blood cell count was associated with early death, higher white blood cell count and lower platelet count with serious hemorrhage, and leukocytosis during induction therapy and higher body surface area with differentiation syndrome. In conclusion, these results indicate that patients with such high-risk features may benefit from more intensive supportive care. The hemorrhagic risk was not relieved by the introduction of new anticoagulants. Further studies are required to establish the predictive impact of body surface area on differentiation syndrome. This trial is registered with UMIN-CTR as C000000154 on September 13, 2005.

Background: Early death is still the characteristic feature of acute promyelocytic leukemia (APL) despite the advances in the treatment regimen. Analyzing the incidence of early death would prove beneficial as no much substantial information is available pertaining to the rural population. The present study analyzed the incidence of APL-associated early death, its clinical characteristics, and outcome among acute myeloid leukemia patients., Methods: This retrospective study included patients catering to the rural areas of Vijayawada (Andhra Pradesh, India) from January 2013 to June 2017. Chi-square test, Fisher's exact test, independent sample median test, and Kaplan-Meier test for probability of survival were used., Results: Of the 204 acute myeloid cases, 24% cases (median age = 30 years; range=8 to 68 years) were identified as APL. Early death rate was 34.6%, who expired within 30 days from diagnosis with 65% suffering high disease risk. The median time from admission to death was 2 days (range 0-18). Cause of early death was majorly due to hemorrhage (64%). Moreover, 47.1% of early death patients received no prior antileukemic treatment. The overall 5-year cumulative disease-free survival rate among patients with APL was 76% where high disease risk patients had the least disease-free survival (65%-75%), whereas intermediate and low-risk patients had >80% and 100% disease-free survival rate, respectively., Conclusion: Early diagnosis and timely intervention might help to prevent early death as our findings clearly indicate poor awareness of disease and lack of early intervention among the rural population., Competing Interests: None

Introduction: Acute promyelocytic leukemia (APL) is currently considered a highly curable disease. However, an early death (ED) remains one of the main causes of APL treatment failure., Patients and Methods: In this retrospective study, we aimed to analyze the clinical characteristics of 91 children and adolescents with APL, who were consecutively registered at the (name of institution removed) Children's Center from January 1, 1998 to December 31, 2017. Data were assessed for age, sex, ethnicity, body mass index percentile, initial white blood cell count, peripheral blood blast count, and platelet count, hemoglobin value, partial thromboplastin time, prothrombin time, fibrinogen level, serum creatinine level, APL morphology subtype (classic vs. hypogranular variant M3v), and FLT3 gene mutations., Results: ED occurred in 12 of 91 (13.1%) patients and was mainly related to cerebral thromboembolism. Overall 66% of deaths occurred in the second week after diagnosis. ED was associated with white blood cell ≥10×10 cells/L (odds ratio of 8.44; 95% confidence interval [CI]=1.48-48.26; P=0.0016), initial promyelocytes ≥20×10/L (odds ratio of 9.29; 95% CI=2.45-35.8; P=0.001), morphologic subtype M3v (odds ratio of 3.63; 95% CI=1.04-12.64; P=0.043), and creatinine serum levels >0.7 mg/dL (odds ratio of 6.78; 95% CI=1.83-25.13; P=0.004). In multivariate analyses, ED was associated with initial peripheral promyelocytes ≥20×10 blasts/L and creatinine serum levels >0.7 mg/dL., Conclusions: EDs were mainly caused by thrombohemorrhagic events and occurred within the second week after diagnosis. High peripheral promyelocytes and creatinine levels were predictors of ED in APL.

Patients with high-risk acute promyelocytic leukemia (APL) have inferior outcomes compared with patients with low-risk APL, predominantly due to higher risk of early mortality related to hemorrhage. The majority of regimens contain prolonged maintenance, but the impact of this phase is not clear in the era of all trans retinoic acid (ATRA) and arsenic trioxide (ATO). We present a retrospective analysis of 10 patients that were treated for high risk APL based on the consolidation treatment phase of APL 0406 study without subsequent maintenance. With a median follow up of 38 months, all patients remain in remission., Competing Interests: Declaration of Competing Interest H.P.E. reports honoraria from Agios, Celgene, Incyte, Jazz, and Novartis for speaker bureau participation. He has served as a paid consultant for Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, Immunogen, Incyte, Jazz, MacroGenics, Novartis, Pfizer, and Seattle Genetics. He has received fees from Covance as Chair of the Independent Review Committee of the AbbVie-sponsored VIALE-A and VIALE-C phase III studies. The other authors declare no conflicts of interest., (Copyright © 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

We stratified patients with newly diagnosed acute promyelocytic leukemia (APL) according to a white blood cell (WBC) count of ≥ 3 × 10 9 /L (high risk) or < 3 × 10 9 /L (low risk) before administering risk-adapted chemotherapy in combination with all-trans retinoic acid (ATRA). In total, 27 low-risk and 23 high-risk patients were assigned to receive induction and three courses of consolidation with ATRA and anthracycline, followed by 2-year maintenance regimen. High-risk group additionally received cytarabine during 1st consolidation and another one-shot idarubicin treatment during 3rd consolidation. We prospectively monitored measurable residual disease (MRD) after induction and each consolidation. In the low-risk and high-risk groups, 5-year disease-free survival (DFS) rates were 86.5% and 81.2% (p = 0.862), and 5-year overall survival rates were 100% and 84.8% (p = 0.062), respectively. In the MRD-negative and MRD-positive groups, 5-year DFS rates were 91.7% and 78.4% (p = 0.402) and 84.7% and 60.0% (p = 0.102) after induction and 1st consolidation, respectively. Relapse rates were 8.3% and 13.3% (p = 0.570) and 9.0% and 40.0% (p = 0.076) after induction and 1st consolidation, respectively. Achieving MRD-negativity after 1st consolidation, rather than after induction, was a potential predictor of relapse and DFS in patients with APL treated with ATRA + chemotherapy.

Background: After the inclusion of all-trans retinoic acid (ATRA) into the treatment of Acute Promyelocytic leukemia (APL), a notable improvement concerning the survival rates of patients with APL has been observed. However, the population-based studies demonstrated that there was no marked improvement in the survival of patients after the 2000s. We aim to describe the clinical response and prognosis of adult patients diagnosed with APL and examine the change in these outcomes by the time period of diagnosis., Methods: We retrospectively reviewed thirty-six unselected APL patients who were diagnosed between September 2003 and February 2016., Results: The probability of survival at two years was 58%, while disease-free survival (DFS) was 87%. The overall early death (ED) rate was 33% and remain stable over time [42% in 2003-2009 vs. 24% in 2010-2016 (p=.20)]. In addition, the 2-year overall survival (OS) rates were 47% in 2003-2009 and 70% in 2010-2016 (p=.29), and no differences were noted. Univariate analyses showed possible predictors of poor OS were defined as leukocytosis (≥10x109/L), high Sanz score, hemorrhage, infection, disseminated intravascular coagulopathy (DIC) at presentation and microgranular morphologic subtype., Conclusions: This study shows that long-term survival remains low in APL patients, particularly related to a high ED rate. Initiatives to reduce ED are exceedingly substantial for improving the survival in APL.

Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.

Background: Acute myeloid leukemia (AML) evolves from neoplastic transformation of stem cell disease termed "leukemia stem cells" (LSCs). An unsatisfactory response to AML therapy is determined by the presence of minimal residual disease (MRD). The predominance of LSCs might anticipate sustained MRD results. The present study aimed to demonstrate the effect of LSCs on MRD at induction days 14 and 28 on overall survival (OS) and disease-free survival (DFS) and to compare LSC expression with MRD status., Patients and Methods: A total of 84 patients with de novo adult AML underwent testing using LSC panels for CD38/CD123/CD34/CD45 and CD90/CD133/CD45/CD33 and different regular MRD panels., Results: At day 14 after induction, the high expression of CD123 and CD133 had adverse effects on both OS and DFS (P = .004 and P ≤ .001 and P ≤ .001 and P ≤ .001, respectively). Greater expression of CD34 + /CD38 - /CD123 + resulted in unfavorable OS and DFS (P ≤ .001 for both). Both CD34 + /CD38 - /CD123 + and CD34 - /CD38 + /CD123 + expression at day 14 after induction had an adverse effect on DFS only (P < .001 and P = .029, respectively). On multivariate analysis, CD133 expression and MRD status were independent prognostic parameters (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.2-4.4; P = .015; and HR, 2.9; 95% CI, 1.0-7.9; P = .041). At day 28 after induction, MRD and increased CD123 + /CD34 - , CD34 + /CD38 - /CD123 + , CD133 + /CD33 - expression were associated with inferior OS (P = .016, P = .0035, P = .0.002, and P = .002, respectively). MRD and high expression of CD34 + CD123 + , CD133 + /CD33 - , CD34 + /CD38 - /CD123 + were associated with inferior DFS (P < .001, P = .002, P < .001, P < .001, respectively). On multivariate analysis, only CD133 + /CD33 - expression was the independent prognostic factor (HR, 3.1; 95% CI, 1.5-6.7; P = .003)., Conclusions: Estimation of LSC expression is a sensitive indicator of the response to therapy in adult patients with AML and might be a better prognosticator than the findings from regular MRD panels., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The number of hematopoietic stem cell transplantation (HSCT) procedures performed for pediatric acute promyelocytic leukemia (APL) has decreased in the all-trans retinoic acid (ATRA) era. Although HSCT is still widely adopted as part of salvage therapy for relapsed patients, there is no general consensus about the optimal transplant type (autologous [auto-HSCT] or allogeneic HSCT [allo-HSCT])., Procedures: We retrospectively reviewed the clinical data of 95 childhood APL patients who underwent their first HSCT between 1990 and 2014. Of the 95 patients, 40 (42%), 41 (43%), and 3 (3%) underwent HSCT procedures after achieving their first complete remission (CR1), CR2, and CR3, respectively, and 11 (12%) underwent HSCT while in a non-CR state., Results: The non-CR group exhibited significantly worse five-year overall survival (5yOS) and disease-free survival (5yDFS) (5yOS: 46%; 5yDFS: 46%) than the CR1 (5yOS: 80%; 5yDFS: 78%) and CR2 + CR3 groups (5yOS: 81%; 5yDFS: 76%) (P = 0.013 and P < 0.01, respectively). Of the patients treated in CR2, no significant differences in 5yOS or the five-year cumulative incidence of relapse (5yRI) were detected between the auto-HSCT and allo-HSCT groups (5yOS: 85%, vs 78%, P = 0.648; 5yRI: 9%, vs 11%, P = 0.828). Among the patients who underwent allo-HSCT in CR2, those with matched sibling donors displayed a significantly higher 5yRI (33%) than those with other types of donors (0%, P = 0.015)., Conclusions: Even after relapsing, childhood APL can be cured with HSCT if CR is achieved. These findings demonstrate that achieving CR followed by HSCT is the preferred strategy for treating children with relapsed or refractory APL., (© 2020 Wiley Periodicals, Inc.)

In this study, we investigated the safety and efficacy of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). The patients had been classified as unfit to receive anthracycline-based chemotherapy due to high-risk factors for early death. Twenty-five patients with APL receiving ATO/ATRA between 2007 and 2018 were divided into 3 groups as follows: elderly patients (age ≥ 70 years) with poor performance status (32%); patients with severe active infections at diagnosis (56%); and patients with multiple significant comorbidities (24%) who were unfit for conventional chemotherapy, regardless of age. Induction therapy comprised 0.15 mg/kg/day ATO combined with 45 mg/m 2 /day ATRA until patients attained complete remission (CR). Notably, only one patient (4.0%) died of septic shock 2 days after the ATO treatment had been initiated. The remaining 24 patients attained CR despite their serious and desperate conditions at diagnosis. In total, 44%, 28%, and 32% of the patients experienced neutropenia (grade 3 or 4), thrombocytopenia, and hepatopathy, respectively. Twenty-three of the 24 patients in CR proceeded to consolidation therapy and attained complete molecular remission with favorable overall survival (90.7%). This study demonstrates the safety and efficacy profile of ATO/ATRA first-line therapy for patients with APL and high-risk features for early death.

Background: Acute promyelocytic leukemia (APL), a distinct variant of acute myeloid leukemia (AML), accounts for 10% of AML cases. Over the past decade, APL has emerged from a highly fatal disease to a highly curable one. The published data on outcomes of APL from India are scant. The present study was designed to analyze the clinicopathologic features and outcomes in adult APL., Materials and Methods: The present report is a single institutional, observational, retrospective study, and data of patients diagnosed with APL from 2006 to 2018 were analyzed. All patients with APL, diagnosed by morphology and confirmed by reverse transcriptase polymerase chain reaction (promyelocytic leukemia/retinoic acid receptor alpha) and over 18 years of age, were included in this study. SPSS software v25.1 was used for statistical analysis., Results: A total of 1396 patients with AML were seen between January 2005 and June 2018, of which 190 (13.6%) had APL. Of these, 111 patients met the inclusion criteria and were analyzed. The median age at presentation was 33 years (range, 19-60 years). The median duration of symptoms before presentation was 15 days (range, 3-180 days). High risk, intermediate risk, and low risk were seen in 43.3%, 41.4%, and 15.3% of patients, respectively. At the end of induction chemotherapy, 88 (79%) patients achieved complete hematologic remission, and 23 (21%) succumbed during induction. The median time to attain complete hematologic remission was 30 days (range, 19-47 days). At a median follow-up of 34 months, the event-free survival and overall survival were 69.3% and 74.7%, respectively. On univariate analysis, bcr3 variant and high-risk category at presentation had significant impact on event-free survival (P = .029 and P = .003, respectively) and overall survival (P ≤ .001 and P = .007, respectively). On multivariate analysis, only high risk at presentation was significant for event-free survival (P = .04) and overall survival (P = .02)., Conclusion: APL constituted one-tenth of patients with AML. The majority of patients were high risk at presentation. Sanz high risk category and bcr3 variant at presentation had significant impact on outcomes in APL., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The obesity/overweight may have an influence on APL outcomes., Methods: This is the biggest multicentre analysis on 1320 APL patients treated with AIDA-induction and risk-adapted consolidation between 1996 and 2012. Patients body mass index (BMI) was classified as underweight (<18.5 kg/m 2 ), normal (18.5-25 kg/m 2 ), overweight (25-29.9 kg/m 2 ), and obese (≥30 kg/m 2 ) according to the World Health Organization (WHO) criteria., Results and Conclusions: Relationship between male gender, older age, and other known laboratory abnormalities in overweight/obese patients was significant. The induction mortality rate was significantly higher in APL with BMI ≥25 vs BMI <25 (10% vs 6%; P = .04). APL patients with BMI ≥25 had a trend to lower OS (74% vs 80%; P = .06). However, in the multivariate analysis, BMI did not retain the independent predictive value (P = .46). There was no higher incidence of differentiation syndrome with BMI ≥25, but there was a trend in obese. There was no difference in relapse rate according to the BMI. In summary, overweight/obesity does not represent an independent risk factor for APL outcomes. The influence of obesity in APL patients treated with chemotherapy-free regimens remains to be established., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Acute promyelocytic leukemia (APL) has a characteristic peculiar morphologic and genetic features as well as a more favorable outcome. We studied the differential effect of bcr-1 and bcr-3 isoforms of the promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA) transcript together with FLT3 internal tandem duplication (FLT3-ITD) mutation status on the outcome of newly diagnosed de novo APL patients., Patients and Methods: This cohort study included all patients diagnosed with APL at outpatient medical and pediatric oncology clinics of the National Cancer Institute, Cairo University, Cairo, Egypt, from May 2012 to January 2018., Results: The study included 118 patients with APL, 71 adults (60.2%) and 47 children (39.8%). Median (range) age was 25 (1.5-70) years. Children had significantly higher total leukocyte count (≥10 × 10 9 /L), disseminated intravascular coagulation (DIC), and thrombocytopenia (< 40 × 10 9 /L) than adults (P = .04, .03, and .04, respectively), while the latter group had significantly higher hemorrhage than children (P = .04). FLT3-ITD mutation was detected in the whole group, children, and adults in 23.7%, 30.6%, and 24.6%, respectively. FLT3-ITD mutation was significantly associated with leukocytosis in the whole group (P = .039). bcr-3 was significantly associated with FLT3-ITD mutation in the whole APL cohort and in adults (P = .011, P = .022). All children (both bcr-1 and bcr-3) and all adult patients with bcr-3 experienced CR, while 22 (78.5%) of 28 patients with bcr-1 experienced CR (P = .04). APL patients with DIC and hemorrhage had significantly lower overall survival (P = .002 and < .001, respectively). Overall survival for APL in children was significantly better than in adults (P = .005). Multivariate analysis indicated that age was an independent prognostic variable affecting survival (hazard ratio = 2.6; 95% confidence interval, 1.3-5.3; P = .007) (adults had hazard ratio of death 2.6 times higher than children). DIC and FLT3-ITD were independent prognostic variables affecting survival in children with APL (hazard ratio = 12.3; 95% confidence interval, 1.46-104.61; P = .021; and hazard ratio = 5.2; 95% confidence interval, 1.01-26.95; P = .048, respectively)., Conclusion: Age is an independent prognostic factor for APL. bcr-3 is significantly associated with FLT3-ITD in adults with APL. DIC and FLT3-ITD are adverse prognostic factors in children with APL. Despite children being at higher risk, outcome is better than in adults., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Acute promyelocytic leukemia (APL) has a favorable prognosis. However, results of randomized studies do not necessarily reflect the outcomes of a real-life population., Patients and Methods: We analyzed 283 unselected APL patients treated in 20 Polish hospitals between 2005 and 2017. All patients were intended to be treated with PETHEMA (Programa Español para el Tratamiento de las Hemopatías Malignas) protocols based on all-trans retinoic acid plus chemotherapy., Results: The probability of overall survival at 4 years was 67%, while event-free survival was 64%. The early death (ED) rate was 20.1% (n = 57), while 3.5% (n = 10) patients died before induction therapy was started. The main causes of ED included hemorrhage (45.6%), infections (17.5%), and differentiation syndrome (14.5%). Of 273 treated patients, 214 (78.4%) experienced hematologic morphologic remission, 2 (0.7%) were found to have resistant disease, 47 (17.2%) could not be evaluated for response because of ED, and in 6 (3.7%) no data concerning the response were available. Multivariate analyses showed that predictors of ED and overall survival were Eastern Cooperative Oncology Group performance status > 2, age > 60 years, and all types of bleeding episodes that occurred before starting therapy, while an additional predictor of event-free survival was high white blood cell count (> 10 10 9 /L)., Conclusion: ED remains a major problem in APL patients, especially in a real-life population. Shortening of the time between the initial contact with a health care professional, and all-trans retinoic acid administration and the use of appropriate supportive care could improve the outcome of unselected APL population, mainly by reducing the ED rate., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Early death (ED) is the main cause of acute promyelocytic leukemia (APL) treatment failure, and the ED rate is higher for elderly patients than that for young ones. To date, no studies have been found focusing on ED in elderly patients with APL., Methods: This study retrospectively analyzed the clinical data of 409 consecutive patients with APL (139 patients ≥ 50 years old, 270 patients < 50 years old). All patients received arsenic trioxide alone as induction therapy. The baseline clinical characteristics and ED occurrence and predictors between elderly and young patients with APL were compared and analyzed., Results: The clinical features of elderly patients at admission were not significantly different from those of young ones. The ED rate of elderly patients was significantly greater than that of young patients (23.74% vs 11.85%, P = 0.0018). Hemorrhage is the main cause of ED in elderly patients, followed by infection and differentiation syndrome. From the 15th to 30th days of treatment, elderly patients had a higher mortality rate than that of young patients (7.83% vs 2.06%, P = 0.009). Male, white blood cell (WBC) count > 10 × 10 9 /L, fibrinogen < 1.0 g/L and low albumin levels were independent risk factors for ED in elderly patients, while ED was only correlated with WBC count, fibrinogen and creatinine levels in young patients., Conclusion: The results of this study may help design more rational treatment plans for elderly patients with APL based on early mortality risk to reduce the ED rate.

Background: The objective of this study was to conduct the first systematic evaluation of the long-term economic impact of arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) for the treatment of patients with newly diagnosed acute promyelocytic leukemia (APL) from the perspective of the Chinese health care system., Methods: On the basis of clinical data from a randomized phase 3 trial, a time-dependent Markov model with 4 health states (complete remission, relapse or treatment failure, post-treatment failure, and death) was used to evaluate the incremental costs per quality-adjusted life-year (QALY) gained from the ATO plus ATRA regimen compared with the ATRA plus chemotherapy (CT) regimen over a 30-year period. All costs were adjusted to 2018 levels based on the Chinese Consumer Price Index. Both costs and health outcomes were discounted by 3% annually. One-way sensitivity analysis and probability sensitivity analysis were performed., Results: Compared with the ATRA plus CT strategy, the ATO plus ATRA strategy was associated with 1.38 additional QALYs gained and $392.05 (estimated in 2018 US dollars) in incremental costs per patient over 30 years. Consequently, the incremental cost-effectiveness ratio was $284.02 per QALY gained, which was far below the Chinese willingness-to-pay threshold of $29,306 per QALY gained. Sensitivity analyses demonstrated the robustness of these results., Conclusions: From the perspective of the Chinese health care system, the ATO plus ATRA strategy is cost-effective for patients with newly diagnosed APL compared with the ATRA plus CT strategy. Therefore, the authors strongly suggest that China's health authorities choose the former strategy for these patients, whether for the elderly or for young people., (© 2019 American Cancer Society.)

Autologous hematopoietic cell transplantation (HCT) has not gained universal popularity in the treatment of acute myeloid leukemia (AML), and its status remains unclear. To determine the implementation status and outcomes of autologous HCT for adults with AML in Japan, we analyzed data from 1,174 patients (including 446 with acute promyelocytic leukemia [APL]) who underwent autologous HCT between 1992 and 2016 consecutively reported to the Japanese nationwide transplantation registry. The annual number of transplantations peaked at 82 cases in 1997, and has recently remained at around 40 cases. The percentage of APL has increased sharply since 2004, and currently exceeds 70%. While most non-APL patients underwent autologous HCT during first complete remission (CR), transplantation during second CR has become mainstream for APL patients since the early 2000s. The 5-year survival, relapse, and non-relapse mortality rates were 55.3%, 42.1%, and 8.6% for non-APL patients, and 87.6%, 12.9%, and 3.4% for APL patients, respectively. Patients transplanted in the later period showed better survival than those transplanted in the earlier period, both for non-APL (P < 0.001) and APL (P = 0.036). These results clearly show the various changes in transplantation practice and post-transplant outcomes in Japan over the past 25 years.

The application of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the treatment of acute promyelocytic leukemia (APL). More than 80-90% of patients are expected to be cured with a combination of ATRA, ATO and/or chemotherapy. In this review, we focus on the remaining obstacles to a cure for all patients with APL. We review the issue of early death and coagulopathy and discuss the particular challenges in the care of patients with high-risk APL and patients with relapsed APL. We also give recommendations and highlight ongoing efforts to improve the persistently high early death rate and the outcomes of high risk and relapsed APL patients.

The treatment regimens for acute promyelocytic leukemia (APL) dramatically changed over time. However, its survival trend, based on a large sample size has not been reported. Patients diagnosed with APL were accessed from the Surveillance, Epidemiology, and End Results database. Their incidence and survival trend were evaluated in overall and subgroup levels. The overall incidence of APL increased with an annual percentage change of 5.5% from 1992 to 2006 and remained stable thereafter. In addition, the 5-year relative survival rates of APL improved significantly, from 12.3 to 32.2% to 59.5 to 72.1% over past four decades ( p  < .0001), sharing similar trend with different subgroups. Importantly, survival disparities exist among races and different socioeconomic status groups, with superior survival in whites and patients in low-poverty regions. Increasing incidence urges for increased awareness of clinicians over diagnosis of APL. In addition, a wider insurance coverage may help balance survival gap.