Acute promyelocytic leukemia in childhood and adolescence: treatment results of a modified AIDA protocol at a Brazilian center

ABSTRACT Introduction: Acute promyelocytic leukemia currently presents an excellent chance of cure with protocols based on all-trans-retinoic acid (ATRA) and anthracycline or only differentiation agents. However, high early mortality rates continue to be reported Methods: Between 2000 and 2018, patients were enrolled and retrospectively analyzed by medical records. A modified AIDA protocol, with a 1-year shortening of the treatment duration, reduction in the number of drugs and a strategy to reduce early mortality by the postponement of the initiation of anthracyclines were employed. Overall and event-free survival rates and toxicity were analyzed Results: Thirty-two patients were enrolled, of whom 56% were female, with a median age of 12 years and 34% belonged to the high-risk group. Two patients had the hypogranular variant and three had another cytogenetic alteration, in addition to the t(15;17). The median start of the first anthracycline dose was 7 days. There were two early deaths (6%) due to central nervous system (CNS) bleeding. All patients achieved molecular remission after the consolidation phase. Two children relapsed and were rescued by arsenic trioxide and hematopoietic stem cell transplantation. The presence of disseminated intravascular coagulation (DIC) at diagnosis (p = 0.03) was the only factor with survival impact. The five-year event-free survival (EFS) was 84% and 5-year overall survival (OS) was 90% Conclusion: The survival results were comparable to those found in the AIDA protocol, with a low rate of early mortality in relation to the Brazilian reality.

Correlation between D-Dimer/Fibrinogen Ratio and Bleeding in Patients with Newly Diagnosed Acute Promyelocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To further explore the better indicators for predicting the degree of bleeding associated with newly diagnosed acute promyelocytic leukemia (APL).@*METHODS@#A total of 131 patients with newly diagnosed APL were classified according to WHO bleeding scales before treatment and divided into two groups: scales 0, 1 and 2 were included in no severe bleeding group, scales 3 and 4 were included in severe bleeding group. The information of the patients were collected, including sex, age, hemoglobin (Hb), white blood cell (WBC) count and platelet (PLT) count, peripheral blood lymphocyte percentage (LYMPH%), peripheral blood monocyte percentage (MONO%), percentage of leukemic cells in pripheral blood and bone marrow, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) levels, D-dimer (D-D), D-dimer/fibrinogen ratio (DFR).@*RESULTS@#Among 131 patients, 110 were classified as no severe bleeding, and 21 were severe bleeding. The results of univariate analysis showed that patients with severe bleeding had significantly higher percentage of leukemic cells in pripheral blood, WBC, D-D, and DFR, as well as longer PT and lower LYMPH%, compared to those with no severe bleeding. Multivariate analysis revealed that DFR (OR =1.054, 95%CI : 1.024-1.084, P < 0.001) and percentage of peripheral blood leukemic cells (OR=1.026, 95%CI: 1.002-1.051, P =0.033) were independent risk factors for severe bleeding. The area under ROC curve (AUC) of peripheral blood leukemic cells, D-D and DFR were 0.748, 0.736 and 0.809, respectively. There was no statistical difference between the peripheral blood leukemic cells and D-D in diagnostic efficacy (P =0.8708). Compared with D-D, DFR had a higher predictive value (P =0.0302). The optimal cut-off value of DFR was 16.50, with a sensitivity of 90.5% and a specificity of 70.0%.@*CONCLUSION@#DFR has a significant advantage in predicting the degree of bleeding associated with newly diagnosed APL. The greater the DFR value, the heavier the degree of bleeding. The risk of severe or fatal bleeding increases when DFR is greater than 16.50.

Effects of Cytokines on Early Death in Patients with Newly Diagnosed Acute Promyelocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explore the effect of cytokine levels on early death and coagulation function of patients with newly diagnosed acute promyelocytic leukemia (APL).@*METHODS@#Routine examination was performed on 69 newly diagnosed APL patients at admission. Meanwhile, 4 ml fasting venous blood was extracted from the patients. And then the supernatant was taken after centrifugation. The concentrations of cytokines, lactate dehydrogenase (LDH) and ferritin were detected by using the corresponding kits.@*RESULTS@#It was confirmed that cerebral hemorrhage was a major cause of early death in APL patients. Elevated LDH, decreased platelets (PLT) count and prolonged prothrombin time (PT) were high risk factors for early death (P <0.05). The increases of IL-5, IL-6, IL-10, IL-12p70 and IL-17A were closely related to the early death of newly diagnosed APL patients, and the increases of IL-5 and IL-17A also induced coagulation disorder in APL patients by prolonging PT (P <0.05). In newly diagnosed APL patients, ferritin and LDH showed a positive effect on the expression of IL-5, IL-10 and IL-17A, especially ferritin had a highly positive correlation with IL-5 (r =0.867) and IL-17A (r =0.841). Moreover, there was a certain correlation between these five high-risk cytokines, among which IL-5 and IL-17A (r =0.827), IL-6 and IL-10 (r =0.823) were highly positively correlated.@*CONCLUSION@#Elevated cytokine levels in newly diagnosed APL patients increase the risk of early bleeding and death. In addition to the interaction between cytokines themselves, ferritin and LDH positively affect the expression of cytokines, thus affecting the prognosis of APL patients.

Mechanism of Proliferation and Apoptosis of Acute Promyelocytic Leukemia Cell Line NB4 Induced by TPA / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of phorbol-12-myristate-13-ace-tate (TPA) on the proliferation and apoptosis of acute promyelocytic leukemia cell line NB4 and its molecular mechanism.@*METHODS@#The effect of different concentrations of TPA on the proliferation of NB4 cells at different time points was detected by CCK-8 assay. The morphological changes of NB4 cells were observed by Wright-Giemsa staining. The cell cycle and apoptosis of NB4 cells after TPA treatment were detected by flow cytometry. The mRNA expressions of NB4 cells after TPA treatment were analyzed by high-throughput microarray analysis and real-time quantitative PCR. Western blot was used to detect the protein expression of CDKN1A, CDKN1B, CCND1, MYC, Bax, Bcl-2, c-Caspase 3, c-Caspase 9, PIK3R6, AKT and p-AKT.@*RESULTS@#Compared with the control group, TPA could inhibit the proliferation of NB4 cells, induce the cells to become mature granulocyte-monocyte differentiation, and also induce cell G1 phase arrest and apoptosis. Differentially expressed mRNAs were significantly enriched in PI3K/AKT pathway. TPA treatment could increase the mRNA levels of CCND1, CCNA1, and CDKN1A, while decrease the mRNA level of MYC. It could also up-regulate the protein levels of CDKN1A, CDKN1B, CCND1, Bax, c-Caspase 3, c-Caspase 9, and PIK3R6, while down-regulate MYC, Bcl-2, and p-AKT in NB4 cells.@*CONCLUSION@#TPA induces NB4 cell cycle arrest in G1 phase and promotes its apoptosis by regulating PIK3/AKT signaling pathway.

Construction of eukaryotic expression plasmid of human promyelocytic leukemia gene of six transcripts and subcellular location analysis of its recombinant proteins / 中国生物制品学杂志

@#Objective To construct eukaryotic expression plasmids of human promyelocytic leukaemia(hPML) gene of six transcripts and analyze the subcellular location of the recombinant proteins.Methods Primers were designed according to the hPML gene sequences registered in GenBank databases.Six transcripts of hPML gene fragments(hPML Ⅰ,Ⅱ,Ⅳ,Ⅴ,Ⅵ and Ⅶ) were amplified by RT-PCR,which were linked to the eukaryotic expression vector pCAGGS respectively.The obtained eukaryotic expression plasmids of six transcripts of hPML gene were transfected into 293T cells respectively and detected for their protein expression by Western blot,while transfected into Vero cells and detected for their subcellular location by indirect immunofluorescence assay(IFA).Results The target gene fragments of the six eukaryotic expression plasmids were consistent with the hPML gene sequences registered in GenBank.All the six recombinant proteins showed specific binding with Myc antibody,among which the recombinant protein hPML Ⅰ,Ⅱ,Ⅳ,Ⅴ and Ⅵ were located in the nucleus and cytoplasm,while the recombinant protein hPML Ⅶ was mainly located in the cytoplasm,rarely in the nucleus.Conclusion The eukaryotic expression plasmids of six transcripts of hPML gene all can be expressed correctly in mammalian cells,and the expressed recombinant proteins were located in nucleus and cytoplasm simultaneously or mainly in cytoplasm.This study provides an experimental basis for subsequent study on the antiviral and other biological functions of recombinant protein hPML.

Adult acute promyelocytic leukemia with thrombosis as the first manifestation: a clinical analysis of 6 cases / 中华全科医师杂志

The clinical data of 6 acute promyelocytic leukemia (APL) patients with thrombosis as the first manifestation were retrospectively analyzed. Among 6 patients, 5 were males and 1 female.The median age at diagnosis was 55 years old. All patients had risk factors for cardiovascular disease (CVD), and 5 patients met the diagnostic criteria for disseminated intravascular coagulation (DIC). There were 3 patients at low risk (bcr1 subtype), 1 at intermediate risk (bcr2 subtype) and 2 at high risk (1 bcr3 subtype and 1 unknown). FLT3-ITD mutations were tested in 3 cases, all of whom showed negative results. Arterial thrombosis was found in all 6 cases, 4 cases had cerebral infarction, 1 had lower limb arterial embolism, and 1 had multiple arterial and venous thrombosis. Four patients with cerebral infarction received all-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO)±chemotherapy and symptomatic treatment (1 patient at high risk did not receive ATRA), 2 patients achieved complete remission (CR), and the other 2 patients died of cerebral hemorrhage and cerebral infarction, respectively. One patient with lower extremity arterial thrombosis died suddenly within 12 h after admission likely due to acute myocardial infarction. One patient with mixed thrombosis received low molecular weight heparin and rivaroxaban successively after inferior vena cava filter implantation, and achieved CR after ATRA+ATO treatment. Thrombosis is a less common and under-recognized presentation in APL.Thrombosis patients with blood cells and/or coagulation abnormalities should consider the possibility of APL. APL patients complicated with thrombosis have a high probability of DIC and remain mostly intractable to existing treatments, who are at high risk of death and poor prognosis.

Clinical Analysis of Children with High-Risk Acute Promyelocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explore the treatment of children with high-risk acute promyelocytic leukemia (APL), aiming to improve the prognosis.@*METHODS@#The clinical datas of 24 children with high-risk APL in our hospital from January 2015 to June 2021 were retrospectively analyzed.@*RESULTS@#The main manifestations of 24 children (including 15 males and 9 females) were purpura, gingiva bleeding and nasal hemorrhage, with a median age of 7 years old and a median leukocyte count of 28.98 (10-232)×109/L, including 15 cases with leukocyte count between 10×109/L and 50×109/L, 2 cases between 50×109/L and 100×109/L, and 7 cases >100×109/L. The leukocyte count of 2 cases in 3 children admitted from 2015 to November 2016 was >100×109/L, in which 1 case was first treated with homoharringtonine for cytoreduction, 7 days later treated with all-trans retinoic acid (ATRA) after genetic diagnosis, then died of differentiation syndrome and pulmonary hemorrhage after 3 days. The other one was treated with reduced ATRA+daunorubicin+arsenic trioxide (ATO) for induction, then achieved complete remission. The third one with leukocyte count 12×109/L had cerebral hemorrhage before admission and died on the 7th day of treatment. The remaining 21 children were treated with chemotherapy according to the APL regimen for children in South China, including 14 cases with leukocyte count between 10×109/L and 50×109/L, 2 cases between 50×109/L and 100×109/L, and 5 cases >100×109/L. In the 5 children with leukocyte count >100×109/L, 1 case died of cerebral hemorrhage on the second day of oral ATRA before the addition of anthracyclines, 3 cases died of cerebral hemorrhage after the addition of anthracyclines to chemotherapy on the second day of oral ATRA, and another one developed differentiation syndrome after the addition of mitoxantrone on the second day of oral ATRA, then achieved complete remission after ATRA reduction chemotherapy and survived without disease till now. In the 2 children with leukocyte count between 50×109/L and 100×109/L, 1 case died of cerebral hemorrhage on the second day of oral ATRA before the addition of anthracyclines. All the children were followed up until 1st August, 2021, with a median follow-up time of 40 months, including 7 deaths and 1 recurrence in maintenance therapy who achieved second remission after chemotherapy, 14 cases survived in 3 years and 13 cases survived without event. The 7 dead children had a median time from treatment to death of 5 days, including 1 case with leukocyte count between 10×109/L and 50×109/L, 1 case between 50×109/L and 100×109/L, and 5 cases >100×109/L.@*CONCLUSION@#High-risk APL children with leukocyte count >100×109/L have a high mortality rate. Gradual addition of chemotherapy starting at small doses and early addition of ATO may help to improve the prognosis.

Effect of a Novel Dihydroartemisinin Dimer Containing Nitrogen Atoms SM 1044 on Apoptosis of Human Leukemia Cell Line NB4-R1 / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of a water-soluble novel dihydroartemisinin dimer containing nitrogen atoms SM 1044 on the apoptosis of all-trans retinoic acid (ATRA) resistant acute promyelocytic leukemia (APL) NB4-R1 cells and its potential mechanism.@*METHODS@#The effects of SM 1044 on cell apoptosis, mitochondrial transmembrane potential, and the level of reactive oxygen species (ROS) were assessed by flow cytometry. Expressions of apoptosis-related proteins were determined by Western blot. The effects of SM 1044 on MAPK (ERK, JNK) signaling pathway, PML/RARα fusion protein, and expressions of apoptosis-related proteins were detected by Western blot.@*RESULTS@#SM 1044 could significantly induce apoptosis and the loss of mitochondrial transmembrane potential in NB4-R1 cells, and activate apoptosis-related proteins caspase-3, caspase-8, caspase-9 and poly (ADP-ribose) polymerase (PARP). SM 1044 could also induce NB4-R1 cells to produce ROS. Western blot showed that SM 1044 activated the phosphorylation of MAPK (ERK, JNK) signaling pathway and down-regulated the expression of PML/RARα fusion protein.@*CONCLUSION@#SM 1044 can induce apoptosis of ATRA resistant APL NB4-R1 cells, which may be related to ROS/ERK and ROS/JNK signaling pathway, and can also induce by down-regulating PML/RARα fusion protein.

A Leucemia Mieloide Aguda Poderia ter se Apresentado Ainda Pior? "Causa Incomum de Trombose Multiarterial Concomitante" / Could Acute Myeloid Leukemia Have Presented Even Worse? "Uncommon Cause of Concurrently Multivessel Thrombosis"

Resumo A leucemia promielocítica aguda (LPA) é um subgrupo da leucemia mieloide aguda (LMA). Embora se saiba que as complicações hemorrágicas são comuns, as complicações trombóticas não são tão raras quanto se pensa. No entanto, infarto do miocárdio e incidência de acidente vascular cerebral isquêmico são muito raros durante a LMA. Aqui, apresentamos o caso surpreendente de LPA diagnosticada com pancitopenia em sua apresentação com infarto agudo do miocárdio e acidente vascular cerebral isquêmico.

Abstract Acute promyelocytic leukemia (APL) is a subgroup of acute myeloid leukemia (AML). Although it is known that hemorrhagic complications are common, thrombotic complications are not as rare as thought. However, myocardial infarction and ischemic stroke incidence are very rare during AML. Here, we present the astonishing case of APL diagnosed with pancytopenia in its presentation with acute myocardial infarction and ischemic stroke.

Leucemia promielocítica aguda durante el embarazo: reporte de 17 casos de un país en desarrollo / Acute promyelocytic leukemia during pregnancy: report of 17 cases from a developing country

Resumen OBJETIVO: Recopilar casos atendidos en centros oncológicos de México y reportar los tratamientos exitosos, con respuestas completas y las complicaciones del embarazo. MATERIALES Y MÉTODOS: Estudio retrospectivo de serie de casos que incluyó a pacientes con leucemia promielocítica aguda asociada con el embarazo atendidas en diferentes hospitales de la zona metropolitana de la Ciudad de México entre 1999 y 2021. RESULTADOS: Se identificaron 17 pacientes con leucemia promielocítica aguda asociada con el embarazo, con mediana de edad de 23 años (14-40 años); 7 correspondieron a madres menores de 20 años. En relación con su entorno social 9 tenían baja escolaridad, 12 se dedicaban al hogar y 13 tenían una pareja al momento de la concepción. Por último, 11 eran originarias de una zona urbana. Las pacientes atendidas entre 1999-2010 se trataron con interferón plus citarabina (7 de 17) o mediante soporte transfusional y esteroide (2 de 17), en 8 de los 17 casos el tratamiento se inició con tretinoína en combinación con quimioterapia (daunorrubicina) como tratamiento de inducción. CONCLUSIONES: El tratamiento de pacientes embarazadas y con leucemia promielocítica aguda representa un reto debido al riesgo trombótico y hemorrágico. Si bien la adición de tretinoína ha modificado el pronóstico de las pacientes con esta leucemia, su indicación a las embarazadas sigue siendo motivo de controversia, sobre todo por el riesgo de teratogenicidad.

Abstract OBJECTIVE: To collect cases attended in oncology centers in Mexico and to report successful treatments, with complete responses and complications around gestation. MATERIALS AND METHODS: Retrospective case series study including patients with pregnancy-associated acute promyelocytic leukemia attended in different hospitals in the metropolitan area of Mexico City between 1999 and 2021. RESULTS: Seventeen patients with pregnancy-associated acute promyelocytic leukemia were identified, with a median age of 23 years (14-40 years); 7 corresponded to mothers younger than 20 years. In relation to their social environment, 9 had low schooling, 12 were homebased and 13 had a partner at the time of conception. Finally, 11 were originally from an urban area. Patients seen between 1999-2010 were treated with interferon plus cytarabine (7 of 17) or by transfusion support and steroid (2 of 17), in 8 of the 17 cases treatment was initiated with tretinoin in combination with chemotherapy (daunorubicin) as induction therapy. CONCLUSIONS: Treatment of pregnant patients and patients with acute promyelocytic leukemia represents a challenge due to thrombotic and hemorrhagic risk. Although the addition of tretinoin has modified the prognosis of patients with this leukemia, its indication in pregnant women remains controversial, especially because of the risk of teratogenicity.

Osteonecrosis of the jaw induced by arsenic trioxide therapy in acute promyelocytic leukemia patient: a case report and literature review / 口腔疾病防治

Objective @#To investigate the etiology, clinical manifestations, treatment and prevention of jaw necrosis caused by arsenic trioxide to provide a reference for clinical diagnosis and treatment. @*Methods@#To analyze the clinical data and related literature of patients with jaw necrosis caused by acute promyelocytic leukemia treated with arsenic trioxide@*Results@#We report a case of jaw necrosis caused by the use of arsenic trioxide (10 mg once a day for one month) during the treatment of acute promyelocytic leukemia. About 20 days after treatment, the patient developed right maxillary pain accompanied by gingival redness and swelling and mucosal ulcer, 14-17 teeth had buccal and palatal alveolar bone exposed, gingival mucosa was missing, gingival tissue was damaged to the bottom of vestibular groove, and palatal soft tissue was damaged to 5-8 mm of palatal suture. Due to the unstable condition of acute promyelocytic leukemia, the patient was given conservative treatment such as oral vitamin and Kangfuxin liquid gargle to keep his mouth clean. Drug induced jaw necrosis reported in the literature can be caused by bisphosphonates. Arsenic trioxide can also cause local jaw necrosis. Clinically, it is often manifested as long-term wound nonunion, pus, alveolar bone or jaw bone exposure, dead bone formation, accompanied by pain, loose teeth, facial swelling and other symptoms. Anti inflammation, debridement and surgical removal of dead bone are commonly used treatment methods.@*Conclusion @# In clinical practice, we should be alert to drug-induced jaw necrosis and strengthen prevention.

Derivative 6 as an additional chromosomal abnormality along with t(15;17): A case report

Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) characterized by the presence of t(15;17)(q22;q21) translocation leading to fusion between PML and RARa gene. Treatment combining all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has dramatically improved the prognosis of APL. We report a rare finding of primary clone of t(15;17) followed by a sequential clonal evolution of additional derivative chromosome 6 formation by a two hit mechanism. Our case showed a good clinical response with a four years and nine months event free survival after ATRA and ATO combination therapy in spite of existence of three chromosomal abnormalities stating that targeted therapy overcomes the adverse effects of additional genetic markers. However, close monitoring with assessment for long term prognostic behavior is required.

Transcritos de fusión del gen PML/RARα en pacientes con leucemia promielocítica / Fusion transcripts of the PML/RARα gene in patients with promyelocytic leukemia

Introducción: La leucemia promielocítica se considera una enfermedad bien definida por sus peculiares características clínicas, morfológicas, citogenéticas y moleculares. El descubrimiento de los mecanismos oncogenéticos implicados en la génesis de la enfermedad hacen de esta variante de leucemia uno de los modelos más relevantes de investigación traslacional. Objetivo: Caracterizar los transcritos de fusión del gen PML/RARα en pacientes con leucemia promielocítica. Métodos: Se realizó una investigación observacional, ambispectiva, descriptiva, longitudinal, en pacientes con diagnóstico de leucemia promielocítica, en el Instituto de Hematología e Inmunología, entre enero de 2001 y diciembre de 2020. El universo estuvo constituido por 105 pacientes que cumplieron los criterios de inclusión y exclusión. Resultados: No existe relación entre los transcritos y la edad, sexo, color de piel y las características clínicas. La presencia del transcrito de fusión bcr3 se asoció a mayores cifras de hemoglobina y menor valor de plaquetas. La incidencia de recaída no se relacionó con los transcritos de fusión y no se comprobó que existiera influencia de éstos, sobre la supervivencia global en pacientes con leucemia promielocítica. Conclusiones: Las características de los transcritos de fusión del gen PML/RARα son similares a los reportes internacionales, sobre todo en poblaciones de origen latino(AU)

Introduction: Promyelocytic leukemia is considered a well-defined entity due to its peculiar clinical, morphological, cytogenetic and molecular characteristics. The discovery of the oncogenetic mechanisms involved in the genesis of the disease makes this variant of leukemia one of the most relevant models for translational research. Objective: To characterize the fusion transcripts of the PML/RARα gene in patients with promyelocytic leukemia. Methods: An observational, ambispective, descriptive, longitudinal investigation was carried out in patients diagnosed with promyelocytic leukemia at the Institute of Hematology and Immunology, between January 2001 and December 2020. The sample consisted of 105 patients who met the criteria for inclusion and exclusion. Results: There is no relationship between the transcripts and age, sex, skin color and clinical characteristics. The presence of the bcr3 fusion transcript was associated with higher hemoglobin levels and lower platelet counts. The incidence of relapse was not related to fusion transcripts and their influence on overall survival in patients with promyelocytic leukemia was not proven. Conclusions: The fusion transcripts´scharacteristicsof the PML/RARα gene are similar to international reports, especially from populations of Latin origin(AU)

Leucemia promielocítica: enfoques oncogenéticos y moleculares en la era de la medicina de precisión / Promyelocytic leukemia: oncogenetic and molecular approaches in the precision´s medicine era

Introducción: El estudio de la patogenia molecular de la leucemia promielocítica revolucionó las bases de la medicina personalizada al identificar la oncoproteína PML/RARα como diana de terapias dirigidas al mecanismo oncogenético fundador de la enfermedad. Sin embargo, en las últimas décadas, se realizaron otros descubrimientos que aportan mayor información acerca de su biogénesis y desarrollo y el impacto potencial de los mismos en la implementación de técnicas de diagnóstico y herramientas pronósticas como expresión del rápido perfeccionamiento de la medicina traslacional. Objetivo: Exponer los principales descubrimientos en los mecanismos oncogenéticos y moleculares de actualidad en la leucemia promielocítica. Métodos: Se realizó una búsqueda exhaustiva en bases de datos como Scielo, Pubmed, ScienceDirect, Redalyc, Google académico. Se utilizaron como referencias los artículos actualizados publicados en los últimos 5 años en idioma inglés y español. Se efectuó un análisis y resumen de la bibliografía y se tomaron los aspectos más importantes referidos al tema. Análisis y síntesis de la información: Se abordaron los principales aportes de la biología molecular al conocimiento del origen de ésta enfermedad, más allá del enfoque clásico basado en el gen PML/RARα, así como sus variantes y otros aspectos de interés en su monitorización. Conclusiones: Las características genéticas de esta enfermedad evidencian un paisaje mutacional diferente al de otras neoplasias mieloides malignas y señalan con especial énfasis la importancia de la integración clínico-biológica para facilitar, perfeccionar y desarrollar el proceso de atención integral a los pacientes con hemopatías malignas(AU)

Introduction: The study of the molecular pathogenesis of promyelocytic leukemia revolutionized the foundations of personalized medicine by identifying the PML/RARαoncoprotein as a target for therapies directed at the founding oncogenetic mechanism of the disease. However, in recent decades, other discoveries that provide more information about their biogenesis and development, and their potential impact on the implementation of diagnostic techniques and prognostic tools as an expression of the rapid improvement of translational medicine. Objective: To expose the main discoveries in the current oncogenetic and molecular mechanisms in promyelocytic leukemia. Methods: An exhaustive search was carried out in databases such as Scielo, Pubmed, ScienceDirect, Redalyc, Google Scholar, and updated articles published in the last 5 years in English and Spanish were used as references. An analysis and summary of the bibliography was carried out and the most important aspects related to the subject were taken. Analysis and synthesis of information: the main contributions of molecular biology to the knowledge of the origin of this entity were addressed, beyond the classical approach based on the PML/RARα gene, as well as its variants and other aspects of interest in the monitoring of the illness. Conclusions: The genetic characteristics of this disease show a mutational landscape different from that of other malignant myeloid neoplasms and point out with special emphasis the importance of clinical-biological integration to facilitate, improve and develop the comprehensive care process for patients with malignant blood diseases(AU)

Research progress in nephrotoxicity and prevention of arsenic trioxide / 中国药理学通报

Aim Arsenic trioxide (ATO, As203 ) can effectively treat acute promyelocyte leukemia (APL) and other malignant tumors.However.ATO has been found to have nephrotoxic effects during the treatment process, which limits the clinical application of ATO.Studies have shown that the use of ATO can interfere with the body's oxidation, causing to oxidative stress, damage DNA repair pathways, and induce DNA mutations.leading to cell cancer.This is currently one of the important mechanisms of ATO nephrotoxicity.Apoptosis, DNA methyl a- tion caused by ATO are also causes of nephrotoxicity.This article summarizes the research and prevention of ATO nephrotoxicity mechanism.

Comparison of clinical efficacy and treatment costs in different regimens for patients with acute promyelocytic leukemia / 白血病·淋巴瘤

Objective:To explore the clinical efficacy and treatment costs of different regimens for newly diagnosed acute promyelocytic leukemia (APL).Methods:The clinical data of 37 newly diagnosed APL patients admitted to Jingjiang People's Hospital from January 2011 to December 2020 were retrospectively analyzed. They received different induction therapy regimens and consolidation therapy after achieving complete remission (CR). Among them, 11 patients received induction chemo therapy with all-trans retinoic acid (ATRA) combined with anthracycline, which was consolidated with ATRA combined with chemotherapy after CR (ATRA+chemotherapy group); 13 patients were treated with ATRA combined with arsenite acid (ATO) and anthracycline, which was consolidated with ATRA combined with chemotherapy after CR(ATRA+ATO+ chemotherapy group). The other 13 patients received double induction therapy of ATRA combined with ATO, which was consolidated with ATRA combined with ATO after CR (ATRA+ATO double induction group). The clinical efficacy and treatment costs of newly diagnosed APL patients in 3 groups were analyzed.Results:There were 10, 12, 12 patients with newly diagnosed APL achieving CR, respectively in ATRA+chemotherapy group, ATRA+ATO+chemotherapy group, ATRA+ATO double induction group, and the difference was statistically significant ( P > 0.05). The differences of hematological, cardiac, gastrointestinal adverse reactions and infection incidence in the 3 groups were not statistically significant (all P > 0.05). The costs of induction therapy in ATRA+chemotherapy group, ATRA+ATO+chemotherapy group and ATRA+ATO double induction group were (73 755±4 820) yuan, (74 101±5 097) yuan, (52 944±4 099) yuan, respectively; the costs of consolidation treatment were (26 366±2 497) yuan, (25 801±2 528) yuan, (19 674±1 940) yuan, and the treatment time was (41±4) d, (39±4) d, (34±3) d, respectively; and the differences were statistically significant ( F value was 84.77, 31.90, 9.62, all P < 0.001). Conclusion:The chemotherapy-free therapy regimen of induction and consolidation with ATRA and ATO has the advantage of high cost-effectiveness with no significant difference in clinical efficacy.

Effects of interferon regulatory factor 9 on the biological phenotypes in PML-RARα-induced promyelocytic leukemia / 中华血液学杂志

Objective: To investigate the prognostic significance of interferon regulatory factor 9 (IRF9) expression and identify its role as a potential therapeutic target in acute promyelocytic leukemia (APL) . Methods: The gene expression profile and survival data applied in the bioinformatic analysis were obtained from The Cancer Genome Atlas and Beat acute myeloid leukemia (AML) cohorts. A dox-induced lentiviral system was used to induce the expression of PML-RARα (PR) in U937 cells, and the expression level of IRF9 in U937 cells treated with or without ATRA was examined. We then induced the expression of IRF9 in NB4, a promyelocytic leukemia cell line. In vitro studies focused on leukemic phenotypes triggered by IRF9 expression. Results: ①Bioinformatic analysis of the public database demonstrated the lowest expression of IRF9 in APL among all subtypes of AML, with lower expression associated with worse prognosis. ②We successfully established a PR-expression-inducible U937 cell line and found that IRF9 was downregulated by the PR fusion gene in APL, with undetectable expression in NB4 promyelocytic cells. ③An IRF9-inducible NB4 cell line was successfully established. The inducible expression of IRF9 promoted the differentiation of NB4 cells and had a synergistic effect with lower doses of ATRA. In addition, the inducible expression of IRF9 significantly reduced the colony formation capacity of NB4 cells. Conclusion: In this study, we found that the inducible expression of PR downregulates IRF9 and can be reversed by ATRA, suggesting a specific regulatory relationship between IRF9 and the PR fusion gene. The induction of IRF9 expression in NB4 cells can promote cell differentiation as well as reduce the colony forming ability of leukemia cells, implying an anti-leukemia effect for IRF9, which lays a biological foundation for IRF9 as a potential target for the treatment of APL.

Study on Herpes Zoster Reactivation Induced by Arsenic in Patients with Acute Promyelocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate herpes zoster reactivation induced by arsenic in patients with acute promyelocytic leukemia (APL).@*METHODS@#The clinical data of 212 patients with APL treated in the Department of Hematology of the First Affiliated Hospital of Xi'an Jiaotong University from 2008 to 2019 were retrospectively analyzed to observe the activation of varicella zoster virus induced by arsenic. Kaplan-Meier analysis, chi-square test, and boxplot were used to analyze and describe the cumulative dose of arsenic and the time from the beginning of arsenic treatment to the occurrence of herpes zoster.@*RESULTS@#Excluding early death cases and early automatic discharge cases, 17 cases developed herpes zoster reactivation in 175 patients with APL treated with arsenic, and the cumulative median dose of arsenic was 6.2(2-12) mg/kg. Precise risk of reactivation of herpes zoster with 10 months in APL patients treated by arsenic was 9.7%.@*CONCLUSION@#Arsenic treatment can induce high reactivation rate of herpes zoster virus.

Effects of Monoammonium Glycyrrhizinate on Stem Cell-like Characteristics, Oxidative Stress and Mitochondrial Function of Acute Promyelocytic Leukemia NB4 Cells / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of monoammonium glycyrrhizinate on the stem cell-like characteristics, oxidative stress and mitochondrial function of acute promyelocytic leukemia cells NB4.@*METHODS@#CCK-8 method was used to detect the viability of acute promyelocytic leukemia cells NB4, and the appropriate dose was screened; Cloning method was used to detect the proliferation rate of NB4 cell; Western blot was used to detect the expression of cell cycle-related protein; flow cytometry was used to detect cell apoptosis and sort NB4 stem cells positive (CD133+); Stem cell markers (Oct4, ABCG2, Dclk1) were detected by RT-PCR; ROS was detected by fluorescence; The kit was used to detect the level of oxidative stress markers (MDA); The flow cytometry was used to detect the change of mitochondrial membrane potential; Western blot was used to detect the expression of mitochondrial damage index-related proteins (Bax/BCL-2).@*RESULTS@#Compared with the control group, if the concentration of MAG was less than 5 μmol/L, the cell NB4 viability showed no significant difference; if the concentration was higher than 5 μmol/L, the inhibitory effect on the growth of cell NB4 increased and showed significant difference (P<0.05), according to the results of CCK-8 experiment, four groups were set based on the concentration of MAG 0 μmol/L, MAG 5 μmol/L, MAG 10 μmol/L, and MAG 20 μmol/L; compared with the control group (MAG 0 μmol/L), the cells in MAG 5 μmol/L group showed no significant difference, while the proliferation rate, cyclin expression, mitochondrial membrane potential, stem cell CD133+ ratio, and marker mRNA level ( Oct4, ABCG2, Dclk1) of NB4 cell were significantly reduced (P<0.05); the apoptosis rate, reactive oxygen species, MDA content and Bax/BCL-2 expression of NB4 cell significantly increased (P<0.05).@*CONCLUSION@#Monoammonium glycyrrhizinate has a significant inhibitory effect on acute promyelocytic leukemia cells NB4, which may be related to the regulation of stem cell-like characteristics, oxidative stress and mitochondrial function.

Caracterización clínica y citogenética de una cohorte de pacientes con leucemia promielocítica aguda atendidos en un Hospital Universitario en Medellín, Colombia / Clinical and cytogenetic characterization of a cohort of patients with acute promyelocytic leukemia treated at a University Hospital in Medellín, Colombia

Introducción. La leucemia promielocítica aguda (LPA) es un subtipo poco frecuente de leucemia mieloide aguda (LMA), que se caracteriza por un comportamiento clínico particularmente agresivo, y en ausencia de tratamiento, su curso generalmente es fatal. El objetivo de este trabajo fue determinar las características clínicas y citogenéticas de una cohorte de pacientes con LPA, con la finalidad de evaluar su relación con las complicaciones, el pronóstico y el desenlace de estos pacientes. Metodología. Se realizó un estudio observacional, descriptivo, retrospectivo de los pacientes mayores de 15 años con diagnóstico de LPA, atendidos en el Hospital Universitario San Vicente Fundación, entre los años 2012 a 2020. Resultados. Un total de 32 pacientes fueron incluidos. La edad media del diagnóstico fue 37 años. El 84,4% de los pacientes tenía la traslocación (15;17) en el cariotipo, y el 93,75% tenían FISH positivo. El 12,5% de los casos tenían cariotipo complejo. La mortalidad en los primeros 30 días fue del 15,6%, siendo el sangrado la causa de muerte más frecuente. Todos los pacientes que sobrevivieron alcanzaron la remisión completa (84,3%). En un promedio de seguimiento de 24 meses, el 14,8% de los casos recayeron. En el análisis bivariado se encontró relación entre sexo masculino y tener cariotipo complejo (p=0,015). No se encontró relación entre cariotipo complejo y mortalidad temprana (p=0,358), tampoco entre cariotipo complejo y recaída (p=0,052). Conclusiones. Se presentan las características clínicas y citogenéticas de una cohorte de pacientes con LPA en Colombia. El sangrado en el sistema nervioso central fue la principal causa de mortalidad temprana, todos los pacientes que sobrevivieron alcanzaron la remisión completa con la terapia de inducción. Las tasas de mortalidad, remisión completa y recaída fueron similares a las reportadas por otras series latinoamericanas, pero inferiores a estudios provenientes de países europeos. Contrario a lo reportado en otros estudios, no se encontró relación entre el cariotipo complejo y la mortalidad temprana o recaída.

Introduction. Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML), characterized by a particularly aggressive clinical behavior, that in the absence of treatment is usually fatal. The objective of this work was to determine the clinical and cytogenetic characteristics of a cohort of patients with APL, in order to evaluate their relationship with the outcome and prognosis of these patients. Methodology. An observational, descriptive, retrospective study of patients older than 15 years with a diagnosis of APL treated at the Hospital Universitario San Vicente Fundación, between 2012 and 2020, was carried out. Results. A total of 32 patients were included. The mean age at diagnosis was 37 years, 84.4% of the patients had the t(15;17) in the karyotype, and 93.75% had positive FISH. 12.5% of cases had a complex karyotype. Mortality in the first 30 days was 15.6%, with bleeding being the most common cause of death. All patients who survived achieved complete remission (84.3%). In an average follow-up of 24 months, 14.8% of cases relapsed. In the bivariate analysis, a relationship was found between the male sex and having a complex karyotype (p<0.015). No relationship was found between complex karyotype and early mortality (p=0.358), nor between complex karyotype and relapse (p=0.052). Conclusions. We present the clinical and cytogenetic characteristics of a cohort of patients with APL in Colombia. Central nervous system bleeding was the main cause of early mortality, with all surviving patients achieving complete remission on induction therapy. Mortality, complete remission and relapse rates were similar to those reported by other Latin American series, but lower than studies from European countries. Contrary to what has been reported in other studies, no relationship was found between complex karyotype and early mortality or relapse