Advances in key pathogenesis of atypical acute promyelocytic leukemia and mechanisms of all-trans retinoic acid resistance / 白血病·淋巴瘤

Due to the successful application of all-trans retinoic acid (ATRA) and arsenic, the treatment of acute promyelocytic leukemia (APL) with PML::RARA fusion gene has achieved great success. However, some patients are presented with APL phenotype in cellular morphology, immunophenotype, and gene expression profile, while PML::RARA is negative, which is known as atypical APL (aAPL). In aAPL patients, more than 20 fusion genes related to retinoic acid receptors have been reported. It has been discovered that all evaluable patients with RARG fusion genes and approximately half of those with rare RARA fusion genes are resistant to ATRA, however, the molecular mechanisms of this resistance remain poorly studied. Combining with the reports in the 65th American Society of Hematology Annual Meeting, this paper reports great progresses of the key pathogenesis of aAPL and ATRA resistance mechanisms.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Safety and efficacy of Compound Huangdai Tablets combined with all-trans retinoic acid for treatment of acute promyelocytic leukemia: Clinical evidence and potential mechanisms / 中草药·英文版

Objective: To evaluate the safety and efficacy of Compound Huangdai Tablets (Realgar-Indigo Naturalis formula, RIF) combined with all-trans retinoic acid (ATRA) to treat acute promyelocytic leukemia (APL). Methods: This study was registered in PROSPERO (CRD42018108118). The relevant literatures on RIF treatment of APL were systematically searched in the following databases: China National Knowledge Infrastructure, Wanfang, VIP Medical Information System, Chinese Biomedical Database, EMBASE, Cochrane Library, and PubMed. The quality of the included studies was evaluated and Review Manager 5.3 software and Stata 13.0 software were used to perform the Meta-analysis. In addition, this study used the method of network pharmacology to conduct a preliminary exploration of the mechanism of RIF on APL. Results: The study included 12 studies involving 775 APL patients. The Meta-analysis showed that there was no significant difference (P 0.05) between the RIF group and the arsenic trioxide (ATO) group for primary outcomes, secondary outcomes apart from liver dysfunction. The incidence of liver dysfunction (P = 0.006) in the RIF group were significantly lower than those in the ATO group. In addition, the cost of maintenance therapy in the RIF group was significantly lower (P 0.05) than the ATO group. Besides, the active ingredients in RIF mainly act on targets proteins such as ACHE, NCOA2, RXRA, and then play a role in the treatment of APL through regulating multiple molecular mechanisms, such as TP53 regulates transcription of cell cycle genes, nuclear receptor transcription pathway. Conclusion: There was no significant difference in efficacy of oral RIF combined with ATRA compared with intravenous ATO combined with ATRA for the treatment of APL. The oral RIF exposed patients to less risk, offered more convenience and had lower prices. RIF can treat APL by multi-target and multi-pathway interventions that inducing apoptosis of APL cells and inhibiting the proliferation of APL cells, and so on. Therefore, oral RIF in the treatment of APL is worthy of further research and development.

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.

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

CLINICOPATHOLOGICAL STUDY OF ACUTE PROMYELOCYTIC LEUKEMIA: AN EXPERIENCE FROM A TEACHING HOSPITAL IN INDIA

Data on the clinicopathological features of acute promyelocytic leukemia (APL) patients from India is limited. Present study was a cross sectional study which included 18 patients of APL. Medical records of these 18 patients were reviewed to collect their clinical details and laboratory results. High risk patients (total leucocyte count >10,000/cmm) were treated with modified APML 4 protocol.Low risk patients (total leucocyte count <10,000/cmm) were treated with protocol APL- 0406-Intergroup Study AL WP GIMEMA-DSIL protocol. Outcomes in terms of complete remission were assessed in both these groups. Mean haemoglobin levels was 7.03gm%, mean total leucocyte count was 30,462per cmm, mean platelet count was 27,222/cmm. Bone marrow was reported as suggestive of APL in 17 cases while in 1 case, BM aspirate was inadequate. Average percentage of abnormal promyelocytes in bone marrow was 84.25%. PT was prolonged in 15 cases, while APTT was prolonged in 3 cases. Flow cytometry analysis was done in 12 patients. All patients were CD45, MPO, CD13, CD33 and CD64 positive. Chromosomal analysis was possible in 11 cases. t(15;17)(q22;21) was identified in 6 cases (54.62%). 3 cases (27.27%) showed normal karyotype. 2 (18.18%) cases had additional cytogenetic abnormalities. All patients under high risk category attained CR. 1 patient under low risk category with additional cytogenetic abnormality died 6 days after induction therapy was started. 10 (55.55%) patients developed complications such as neutropenic sepsis, intracranial hemorrhage, differentiation syndrome, cerebral venous sinus thrombosis, pseudotumorcerebri, QTc interval prolongation, and pneumonia.

Cost-effectiveness of the regimen proposed by the International Consortium on Acute Promyelocytic Leukemia for the treatment of newly diagnosed patients with Acute Promyelocytic Leukemia

ABSTRACT Introduction: We performed cost-effectiveness and cost-utility analyses of the modified International Consortium on Acute Promyelocytic Leukemia protocol in Mexico for the treatment of acute promyelocytic leukemia Acute Promyelocytic Leukemia. Methods: We performed a three-state Markov analysis: stable disease (first line complete response [CR]), disease event (relapse, second line response and CR) and death. The modified IC-APL protocol is composed of three phases: induction, consolidation and maintenance. Cost and outcomes were used to calculate incremental cost-effectiveness ratios (ICERs); quality-adjusted life-years were used to calculate incremental cost-utility ratios (ICURs). Results: The CR was achieved in 18 patients (90%), treated with the IC-APL protocol as the first-line option; one patient (5%) died in induction, another one never achieved CR (5%); of the 18 patients that achieved CR, 1 relapsed (5.5%). The median treatment cost of the IC-APL protocol was $21,523 USD. The average life-year in our study was 7.8 years, while the average quality-adjusted life-year (QALY) was 6.1 years. When comparing the ICER between the IC-APL and the all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) protocols, we found the different costs of $6497, $19,133 and $17,123 USD in Italy, the USA and Canada, respectively. In relation to the ICUR, we found the different costs to be $13,955 and $11,979 USD in the USA and Canada, respectively. Conclusion: Taking into account the similar response rates, lower cost and easy access to the modified IC-APL regimen, we consider it a cost-effective and cost-utility protocol, deeming it the treatment of choice for our population.

Leucemia promielocítica aguda y trombosis. Presentación de un caso / Acute promyelocytic leukemia and thrombosis. Presentation of a case

Introducción: En los últimos años se ha comprobado que el riesgo de trombosis en pacientes con enfermedades oncohematológicas es elevado. Presentación del caso: Paciente masculino de 51 años de edad, con diagnóstico de leucemia promielocítica, recibió tratamiento de inducción con trióxido de arsénico y ya alcanzada la remisión morfológica de la leucemia, y sin antecedentes personales ni familiares de eventos trombóticos, presentó una trombosis venosa profunda del miembro inferior izquierdo, se trató con heparina de bajo peso molecular y warfarina. Conclusiones: El paciente evolutivamente tuvo una evolución favorable del evento trombótico y se alcanzó la remisión completa hematológica, citogenética y molecular con una adecuada calidad de vida que permitió su reinserción a su vida personal, familiar y social(AU)

Introduction: In recent years it has been proven that the risk of thrombosis in patients with oncohematological diseases has increased. Case presentation: A 51-year-old male patient, diagnosed with Promyelocytic Leukemia, received induction treatment with arsenic trioxide and the morphological remission of the leukemia had already been achieved and with no personal or family history of thrombotic events, presented a deep vein thrombosis of the left lower limb. He was treated with low molecular weight heparin and warfarin. Conclusions: The patient progressively had a favorable evolution of the thrombotic event and complete hematological, cytogenetic and molecular remission was achieved with an adequate quality of life that allowed his reinsertion into his personal, family and social life(AU)

Prevalence and outcomes of thrombotic and hemorrhagic complications in pediatric acute promyelocytic leukemia in a tertiary Brazilian center

Abstract Introduction: Little attention is given to thrombosis associated with pediatric acute promyelocytic leukemia (APL). This study describes the thrombotic and hemorrhagic manifestations of APL in pediatric patients and evaluates their hemostasis, based on coagulation tests. Methods: Inclusion criteria were age 0-18 years and APL diagnosis between April 2005 and November 2017. Patients who had received blood transfusion prior to coagulation tests were excluded. Baseline coagulation tests, hematologic counts, and hemorrhagic/thrombotic manifestations were evaluated. Results: Median age was 10.7 years (1-15 years). The initial coagulation tests revealed a median Hgb of 8.3 g/dL (4.7-12.9 g/dL), median leucocyte count of 10.9 × 109/L (1.1-95.8 × 109/L), median platelet count of 31.8 × 109/L (2.0-109.0 × 109/L), median activated partial thromboplastin time (aPTT) of 31.7 s (23.0-50.4 s), median aPTT ratio of 1.0 (0.78-1.6), median thromboplastin time (PT) of 17.5 s (13.8-27.7 s), median PT activity of 62% (25-95 %), and median fibrinogen of 157.7 mg/dL (60.0-281.0 mg/dL). Three patients (13%) had thrombosis. At diagnosis, 21 patients (91.3%) had bruising, one patient (4.3%) had splenic vein and artery thrombosis and one patient (4.3%) presented without thrombohemorrhagic manifestations. During treatment, two patients (8.6%) had thrombosis. Conclusion: Knowledge of thrombosis in pediatric APL is important to determine its risk factors and the best way to treat and prevent this complication.

Results of the implementation of the PETHEMA LPA 99 protocol for treating children with acute promyelocytic leukemia in Bogotá, Colombia / Resultados de la implementación del protocolo PETHEMA LPA 99 en el tratamiento de niños con leucemia promielocítica aguda en Bogotá, Colombia

Abstract Introduction: In the United States, between 4 and 8% of children with acute myeloid leukemia have acute promyelocytic leukemia (APL), but a higher incidence of this malignancy has been reported in Latin America (20%-28%). The implementation of the PETHEMA LPA 99 protocol, designed for the treatment of APL in adults, has shown an overall survival (OS) >80%. Objective: To describe the results obtained after the implementation of the PETHEMA LPA 99 protocol to treat children with APL at the Fundación Hospital Pediátrico La Misericordia in Bogotá, D.C., Colombia. Materials and methods: Descriptive and retrospective cohort study. The medical records of 30 pediatric patients (<18 years) with APL, who were treated using the PETHEMA LPA 99 protocol between January 2005 and December 2012, were reviewed. Data on the following variables were obtained: early death, death during induction therapy, OS, event-free survival (EFS), and relapse. Results: The male sex was predominant (60%) among the 30 patients included in the study. Regarding risk classification, 13 (43%) were classified as high-risk patients, 12 (40%) as medium-risk, and 5 (17%) as low-risk. Seven individuals died: 2 before receiving cancer treatment, 2 during induction therapy, and 3 after relapse. Relapse was reported in 5 patients. There were no deaths during the consolidation or maintenance phases. OS was 75.4% (95%CI: 55.1-87.5) and EFS was 64.3% (95%CI: 40-80.5). Moreover, OS at 11 years was 80%, 91.7%, and 59.2% for low-risk, intermediate-risk, and high-risk patients, respectively. The median follow-up time was 6.35 years (0-11.43 years). Conclusions: In general, the implementation of the PETHEMA LPA 99 protocol to treat APL in the study population showed very satisfactory results. Therefore, its use in pediatric population is recommended, taking into account the adjustments described in the protocol regarding the characteristics of this age group.

Resumen Introducción. En Estados Unidos de América, entre 4 y 8% de niños con leucemias mieloides agudas tienen leucemia promielocítica aguda (LPA), mientras que en Latinoamérica se ha descrito una mayor incidencia de esta neoplasia (20-28%). La implementación del protocolo PETHEMA LPA 99, diseñado para el tratamiento de LPA en adultos, ha mostrado una supervivencia global (SG) >80%. Objetivo. Describir los resultados de la aplicación del protocolo PETHEMA LPA 99 en el tratamiento de niños con LPA en la Fundación Hospital Pediátrico la Misericordia, en Bogotá D.C., Colombia. Materiales y métodos. Estudio de cohorte descriptivo y retrospectivo. Se revisaron las historias clínicas de 30 pacientes pediátricos (<18 años) con LPA que recibieron tratamiento mediante el protocolo PETHEMA LPA 99 entre enero de 2005 y diciembre de 2012. Se obtuvieron datos sobre las siguientes variables: muerte temprana, muerte en terapia de inducción, SG, supervivencia libre de evento (SLE) y recaída. Resultados. De los 30 pacientes, la mayoría eran de sexo masculino (60%). Respecto a la clasificación de riesgo, 13 (43%) fueron clasificados como pacientes de riesgo alto; 12 (40%), de riesgo intermedio, y 5 (17%), de riesgo bajo. 7 individuos murieron: 2 antes del tratamiento oncológico, 2 durante la terapia de inducción y 3 luego de presentar recaída. Se reportó recaída en 5 pacientes. No hubo muertes durante las fases de consolidación o de mantenimiento. La SG fue de 75.4% (IC95%: 55.1-87.5) y la SLE fue de 64.3% (IC95%: 40-80.5). La SG a 11 años fue de 80%, 91.7% y 59.2% para los pacientes de riesgo bajo, riesgo intermedio y riesgo alto, respectivamente. La mediana de seguimiento fue 6.35 años (0-11.43 años). Conclusiones. En general, la implementación del protocolo PETHEMA LPA 99 en el tratamiento de la LPA en la población de estudio mostró resultados muy satisfactorios, por lo que se recomienda su uso en población pediátrica, teniendo en cuenta los ajustes recomendados por el protocolo en relación con las características de este grupo etario.