Trióxido de arsénico en pacientes con leucemia promielocítica aguda en recaída / Trióxido de arsénico em pacientes com leucemia promielocítica aguda recuperável

INTRODUCCIÓN: Cuadro clínico: La leucemia promielocítica aguda (LPA) representa el 5% a 20% de los casos de leucemia mieloide aguda (LMA) (1,2); sin embargo, entre pacientes de origen latino se ha reportado una frecuencia de 38%. En Perú, a pesar de que no se tienen reportes de la frecuencia de la leucemia promielocítica aguda (LPA), en un estudio realizado entre el año 1996 y 2008 en el Hospital Nacional Edgardo Rebagliati Martins se observó que el 52% y 38% de los pacientes con LPA se encontraban entre los grupos etarios de 16 - 40 años y 41 - 60 años, respectivamente (3). En pacientes con LPA sin tratamiento la mediana de sobrevida es menor a un mes, debido al sangrado descontrolado (4). Sin embargo, con los avances recientes en las terapias, la sobrevida ha mejorado y la mayoría de los pacientes alcanza la remisión completa y se mantiene. El tratamiento de la LPA comprende tres etapas: remisión o inducción, consolidación y mantenimiento. Del total de pacientes con LPA tratados con ácido trans-retinoico (ATRA) más quimioterapia con antraciclinas, el 10 % al 20% sufre una recaída. El objetivo de tratamiento de este grupo de pacientes es alcanzar la remisión molecular, con planes de proseguir con quimioterap

Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia.

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.

PML/RARa leukemia induced murine model for immunotherapy evaluation.

Even though leukemia murine models are valuable tools for new drug therapy studies, most of these models consist of immunocompromised mice, which do not exhibit immune responses. In order to obtain an adequate leukemia model, we established an acute promyelocytic leukemia transplantation-based model (PML/RARa) in immunocompetent BALB/c mice, thus making it possible to study drug-induced cellular immune responses in leukemia. The development of PML/RARa leukemia was confirmed by leukocytosis (76.27 ± 21.8 vs. 3.40 ± 1.06; P < 0.0001), anemia (7.46 ± 1.86 vs. 15.10 ± 0.96; P < 0.0001), and thrombocytopenia (131.85 ± 39.32 vs. 839.50 ± 171.20; P < 0.0001), and the presence of blasts in the peripheral blood of mice (approximately 50% blasts; P < 0.0001), 15 days after the transplants. These findings were corroborated through differential counts, flow cytometry, and in vivo imaging, which indicated increased number of immature cells in the bone marrow (15.75 ± 3.30 vs 6.69 ± 0.55; P < 0.001), peripheral blood (7.88 ± 2.67 vs 1.22 ± 0.89; P < 0.001), and spleen (35.21 ± 4.12 vs 1.35 ± 0.86; P < 0.0001), as well as promyelocytes in the bone marrow (41.23 ± 4.80 vs 5.73 ± 1.50; P < 0.0001), peripheral blood (46.08 ± 7.52 vs 1.10 ± 0.59; P < 0.0001) and spleen (35.31 ± 8.26 vs 2.49 ± 0.29; P < 0.0001) of PML/RARa mice. Compared to basal conditions of untransplanted mice, the PML/RARa mice exhibited frequencies of T lymphocytes CD4 helper = 14.85 ± 2.91 vs 20.77 ± 2.9 in the peripheral blood (P < 0.05); 12.75 ± 1.33 vs 45.90 ± 2.02 in the spleen (P < 0.0001); CD8 cytotoxic = 11.27 ± 3.44 vs 11.05 ± 1.22 in the peripheral blood (P > 0.05); 10.48 ± 1.16 vs 30.02 ± 1.80 in the spleen (P < 0.0001); natural killer (NK) cells = 3.68 ± 1.35 vs 6.84 ± 0.52 in the peripheral blood (P < 0.001); 4.43 ± 0.57 vs 6.40 ± 1.14 in the spleen (P < 0.05); B cells 2.50 ± 0.60 vs 15.20 ± 5.34 in the peripheral blood (P < 0.001); 17.77 ± 4.39 vs 46.90 ± 5.92 in the spleen (P < 0.0001); neutrophils = 5.97% ± 1.88 vs 31.57 ± 9.14 (P < 0.0001); and monocytes = 6.45 ± 2.97 vs 15.85 ± 2.57 (P < 0.001), selected as classical (3.33 ± 3.40 vs 57.80 ± 16.51, P < 0.0001), intermediate (57.42 ± 10.61 vs 21.75 ± 5.90, P < 0.0001), and non-classical monocytes (37.51 ± 10.85 vs 18.08 ± 7.13, P < 0.05) in the peripheral blood; and as classically activated (M1) within in the bone marrow (3.70 ± 0.94 vs 1.88 ± 0.39, P < 0.05) and spleen 15.19 ± 3.32 vs 9.47 ± 1.61, P < 0.05), in addition to alternatively activated (M2) macrophages within the bone marrow (23.06 ± 5.25 vs 1.76 ± 0.74, P < 0.0001) and spleen (46.51 ± 11.18 vs 30.58 ± 2.64, P < 0.05) compartments. All-trans retinoic acid (ATRA) treatment of PML/RARa mice reduced blast (immature cells) in the bone marrow (8.62 ± 1.81 vs 15.76 ± 1.25; P < 0.05) and spleen (8.75 ± 1.31 vs 35.21 ± 1.55; P < 0.0001) with no changes in the peripheral blood (10.13 ± 3.33 vs 7.88 ± 1.01; P > 0.05), as well as reduced promyelocytes in the bone marrow (19.79 ± 4.84 vs 41.23 ± 1.81; P < 0.05), peripheral blood (31.65 ± 3.92 vs 46.09 ± 2.84; P < 0.05) and spleen (24.84 ± 2.03 vs 41.46 ± 2.39; P < 0.001), and increased neutrophils of the peripheral blood (35.48 ± 7.24 vs 7.83 ± 1.40; P < 0.05) which was corroborated by reducing of immature cells and increase of neutrophil in the stained smears from PML/RARa mice, thus confirming that this model can be used in drug development studies. Our results show the effective induction of PML/RARa leukemia in BALB/c mice, thus producing a low-priced and reliable tool for investigating cellular immune responses in leukemia.

Assessing the Efficacy of Mitoxantrone and Doxorubicin as Frontline Anthracyclines During Induction Therapy of Newly Diagnosed Acute Promyelocytic Leukemia.

BACKGROUND: Therapeutic advances in acute promyelocytic leukemia (APL) have transformed it into today's most curable form of leukemia. However, recommended agents, including arsenic trioxide, idarubicin, or daunorubicin, are not easily available in low-middle-income countries, where outcomes remain suboptimal. We aimed to assess the efficacy and safety of more accessible anthracyclines. METHODS: We conducted a retrospective cohort study including sixty-one patients diagnosed with APL over a 15-year period. Patients received low-dose all-trans retinoic acid (ATRA, 25 mg/m2) with mitoxantrone or doxorubicin as an induction to remission therapy. Groups were compared using the χ2 and Student's t-tests. Kaplan-Meier analysis was used for survival analyses. RESULTS: Thirty (49.18%) patients received mitoxantrone, and 31 (50.82%) received doxorubicin. The median follow-up was 24.6 months (1-146). Twenty-eight (93.3%) patients achieved complete remission (CR) in the mitoxantrone group and 28 (87.1%) in the doxorubicin group (p=0.103), and the median time to CR was 40 and 31 days, respectively. Mitoxantrone had a 6.7% early mortality rate and a 16.7% relapse rate compared with doxorubicin (3.2% and 32.3%, respectively). No differences were found in survival (p = 0.795), hospitalization days (p = 0.261), or adverse events (p = 0.554). CONCLUSIONS: Using mitoxantrone or doxorubicin as induction therapy in newly diagnosed APL is a safe and adequate alternative with comparable outcomes to first-line agents in scenarios where the latter might not be readily available, such as in low-middle-income countries.

Flexible genosensors based on polypyrrole and graphene quantum dots for PML/RARα fusion gene detection: A study of acute promyelocytic leukemia in children.

Acute promyelocytic leukemia (APL) in children is associated with a favorable initial prognosis. However, minimal residual disease (MRD) follow-up remains poorly defined, and relapse cases are concerning due to their recurrent nature. Thus, we report two electrochemical flexible genosensors based on polypyrrole (PPy) and graphene quantum dots (GQDs) for label-free PML-RARα oncogene detection. Atomic force microscopy (AFM), scanning electron microscope (SEM), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) were used to characterize the technological biosensor development. M7 and APLB oligonucleotide sequences were used as bioreceptors to detect oncogenic segments on chromosomes 15 and 17, respectively. AFM characterization revealed heterogeneous topographical surfaces with maximum height peaks for sensor layers when tested with positive patient samples. APLB/Genosensor exhibited a percentage change in anode peak current (ΔI) of 423 %. M7/Genosensor exhibited a ΔI of 61.44 % for more concentrated cDNA samples. The described behavior is associated with the biospecific recognition of the proposed biosensors. Limits of detection (LOD) of 0.214 pM and 0.677 pM were obtained for APLB/Genosensor and M7/Genosensor, respectively. The limits of quantification (LOQ) of 0.648 pM and 2.05 pM were estimated for APLB/Genosensor and M7/Genosensor, respectively. The genosensors showed reproducibility with a relative standard deviation of 7.12 % for APLB and 1.18 % for M7 and high repeatability (9.89 % for APLB and 1.51 % for M7). In addition, genetic tools could identify the PML-RARα oncogene in purified samples, plasmids, and clinical specimens from pediatric patients diagnosed with APL with high bioanalytical performance. Therefore, biosensors represent a valuable alternative for the clinical diagnosis of APL and monitoring of MRD with an impact on public health.

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

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.

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.

Tocotrienols-enriched Self-nanoemulsifying Drug Delivery System Enhances the Antileukemic Activity of All-trans Retinoic Acid but not Electrocardiogram Alterations Evoked by Its Combination with Arsenic Trioxide.

All-trans retinoic acid and arsenic trioxide are the leading choices for the treatment of acute promyelocytic leukemia. Notwithstanding the impressive differentiative properties of all-trans retinoic acid and the apoptotic properties of arsenic trioxide, some problems still occur in acute promyelocytic leukemia treatment. These problems are due to patients' relapses, mainly related to changes in the ligand-binding domain of RARα (retinoic acid receptor α) and the cardiotoxic effects caused by arsenic trioxide. We previously developed a self-nanoemulsifying drug delivery system enriched with tocotrienols to deliver all-trans retinoic acid (SNEDDS-TRF-ATRA). Herein, we have evaluated if tocotrienols can help revert ATRA resistance in an APL cell line (NB4-R2 compared to sensitive NB4 cells) and mitigate the cardiotoxic effects of arsenic trioxide in a murine model. SNEDDS-TRF-ATRA enhanced all-trans retinoic acid cytotoxicity in NB4-R2 (resistant) cells but not in NB4 (sensitive) cells. Moreover, SNEDDS-TRF-ATRA did not significantly change the differentiative properties of all-trans retinoic acid in both NB4 and NB4-R2 cells. Combined administration of SNEDDS-TRF-ATRA and arsenic trioxide could revert QTc interval prolongation caused by ATO but evoked other electrocardiogram alterations in mice, such as T wave flattening. Therefore, SNEDDS-TRF-ATRA may enhance the antileukemic properties of all-trans retinoic acid but may influence ECG changes caused by arsenic trioxide administration. SNEDDS-TRF-ATRA presents cytotoxicity in resistant APL cells (NB4-R2). Combined administration of ATO and SNEDDS-TRF-ATRA in mice prevented the prolongation of the QTc interval caused by ATO but evoked ECG abnormalities such as T wave flattening.

Acute myeloid leukemia: challenges for diagnosis and treatment in Latin America.

OBJECTIVE: to review the current diagnostic and therapeutic landscape of AML in Latin America as a reflection of other low- and middle-income countries and regions of the world. Encompassing both acute promyelocytic and non-promyelocytic disease types. METHODS: We reviewed the literature and study registries concerning epidemiological features of patients with AML/APL treated in Latin America, as well as evaluated diagnostic and genetic stratification and patient fitness assessment challenges, the importance of early mortality and supportive care capacity, intensive and non-intensive chemotherapy alternatives, consolidation, and maintenance strategies including novel agents and hematopoietic stem cell transplantation. RESULTS: Although most of the current technologies and treatment options are available in the region, a significant fraction of patients have only limited access to them. In addition, mortality in the first weeks from diagnosis is higher in the region compared to developed countries. CONCLUSIONS: Disparities in access to technologies, supportive care capacity, and availability of novel agents and HSCT hinder results in our region, reflecting barriers common to other LMICs. Recent developments in the diagnosis and treatment of this disease must be implemented through education, collaborative clinical research, and advocacy to improve outcomes.

Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia.

Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.

Glomerulonephritis Secondary to Acute Promyelocytic Leukemia that Resolved after Induction Therapy.

The association of glomerulonephritis and malignant hematological disease is uncommon, but well known in chronic leukemias, lymphomas, and monoclonal gammopathies. However, only a few cases of glomerulonephritis and acute myeloid leukemia have been reported in the literature. We describe the first case of a genetically diagnosed acute promyelocytic leukemia presenting with nephrotic range proteinuria that resolved with induction therapy with ATRA and ATO and performed a comprehensive review of the literature.

Biased Clonal Evolution in Acute Promyelocytic Leukemia through Imbalances Affecting the der(17) but Not the der(15) Chromosome: Report of Two Cases.

Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15;17)(q24;q21), raising two hybrid genes: PML::RARA and RARA::PML. There is a biased clonal evolution in APL since imbalances affecting the der(15) chromosome (the one that carries the transforming PML::RARA gene) have never been reported; instead, imbalances of the der(17), mainly in form of an ider(17)(q10), have been repeatedly documented. We here present two cases with APL who acquired an ider(17)(q10) as a secondary chromosomal change. The presence of the ider(17)(q10) implies several genomic consequences with potential to fuel tumor progression: (1) a duplication of the hybrid gene RARA::PML; (2) a cumulative haploinsufficiency for tumor suppressor genes located in the 17p arm; and (3) a cumulative triplosensitivity of genes located in 17q10→RARA::PML→15qter. Both our patients were treated following the PETHEMA LPA 2012 protocol with ATRA plus idarubicin and they have had a long event-free survival.

STMN1 is highly expressed and contributes to clonogenicity in acute promyelocytic leukemia cells.

Stathmin 1 (STMN1) is a microtubule-destabilizing protein highly expressed in hematological malignancies and involved in proliferation and differentiation. Although a previous study found that the PML-RARα fusion protein, which contributes to the pathophysiology of acute promyelocytic leukemia (APL), positively regulates STMN1 at the transcription and protein activity levels, little is known about the role of STMN1 in APL. In this study, we aimed to investigate the STMN1 expression levels and their associations with laboratory, clinical, and genomic data in APL patients. We also assessed the dynamics of STMN1 expression during myeloid cell differentiation and cell cycle progression, and the cellular effects of STMN1 silencing and pharmacological effects of microtubule-stabilizing drugs on APL cells. We found that STMN1 transcripts were significantly increased in samples from APL patients compared with those of healthy donors (all p < 0.05). However, this had no effect on clinical outcomes. STMN1 expression was associated with proliferation- and metabolism-related gene signatures in APL. Our data confirmed that STMN1 was highly expressed in early hematopoietic progenitors and reduced during cell differentiation, including the ATRA-induced granulocytic differentiation model. STMN1 phosphorylation was predominant in a pool of mitosis-enriched APL cells. In NB4 and NB4-R2 cells, STMN1 knockdown decreased autonomous cell growth (all p < 0.05) but did not impact ATRA-induced apoptosis and differentiation. Finally, treatment with paclitaxel (as a single agent or combined with ATRA) induced microtubule stabilization, resulting in mitotic catastrophe with repercussions for cell viability, even in ATRA-resistant APL cells. This study provides new insights into the STMN1 functions and microtubule dynamics in APL.

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

Sarcoma Granulocítico Cutâneo de Apresentação Concomitante ao Diagnóstico de Leucemia Promielocítica Aguda / Cutaneous Granulocytic Sarcoma Concomitant to the Diagnosis of Acute Promyelocytic Leukemia / Sarcoma Granulocitico Cutaneo de Presentacion Concomitente al Diagnostico de Leucemia Promielocitica Aguda

Introdução: O sarcoma granulocítico (SG) é um tumor extramedular raro, composto por células mieloides imaturas. Ocorre em 2% a 14% dos pacientes com leucemia mieloide aguda (LMA). A associação com leucemia promielocítica (LPA) é ainda mais rara, especialmente como manifestação no momento do diagnóstico. O presente estudo expõe o caso de um paciente com SG cutâneo de apresentação concomitante ao diagnóstico de LPA. Relato do caso: Paciente do sexo masculino, 30 anos, encaminhado ao Departamento de Hematologia por febre, odinofagia, intensa adinamia, hiporexia, perda de 5 kg, sudorese noturna, além de dispneia progressiva ao longo de um mês. Realizou exames laboratoriais com evidência de anemia grave, prosseguindo investigação etiológica com mielograma, que evidenciou 84% de blastos, e imunofenotipagem compatível com LPA, PML-RARA positivo (90%). Apresentava ainda lesões ulceradas em região genital e coxa direita, cuja biópsia evidenciou proliferação de células redondas suspeita para infiltração por LMA/SG. A imuno-histoquímica confirmou SG. O paciente foi submetido à quimioterapia, com boa resposta ao tratamento e melhora das contagens sanguíneas. As lesões cutâneas evoluíram com cicatrização. Após terceira consolidação, o PML-RARA negativou. Conclusão: Este relato de caso descreve uma apresentação rara de uma doença hematológica maligna, o SG, também conhecido como cloroma, na pele. Uma estratégia de diagnóstico incluindo imagens, histopatologia, imuno-histoquímica e exames laboratoriais foi necessária para confirmá-lo. O diagnóstico oportuno é essencial para que o tratamento adequado seja instituído logo, beneficiando o paciente em sobrevida e qualidade de vida

Introduction: Granulocytic sarcoma (GS) is a rare extramedullary tumor, made up by immature myeloid cells. It occurs in 2% to 14% of patients with acute myeloid leukemia (AML). The association with promyelocytic leukemia (APL) is even more rare, especially as manifestation at the time of diagnosis. The present study exposes the case of a patient with cutaneous GS concomitant with a diagnosis of APL. Case report: Male patient, 30 years old, referred to the Hematology Department due to fever, odynophagia, intense adynamia, hyporexia, loss of 5 kg, night sweating, in addition to progressive dyspnea over one month. Laboratory exams were run with evidence of severe anemia, proceeding to etiological investigation with myelogram, which showed 84% of blasts, and immunophenotyping compatible with promyelocytic leukemia (APL), PML-RARA positive (90%). Also, presented ulcerated lesions in the genital region and right leg, whose biopsy showed proliferation of suspected round cells for infiltration by AML/GS. Immunohistochemistry confirmed GS. The patient underwent chemotherapy, with good response to the treatment and improvement of blood counts. Skin lesions evolved with healing. After the 3rd consolidation, PML-RARA was negative. Conclusion: This case report describes a rare presentation of a malignant hematological disease, GS, also known as skin chloroma. A diagnostic strategy including images, histopathology, immunohistochemistry and laboratory tests were needed for confirmation. Timely diagnosis is essential, so that appropriate treatment is instituted soon, benefiting the patient regarding survival and quality of life

Introducción: El sarcoma granulocítico (SG) es un tumor extramedular poco frecuente, compuesto por células mieloides inmaduras. Ocurre en 2% a 14% de los pacientes con leucemia mieloide aguda (AML). La asociación con leucemia promielocítica (LPA) es aún más rara, especialmente como manifestación en el momento del diagnóstico. El presente estudio expone el caso de un paciente con SG cutáneo que presenta un diagnóstico de LPA. Relato del caso: Paciente masculino de 30 años, remitido al Servicio de Hematología por fiebre, odinofagia, adinamia intensa, hiporexia, pérdida de 5 kg, sudoración nocturna, además de disnea progresiva a lo largo de un mes. Realizó exámenes de laboratorio con evidencia de anemia severa, continuando investigación etiológica con mielograma, que mostró 84% de blastos, e inmunofenotipificación compatible con LPA, PML-RARA positivo (90%). También presentaba lesiones ulceradas en región genital y muslo derecho, en las que la biopsia mostró proliferación de células redondas sospechadas para infiltración por LMA/SG. La inmunohistoquímica confirmó SG. El paciente fue sometido a quimioterapia, con buena respuesta al tratamiento y mejoría de los hemogramas. Las lesiones cutáneas evolucionaron con la curación. Después de la tercera consolidación, el PML-RARA fue negativo. Conclusión: Este reporte de caso describe una presentación poco común de una enfermedad hematológica maligna, el SG, también conocido como cloroma, en la piel. Se necesitaba una estrategia de diagnóstico que incluyera imágenes, histopatología, inmunohistoquímica y pruebas de laboratorio para confirmarlo. El diagnóstico oportuno es fundamental para que pronto se instaure el tratamiento adecuado

Activity of Free and Liposomal Antimony Trioxide in the Acute Promyelocytic Leukemia Cell Line NB4.

BACKGROUND/AIM: Antimony is a chemical element used in the therapy of parasitic diseases with a promising anticancer potential. The aim of this study was to evaluate in vitro activity of free or liposomal vesicle-packed antimony trioxide (AT or LAT) in the t(15;17)(q22;q21) translocation-positive acute promyelocytic leukemia (APL) cell line NB4. MATERIALS AND METHODS: Cytotoxicity was analysed with trypan blue exclusion, the MTT assay and neutral red exclusion assay; cell proliferation with PicoGreen®; and reactive oxygen species (ROS) production with DCFDA. RESULTS: Liposomal particles did not change the pH of the cell culture medium and entered the cells. Both formulations resulted in a time- and concentration-dependent cytotoxicity and production of ROS. LAT showed higher toxicity at lower concentrations compared to AT. CONCLUSION: LAT may be used to decrease drug dosage and maintain high anti-tumoral effects on APL cells.