High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia.

The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.

Survival benefit of pediatric-based regimen for adults with acute lymphoblastic leukemia: A single-center retrospective cohort.

INTRODUCTION: Improving survival of Acute Lymphoblastic Leukemia (ALL) in adult patients has been a challenge. Despite intensive chemotherapy treatment, overall survival is poor. However, several studies demonstrate that young adult patients have better survival when treated with pediatric-based intensive regimens. Considering these results, We decided to treat newly diagnosed ALL patients according to age and risk factors. The goal of this study was to describe the results of this intensive chemotherapy treatment approach for ALL adult patients diagnosed at our institution. METHODS: Fifty-eight ALL patients, diagnosed from 2004 to 2013, were included in the analysis. Patients were assigned to either the St. Jude Total Therapy XIIIB high-risk arm (St Jude) or the CALGB 8811 (CALGB). The Kaplan-Meier survival curve was used for the survival analyses and the Cox proportional hazard regression, for multivariable analysis. RESULTS: The overall survival was 22.9% at 10 years. The St. Jude improved survival, compared to the CALGB (p = 0.007), with 32.6% vs. 7.4% survival rate at 10 years. However, no survival benefit was found for patients younger than 20 years old (p = 0.32). The multivariable analysis demonstrated that undetectable minimal residual disease (MRD) and hematopoietic stem cell transplantation (HSCT) had beneficial impact on survival (p = 0.0007 and p = 0.004, respectively). CONCLUSION: ALL is a disease of poor prognosis for adults. The joint effort to standardize treatment and seek solutions is the way to start improving this scenario.

Philadelphia-positive B-lymphoblastic leukemia in a middle-income country - A real-world multicenter cohort.

Outside of clinical trials, few studies have addressed the outcomes of Ph+ acute lymphoblastic leukemia (ALL) in adults, especially from developing world. In this study, we conducted a multicenter analysis on the outcomes of patients aged > 15 years with Ph+ ALL, aiming to get to know an overview of the Brazilian experience as well as to explore baseline factors associated with relapse and mortality in our setting. Over these 10 years, patients were treated with diverse protocols, all of them always combined with a frontline tyrosine-kinase inhibitor. A total of 123 Ph+ ALL patients was included. Imatinib was the first line TKI in 97 %. The complete response rate was 79 %. The early death rate was 15 %, being associated with increasing age at diagnosis (p = 0.06). The use of intensive versus attenuated induction regimen was not associated with higher induction mortality (p = 0.99). Overall, 29 % of patients aged ≤ 60 years underwent allogeneic transplantation, 87 % in first CR. 4-year overall survival (OS) and relapse-free survival were 25 % and 24 %, respectively. The incidence of relapse (death as a competitor) was 29 %, while the non-relapse mortality was 42 %. Only age was independently associated with OS, and lactate dehydrogenase level and central nervous disease at diagnosis were related to relapse in our cohort. This is the first historical cohort multicenter study on Ph+ ALL from Brazil. Reporting these outcomes is essential to encourage public policies to expand access to new drugs and transplantation in middle-income countries.

Toxicity Profile of PEG-Asparaginase in Adult Patients With Acute Lymphoblastic Leukemia in Brazil: A Multicenter Cross-Sectional Study.

BACKGROUND: Currently, pediatric-inspired regimens are commonly applied to adults with acute lymphoblastic leukemia (ALL) after the recent recognition that these protocols improve survival. While asparaginase in whatever available formulation is a key component of modern treatment of ALL, many adult oncologists and hematologists struggle to deal with its particular toxicities in clinical practice. We reviewed toxicity outcomes of pegylated asparaginase (PEG-ASP) in adults with ALL treated in 3 reference centers in Brazil. PATIENTS AND METHODS: This was a cross-sectional retrospective chart-review study encompassing patients aged 15 years and older diagnosed with ALL or ambiguous-lineage leukemia who received at least one dose of PEG-ASP, regardless of the adopted regimen. RESULTS: A total of 57 patients were included (age range, 15-57 years). Most patients (70%) received 2000 IU/m2 as the initial dose, by intravenous route (72%). The incidence of thromboembolic events was 17.5%, and the main site was cerebral venous sinus (4/10). Thrombosis was more frequent in patients receiving second-line treatment. In obese patients, grade 3 hepatotoxicity and hyperbilirubinemia were more common. Clinical pancreatitis (grade 3 or higher) was found in 2 of 57 cases. PEG-ASP had to be discontinued in 19.3% of exposed patients (11/57). CONCLUSION: By reviewing the medical charts of adult patients with ALL from 3 reference centers, we found that our incidence of thrombotic and hepatic adverse events is similar to those reported in other trials involving PEG-ASP. Usually these effects should not preclude further use of the drug because most events are manageable in routine clinical practice.

Survival benefit of pediatric-based regimen for adults with acute lymphoblastic leukemia: A single-center retrospective cohort

ABSTRACT Introduction: Improving survival of Acute Lymphoblastic Leukemia (ALL) in adult patients has been a challenge. Despite intensive chemotherapy treatment, overall survival is poor. However, several studies demonstrate that young adult patients have better survival when treated with pediatric-based intensive regimens. Considering these results, We decided to treat newly diagnosed ALL patients according to age and risk factors. The goal of this study was to describe the results of this intensive chemotherapy treatment approach for ALL adult patients diagnosed at our institution. Methods: Fifty-eight ALL patients, diagnosed from 2004 to 2013, were included in the analysis. Patients were assigned to either the St. Jude Total Therapy XIIIB high-risk arm (St Jude) or the CALGB 8811 (CALGB). The Kaplan-Meier survival curve was used for the survival analyses and the Cox proportional hazard regression, for multivariable analysis. Results: The overall survival was 22.9% at 10 years. The St. Jude improved survival, compared to the CALGB (p = 0.007), with 32.6% vs. 7.4% survival rate at 10 years. However, no survival benefit was found for patients younger than 20 years old (p = 0.32). The multivariable analysis demonstrated that undetectable minimal residual disease (MRD) and hematopoietic stem cell transplantation (HSCT) had beneficial impact on survival (p = 0.0007 and p = 0.004, respectively). Conclusion: ALL is a disease of poor prognosis for adults. The joint effort to standardize treatment and seek solutions is the way to start improving this scenario.

Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines.

We report an increased incidence of high relapse risk features in 157 APL Brazilian patients. Out of 134 patients treated with ATRA and anthracyclines, only 91 (67.9%) achieved remission because 43 (32%) died during induction. The death rate during consolidation was 10.5%. Bleeding complications were the most frequent cause of failure (21.6%).

Acute promyelocytic leukemia: evaluation of diagnostic tests from 2000 to 2018 in a public hospital / Leucemia promielocítica aguda: avaliação dos testes diagnósticos entre o período de 2000 e 2018 em um hospital público

ABSTRACT Introduction: Acute promyelocytic leukemia (APL) is caused by t(15;17)(q24;q21) translocation, which product is the fusion oncoprotein PML-RARa (promyelocytic leukemia-retinoic acid receptor alpha). The morphology of leukemic promyelocytes is usually characteristic, with the presence of faggot cells and coarse cytoplasmic granulations; immunophenotype is characteristic in most cases. However, definitive laboratory diagnosis should be performed by detecting t(15;17) or by PML-RARa fusion protein. Objectives: To compare cytomorphology, flow cytometry, and classical cytogenetic of bone marrow samples from patients with APL, treated at the Complexo Hospital de Clínicas da Universidade Federal do Paraná (CHC-UFPR), as well as describe the possible discrepancies between the methodologies. Method: Retrospective analysis of APL cases treated at the CHC-UFPR from January 2000 to July 2018. Results: Eighty-eight patients (42 man/ 46 woman; mean age: 34 years), 42.1% of them presented a high-risk prognosis. Flow cytometry was performed in 83 cases (94.3%); karyotype was performed in 79 cases (89.7%), but translocation t(15;17) was confirmed in only 53 cases (60.2%). From the 28 patients with a non-conclusive karyotype; fourteen (15.9%) of them presented the PML-RARa transcript in the molecular analysis. In total, 35 patients (39 8%) performed research of the PML-RARa gene by molecular biology. Only 45 patients (51.1%) presented concordant diagnosis among the three technical exams (morphology, flow cytometry and cytogenetics). Overall survival was 67% at 4.8 years, with 29 deaths. Conclusion: Genetic confirmation was observed in 76.1% of samples, 60.2% by conventional cytogenetics and 15.9% by molecular biology. There was a disagreement between the methodologies, and a low sensibility of the conventional cytogenetics, demonstrating the importance of performing molecular techniques for diagnostic confirmation.

RESUMEN Introducción: La leucemia promielocítica aguda (LPA) es causada por la translocación t(15;17)(q24;q21), cuyo producto es la oncoproteína de fusión PML-RARa (proteína de la leucemia promielocítica-receptor alfa de ácido retinoico). La morfología de los promielocitos leucémicos suele ser típica, con presencia de células faggot (células en haces) y gruesasgranulaciones citoplásmicas; el inmunofenotipo es característico en la mayor parte de los casos. No obstante, el diagnóstico final de laboratorio debe ser hecho por la detección de la t(15;17) o por la oncoproteína PML-RARa. Objetivos: Comparar la citomorfología, la citometría de flujo y la citogenética clásica de muestras de médula ósea de pacientes con LPA asistidos en el Complexo Hospital de Clínicas da Universidade Federal do Paraná (CHC-UFPR), así como describir lasposibles discrepancias entre los métodos. Método: Análisis retrospectivo de los casos de LPA asistidos en el CHC-UFPR entre enero de 2000 y julio de 2018. Resultados: De los 88 pacientes (42 hombres y 46 mujeres; edad promedio: 34 anos), 42,1% presentaron pronóstico de alto riesgo. Citometría de flujo se realizó en 83 casos (94,3%); cariotipo en 79 casos (89,7%),pero la translocación se confirmó en sólo53 (60,2%) casos. Entre los28 pacientes con cariotipo no concluyente, 14 (15,9%) presentaron el transcripto PML-RARa. En total, 35 pacientes (39,8%) realizaron la pesquisa del gen PML-RARa por biología molecular. Cuarenta y cinco pacientes (51,1%) tuvieron diagnóstico acorde entre los métodos (morfología, citometría de flujo y citogenética). La supervivencia global fue de 67% en 4,8 anos, con 29 muertes. Conclusión: Hubo confirmación genética en 76,1% de las muestras, siendo 60,2% por citogenética y 15,9%por biología celular. Hubo desacuerdo entre los métodos y baja sensibilidad de la citogenética convencional, lo que demuestra la importancia de la realización de técnicas moleculares para confirmación diagnóstica.

RESUMO Introdução: A leucemia promielocítica aguda (LPA) écausada pela translocação t(15;17)(q24;q21), cujo produto éa oncoproteína de fusão PML-RARa (leucemia promielocítica-receptor alfa do ácido retinoico). A morfologia dos promielócitos leucêmicos é habitualmente característica, com presença de faggot cells (células em maços ou feixes) e granulações citoplasmáticas grosseiras; o imunofenótipo é característico na maioria dos casos. Porém, o diagnóstico laboratorial definitivo deve ser feito pela detecção da t(15;17) ou pela oncoproteína PML-RARa. Objetivos: Comparar a citomorfologia, a citometria de fluxo e a citogenética clássica de amostras de medula óssea de pacientes com LPA atendidos no Complexo Hospital de Clínicas da Universidade Federal do Paraná (CHC-UFPR), bem como descrever as possíveis discrepâncias entre as metodologias. Método: Análise retrospectiva dos casos de LPA atendidos no CHC-UFPR entre janeiro de 2000 e julho de 2018. Resultados: Dos 88 pacientes (42 homens e 46 mulheres; média de idade: 34 anos), 42,1% apresentaram prognóstico de alto risco. A citometria de fluxo foi realizada em 83 casos (94,3%); o cariótipo, em 79 casos (89,7%), mas a translocação foi confirmada em apenas 53 (60,2%) casos. Dos 28 pacientes com cariótipo não conclusivo, 14 (15,9%) tinham a presença do transcrito PML-RARa. No total, 35 pacientes (39,8%) realizaram a pesquisa do gene PML-RARa por biologia molecular. Quarenta e cinco pacientes (51,1%) obtiveram diagnóstico concordante entre as metodologias (morfologia, citometria de fluxo e citogenética). A sobrevida global foi de 67% em 4,8 anos;com 29 óbitos. Conclusão: A confirmação genética foi realizada em 76,1% das amostras, sendo 60,2%por citogenética e 15,9% por biologia molecular. Houve discordância entre as metodologias e baixa sensibilidade da citogenética convencional, o que demonstra a importância da realização de técnicas moleculares para confirmação diagnóstica.

Insuficiência renal aguda como manifestação inicial de linfoma de Burkitt renal / Acute renal failure as first clinical presentation of BurkittÆs renal lymphoma

Relatamos o caso de um jovem de 14 anos que procurou atendimento médico por edema e hipertensão, sendo insuficiência renal aguda secundária a linfoma de Burkitt renal diagnosticada após avaliação laboratorial, de imagem e biópsia de massa tumoral renal.

This case report is from a 14-year-old boy who had edema and hypertension due to a primary renal Burkitt's lymphoma, diagnosed through laboratory and image evaluation and kidney tumor biopsy.

Alta frequência de fatores de alto risco e de mortalidade precoce em pacientes brasileiros com leucemia promielocítica aguda / Increased frequency of high risk factors and elevated early mortality among Brazilian patients with acute promyelocytic leukemia

O tratamento da leucemia promielocítica aguda (LPA) com antrciclínicos e ácido trans-retinóico (ATRA) tem sido amplamente empregado e resultou em taxas de sobrevida a longo prazo de 80% a 90% em diferentes ensaios clínicos. A despeito da alta prevalência de LPA na América Latina, a efetividade de regimes de tratamento com ATRA e antraciclínicos não é conhecida. No Brasil, mais de 20% das leucemias mielóides agudas são do subtipo LPA. Neste estudo descrevemos uma análise retrospectiva de 157 pacientes brasileiros com LPA. Comparado com pacientes de países desenvolvidos, observamos uma alta prevalência de pacientes de alto risco e ma sobrevida e três anos de 49,9%. A taxa de mortalidade precoce foi de 28%, principalmente devido a sangramento (88,6%), com 45,2% dos pacientes apresentando evidências laboratoriais de coagulação intravascular disseminada ao diagnóstio. A despeito do fato de que nõ foram excluídos pacientes com base na idade ou no performance status, esta alta taxa de óbito mostra que é necessária uma melhora urgente no acesso dos pacientes a centros médicos especializados.

Therapy based on anthracyclines and all-trans-retinoic acid (ATRA) hás been widely used for acute promyelocytic leukemia (APL) and result in long term survival rates of 80% to 90% in different clinical trials. Despite the higher incidence of APL in Latin America, the effectiveness of ATRA + anthracyclines treatment is not known. In Brazil, more than 20% of acute myeloid leukemia are of the APL subtype. We describe a retrospective analysis including 157 Brazilian APL patients. Compared to developed countries, a higher incidence of higher incidence of high risk patients was observed and the overwall survival in three years was only 49.9%. Early mortality was 28%, mainly due to bleeding (88.6%), and laboratorial evidence of disseminated intravascular coagulation at diagnosis was present in 45.2% of the patients. Despite the fact that no patient was excluded based on age and performance status, the high death rates shows that urgent improvement in acess to specialized medical care is necessary in Brazil. Aiming to improve the outcome of APL patients in developing countries, the American Society of Hematology launched the International Consortium on APL, an educational iniative based on the use of an unified simplified treatment protocol, on line discussion tools and centralized laboratory diagnosis.