Temporal trends in Hematopoietic Stem Cell Transplantation in Argentina: regional differences that mirror the global reality

Introduction: Hematopoietic stem cell transplantation is the only curative treatment for many disorders and international data shows a growing trend. Method: We aimed to evaluate the temporal trends in HSCT transplant rates in Argentina. A time-series analysis was performed for the period 2009 to 2018 using the national database from the National Central Coordinating Institute for Ablations and Implants. Crude and standardized transplant rates were calculated. A permutation joinpoint regression model analysis was used to identify significant changes over time. Results: Altogether, 8,474 transplants were reported to INCUCAI by 28 centers (autologous 67.5%); the main indication was multiple myeloma (30%). The WHO age-sex standardized HSCT rates for the entire country were 153.3 HSCT/10 million inhabitants (95% CI 141.7 −165.8) in 2009 and 260.1 HSCT/10 million inhabitants (95% CI 245.5−275.5) in 2018. There was a large gap in HSCT rates among the states and regions. The transplant rate was higher for autologous transplants throughout the years. Within the allogeneic group, the related donor transplant rate was higher than the unrelated donor transplant rate. The joinpoint regression analysis of HSCT rates for the whole country over time showed an observed annual percentage change of 6.3% (95% CI 5.4-7.3; p < 0.01). No changes were observed for unrelated donors during the study period. Conclusions: Age-sex standardized HSCT rates in Argentina are increasing, mainly due to autologous and family donor allogeneic transplants. A wide variation across the country was found, demonstrating differences in the access to transplantation among Argentine regions

Salvage treatment for refractory or relapsed acute myeloid leukemia: a 10-year single-center experience

OBJECTIVES: The outcomes of refractory and relapsed acute myeloid leukemia (AML) patients in developing countries are underreported, even though the similar classic regimens are widely used. METHODS: We conducted a retrospective comparison of "MEC" (mitoxantrone, etoposide, and cytarabine) and "FLAG-IDA" (fludarabine, cytarabine, idarubicin, and filgrastim) in adults with first relapse or refractory AML. RESULTS: In total, 60 patients were included, of which 28 patients received MEC and 32 received FLAG-IDA. A complete response (CR) rate of 48.3% was observed. Of the included patients, 16 (27%) died before undergoing bone marrow assessment. No statiscally significant difference in CR rate was found between the two protocols (p=0.447). The median survival in the total cohort was 4 months, with a 3-year overall survival (OS) rate of 9.7%. In a multivariable model including age, fms-like tyrosine kinase 3 (FLT3) status, and stem-cell transplantation (SCT), only the last two indicators remained significant: FLT3-ITD mutation (hazard ratio [HR]=4.6, p<0.001) and SCT (HR=0.43, p=0.01). CONCLUSION: In our analysis, there were no significant differences between the chosen regimens. High rates of early toxicity were found, emphasizing the role of supportive care and judicious selection of patients who are eligible for intensive salvage therapy in this setting. The FLT3-ITD mutation and SCT remained significant factors for survival in our study, in line with the results of previous studies.

Targeting the mitochondria in acute myeloid leukemia

Acute myeloid leukemia (AML) is a clonal hematologic neoplasm characterized by heterogeneity of genetic abnormalities found at diagnosis. These abnormalities serve to classify patients by risk group into low, intermediate, and high risk. It also provides specific targets for the development of new combinational therapies. However, because of the heterogeneity of genetic abnormalities, targeted therapy is not always possible. Altered mitochondrial metabolism is a common feature in cancer cells, a phenomenon first described by Otto Warburg. In AML patients, the discovery of mutations in the isocitrate dehydrogenase gene provided for the first time a link between altered mitochondrial metabolism and AML. This raised the possibility of testing drugs known as mitocans for new combinational therapeutic approaches. Mitocans are a diverse group of anti-cancer compounds that target mitochondria. They disrupt energy production leading to enhanced generation of reactive oxygen species along with the activation of the intrinsic pathway of apoptosis. The present review discusses the different types of mitocans and their mechanism of action along with preclinical and clinical studies in AML (AU)

Coagulation abnormalities in acute promyelocytic leukemia / Alterações da coagulação associadas à leucemia promielocítica aguda

Acute promyelocytic leukemia is frequently accompanied by coagulation abnormalities usually described as laboratorial disseminated intravascular coagulation, which is the main cause of morbidity and early mortality. Aberrant activation of the coagulation cascade and hyperfibrinolysis play an important role in the pathogenesis of bleeding diathesis, but their contribution varies from case to case. Here we review the main laboratorial findings and the recommended clinical management of coagulopathy associated with acute promyelocytic leukemia.

A leucemia promielocítica aguda (LPA) é geralmente acompanhada por anormalidades da coagulação usualmente descritas como coagulação intravascular disseminada e que são a principal causa de mortalidade precoce. A ativação anormal da cascata de coagulação e a hiperfibrinólise desempenham importante papel na patogênese da diátese hemorrágica, mas a contribuição de cada fator varia de caso a caso. Apresentamos aqui uma revisão dos principais achados laboratoriais e da recomendação para o manejo clínico da coagulopatia associada a LPA.

Smudge cells in peripheral blood smears did not differentiate chronic lymphocytic leukemia from other B-cell chronic lymphoprolipherative diseases / Sombras nucleares no esfregaço do sangue periférico não diferenciam a leucemia linfocítica crônica das outras doenças linfoproliferativas B crônicas

Smudge cells has been classically associated with chronic lymphocytic leukemia (CLL), but they are found in peripheral blood tests for other chronic B-cell lymphoproliferative diseases (CLD). We investigated whether the percentage of smudge cells in peripheral blood smears can be used in the clinical practice to differentiate CLL from other B-cell CLD. The peripheral blood smears of 63 patients with the diagnosis of CLL and 62 with other B-cell CLD were analyzed. Three hundred cells (both lymphoid cells and smudge cells) were counted for each peripheral blood smear. A comparison of the percentage of smudge cells between the two groups was performed and, subsequently, 5 cut-off values were fixed (10 percent, 20 percent, 30 percent, 40 percent and 50 percent of smudge cells) with the aim of defining cases as "positive" or "negative" for smudge cells and verifying whether there are any differences between CLL and the other B-cell CLD. The percentage of smudge cells in patients with CLL (median 26 percent, 4 percent-86 percent) was higher than in patients with B-cell CLD (median 14 percent, 1 percent-64 percent). However, none of the cut-off values tested presented suitable values of sensitivity, specificity and positive predictive value to separate the two groups. As it is necessary to have a single cut-off value with high sensitivity, specificity and positive predictive value to infer the diagnosis of CLL in the clinical practice, we concluded that smudge cells are not fitting to differentiate CLL from other B-cell CLD.

As sombras nucleares têm sido classicamente associadasà leucemia linfocítica crônica (LLC), embora possam ser encontradas nos esfregaços do sangue periférico de outras doenças linfoproliferativas B crônicas (DLBC). Nesse estudo, nós investigamos se a porcentagem de sombras nucleares nos esfregaços do sangue periférico pode ser utilizada na prática clínica da hematologia para diferenciar a LLC das outras DLBC. Foram analisados os esfregaços do sangue periférico de 63 pacientes com o diagnóstico de LLC e 62 com outras DLPC. Trezentas células, entre células linfoides e sombras nucleares, foram contadas em cada esfregaço. A comparação da porcentagem de sombras nucleares entre os dois grupos foi realizada e, subsequentemente, foram fixados 5 cut-offs de mais de 10 por cento, 20 por cento, 30 por cento, 40 por cento e 50 por cento de sombras nucleares com o propósito de definir um caso como "positivo para sombras nucleares" e verificar se havia diferenças entre a LLC e as outras DLBC. A porcentagem das sombras nucleares em pacientes com LLC (mediana 26 por cento, 4 por cento-86 por cento) foi maior do que em pacientes com DLBC (mediana 14 por cento, 1 por cento-64 por cento). Entretanto, nenhum dos cut-offs testados apresentou valores apropriados de sensibilidade, especificidade e valor preditivo positivo para distinguir os dois grupos. Desde queé necessário se dispor de um único valor de cut-off com alta sensibilidade, especificidade e valor preditivo positivo para inferir o diagnóstico de CLL na prática clínica, conclui-se que as sombras nucleares não são úteis para diferenciar a LLC das outras DLBC.

Papel da imunofenotipagem por citometria de fluxo no diagnóstico diferencial das pancitopenias e das linfocitoses / The role of flow cytometer-based immunophenotyping in the differential diagnosis of pancytopenia and of lymphocytosis

A imunofenotipagem por citometria de fluxo (CMF) é atualmente uma ferramenta indispensável para o diagnóstico hematopatológico. Nos últimos anos muitos progressos foram alcançados em instrumentação, novos anticorpos e fluorocromos e programas de análise. Consequentemente, houve um grande avanço no conhecimento da patogênese das neoplasias hematológicas e novos marcadores diagnósticos e prognósticos foram descritos. Revisamos aqui a contribuição destas novas técnicas no diagnóstico diferencial de pacientes com bi- ou pancitopenia e linfocitose. São apresentados os achados mais frequentes e as dificuldades na interpretação dos resultados. Além disto, a importância do uso concomitante de um conjunto de outras técnicas diagnósticas é demonstrada.

The use of flow cytometry for immunophenotyping is currently an essential tool in the diagnosis of hematological abnormalities. In recent years, new equipment, antibodies, fluorochromes and computer programs have become available. As a result, a better understanding of the pathogeneses of hematological malignancies has emerged and new markers with diagnostic and prognostic relevance have been described. Here we review how this new technology may contribute to the differential diagnosis of patients with bi- or pancytopenia and of lymphocytosis. The common findings as well as the difficulties in interpreting the results obtained by flow cytometry will be discussed. The importance of the concomitant analyses by different methods is also demonstrated.

Risk assessment for multiple myeloma: preliminary results of the brazilian myeloma study group / Avaliação de risco em mioloma múltiplo: resultados preliminares do grupo brasileiro de estudos de mieloma

The Durie/Salmon staging system continues to be used worldwide in patients with multiple myeloma. However, in recent years, new systems have been proposed. The International Myeloma Working Group performed a retrospective study with 11,179 patients and proposed an "International Staging System" utilizing serum levels of â2 microglobulin and albumin. In addition, current research has focused on the usefulness of cytogenetic and molecular data as prognostic factors. These data suggest that these parameters are powerful discriminators of a poor prognostic group of myeloma patients. Indeed, these prognostic indexes have been utilized in clinical trials, with interesting and encouraging results.

O esquema de Durie / Salmon continua a ser utilizado para estadiar os pacientes com mieloma múltiplo. Recentemente, um novo sistema mais simples e eficaz foi proposto. O "International Myeloma Working Group" realizou um estudo retrospectivo com 11.179 pacientes e a partir destes dados propôs a criação de um "International Staging System (ISS)" utilizando os níveis séricos de ß2 microglobulina e de albumina ao diagnóstico. Além do ISS a pesquisa está voltada para identificar alterações citogenéticas e moleculares que se correlacionem com o prognóstico no mieloma múltiplo. Estes fatores prognósticos têm sido utilizados para estratificar pacientes em ensaios clínicos com resultados promissores.

Differentiation syndrome in acute promyelocytic leukemia: pathogenesis and risk factors / Síndrome da diferenciação na leucemia promielocítica aguda: patogênese e fatores de risco

Differentiation syndrome is a treatment complication which can occur in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO), which is characterized by enhanced leukocyte transmigration. Several cellular and molecular mechanisms participate in differentiation syndrome development. This review discusses the changes in expression of adhesion molecules induced during ATRA and ATO treatments and their possible implications in the pathogenesis of this potentially fatal complication.

A síndrome da diferenciação (DS) é um efeito colateral que pode ocorrer em pacientes com leucemia promielocítica aguda (APL) tratados com ácido all-trans-retinóico (ATRA) ou trióxido de arsênico (ATO), sendo caracterizada pelo aumento da transmigração de leucócitos. Vários mecanismos celulares e moleculares participam no desenvolvimento da DS. Esta revisão discute as mudanças na expressão de moléculas de adesão induzidas durante o tratamento com ATRA e ATO e possíveis implicações na patogênese desta complicação potencialmente fatal.

Molecular basis of Acute Myelogenous Leukemia

A leucemia mielóide aguda (LMA) está freqüentemente associada a translocações cromossômicas recorrentes. Em muitos casos, os genes presentes nos pontos de quebra cromossômica são conhecidos e, quase todos codificam para fatores de transcrição. O gene híbrido, resultante da justaposição de exons de genes distintos, codifica para proteínas de fusão. Como estas retêm a maior parte dos domínios funcionais das proteínas selvagens, elas interferem direta ou indiretamente com regulação da transcrição gênica, conferindo vantagem à sobrevivência das células leucêmicas. A maioria dos fatores de transcrição afetados pelas translocações cromossômicas associadas a LMA pode ser agrupada numa das seguintes famílias: dos core binding factors (CBF), do receptor a do ácido retinóico (RARa), do homeobox (HOX), ou do mixed lineage leukemia (MLL). Estudos in vivo, empregando modelos transgênicos, revelaram um mecanismo molecular comum a estas proteínas de fusão: a desregulação da transcrição gênica via recrutamento de fatores co-ativadores ou co-repressores. Embora necessária, a expressão das proteínas de fusão não é suficiente para o desenvolvimento da leucemia. A existência de uma longa fase pré leucêmica observada nos modelos transgênicos sugere que outros eventos mutagênicos devam ocorrer para o desenvolvimento das leucemias.