Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review.

Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).

Apoptotic regulator BCL-2 blockade as a potential therapy in classical Hodgkin Lymphoma.

The challenge in classical Hodgkin Lymphoma (cHL) management is the 30-40% of refractory/relapsed cases. AIMS: The aim of this work was to determine whether NIK and BCL-2 could be useful as prognosis biomarkers in cHL. In addition, we evaluated BCL-2 as a directed-therapy in cHL cell lines using venetoclax. MAIN METHODS: We evaluated NIK and BCL-2 expression in 112 untreated cHL patients' lymph-node biopsies by immunohistochemistry. cHL cell lines were treated with venetoclax alone or combined with vincristine or doxorubicin. Cell viability, metabolic activity and cell death were analyzed by trypan-blue exclusion method, MTS assay and FDA/IP staining respectively. KEY FINDINGS: No correlation between NIK or BCL-2 expression and the majority of the clinical parameters was found. Patients with ≥60% BCL-2+ HRS-cells had a shorter disease-free survival (DFS) and overall survival (OS) (p = 0.002, p = 0.02 respectively). A decision tree analysis, in a 30 patients subgroup, showed that patients with <60% NIK+ HRS-cells but with ≥60% BCL-2+ HRS-cells had a worse outcome in terms of DFS and OS. These parameters performed better as prognosis indicators as compared to the diagnosis bone marrow status. Human cHL cell lines U-H01, KM-H2, L1236, SUPHD1, L540 showed sensitivity to venetoclax. The co-treatment effect of venetoclax and vincristine or doxorubicin on cell viability was diverse depending on the cell line evaluated. SIGNIFICANCE: BCL-2 should be considered as a prognosis biomarker as well as a potential new therapeutic target in cHL. We report for the first time the cytotoxic effect of venetoclax in human cHL cell lines.

MGMT and CALCA promoter methylation are associated with poor prognosis in testicular germ cell tumor patients.

Testicular germ cell tumors (TGCT) represent the second main cause of cancer-related death in young men. Despite high cure rates, refractory disease results in poor prognosis. Epigenetic reprogramming occurs during the development of seminomas and non-seminomas. Understanding the molecular and genetic basis of these tumors would represent an important advance in the search for new TGCT molecular markers. Hence the frequency of methylation of a gene panel (VGF, MGMT, ADAMTS1, CALCA, HOXA9, CDKN2B, CDO1 and NANOG) was evaluated in 72 primary TGCT by quantitative methylation specific PCR. A high frequency of MGMT (90.9%, 20/22; p=0.019) and CALCA (90.5%, 19/21; p<0.026) methylation was associated with non-seminomatous tumors while CALCA methylation was also associated with refractory disease (47.4%, 09/19; p=0.005). Moreover, promoter methylation of both genes predicts poor clinical outcome for TGCT patients (5-year EFS: 50.5% vs 77.1%; p=0.032 for MGMT and 51.3% vs 77.0%; p=0.029 for CALCA). The findings of this study indicate that methylation of MGMT and CALCA are frequent and could be used as new molecular markers of prognosis in TGCT.

Hepatitis autoinmune refractaria: ¿cómo escoger el tratamiento de segunda línea o de rescate? / Refractory autoimmune hepatitis: how to choose second-line or rescue therapy?

Autoimmune hepatitis (AIH) is a liver disease of unknown etiology, with a breakdown in peripheral selftolerance against hepatocytes with both genetic and environmental factors involved. It is characterized by an immune mediated liver injury, with detectable autoantibodies, elevated levels of immunoglobulin G and histological criteria including, necroinflammation, lymphoplasmacytic infiltrates and hepatitis interface. It can be asymptomatic or can present as acute hepatitis or liver cirrhosis. Most patients (70-80%) respond to first line therapy (based on steroids ± azathioprine). In those patients not tolerating azatioprine, in steroid resistant, and those with repeated relapses (20-40%), a long-term second line therapy must be considered to avoid progression of liver disease. This last medications include other immunosuppressants like mycophenolate mophetil, calcineurin inhibitors (cyclosporine or tacrolimus), biologic agents (infliximab and rituximab), and other immunosuppressive agents (sirolimus, everolimus), all with good overall clinical results, but not exempt of side effects. Other difficult scenarios include fulminant AIH, end-stage AIH cirrhosis and the management of post-transplant AIH. In this article we will review the literature related to second- line therapy especially of steroid resistant AIH. Future directions in the treatment of HAI should be guided to the individual patient (personalized) and may include cell therapies, such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance

La hepatitis autoinmune (HAI) es una hepatopatía de etiología desconocida, con pérdida de la tolerancia inmune contra los hepatocitos con factores genéticos y ambientales asociados. Se caracteriza por fenómenos de daño inmunológicos, con autoanticuerpos circulantes, una concentración elevada de gammaglobulina sérica y en la biopsia de hígado actividad necroinflamatoria, infiltrados linfoplasmocitarios y daño de interfase. La HAI es una entidad que se puede presentar en forma asintomática, como hepatitis aguda o como cirrosis hepática. El 70-80% de los pacientes responden adecuadamente al tratamiento inmunosupresor de primera línea (corticoides ± azatioprina). En los pacientes que no toleran azatioprina, en los corticorresistentes o en aquellos con recaídas repetidas a pesar de terapia (20-40%), es necesario recurrir a terapias de segunda línea de largo plazo, para evitar la progresión de la hepatopatía. Estas últimas incluyen micofenolato mofetil, inhibidores calcineurínicos (ciclosporina o tacrolimus), agentes biológicos (infliximab y rituximab), y otros fármacos inmunosupresores (sirolimus, everolimus), con resultados alentadores, pero no exentos de efectos colaterales. Otros escenarios complejos incluyen: la HAI de presentación aguda grave y fulminante, la cirrosis terminal autoinmune y la HAI post-trasplante. En este trabajo se revisa la literatura en relación a terapias de segunda línea especialmente en HAI corticoide resistente. El futuro del tratamiento de la HAI va encaminado a una terapia personalizada y que podría incluir terapias celulares como la infusión de células T regulatorias, antígeno específicas y autólogas, para reestablecer los mecanismos de tolerancia inmune hepática.

The issue of refractory disease in follicular and other lymphoma subtypes / A refratariedade no linfoma folicular e em outros linfomas

The outcome of lymphoma has definitely improved over the last few decades which is mainly due to the introduction and development of novel and effective therapeutic approaches. Nevertheless, a small though notable group of patients may display a poor response to treatments, with a true refractoriness or a transient response followed by early relapse. The present review addresses the issue of refractory disease among patients with lymphoma, focusing on the overall incidence and the main clinical aspects associated with refractoriness.

A evolução dos linfomas tem sido definitivamente melhorada ao longo das últimas décadas. Isto se deve principalmente devido à introdução e desenvolvimento de novas e efetivas abordagens terapêuticas. Apesar disto, uma pequena parcela deste notável grupo de pacientes pode apresentar uma pobre resposta aos tratamentos, com uma verdadeira refratariedade, ou com resposta transitória e precocemente uma recidiva. A presente revisão aborda este assunto da doença refratária nos pacientes com linfoma, enfocando sua incidência global e os principais aspectos clínicos associados à refratariedade.

Tratamento do linfoma de Hodgkin após falha do transplante autólogo / Treatment of Hodgkin's lymphoma after failure of autologous stem cell transplant

O linfoma de Hodgkin (LH) é uma neoplasia do tecido linfóide de excelente prognóstico, porém, aproximadamente 15 por cento dos pacientes em estádios precoces e 35 por cento dos em estádios avançados progridem após o tratamento inicial. O transplante autólogo de medula óssea ou de células-tronco periféricas (ATMO) é o tratamento de escolha nesses casos. Nosso estudo tem como objetivo avaliar o tipo de tratamento utilizado, a taxa de resposta e a sobrevida de pacientes recidivados ou refratários ao ATMO. De 38 pacientes com LH submetidos a ATMO entre abril de 1996 e novembro de 2005, foram avaliados 17 que apresentaram recidiva/refratariedade ao ATMO. Nesses casos, o tratamento de resgate foi individualizado, a depender das condições clínicas de cada um, sendo constituído usualmente de drogas citotóxicas não utilizadas previamente. Após o ATMO, dez (59 por cento) dos 17 pacientes obtiveram remissão completa, um (6 por cento) remissão parcial e seis (35 por cento) foram refratários. Em 14 dos 17 pacientes foi instituída quimioterapia de resgate com diversos esquemas no momento da recidiva/refratariedade após ATMO; um paciente foi tratado com radioterapia exclusiva e dois foram a óbito antes de qualquer terapia. Observamos uma taxa de resposta global de 57,4 por cento (IC95 por cento: 23,2 - 90,7 por cento). A mediana da sobrevida livre de progressão foi de 19 meses e a mediana de sobrevida global foi de 32 meses. Apesar do LH recidivado/refratário ao ATMO não ser curável com os quimioterápicos atualmente disponíveis, os pacientes apresentaram longa sobrevida, com freqüentes exacerbações da doença.

Hodgkin's lymphoma (HL) is a lymphoid malignancy with excellent prognosis, however nearly 15 percent of the patients in early stages and 35 percent in advanced stages have progressive disease after initial treatment. Autologous bone marrow or hematopoietic stem cell transplantation (ABMT) are the treatments of choice in these cases. This report presents the therapeutic approach and the outcome of HL patients who experience relapse after or are refractory to ABMT. Of 38 patients with LH who underwent ABMT between April 1996 and November 2005, 17 presented with relapsed/refractory disease and were included in this analysis. In these cases, the choice of rescue therapy varied upon the clinical conditions of each patient and was based on previously unused chemotherapy agents. After ABMT, 10 (59 percent) of the 17 patients were in complete remission, one (6 percent) in partial remission and six (35 percent) were refractory. Fourteen of the 17 patients received different schemes of rescue therapy at the time of ABMT failure, one patient was treated exclusively with radiotherapy and two died before any treatment. We observed an overall response rate of 57.4 percent (95 percent CI: 23.2 - 90.7 percent). The median progression-free survival was 19 months and the median overall survival was 32 months. Despite ABTM, relapsed/refractory LH can not be cured with currently available chemotherapeutic agents, the patients had long survival times with frequent exacerbations of the diseas.