Leucemia mieloide crônica : expansão de células natural killer de pacientes refratários ou intolerantes aos inibidores de tirosino quinase

Introdução: A leucemia mieloide crônica (LMC) é uma desordem mieloproliferativa clonal cuja transformação neoplásica da célula-tronco hematopoiética ocasiona o acúmulo das células mieloides e seus progenitores. As células Natural Killer (NK) são componentes fundamentais da imunidade inata, apresentando a habilidade de defender rapidamente o organismo contra patógenos infecciosos e também possui ação contra células tumorais. No entanto, pacientes com LMC parecem ter menor contagem de células NK à medida que a doença progride, bem como a citotoxicidade diminuída nas células NK restantes. A terapia adotiva com células NK pode ter um papel potencial no tratamento de pacientes com LMC. Materiais e métodos: Nosso estudo pretende explorar a viabilidade de se utilizar células NK autólogas para o tratamento de portadores de LMC, resistentes ou intolerantes aos inibidores de tirosino quinase (TKIs), além de conhecer o perfil epidemiológico desta população. Para tanto, precisamos esclarecer se, a partir de uma amostra de sangue periférico destes pacientes, conseguimos expandir células NK em número suficiente para a infusão in vivo no futuro. Foram analisadas amostras de sangue periférico de 6 pacientes com LMC. As células NK foram expandidas a partir de células mononucleares do sangue periférico após depleção dos linfócitos T. Elas foram co-culturadas com células apresentadoras de antígeno clone 9 K562, posteriormente modificadas para expressar interleucina-21 na membrana (mIL-21). Resultados: Trinta e nove porcento dos pacientes acompanhados no Hospital de Clínicas de Porto Alegre (HCPA) foram refratários ou intolerantes ao imayinibe. A sobrevida global em 8 anos de pacientes que fizeram uso de três ou mais linhas de tratamento foi significativamente menor quando comparada aos pacientes que conseguiram manter o imatinibe como a primeira linha de tratamento. Falha em atingir resposta citogenética complete, resposta molecular maior e interrupção do tratamento foram associadas com maior chance de progressão para terceira linha de tratamento. Todas as culturas apresentaram expansão adequada e clinicamente significativa das células NK. Aparentemente, não há diferença para a expansão das células NK conforme TKI em uso, tempo de evolução da doença e resposta atual. Conclusão: Este estudou demontrou a efetividade da plataforma com mIL-21 para expansão de células NK em pacientes com CML refratários ou intolerantes aos inibidores de tirosino quinase. Os achados do nosso estudo são promissores e criam a possibilidade do uso de células NK autólogas neste grupo de pacientes.Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder which neoplastic transformation of hematopoietic stem cells leads to the accumulation of myeloid cells and their progenitors. Natural killer (NK) cells are a fundamental part of innate immunity, with a major role in rapid response against infectious agents and activating immune system against tumoral cells. Patients with CML, however, seem to have lower NK cell counts as disease progresses, as well as diminished cytotoxicity in those NK cells remaining. Adoptive NK cell therapy may have a potential role in treatment of CML patients. Methods: The study aims to explore the feasibility of using autologous NK cells for the treatment of patients with CML resistant or intolerant to tyrosine-kinase inhibitors (TKIs), and the epidemiological profile of this population. Therefore, we need to clarify whether, from a peripheral blood sample of these patients, we were able to expand enough NK cells for infusion in vivo in the future. Peripheral blood samples from 6 CML patients were analyzed. NK cells were expanded from peripheral blood mononuclear cells after depletion of T cells. They were co-cultured with clone 9 K562 aAPCs (artificial antigen presenting cells), which were posteriorly modified to also express membrane interleukin-21 (mIL-21). Results: Thirty nine percent of patients were refractory or intolerant to imatinib. Overall 8-year survival rate of the patients who went through three or more lines of treatment was significantly lower compared to the ones who were able to maintain imatinib as their first-line therapy. Failure in achieve complete cytogenetic response, major molecular response and treatment interruption were associated with progressing to the third line treatment. All cultures performed had adequate and clinically significant expansion of NK cells. Seemingly, there is no difference for NK cell expansion according to TKI in use, disease evolution time and current response. Conclusion: The study demonstrated the effectiveness of the mIL-21 platform for NK cell expansion in CML patients refractory or intolerant to TKIs. Findings of this study are promising and generate the prospect of the possibility of using autologous NK cells in this group of patients

Prophylaxis in hemophilia

Hemophilia is an inherited X-linked coagulopathy defined by a deficiency or abnormality in the clotting function of factor VIII (Hemophilia A) or factor IX (Hemophilia B). Prophylaxis – the regular administration of therapeutic products to maintain hemostasis and prevent bleeding – is the mainstream of treatment. Addressing the development and scientific evidence for administrating prophylaxis is the goal of this review. Prophylaxis is the therapeutic modality of choice for people with severe hemophilia, being considered, in principle, a lifelong treatment. It should have an early onset, ideally as a primary, or at least secondary. Even lifelong tertiary prophylaxis seems to offer benefit, although further studies are still lacking. Individualized strategies should lead to an optimization of the dilemma between better joint outcomes versus involved costs

Hemophilia: a biography on therapeutical approaches

The history of hemophilia is ancient, with descriptions dated to the 2nd century AD. The first modern narratives appeared in 1800s, when total blood transfusion was the only available treatment and life expectancy was remarkably low. Advances occurred with the use of plasma and cryoprecipitate, but only the discovered of factor concentrates revolutionized the treatment. The implantation of prophylaxis allowed hemophilic patients to prevent bleeding and the development of chronic arthropathy, although with a significant burdensome with the regular infusions. In the past 20 years, this field has witnessed major improvements, including the development of gene therapy and other pharmacological approaches

Prophylaxis in Hemophilia

Hemophilia is an inherited X-linked coagulopathy defined by a deficiency or abnormality in the clotting function of factor VIII (Hemophilia A) or factor IX (Hemophilia B). Prophylaxis – the regular administration of therapeutic products to maintain hemostasis and prevent bleeding – is the mainstream of treatment. Addressing the development and scientific evidence for administrating prophylaxis is the goal of this review. Prophylaxis is the therapeutic modality of choice for people with severe hemophilia, being considered, in principle, a lifelong treatment. It should have an early onset, ideally as a primary, or at least secondary. Even lifelong tertiary prophylaxis seems to offer benefit, although further studies are still lacking. Individualized strategies should lead to an optimization of the dilemma between better joint outcomes versus involved costs

Epidemiological characteristics of hemophilia in the pre-primary prophylaxis era: a historical cohort

Introduction: Epidemiological studies on hemophilia in the Brazilian population are historically scarce. Despite the continuous effort made by the National Program of Inherited Bleeding Disorders to map this condition, little information is available, especially on the period prior to program conception. Therefore, the present study aims to assess the epidemiological, serological, and clinical characteristics of patients with hemophilia in the state of Rio Grande do Sul, Brazil. Methods: A total of 455 patients had their medical records reviewed from January 1, 2003 to December 31, 2007. Results: We observed a remarkable prevalence of hepatitis C virus (HCV) infection in patients with both hemophilia A and B, and this prevalence significantly increased along with age (p < 0.001). No positive anti-HCV results were observed among children younger than 5 years old. There was a significant correlation between the severity of hemophilia and the number of arthropathies in all age categories. Considering the presence of inhibitors, a significant difference was observed between age groups, as older patients had higher inhibitor titers. There was a significant correlation between mean coagulation factor consumption and the number of arthropathies in patients over 5 years old. Conclusions: This profile analysis of patients with hemophilia reflects a gradual improvement in treatment safety and efficiency, as well as the need for continued investment in this population

What happens to intolerant, relapsed or refractory chronic myeloid leukemia patients without access to clinical trials?

Objective: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. Methods: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. Results: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p < 0.01). Decreased overall survival was associated with advanced-phase disease (p < 0.01), failure to achieve major molecular response in first-line treatment (p < 0.01) and interruption of first-line treatment due to any reason (p = 0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. Conclusion: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies

Leucemia mieloide crônica : expansão de células natural killer de pacientes refratários ou intolerantes aos inibidores de tirosino quinase

Introdução: A leucemia mieloide crônica (LMC) é uma desordem mieloproliferativa clonal cuja transformação neoplásica da célula-tronco hematopoiética ocasiona o acúmulo das células mieloides e seus progenitores. As células Natural Killer (NK) são componentes fundamentais da imunidade inata, apresentando a habilidade de defender rapidamente o organismo contra patógenos infecciosos e também possui ação contra células tumorais. No entanto, pacientes com LMC parecem ter menor contagem de células NK à medida que a doença progride, bem como a citotoxicidade diminuída nas células NK restantes. A terapia adotiva com células NK pode ter um papel potencial no tratamento de pacientes com LMC. Materiais e métodos: Nosso estudo pretende explorar a viabilidade de se utilizar células NK autólogas para o tratamento de portadores de LMC, resistentes ou intolerantes aos inibidores de tirosino quinase (TKIs), além de conhecer o perfil epidemiológico desta população. Para tanto, precisamos esclarecer se, a partir de uma amostra de sangue periférico destes pacientes, conseguimos expandir células NK em número suficiente para a infusão in vivo no futuro. Foram analisadas amostras de sangue periférico de 6 pacientes com LMC. As células NK foram expandidas a partir de células mononucleares do sangue periférico após depleção dos linfócitos T. Elas foram co-culturadas com células apresentadoras de antígeno clone 9 K562, posteriormente modificadas para expressar interleucina-21 na membrana (mIL-21). Resultados: Trinta e nove porcento dos pacientes acompanhados no Hospital de Clínicas de Porto Alegre (HCPA) foram refratários ou intolerantes ao imayinibe. A sobrevida global em 8 anos de pacientes que fizeram uso de três ou mais linhas de tratamento foi significativamente menor quando comparada aos pacientes que conseguiram manter o imatinibe como a primeira linha de tratamento. Falha em atingir resposta citogenética complete, resposta molecular maior e interrupção do tratamento foram associadas com maior chance de progressão para terceira linha de tratamento. Todas as culturas apresentaram expansão adequada e clinicamente significativa das células NK. Aparentemente, não há diferença para a expansão das células NK conforme TKI em uso, tempo de evolução da doença e resposta atual. Conclusão: Este estudou demontrou a efetividade da plataforma com mIL-21 para expansão de células NK em pacientes com CML refratários ou intolerantes aos inibidores de tirosino quinase. Os achados do nosso estudo são promissores e criam a possibilidade do uso de células NK autólogas neste grupo de pacientes.Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder which neoplastic transformation of hematopoietic stem cells leads to the accumulation of myeloid cells and their progenitors. Natural killer (NK) cells are a fundamental part of innate immunity, with a major role in rapid response against infectious agents and activating immune system against tumoral cells. Patients with CML, however, seem to have lower NK cell counts as disease progresses, as well as diminished cytotoxicity in those NK cells remaining. Adoptive NK cell therapy may have a potential role in treatment of CML patients. Methods: The study aims to explore the feasibility of using autologous NK cells for the treatment of patients with CML resistant or intolerant to tyrosine-kinase inhibitors (TKIs), and the epidemiological profile of this population. Therefore, we need to clarify whether, from a peripheral blood sample of these patients, we were able to expand enough NK cells for infusion in vivo in the future. Peripheral blood samples from 6 CML patients were analyzed. NK cells were expanded from peripheral blood mononuclear cells after depletion of T cells. They were co-cultured with clone 9 K562 aAPCs (artificial antigen presenting cells), which were posteriorly modified to also express membrane interleukin-21 (mIL-21). Results: Thirty nine percent of patients were refractory or intolerant to imatinib. Overall 8-year survival rate of the patients who went through three or more lines of treatment was significantly lower compared to the ones who were able to maintain imatinib as their first-line therapy. Failure in achieve complete cytogenetic response, major molecular response and treatment interruption were associated with progressing to the third line treatment. All cultures performed had adequate and clinically significant expansion of NK cells. Seemingly, there is no difference for NK cell expansion according to TKI in use, disease evolution time and current response. Conclusion: The study demonstrated the effectiveness of the mIL-21 platform for NK cell expansion in CML patients refractory or intolerant to TKIs. Findings of this study are promising and generate the prospect of the possibility of using autologous NK cells in this group of patients

Immune Thrombocytopenic Purpura following CoronaVac vaccination: a case report

Immune thrombocytopenic purpura (ITP), an autoimmune disorder, has been documented as a result of SARS-CoV-2 infection and a vaccination side effect. The COVID-19 pandemic has led to the creation of CoronaVac vaccine and has been widely administered in Brazil. Patient, in the case, is an 82-years-old female who received the vaccine two days before an acute episode of gingivorrhagia and diffuse cutaneous petechiae. Other exams were made to look for other causes of secondary thrombocytopenia and all the results were normal.  The patient showed improvement on the platelet levels three day after the beginning of the treatment with high dosage methylprednisolone.Knowing that other kinds of vaccine can generate ITP, the SARS-CoV-2 vaccine could be related to the symptoms