Can SARS-CoV-2 induce hematologic malignancies in predisposed individuals? A case series and review of the literature

Abstract Introduction Coronavirus disease 2019 (COVID-19) may present with extrapulmonary manifestations, including hematologic changes. Previous studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) can interact with the renin-angiotensin system, ultimately causing increased production of angiotensin II. By reporting the cases of previously healthy young adults diagnosed with a hematologic malignancy after experiencing COVID-19, we raise the hypothesis that the SARS-Cov-2 infection could act as a trigger for leukemogenesis in predisposed individuals. Methods This was a case series performed through extraction of relevant clinical information from the medical records of three patients admitted to our Hematology unit between August 2020 and September 2020. Main Results Considering the relatively rapid development of cytopenias following recovery from COVID-19, it cannot be ruled out that SARS-Cov-2 played a role in leukemogenesis in those patients. Based on previous in vitro studies, the renin-angiotensin system imbalance induced by SARS-CoV-2 could potentially promote in vivo leukemogenesis through several mechanisms. Conclusion Despite the advances in pathophysiological and clinical characterization of COVID-19, the consequences of the pandemic to the incidence of hematologic diseases are still to be elucidated. In this context, future dissection of the status of the local bone marrow renin-angiotensin system in leukemogenesis is a clinically relevant basic research area.

Post Transplant Lymphoproliferative Disease Isolated to Kidney Allograft / Doença Linfo Proliferativa Pós-Transplante Isolada ao Enxerto Renal

ABSTRACT Post-transplantation lymphoproliferative disease (PTLD) comprises a heterogeneous group of hematolymphoid proliferations resulting from a monoclonal or polyclonal proliferation of lymphoid cells. The clinical presentation varies according to the affected sites. The gastrointestinal tract and the central nervous system are the most common, and constitutional symptoms are frequent. Isolated allograft involvement is rare. We report a case of polyclonal PTLD isolated in the kidney allograft in a patient who received an HLA-identical living donor seven years before. Noteworthy, this patient did not present constitutional symptoms, and his only clinical manifestation was graft dysfunction, expressed by an increase in serum creatinine and mild proteinuria. The diagnosis was performed through renal biopsy, which showed dense lymphoid interstitial infiltrate. The PTLD was polyclonal, unrelated to Epstein-Bar virus (EBV), and it was successfully treated with chemotherapy, reduced immunosuppression, and sirolimus.

RESUMO A doença linfoproliferativa pós-transplante (DLPT) é formada por um grupo heterogêneo de proliferações hematolinfóides resultantes da proliferação mono ou policlonal das células linfoides. O quadro clínico é variado e dependente dos sítios envolvidos, sendo o trato gastrintestinal e o sistema nervoso central os mais comuns, e sintomas constitucionais são frequentes. O envolvimento isolado do enxerto é raro. Relatamos aqui um caso de DLPT policlonal isolada do enxerto em um receptor de transplante renal com doador vivo HLA idêntico, ocorrido sete anos após o transplante. Digno de nota, o paciente não apresentou sintomas constitucionais e sua única manifestação clínica foi disfunção do enxerto, expressa através da elevação da creatinina e discreta proteinuria, sendo o diagnóstico realizado através de biópsia renal, que evidenciou infiltrado intersticial linfoide denso. Tratava-se de DLPT policlonal não relacionada ao vírus Epstein-Bar (EBV) e foi tratado com sucesso com quimioterapia, redução da imunossupressão e sirolimo.

Renal changes in COVID-19 infection

SUMMARY The COVID-19 (SARS-CoV-2) infection started in China, Wuhan City, Hubei Province, in December 2019, and it was declared a pandemic in mid-March 2020, caused by a new coronavirus strain called SARS-CoV-2. The pathogenesis of kidney injury attributed to SARS- CoV-2 is not well defined yet. Observations show that the kidney damage caused by the new virus mutation is mainly tubular, with impairment of glomerular filtration and high levels of urea and creatinine. A study with seriously ill patients with COVID-19 showed that acute kidney injury was present in 29%. In the face of this evidence, based on recent studies, we can see the great renal contribution as an impact factor in the evolution of COVID-19, not just as a complicator of severity, but maybe part of the initial cascade of the process, requiring a deeper analysis using conventional biomarkers of kidney injury and more aggressive clinical intervention in patients at risk, in an attempt to reduce mortality.

RESUMO Infecção pelo COVID-19 (SARS-CoV-2) começou na China, cidade de Wuhan, província de Hubei, em dezembro de 2019, e foi declarada pandemia em meados de março de 2020, causada por uma nova cepa de coronavírus chamada SARS-CoV-2. A patogênese da lesão renal atribuída à SARS-CoV-2 ainda não está bem definida. Observações mostram que o dano renal causado pela nova mutação viral é principalmente tubular, com comprometimento da filtração glomerular e apresentação de altos níveis de uréia e creatinina. Estudo com pacientes gravemente enfermos com COVID-19 mostrou que a lesão renal aguda estava presente em 29%. Diante dessas evidências, com base em estudos recentes, podemos ver a grande contribuição renal como um fator de impacto na evolução do COVID-19, não apenas como um complicador da gravidade, mas talvez como parte da cascata inicial do processo, exigindo uma investigação de análise mais profunda usando biomarcadores convencionais de lesão renal e intervenção clínica mais agressiva em pacientes em risco, na tentativa de reduzir a mortalidade.

Does BCR-ABL transcript type influence the prognosis of patients in chronic myelogenous leukemia chronic phase?

ABSTRACT Introduction and objective: In this study, we evaluated the influence of the transcript type on hematological and clinical parameters, as well as the event-free survival of 50 patients in the Chronic myeloid leukemia chronic phase. Methods: We reviewed the medical records of 55 patients with Chronic myeloid leukemia. The eligibility criteria were based on the availability of hematological and clinical baseline data in the medical records. Data on BCR-ABL transcripts were obtained from medical records. Results: Eighteen patients (36%) had the b2a2 transcript, 24 (48%) had b3a2 and 8 (16%) had b2a2/b3a2. The median platelet count for transcripts b2a2, b3a2 and b2a2/b3a2 was 320.65 × 103/L, 396 × 103/L, and 327.05 × 103/L, respectively (p = 0.896). We could not find any differences in relation to the other hematological parameters, when compared to the transcript type. Comparison between spleen and liver size and type of transcript did not differ inside the groups (p = 0.395 and p = 0.647, respectively) and the association between risk scores and transcript type did not show statistical significance (p > 0.05). The 21-month probability for event-free survival was 21%, 48% and 66% for the transcripts b2a2, b3a2 and b2a2/b3a2 respectively (p = 0.226) Conclusion: We conclude that the expression BCR-ABL transcripts have no influence on hematological, clinical and event-free survival parameters of patients in the Chronic myeloid leukemia chronic phase.

Prolonged response to recombinant human erythropoietin treatment in patients with myelodysplastic syndrome at a single referral centre in Brazil

OBJECTIVES: To evaluate the effects of epoetin (EPO) alfa treatment on overall survival, event-free survival and response duration in patients with myelodysplastic syndrome (MDS) who were treated at a haematological referral centre in northeastern Brazil. METHODS: This was a retrospective cohort study of 36 patients diagnosed with MDS and treated with EPO alfa at 30,000 to 60,000 IU per week. Clinical data were collected from medical records. The events assessed were non-response to treatment and progression to acute myeloid leukaemia (AML). Statistical analyses were performed using GraphPad Prism 7 and SPSS 24 software. RESULTS: The overall survival of patients who received EPO alfa treatment was 51.64%, with a median of 65 months of treatment, and the overall survival of this group was 100% during the first 24 months. We detected a 43.5-month median event-free survival, with a response rate of 80.5%. We observed responses from 25 to 175 months. Patients with transfusion dependence and those with a high-risk stratification, as determined by the International Prognostic Scoring System (IPSS), the Revised International Prognostic Scoring System (IPSS-R), the WHO classification-based Prognostic Scoring System (WPSS) and the WHO 2016, had a lower event-free survival than other patients. CONCLUSIONS: Despite the wide use of EPO alfa in the treatment of anaemia in patients with MDS, the median response duration is approximately only 24 months. Our data provide encouraging results concerning the benefits of using EPO alfa for the improvement of the quality of life, as patients treated with EPO showed higher overall survival, event-free survival rates and longer response durations than have been previously described in the literature.

Wernicke's encephalopathy in a patient with non-Hodgkin's lymphoma post-Autologous HSCT

SUMMARY Wernick's Encephalopathy (WE) is an acute neuropsychiatric syndrome caused by thiamine deficiency post hematopoietic stem cell transplant (HSCT). WE is associated with high mortality and morbidity rates, but due to its rare occurrence, it is rarely considered in patients submitted to this procedure. Considering that, the manuscript reports the clinical characteristics and the possible factors that predisposed the occurrence of WE in a patient with non-Hodgkin's lymphoma post-Autologous HSCT. We conclude that WE should be considered in patients submitted to autologous HSCT associated with prolonged use of TPN and malnutrition.

Association of oxidative stress and DNA damage with grafting time in patients with multiple myeloma and lymphoma submitted to autologous hematopoietic stem cell transplantation / Associação do estresse oxidativo e dano ao DNA com o tempo de enxertia em pacientes com mieloma múltiplo e linfomas submetidos a transplante autólogo de células-tronco hematopoéticas

ABSTRACT The aim of the study was to investigate the association between oxidative stress and DNA damage with grafting time in patients submitted to autologous hematopoietic stem-cell transplantation (HSCT). The study included 37 patients submitted to autologous HSCT diagnosed with Multiple Myeloma (MM) and lymphoma (Hodgkin’s and non-Hodgkin’s). Biomarkers of oxidative stress and DNA damage index (DI) were performed at baseline (pre-CR) of the disease and during the conditioning regimen (CR), one day after the HSCT, ten days after HSCT and twenty days after HSCT, as well as in the control group consisting of 30 healthy individuals. The outcomes showed that both groups of patients had an hyperoxidative state with high DI when compared to baseline and to the control group and that the CR exacerbated this condition. However, after the follow-up period of the study, this picture was re-established to the baseline levels of each pathology. The study patients with MM showed a mean grafting time of 10.75 days (8 to 13 days), with 10.15 days (8 to 15 days) for the lymphoma patients. In patients with MM, there was a negative correlation between the grafting time and the basal levels of GPx (r = -0.54; p = 0.034), indicating that lower levels of this important enzyme are associated with a longer grafting time. For the DI, the correlation was a positive one (r = 0.529; p = 0.030). In the group with lymphoma, it was observed that the basal levels of NOx were positively correlated with grafting time (r = 0.4664, p = 0.032). The data indicate the potential of these biomarkers as predictors of toxicity and grafting time in patients with MM and Lymphomas submitted to autologous HSCT.

RESUMO O objetivo do estudo foi investigar a associação entre estresse oxidativo e dano ao DNA com o tempo de enxertia em pacientes submetidos ao transplante de células-tronco hematopoéticas autólogo (TCTH). Participaram do estudo 37 pacientes submetidos ao TCTH autólogo com diagnóstico de mieloma múltiplo (MM) e Linfomas (Hodgkin e não Hodgkin). Biomarcadores de estresse oxidativo e índice de dano ao DNA (ID) foram determinados no estado basal (Pré-RC) das doenças e durante o regime de condicionamento (RC), um dia após o TCTH, dez dias após o TCTH e vinte dias após o TCTH e no grupo controle composto por 30 individuos saudáveis. Os resultados demonstraram que os dois grupos de pacientes apresentaram um estado hiperoxidativo com elevado ID quando comparados ao estado basal e ao grupo controle e que o RC exacerbou essa condição. No entanto, após o tempo de acompanhamento do estudo, esse quadro foi reestabelecido ao estado basal de cada patologia. Os pacientes do estudo com MM apresentaram uma média do tempo de enxertia de 10,75 dias (8 a 13 dias), e de 10,15 dias (8 a 15 dias) para o grupo Linfoma. Nos pacientes com MM houve uma correlação negativa entre o tempo de enxertia e os níveis basais de GPx (r=-0,54; p=0,034), indicando que níveis mais baixos de GPx estão relacionados a um maior tempo de enxertia, e para o ID, a correlação foi positiva (r=0,529; p=0,030). No grupo com Linfoma, observou-se que os níveis basais de NOx correlacionaram-se positivamente com o tempo de enxertia (r= 0,4664; p=0,032). Os dados apontam para o potencial desses biomarcadores como preditores da toxicidade e do tempo de enxertia em pacientes com MM e Linfomas submetidos ao TCTH autólogo

Relevance of prognostic factors in the decision-making of stem cell transplantation in Myelodysplastic Syndromes / Relevância dos fatores prognósticos na decisão do transplante de células-tronco na Síndrome Mielodisplásica

ABSTRACT The hematopoietic stem cell transplantation (HSCT) is the only curative alternative for Myelodysplastic Syndrome (MDS), but many patients are not eligible for this treatment, as there are several limiting factors, especially in the case of patients with low-risk MDS. The aim of this study is to discuss the factors that can guide the decision-making on referring or not a patient to HSCT. Three cases of MDS, two of which were submitted to HSCT are presented. We intend to report the difficulties in referring patients with MDS to transplant and the prognostic factors that contribute to define eligibility.

RESUMO O transplante de células-tronco hematopoéticas (TCTH) é a única alternativa curativa para Síndrome Mielodisplásica (SMD), porém muitos pacientes não são elegíveis para esta opção, pois existem diversos fatores limitantes, principalmente no caso de pacientes com SMD de baixo risco. O objetivo do estudo é discutir os fatores que podem orientar a decisão no encaminhamento ou não para o TCTH. São apresentados três casos de SMD, dos quais dois foram submetidos ao TCTH. Nos propomos a relatar as dificuldades no encaminhamento dos pacientes com SMD ao transplante e os fatores prognósticos que contribuem para definir a elegibilidade.

Mobilization of hematopoietic progenitor cells for autologous transportation: consensus recommendations / Mobilização de células progenitoras hematopoéticas para transplante autólogo: recomendações de consenso

SUMMARY Selected patients with certain hematological malignancies and solid tumors have the potential to achieve long-term survival with autologous hematopoietic progenitor cell transplant. The collection of these cells in peripheral blood avoids multiple bone marrow aspirations, results in faster engraftment and allows treatment of patients with infection, fibrosis, or bone marrow hypocellularity. However, for the procedure to be successful, it is essential to mobilize a sufficient number of progenitor cells from the bone marrow into the blood circulation. Therefore, a group of Brazilian experts met in order to develop recommendations for mobilization strategies adapted to the reality of the Brazilian national health system, which could help minimize the risk of failure, reduce toxicity and improve the allocation of financial resources.

RESUMO Pacientes selecionados com certas neoplasias hematológicas e tumores sólidos têm o potencial de alcançar sobrevida de longo prazo com o transplante autólogo de células progenitoras hematopoéticas. A coleta dessas células no sangue periférico evita múltiplas aspirações de medula óssea, resulta em enxertia mais rápida, e permite o tratamento de pacientes com infiltração, fibrose ou hipocelularidade medular. Contudo, para o sucesso desse procedimento, é essencial mobilizar um número suficiente de células progenitoras da medula óssea para a circulação sanguínea. Por isso, um painel de especialistas brasileiros se reuniu com o objetivo de desenvolver recomendações para estratégias de mobilização adaptadas à realidade do sistema de saúde nacional, que pudessem contribuir para minimizar os riscos de falha, reduzir a toxicidade e melhorar a alocação de recursos financeiros.

Hodgkin's Lymphoma - evaluation of patients submitted to Autologous transplantation of hematopoietic cells in the Hematology Service of the Hospital Walter Cantídio - Fortaleza, Brazil / Linfoma de Hodgkin - avaliação dos pacientes submetidos a transplante autólogo de células hematopoéticas no Serviço de Hematologia do HUWC

SUMMARY The Autologous HSCT is an important alternative for refractory or recurrent HL patients in terms of survival and improved quality of life. This study analyzes the results of autologous BMT performed in HL patients in the Transplant Unit of the HUWC/ HEMOCE (Fortaleza - CE, Brazil). Fifty-two transplanted patients were studied from January 2009 to October 2015, among them, 30 men and 22 women, mean age of 28.2 years. All of them received GCS-F during the mobilization, in some cases associated with Vinorelbine or Plerixafor, with CD34 collection averaging 4.8 CD34/kg. The conditioning was performed with BEAC, NEAM or BEAM and the grafting with an average of 10 days. The evaluation on D + 100 showed: CR - 42 (82.7%), PR - 08 (13.5%) and 02 (3.8%) deaths, three and six days after cell infusion. After the D+100, 08 patients in CR showed HL recurrence from 06 to 36 months; 03 died and 05 are being treated with brentuximab; among the 08 patients in PR, 01 died due to HL activity, 04 months after BMT and 07 patients are undergoing treatment. The final evaluation of HL transplant patients showed an OS of 88.5% and a DFS of 61.5% in 6 years, with OS of the chemosensitive patients of 81% and of the chemoresistant ones, of 72.6%. It is possible to conclude that the Autologous HSCT has shown to be an excellent rescue therapy regarding tolerance, as well as the overall survival.

RESUMO O TCTH autólogo é uma importante alternativa para os pacientes de LH refratários ou recidivados, em termos de sobrevida e melhora da qualidade de vida. O presente trabalho analisa os resultados do TMO autólogo realizado em pacientes de LH na Unidade de Transplante do SH do HUWC/HEMOCE. Foram estudados 52 pacientes submetidos ao TMO de janeiro de 2009 a outubro de 2015, sendo 30 homens e 22 mulheres, média de idade de 28,2 anos. Todos receberam GCS-F na mobilização, em alguns casos associados a Vinorelbine ou a Plerixafor e coleta de CD34 com média de 4,8CD34/kilo. O condicionamento foi realizado com BEAC, NEAM ou BEAM e a enxertia com média de 10 dias. A avaliação no D+100 mostrou: RC – 42 (82,7%), RP – 08 (13,5%) e 02 (3,8%) óbitos ocorridos 3 e 6 dias após a infusão das células. Após o D+100, 08 pacientes em RC apresentaram recidiva do LH entre 6 e 36 meses; 3 foram a óbito e 5 estão em tratamento com brentuximabe; os 8 pacientes em RP, 1 faleceu por atividade do LH, 4 meses após o TMO e 7 estão em tratamento. A avaliação final dos pacientes de LH transplantados mostrou uma SG de 88,5% e SLD de 61,5% em 6 anos, SG dos pacientes quimiossensiveis de 81% e dos quimioresistentes de 72,6%. É possível concluir que o TCTH Autólogo se coloca como excelente terapia de resgate em relação à tolerância, bem como na sobrevida global.

T-cell/myeloid mixed-phenotype acute leukemia with monocytic differentiation and isolated 17p deletion

Mixed phenotype acute leukemia is a rare subtype of leukemia that probably arises from a hematopoietic pluripotent stem cell. The co-expression of two of myeloid, B- or T-lymphoid antigens is the hallmark of this disease. Herein, the case of a 28-year-old female patient is reported who presented with hemoglobin of 5.8 g/dL, white blood cell count of 138 × 109/L and platelet count of 12 × 109/L. The differential count of peripheral blood revealed 96% of blasts. Moreover, the patient presented with lymphadenopathy, splenomegaly and bone marrow infiltration by monocytoid blasts characterized as 7% positivity by Sudan Black cytochemical staining. Immunophenotyping revealed the involvement of blasts of both T- and monocytic lineages. The cytogenetic analysis showed an isolated 17p deletion. Thus, the diagnosis of T-cell/myeloid mixed phenotype acute leukemia was made with two particular rare features, that is, the monocytic differentiation and the 17p deletion as unique cytogenetic abnormalities. The possibility of concomitant expressions of T-cell and monocytic differentiation antigens in the same blast population is hard to explain using the classical model of hematopoiesis. However, recent studies have suggested that myeloid potential persists even when the lineage branches segregate toward B- and T-cells. The role of an isolated 17p deletion in the pathogenesis of this condition is unclear. At present, the patient is in complete remission after an allogeneic stem cell transplantation procedure...

Tumor suppressor p53 protein expression: prognostic significance in patients with low-risk myelodysplastic syndrome

BACKGROUND: At the time of diagnosis, more than 50% of patients with myelodysplastic syndrome have a normal karyotype and are classified as having a favorable prognosis. However, these patients often show very variable clinical outcomes. Furthermore, current diagnostic tools lack the ability to look at genetic factors beyond karyotyping in order to determine the cause of this variability. OBJECTIVE: To evaluate the impact of p53 protein expression at diagnosis in patients with low-risk myelodysplastic syndrome. METHODS: This study enrolled 38 patients diagnosed with low-risk myelodysplastic syndrome. Clinical data were collected by reviewing medical records, and immunohistochemical p53 staining was performed on bone marrow biopsies. RESULTS: Of the 38 participants, 13 (34.21%) showed p53 expression in their bone marrow. At diagnosis, this group of patients also presented clinical features characteristic of a poor prognosis more often than patients who did not express p53. Furthermore, patients expressing p53 had a shorter median survival time compared to those without p53 expression. CONCLUSION: This study shows that the expression of p53 at diagnosis is a useful indicator of distinct clinical characteristics and laboratory profiles found in low-risk myelodysplastic syndrome patients. These data indicate that the immunohistochemical analysis of p53 may be a prognostic tool for myelodysplastic syndrome and should be used as an auxiliary test to help determine the best therapeutic choice. .

Serum concentrations of nitrite and malondialdehyde as markers of oxidative stress in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

BACKGROUND: Chronic myeloid leukemia is a neoplasm characterized by clonal expansion of hematopoietic progenitor cells resulting from the (9:22)(q34,11) translocation. The tyrosine kinase abl fusion protein,the initial leukemogenic event in chronic myeloid leukemia, is constitutively activated thus inducing the production of reactive oxygen species. Of particular relevance is the fact that an increase in reactive oxygen species can facilitate genomic instability and may contribute to disease progression. OBJETIVE: To evaluate oxidative stress by determining the levels of malondialdehyde and nitrite in chronic myeloid leukemia patients under treatment with 1st and 2nd generation tyrosine kinase inhibitors monitored at a referral hospital in Fortaleza, Ceará. METHODS: A cross-sectional study was performed of 64 male and female adults. Patients were stratified according to treatment. The levels of malondialdehyde and nitrite were determined by spectrophotometry. Statistical differences between groups were observed using the Student t-test and Fisher's exact test. The results are expressed as mean ± standard error of mean. The significance level was set for a p-value < 0.05 in all analyses. RESULTS: The results show significantly higher mean concentrations of nitrite and malondialdehyde in chronic myeloid leukemia patients using second-generation tyrosine kinase inhibitors compared to patients on imatinib. Conclusion: It follows that chronic myeloid leukemia patients present higher oxidative activity and that the increases in oxidative damage markers can indicate resistance to 1st generation tyrosine kinase inhibitors.

Casuistica neurologica do Hospital das Clinicas (HUWC-FMUFC) no periodo de 1959-1979: alicerce da disciplina de neurologia / Casuistry neurologic in Hospital das Clinicas (HUWC-FMUFC) in the period of 1959-1979: base of discipline of neurology

Os autores fazem uma analise estatistica da casuistica neurologica no estado do Ceara de acordo com os dados coletados no Hospital das Clinicas - UFC no periodo de 1959-1979. Eles comparam os dados com as estatisticas internacionais e enfatizam as possibilidades de uma nova nosologia neurologica tropical