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Summary: Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

This manuscript summarizes the results of the consensus meeting composed of hematologists and cardiologists to establish recommendations for the prevention and follow-up of cardiovascular (CV) risk in patients with chronic myeloid leukemia (CML) treated with BCR-ABL tyrosine kinase inhibitors (TKIs) from the point of view of clinical practice and from the perspective of hematology consultation.In the first medical appointment, the CV risk factors should be identified to perform the baseline risk stratification, based on the Brazilian Guideline of Dyslipidemia and Atherosclerosis Prevention Update (risk levels: very high, high, intermediate and low).Once stratified, the treatment of the CV risk factors should be administered. If the patient presents risk factors, such as hypertension, diabetes, renal disease, smoking and hypercholesterolemia, the evaluation and initial treatment may be done by the hematologist, being an option the request for evaluation by a specialist. If the patient has a history of previous CV disease, we recommend referral to a specialist.As the CV risk score is dynamic and the control of risk factors can reduce the patient risk, this expert consensus recommends that the re-evaluation of the CV risk after the baseline should be performed at 3 months, 6 months and 12 months. After this period, it should be done annually and, for specific patients, at the clinician’s discretion.The evaluation of the baseline CV risk and the safe administration of a TKI allow the patient to benefit from the maximum treatment, avoiding unwanted effects.

Mucormicose é uma infecçãoinvasiva causada por fungos da ordem dos Mucorales, ubíquos na natureza, O objetivo deste estudo é descrever as características epidemiológicas, clínicas e microbiológicas de um surto de mucormicose por Rhizomucor pussilus em uma unidade de TCTH) do HC -UFPR, Curitiba,. Métodos: Os casos de Mucormicose Invasiva (MI) foram definidos de acordo com os critérios do EORTC e NIAID MSG; uma curva epidemiológica dos casos de MI identificados na unidade nos últimos 5 anos (Outubro/16 a Setembro/21) foi construída para estabelecer a média de casos no período para definição do surto. Dados epidemiológicos,clínicos e microbiológicos dos pacientes foram analisados, assim como a investigação microbiológica do ambiente da unidade. Os isolados microbiológicos foram identificados fenotipicamente e por espectrometria de massa (MALDI-TOF) e identificação molecular; Resultados:: Nos últimos 12 meses, pudemos identificar 4 casos de MI, número muito acima da médica epidêmica da unidade nos últimos 5 anos. Três casos foram classificados como mucormicose invasiva disseminada provada (2 pediátricos e 1 adulto). Três pacientes Rhizomucor pussilus provadas, sendo que um paciente teve o diagnóstico confirmado pos mortem, e não recebeu tratamento. Outros 3 pacientes receberam terapia baseada em ABLC, combinados com isavuconazol. Ao fim de setembro/21, 0 3 pacientes estão vivos, sendo 1 deles considerado curado (mucormicose intestinal - tratamento cirúrgico e antifúngico), e os outros 2 pacientes ainda recebendo terapia antifúngica ambulatorial com isavuconazol. A investigação da fonte do surto, todos os quartos da unidade dispões de filtro HEPA; foi avaliada a linha do tempo da localização dos pacientes na unidade, mas nenhuma exposição comum pôde ser identificada. Como os esporos de Rhizomucor pussilus podem ser encontrados na água, alimentos e sistemas de ar, foram coletadas amostras de fontes do ambiente, sem achados positivos. Também foi considerada a possibilidade de que construções e reformas dentro e fora do HC-UFPR,pudessem explicar o recente aumento no número de casos de MI observados no último ano. No entanto, também esperaríamos um aumento no número de casos de aspergilose invasive neste cenário, o que não foi observado nas curvas epidemiológicas da unidade durante o período. Em conclusão, descrevemos os aspectos epidemiológicos, clínicos e microbiológicos de um surto de MI causada por Rhizomucor pussilus em uma unidade de TCTH np HC-UFPR.

Introdução: O transplante de células-tronco hematopoiéticas (TCTH) é um dos potenciais tratamentos curativos utilizados para pacientes com doenças hematológicas e outras doenças imunes. Durante o transplante, o paciente é submetido ao condicionamento e a outros tratamentos, como radioterapia e quimioterapia, o que pode causar a perda da diversidade da microbiota intestinal. A manipulação da microbiota intestinal com probióticos vem sendo apontada como uma estratégia de prevenção de complicações nos pacientes submetidos ao TCTH. Objetivo: Identificar se há evidências científicas relacionadas à segurança e aos benefícios da utilização de probióticos em pacientes submetidos ao TCTH. Método: Revisão integrativa com base em estudos que abordassem o uso de probióticos para o caso específico de pacientes submetidos ao TCTH publicados entre 2000 a 2018. Resultados: Foram selecionados cinco estudos que atenderam aos critérios de inclusão e exclusão, com um total de 52 pacientes. A utilização de probióticos na prevenção e/ou tratamento da diarreia tem mostrado resultados positivos em pacientes com diarreia induzida por antibióticos ou por infecções bacterianas, porém os estudos ainda não destacam benefícios no uso de probióticos no caso específico de pacientes submetidos ao TCTH. Poucos estudos mostram o uso de probióticos para auxílio na melhora dos sintomas associados a infecções ou bacteremias em pacientes imunossuprimidos. Conclusão: O uso de probióticos na população submetida ao TCTH e em imunossuprimidos ainda é controverso, sendo necessários mais estudos que demonstrem os benefícios no uso dessa estratégia para esse público.

Introduction: Mutations in the breakpoint cluster region-Abelson murine leukemia 1 gene are the leading cause of resistance to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patients. Mutations have been detected throughout the extension of the kinase domain of this gene and it is important to investigate their positions because there may be a difference in clinical relevance. Objective: To evaluate mutations in the transcripts of the BCR-ABL1 gene in Brazilian patients with chronic myeloid leukemia under tyrosine kinase inhibitor treatment in the Hospital de Clínicas of the Universidade Federal do Paraná. Methods: This retrospective observational cross-sectional study analyzed mutation data of BCR-ABL1 gene transcripts. Three hundred and thirty peripheral blood samples from 193 patients were evaluated with the search for mutations being achieved by Sanger sequencing. Results: Sixteen mutation types were identified in 48/193 (24.87%) patients with T315I (20.83%) being the most common. Furthermore, four polymorphisms (T240T, K247R, E275E and Y275Y) were identified. The highest incidence of mutations (19/53: 35.85%) occurred in the P-loop of the tyrosine kinase domain, whereas no mutation was found in the A-loop. In 43/48 (89.58%) patients only one mutation was found and more than one mutation was found in 5/48 (10.42%). The simultaneous presence of two mutations (E189G/V299L and E255K/T315I) was observed in 2/5 patients while the different mutations were seen in sequential samples of the other three patients (Y253Y/T315I, T315I/E255K and E255K/T315I). Conclusions: This molecular characterization contributed to the identification of the resistance profile to tyrosine kinase inhibitors in Brazilian patients, thus enabling the use of adequate therapeutic strategies in a timely manner. Keywords: Chronic myeloid leukemia, BCR-ABL1 gene, Mutation, Tyrosine kinase inhibitors, Resistance

ABSTRACT Introduction: Pseudoporphyria is a rare photodermatosis with characteristics similar to those of porphyria cutanea tarda, without, however, presenting abnormalities in porphyrin metabolism. Its etiology is related to chronic kidney disease, ultraviolet radiation and certain medications. The aim of the present study is to describe a case of furosemide-related pseudoporphyria in a patient with chronic kidney disease. Case description: A 76-year-old male patient with stage 4 chronic kidney disease and in continuous use of furosemide presented ulcerated lesions with peripheral erythema and central hematic crust in the legs. On a skin infection suspicion, treatment with quinolone and neomycin sulfate was initiated, without improvement. A biopsy of the lesion was performed, with histopathological examination demonstrating findings compatible with porphyria, although the patient did not present high porphyrin levels. The diagnosis of furosemide-induced pseudoporphyria was then established, with medication suspension, and there was a significant improvement of the lesions. Discussion: There are few cases of pseudoporphyria described, but it is believed that this condition is underdiagnosed, especially in patients with chronic kidney disease. Both clinical and histopathological findings closely resemble porphyria, differentiating it from normal levels of porphyrin in plasma, urine, or feces. Conclusions: Although the lesions are mostly benign, they may increase the morbidity and mortality of these patients, so a proper diagnosis and early treatment are extremely important.

BACKGROUND: Published criteria defining the accelerated phase in chronic myeloid leukemia are heterogeneous and little is known about predictors of poor outcome.METHODS: This is a retrospective study of 139 subjects in the accelerated phase of chronic myeloid leukemia treated with imatinib at a single center in Brazil. The objective was to identify risk factors for survival, major cytogenetic response and progression to blast phase in this population. The factors analyzed were: blasts 10-29%, basophils ≥ 20%, platelets > 1 × 106/µL or 1 × 105/µL in the peripheral blood, as well as clonal evolution, splenomegaly, hemoglobin < 10 g/dL, time between diagnosis of chronic myeloid leukemia and imatinib treatment, and hematologic toxicity.RESULTS: Risk factors for poor survival in multivariate analysis were Grades 3-4 hematologic toxicity (p-value = 0.001), blasts 10-29% (p-value = 0.023), and hemoglobin < 10 g/dL (p-value = 0.04). Risk factors for not achieving major cytogenetic response were blasts 10-29% (p-value = 0.007), hemoglobin < 10 g/dL (p-value = 0.001), and previous use of interferon (p-value = 0.032). Risk factors for progression to the blast phase were hemoglobin < 10 g/dL (p-value = 0.005), basophils ≥ 20% (p-value = 0.023), and time from diagnosis of chronic myeloid leukemia to imatinib treatment > 12 months (p-value = 0.030).CONCLUSION: These data indicate that patients with the above risk factors have a worse prognosis. This information can guide the therapy to be used.

OBJECTIVE: Hematopoietic stem cell transplantation has been successfully used to treat the pediatric population with malignant and non-malignant hematological diseases. This paper reports the results up to 180 days after the procedure of all unrelated hematopoietic stem cell transplantations in pediatric patients that were performed in one institution.METHODS: A retrospective review was performed of all under 18-year-old patients who received unrelated transplantations between 1995 and 2009. Data were analyzed using the log-rank test, Cox stepwise model, Kaplan-Meier method, Fine and Gray model and Fisher's exact test.RESULTS: This study included 118 patients (46.8%) who received bone marrow and 134 (53.2%) who received umbilical cord blood transplants. Engraftment occurred in 89.47% of the patients that received bone marrow and 65.83% of those that received umbilical cord blood (p-value < 0.001). Both neutrophil and platelet engraftments were faster in the bone marrow group. Acute graft-versus-host disease occurred in 48.6% of the patients without statistically significant differences between the two groups (p-value = 0.653). Chronic graft-versus-host disease occurred in 9.2% of the patients with a higher incidence in the bone marrow group (p-value = 0.007). Relapse occurred in 24% of the 96 patients with malignant disease with 2-year cumulative incidences of 45% in the bone marrow group and 25% in the umbilical cord blood group (p-value = 0.117). Five-year overall survival was 47%, with an average survival time of 1207 days, and no significant differences between the groups (p-value = 0.4666).CONCLUSION: Despite delayed engraftment in the umbilical cord blood group, graft-versus-host disease, relapse and survival were similar in both groups.

Background: Sub-optimal levels of vitamin D have been found to be highly prevalent in all age groups, with epidemiologic studies demonstrating a link between vitamin D deficiency and disease susceptibility, such as infection and cancer, and mortality rates. In adult transplant patients, it has been suggested that the immunomodulatory properties of vitamin D may have an important role in the prevention and treatment of graft-versus-host disease. Objective: The objective of this study was to assess serum 25-hydroxyvitamin D levels of children and adolescents submitted to allogeneic hematopoietic stem cell transplantation. Methods: Serum 25-hydroxyvitamin D levels of 66 patients, aged 4-20 years, were assessed at three stages: before hospitalization for hematopoietic stem cell transplantation and at 30 and 180 days after hematopoietic stem cell transplantation. The control group consisted of 25 healthy children. Results: At the pre-hematopoietic stem cell transplantation stage, patients had lower levels of 25-hydroxyvitamin D compared to controls (25.7 ± 12.3 ng/mL vs. 31.9 ± 9.9 ng/mL; p-value = 0.01), and a higher prevalence of 25-hydroxyvitamin D deficiency (32% vs. 8%; p-value = 0.01). Prevalence increased significantly after hematopoietic stem cell transplantation (p-value = 0.01) with half of the patients having vitamin D deficiency at 180 days after transplantation. At this stage, mean serum 25-hydroxyvitamin D levels were 20.9 ± 10.9 ng/mL, a significant decline in relation to baseline (p-value = 0.01). No correlation was found between 25-hydroxyvitamin D levels and vitamin D intake, graft-versus-host disease, corticoid use or survival rates. Conclusion: Low levels of 25-hydroxyvitamin D were detected even before hematopoietic stem cell transplantation and were significantly lower at 180 days after hematopoietic stem cell transplantation, thus recommending vitamin D supplementation for children and adolescents submitted to hematopoietic stem cell transplantation.

Long-term survivors of hematopoietic stem cell transplantation are recognized as a risk group for malignization. Malignant oral neoplasms are increasingly being reported in the literature as a consequence of lesions of chronic graft-versus-host disease, and prolonged multidrug treatment to control its manifestations. This report describes a 43-year-old patient who, after allogeneic bone marrow transplantation, developed an oral squamous cell carcinoma secondary to the use of azathioprine, cyclosporine, prednisone, and tacrolimus, associated with multiorgan chronic graft-versus-host disease involving the oral mucosa, skin, eyes, and liver. This report aims to discuss the possible role of immunosuppressant therapy for chronic graft-versus-host disease on the development of oral squamous cell carcinoma, and the relevance of a close oral follow-up of patients to detect dysplastic or malignant alterations at an early stage.

BACKGROUND: New criteria for the diagnosis and classification of chronic graft-versus-host disease were developed in 2005 for the purpose of clinical trials with a consensus sponsored by the National Institute of Health. OBJECTIVES: The aim of this study is to present the results of a multicenter pilot study performed by the Brazil-Seattle chronic graft-versus-host disease consortium to determine the feasibility of using these criteria in five Brazilian centers. METHODS: The study was performed after translation of the consensus criteria into Portuguese and training. A total of 34 patients with National Institute of Health chronic graft-versus-host disease were enrolled in the pilot study between June 2006 and May 2009. RESULTS: Of the 34 patients, 26 (76%) met the criteria of overlap syndrome and eight (24%) the classic subcategory. The overall severity of disease was moderate in 21 (62%) and severe in 13 (38%) patients. The median time from transplant to onset of chronic graft-versus-host disease was 5.9 months (Range: 3 - 16 months); the median time for the overlap syndrome subcategory was 5.9 months (Range: 3 - 10 months) and for the classic subcategory, it was 7.3 months (Range: 3 - 16 months). At a median follow up of 16.5 months (Range: 4 - 39 months), overall survival was 75%. CONCLUSIONS: It was feasible to use the National Institute of Health consensus criteria for the diagnosis and scoring of chronic graft-versus-host disease in a Brazilian prospective multicenter study. More importantly, a collaborative hematopoietic cell transplantation network was established in Brazil offering new opportunities for future clinical trials in chronic graft-versus-host disease and in other areas of research involving hematopoietic stem cell transplantation.

Abstract Background Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia leading to significant reductions of BCR-ABL1 transcript levels in peripheral blood. Objective To evaluate the response to imatinib mesylate treatment (400 mg/day) in Brazilian patients in the chronic phase of chronic myeloid leukemia monitored by quantitative real time polymerase chain reaction. Methods Between October 2002 and October 2010, 3169 peripheral blood samples were collected from 1403 patients from 3 to 5 months, 6 to 11 months, 12 to 17 months, 18 to 23 months and ≥24 months after beginning imatinib treatment. Eighty-two patients had samples available and analyzed for all time intervals. BCR-ABL1 quantification was performed by quantitative real time polymerase chain reaction using the ABL1 gene as the control. Results of the BCR-ABL1 ratio as a percentage were reported by the international scale (IS) using the laboratory conversion factor (0.51). Results In the first interval, 80.8% of patients achieved the optimal response (BCR-ABL1 IS ≤ 10%). In the second period, 69.1% achieved optimal response (BCR-ABL1 IS ≤ 1%) and, between 12 and 17 months, 47.3% achieved major molecular response (BCR-ABL1 IS ≤ 0.1%). Conclusions The results of this retrospective study show that the response to imatinib treatment (400 mg/day) of Brazilian patients in the chronic phase of chronic myeloid leukemia is within the expected profile when compared to patients reported in international prospective randomized studies.

Abstract Background: The aim of this study was to evaluate the prevalence of pre-sarcopenia and bone mineral density after hematopoietic stem cell transplantation. Methods: The study group consisted of over 18-year-old patients who had been submitted to allogeneic transplantation at least one year previously. Patients and healthy controls were matched by sex, ethnic background, age, and body mass index. Body composition and bone mineral density were measured by dual-energy X-ray absorptiometry. A 24-h food recall and food frequency survey were performed. The biochemical evaluation included calcium, parathormone and vitamin D. Eighty-seven patients (52 men; age: 37.2 ± 12.7 years; body mass index: 25 ± 4.5 kg/m2) were compared to 68 controls [31 men; age 35.4 ± 15.5 years (p = 0.467); body mass index 25.05 ± 3.7 kg/m2 (p = 0.927)]. Results: There was no significant difference in the dietary intake between patients and controls. The mean levels of vitamin D were 23.5 ± 10.3 ng/mL; 29 patients (41.0%) had insufficient and 26 (37.14%) deficient levels. A higher prevalence of reduced bone mineral density was observed in 24 patients (25%) compared to 12 controls (19.1% - p < 0.001). Pre-sarcopenia was diagnosed in 14 (14.4%) patients and none of the controls (p = 0.05). There was a higher prevalence of pre-sarcopenia (66%) in patients with grades III and IV compared to those with grades 0-II graft-versus-host disease (10.9%) (p = 0.004). Conclusion: patients submitted to transplantation had a higher prevalence of pre-sarcopenia and greater changes in bone mineral density compared to controls; the severity of graft-versus-host disease had an impact on the prevalence of pre-sarcopenia.