Central Nervous System Infiltration in Chronic Lymphocytic Leukemia: A Study on Behalf of the Registro Brasileiro De Leucemia Linfocitica Cronica

Introduction: Central nervous system (CNS) infiltration in chronic lymphocytic leukemia (CLL) is a rare presentation of CLL that can potentially have disastrous complications. Reported prognosis is poor. The objective of this study is to report a series of cases of CLL with CNS infiltration. Method(s): This is a case-series of a Brazilian CLL registry (Registro Brasileiro de Leucemia Linfocitica Cronica). We included patients with CLL and CNS infiltration. This is a descriptive study. Result(s): A total of 10 (0.28%) in 3610 patients were identified with confirmed (80%) or suspected (20%) CNS infiltration. Median age at CLL diagnosis was 57.5 y/o (range: 50 - 76). Three (30%) patients were diagnosed with CNS infiltration concomitantly with the CLL diagnosis, while others (70%) were diagnosed at a median of 41 months of CLL diagnosis (range: 11 to 119 months). Only three (30%) patients had been previously treated for CLL. Most common symptoms of CNS infiltration were convulsion (30%), altered mental status (30%), headaches (30%), ophthalmologic (30%), and urinary incontinence (20%). Amnesia, asthenia, vomiting, hemiparesis, cervicalgia, and dizziness were also present (one patient each). Of the patients with confirmed CNS infiltration, diagnoses were performed through liquor exam (all patients) and biopsy (one patient). Of the two patients with suspected CNS infiltration, one achieved complete response and the other, partial clinical response, following instituted CLL-directed therapy with (1 patient) or without (1 patient) intrathecal chemotherapy. Of the other 8 patients, 3 achieved complete response, 2 failed treatments, 1 was not evaluated and 2 had missing information. Of all patients, 5 are alive, 3 died of sepsis, multiorgan failure following CNS methotrexate-related toxicity, and COVID, and 2 had missing information. Discussion(s): Our results show that the prognosis of CNS infiltration in CLL can be relatively good, with at least 50% of patients alive at 1 year. However, a series of 18 patients published by Strati et al has shown a poorer outcome, with half of the patients dead at 1 year. Although all patients were diagnosed by liquor exam, that same study reported a low specificity for liquor exam in CLL (42%) due to the frequent presence of leukemic cells in the cerebrospinal fluid in other conditions. Establishing CNS CLL as the cause of the symptoms can be difficult, since up to 70% of patients with CLL have CNS infiltration in autopsy studies, and our results may be superestimated. In summary, CNS infiltration in CLL is a rare event, and further studies are needed to address prognosis and management. Copyright © 2022

DESFECHOS DE PACIENTES PORTADORES DE DOENÇAS LINFOPROLIFERATIVAS INFECTADOS COM COVID-19

Introdução: A pandemia pelo SARS-CoV-2 (COVID-19) vem desafiando a comunidade científica e os serviços de saúde, superando mais de 4 milhões de mortos no mundo. A idade avançada e a presença de comorbidades cardiovasculares são relacionadas a maior mortalidade em relação a população geral, podendo atingir 15% dos casos infectados. Pacientes onco-hematológicos, devido a doença de base e ao seu tratamento, possuem comprometimento do sistema imune por período de tempo prolongado, o que os torna mais suceptiveis a infecções. A infecção pelo COVID-19 nesse grupo de pacientes tem demonstrado piores desfechos. Nesta série de casos avaliamos os desfechos de pacientes portadores de doenças linfoproliferativas diagnosticados com COVID-19 de Fevereiro de 2020 a Agosto de 2021 em duas instituições de São Paulo. Objetivo: Descrever os desfechos de pacientes com COVID-19 em pacientes com doenças linfoproliferativas. Métodos: Estudo multicêntrico, observacional e retrospectivo. Os dados foram obtidos através do prontuário eletrônico. Os critérios de inclusão foram diagnóstico de doença linfoproliferativa e infecção por COVID-19 confirmada através de teste RT-PCR em pacientes sintomáticos realizados nos centros participantes. Resultados: Em um tempo mediano de seguimento de 399 dias foram incluídos 41 pacientes com mediana de idade de 59 anos (DP 16,8). A maior parte dos pacientes eram portadores de linfoma difuso de grandes células B (LDGCB), representando 24% da amostra, seguidos por linfoma folicular (17%) e linfoma de Hodgkin (17%). Em relação as comorbidades, 9 (22%) pacientes diabéticos, 17 (41%) hipertensos e 9 (22%) obesos. A taxa de admissão hospitalar foi de 75% e, mais da metade dos pacientes foram admitidos em unidade de terapia intensiva (UTI). Metade dos pacientes necessitaram de suporte ventilatório sendo, 15% dos pacientes com ventilação mecânica e outros 35% com cateter nasal de oxigênio. A prevalência de eventos trombóticos foi de 17%. Em relação ao tratamento quimioterápico 85% dos pacientes dessa amostra estava em vigência de tratamento quimioterápico no momento da infecção pelo Covid-19, no entando na análise univariada não houve diferença estataisticamente significativa de mortalidade entre o grupo de pacientes que estavam em tratamento quimioterápico e os que não estavam (HR 1,18;IC 0,26-5,33;p = 0,83). A taxa de sobrevida global em 100 dias foi de 66% (IC95 53-83%). Discussão: A mortalidade de pacientes hematológicos com infecção pelo COVID-19 é superior a população geral e foi estimada em 34% dos casos na metanalise publicada por Vijenthira et all. Em um estudo multicêntrico realizado na Alemanha a mortalidade em pacientes hospitalizados sem antecedente de neoplasias foi em torno de 22%. A ausência do aumento da mortalidade em pacientes com exposição recente a tratamento quimio-imunoterápico é condizente com dados apresentados em literatura, no entando não há estudos prospectivos publicados que exaltem esses achados. A idade superior a 60 anos foi o fator de maior impacto na mortalidade dos pacientes com doenças onco-hematológicos de acordo dados de literatura e em nosso estudo esse dado não foi estatisticamente significante possivelmente devido a uma mediana de idade menor que 60 anos da amostra. É importante ressaltar que esse é um estudo retrospectivo, porém que reafirma o pior desfecho clínico dos pacientes com doença onco-hematológicos com infecção pelo COVID-19.

ANEMIA APLÁSTICA ADQUIRIDA SECUNDÁRIA À INFECÇÃO PELO SARS-COV-2

Introdução: A anemia aplástica adquirida (AAA) é uma condição rara, com alta morbidade. Em 70-80% dos casos é idiopática e ocorre por destruição das células tronco-hematopoiéticas por fenômeno autoimune. Com as terapias imunossupressoras e o transplante de medula óssea (TMO), a AAA teve excelentes resultados com taxas de sobrevida de 80% em 10 anos. Pode estar relacionada à outros mecanismos, como exposição a agentes tóxicos e infecções virais, especialmente vírus Epstein Barr, vírus de hepatite, HIV e parvovírus B19. A recente pandemia pelo vírus SARS-Cov-2 foi relacionada ao desenvolvimento de doenças autoimunes, corroborando a associação entre infecção viral e desbalanço imune. Apresentamos o caso de uma paciente, previamente hígida, que 60 dias após infecção pelo Sars-Cov-2 iniciou plaquetopenia, evoluindo para pancitopenia. Relato de caso: Paciente feminina, 29 anos, infecção pelo Sars-Cov-2 em agosto/20, quadro leve, sem necessidade de internação hospitalar. Em outubro/2020, apresentou equimoses persistentes, procurou atendimento médico, com os exames: Hb 11,5 g/dL;neutrófilos 1054/mm3 e 130.000/mm3 plaquetas, com conduta expectante nesse momento. Em janeiro/2021, com piora das equimoses e fadiga, retornou em atendimento com Hb 9,8 g/dL, neutrófilos 1278/mm3 e plaquetas 45.000/mm3. Iniciada investigação com sorologias para hepatites virais, HIV, sífilis, provas reumatológicas, vitamina B12, ácido fólico, função renal, hepática, tireoidiana e pesquisa de clone HPN, todos dentro da normalidade. Como tratamento, foi iniciado prednisona 1 mg/kg/dia e agendado retorno ambulatorial. Antes do previsto, procurou novamente atendimento por gengivorragia com plaquetas de 19.000/mm3, Hb 9,8 g/dL, neutrófilos 900/mm3 e Reticulócitos 46,536/mm3. Submetida a avaliação medular, com biópsia evidenciando hipocelularidade (cerca de 30%) com hipoplasia de todas as séries. O estudo imunofenotípico não mostrou proliferação de células imaturas, anômalas ou displásicas, cariótipo XX, FISH para síndrome mielodisplásica e DEB test negativos. Como pesquisas virais, citomegalovírus e parvovírus B19, além de RNA do vírus SARS-Cov-2 na extração de DNA em medula óssea, resultaram todos negativos. O diagnóstico de AAA foi estabelecido, evoluindo com piora progressiva da pancitopenia e necessidade de suporte transfusional recorrente. Apesar de candidata a transplante alogênico de medula óssea, a paciente não tinha irmãos e então, iniciado tratamento timoglobulina de coelho 3,5 mg/kg/dia por 5 dias, ciclosporina 10 mg/kg/dia e eltrombopag 150 mg/dia, além eritropoetina 40.000 UI/semana. O último exame de 29/06/2021 mostra resposta parcial a terapia estabelecida com Hb 11,7 g/dL, neutrófilos 1889/mm3 e 90.000/mm3 plaquetas. Conclusão: A AAA é uma condição que necessita de rápido diagnóstico e tratamento. O desbalanço imunológico, especialmente a hiperativação de linfócitos T citotóxicos CD8+, desencadeado por infecção viral pode ser gatilho para a condição em predispostos. Outros relatos semelhantes corroboram a associação temporal entre a infecção do SARS-Cov-2 e AAA. Sendo assim, consideramos importante compartilhar essa informação no meio científico.

International Multicenter Study Comparing Cancer to Non-Cancer Patients with COVID-19: Impact of Risk Factors and Treatment Modalities on Outcome

Background. Given the limited collaborative international studies that evaluated COVID-19 in patients with cancer in comparison to patients without cancer, we aimed to determine the independent risk factors associated with increased 30-day mortality and the impact of novel treatment modalities in a large group of cancer and non-cancer patients with COVID-19 from multiple countries. Methods. We retrospectively collected de-identified data on cancer and non-cancer patients diagnosed with COVID-19 between January and November 2020, at 16 centers in Asia, Australia, Europe, North America, and South America. A logistic regression model was used to identify independent predictors of all-cause mortality within 30 days after COVID-19 diagnosis. Results. Of the total 4015 COVID-19 confirmed patients entered, we analyzed 3966 patients, 1115 cancer and 2851 non-cancer patients. Cancer patients were older than non-cancer patients (median age, 61 vs 50 years;p< 0.0001);more likely to be pancytopenic , had pulmonary disorders, hypertension, diabetes mellitus. In addition, they were more likely to present with higher inflammatory biomarkers (D-dimer, ferritin and procalcitonin), but were less likely to present with clinical symptoms. By multivariable logistic regression analysis, cancer was an independent risk factor for 30-day mortality (OR 1.46;95% CI 1.03 to 2.07;p=0.035). Older age (≥65 years) was the strongest predictor of 30-day mortality in all patients (OR 4.55;95% CI 3.34 to 6.20;p< 0.0001). Remdesivir was the only therapeutic agent independently associated with decreased 30-day mortality (OR 0.58;CI 0.39-0.88;p=0.009). Among patients on lowflow oxygen at admission, patients who received remdesivir had a lower 30-day mortality rate than those who were on high flow oxygen (5.9% vs 17.6%;p=0.03). Patients transfused with convalescent plasma within 1 day of diagnosis had a lower 30-day mortality rate than those transfused later (1% vs 7%, p=0.04). Conclusion. Cancer is an independent risk factor for increased 30-day all-cause mortality from COVID-19. Remdesivir, particularly in patients receiving low-flow oxygen, can reduce 30-day all-cause mortality, as well as convalescent plasma given early after COVID-19 diagnosis.

Treatment of COVID-19 Patients: Insights into the Use of Bone Marrow-Derived Mesenchymal Stem Cells

Patients with SARS-CoV-2 may be affected by the acute respiratory distress syndrome (ARDS), which has been associated with high mortality rate. As no specific drugs are available for ARDS, mesenchymal stem cells (MSC) seems to be a promising cell therapy due to immunomodulatory effects on reducing and healing inflammation-induced lung and other tissue injuries. The goal of this Phase I clinical trial was to explore the safety and efficacy of bone marrow-derived MSC (BM-MSC) infusions in patients with COVID-19 ARDS. The inclusions criteria were age between 18 to 70 years and PaO2/FiO2≤200mmHg. The BM-MSC infusions were as follow: one to 3 infusions intravenous doses of BM-MSC of 1x10 6 cells/kg;each dose could be administered with an interval between 3 to 7 days. The primary endpoint was safety (adverse events) within 6 hours;cardiac arrest or death within 24 hours post-infusion. The secondary endpoint includes patient survival at 30 days after the first infusion. Six patients were included in the trial and treated with at least one infusion of BM-MSC. The median age was 60,3 years (54 to 69), 5 were male. The median time between the worsening of respiratory distress and the BM-MSC infusion was 10 days (3 to 31 days). The median of PaO2/FiO2 before infusion was 151.86 (127.80-164.44) and median PaCO2 was 63,85 (39 to 117). One patient was treated with 3 MSC doses, two patients with 2 doses and 3 patients one dose. No serious adverse effects were observed within 24 hours post-infusion;only one death was observed following 30 days of cell administration. None of them showed adverse events during BM-MSC infusion. Only one patient showed signs of pulmonary infection one week after first BM-MSC infusion. This patient was at increased risk for infection due to prolonged intubation and a high dose of corticosteroid. Therefore, it was not possible to conclude its association with BM-MSC treatment. Only two patients showed clinical improvement after BM-MSC infusion. Patient 1 had BM-MSC infusion 72 hours after worsening of respiratory parameters, and thorax CT suggested the hypothesis of cryptogenic organizing pneumonia, which led to decision of using methylprednisolone 125mg I.V. for 3 days and carry on with MSC infusion. We observed a decrease in CRP levels from 126 to 67 mg/dL on day 1 after the first infusion, and PaO2/FiO2 ratio improved from 155 to 297 mmHg on day 5. He received the second dose within 7 days interval and by day 11 of the first infusion a new thorax TC showed complete resolution of alveolar consolidation areas in both lungs (Figure 1A and 1B). Patient 2 had BM-MSC administration 11 days after respiratory worsening and also presented improvement of PaO2/FiO2 ratio (148 to 215 mmHg after 2 days of infusion) and had thorax CT images suggesting cryptogenic organizing pneumonia with administration of methylprednisolone 250mg I.V. Nevertheless, the second dose was not administered due to ventilator-associated pneumonia and urinary infection. Four patients showed a non-sustained increase of PaO2/FiO2 ratio, with higher median PCO2 levels of 69,3 mmHg (range, 61,2 to 117) comparing to 39 and 47,3 mmHg of patients 1 and 2, respectively. PCO2 parameter could be a marker to indicate a worse response to MSC treatment, since it could point out chronic phases of COVID-19 disease. The patients died due to COVID-19 complications. No difference in inflammatory markers, such as interleukin 6, C-protein reactive test, procalcitonin, ferritin was observed before and after treatment. Inclusion criteria did not defined interval between respiratory worsening and first BM-MSC infusion. Four patients had chronic phase of COVID-19 without inflammatory markers and hypercapnia. It could be related to severity of pulmonary disease, such as reported in chronic obstructive pulmonary disease. Two patients were discharged after MSC treatment and they received methylprednisolone to treat cryptogenic organizing pneumonia. There are only a few clinical trials and observational studies evaluating the use of high-dose of glucocorticoid for severe COVID-19 pneumonia. Therefore, it is not possible to conclude that use of glucocorticoid has contributed to favorable outcomes. In conclusion, BM-MSC showed to be a secure therapeutic option for severe COVID-19 pneumonia, possibly with superior benefit in acute phases and lower PCO2 levels. Further studies involving a large cohort or randomized controlled trials are warranted. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Convalescent plasma transfusion for COVID-19: Impact of neutralizing antibodies on respiratory outcomes

Background/Case Studies: In the past months, convalescent plasma (CP) has been used as an alternative therapy to treat COVID-19 patients. Previous studies highlighted the role of neutralizing antibody titers (NAbs) on clinical improvements. We analysed a series of cases of COVID patients treated with CP transfusion and associations between transfused NAbs and patient NAbs on respiratory outcomes. Study Design/Methods: Thirty patients diagnosed with SARS-CoV-2 by RT PCR and severe pneumonia were prospectively analysed at a single center in Brazil. Doses of 300-600ml of CP were transfused. To assess respiratory outcomes, PaO2/FiO2 ratios were determined at Day 0 (day of CP transfusion), Day 5 and by discharge and duration of ventilation support were analysed. Improvements were determined by variations of PaO2/ FiO2 ratios from Day 0 through day 5 (V0-5) and from Day 0 through discharge (V0-D). Neutralizing antibodies from patients prior to transfusion (NAbsP) and neutralizing antibodies of CP units transfused (NAbsCP) were analysed. NAbsCP considers the total amount of antibodies transfused to account for volume differences. We performed a generalized estimating equations (GEE) approach with logit link for binary data to model the effect of Nabs CP and variations on PaO2/FiO2 ratios between Day 0-Day 5 and Day 0-discharge. Regression models were performed to determine the predictive variables associated to improvements on PaO2/FiO2 ratios and duration of ventilation support. Results/Findings: Variations of PaO2/FiO2 ratios from day 0 through Day 5 and day 0 through discharge are displayed on Table 1. Significant improvements on PaO2/ FiO2 ratios were observed from Day 0 through discharge (p<0.001). NAbsP were associated to higher improvements on PaO2/FiO2 on V0-D (mean difference (MD)): 2.8 CI 95% -1.0-4.6 p 0.003), NAbsCP, however, were associated to minor variations in PaO2/FiO2 (MD -4.8 CI95% -7.9;-1.7 p 0.002) on the same interval. At each 100 unit increase in NAbs CP, variations on PaO2/FiO2 on V0-D were expected to be 4.8 units lower. When analysing V0-5, NAbsCP were again associated to minor improvements of PaO2/FiO2 ratios from D0 through D5 (MD -3.6 95%CI -7.2;-0.003 p 0.05). Other variables did not show statistical significance. When considering duration of ventilation support neither NabsP (Mean Ratio MR 0.985 CI 95% 0.962-1.007 p 0.185) nor NAbsCP (MR 0.967 CI95% 0.918 1.018 p 0.198) showed significant statistical differences. Conclusions: In our analysis, NAbs produced from the patient prior to CP transfusion are associated to better improvements on respiratory outcomes when compared to NAbs from transfused units. Regarding duration of mechanical ventilation, neither NAbsP nor Nabs CP had impact on outcomes.

Predictive factors for intensive care unit length of stay in COVID-19 patients treated with convalescent plasma

Background/Case Studies: Convalescent plasma (CP) has emerged in the past months as an alternative treatment for COVID-19. We prospectively analysed the outcomes of critically ill COVID-19 patients treated with CP in order to investigate predictive factors of intensive care unit (ICU) length of stay at a single center in Brazil. Study Design/Methods: Thirty COVID-19 patients laboratory-confirmed by RTPCR with severe pneumonia were recruited at a single center in Brazil. Doses of 300-600ml of CP were administered. Primary outcomes were ICU length of stay and duration of mechanical ventilation support.The following variables were analysed: Severity organ failure assessment score(SOFA) at day 0 (day of CP transfusion), patient ABO blood group, concomitant use of any other therapies (hydroxychloroquine, azythromicin, tocilizumab, immunoglobulin), neutralizing antibody titers of the patients prior to transfusion (NAbsP) and total titers of neutralizing antibody from CP units transfused (NAbsCP). NAbsCP considers the total amount of antibodies transfused to account for volume differences. Multivariate logistic regression was performed. Results/Findings: In our case series, SOFA at day 0, ABO group, and both NAbs P and NAbsCP were predictive factors of ICU length of stay. At each point increased in SOFA, ICU length of stay was 38.7% longer (MR: 1.387 CI 95% 1.254-1.534, p<0.001). Group A had36.1% longer ICU length of stay (MR: 0.639 CI 95% 0.417-0.980, p 0.04). Increases of 100 units in NAbsP resulted in 1% reduction of ICU lenght of stay (MR 0.990 CI 95% 0.982-0.998, p 0.017). Similar results were obtained with NAbs-CP, with 2% reduction in ICU length of stay (MR 0.980 CI95% 0.968-0.993, p 0.002) at each 100 unit increase. Use of other therapies did not influence ICU lenght of stay (p 0.373). We perform the same analysis for duration of mechanical ventilation support, and all the variables failed to demonstrate any association Conclusions: Our findings suggest that severity of disease prior to transfusion, ABO group, patient capacity to produce neutralizing antibodies and transfusion of CP with high titer NAbs are significant predictive factors for ICU length of stay. High titer NAbs CP may add benefit to these patients. No association was found between these same variables and duration of mechanical ventilation.

Anti-A and SARS-CoV-2: An intriguing association

Background/Case Studies: It is not clear which individual characteristics can determine susceptibility and intensity of symptoms, however, age, sex, ethnicity, hypertension and some haematological biomarkers, as Ddimer, thrombocytopenia and lymphopenia were associated with a worse outcome. Recently, it has been hypothesized that ABO blood groups can be related to susceptibility to the SARS-CoV-2 infection. Considering that the first studies reported A group as a risk factor and O group as a protection, some authors have been suggesting that the anti-A antibodies, and not the blood group, could be responsible for the findings. Study Design/Methods: A retrospective study with 430 COVID-19 individuals (268 COVID-19 convalescent plasma donors-CCPD and 162 COVID-19 inpatients-CIP) from two Brazilian reference hospitals, confirmed by RTPCR, and 2,212 healthy volunteer blood donors (VBD) as control group, that were evaluated and divided into two groups: one with anti-A (O/B blood groups) and one without anti-A group (A/AB blood groups). Immunoglobulins and neutralizing antibody titres were measured for CCPD and CIP. Multivariate logistic regression and nonparametric tests were performed. Results/Findings: Although O blood group was the most frequent ABO group among VBD, A blood group was more frequent among COVID-19 individuals (CCPD 47.8%, CIP 43.2%, VBD 35.5%, p<0.001). There was no statistical difference in blood groups distribution between CCPD and CIP (p=0.268). In our cohort, for each increased age year there was 6% more chance for COVID-19 (OR: 1.06;CI 95%: 1.05-1.06, p<0.001), males showed 27% more chance for the disease (OR: 1.27;CI 95%:1.02-1.59, p=0.035) and O/B blood groups showed 38% less infection prevalence (OR: 0.62;CI 95%: 0.5-0.7, p<0.001). Considering the fact that higher anti-A is usually described in the O blood group, data from O versus B blood groups individuals were analysed and the former showed 34% less chance for COVID-19 (OR: 0.66;CI 95%:0.46-0.95, p=0.026). There was no difference regarding ABO group found when COVID-19 inpatients of all blood types were analysed. Immunoglobulins A, M and G (IgA, IgM and IgG) and neutralizing antibodies (NAbs) for SARS-CoV-2 were lower in COVID-19 individuals O/B blood groups (NAbs p=0.008, IgM p=0.03, IgG p=0.02, IgA p=0.03). Conclusions: In our retrospective cohort, the COVID-19 individuals O/B blood groups (which produces anti-A) had 38% less chance to have a diagnosis of COVID-19 (p<0.001) and the same groups showed lower titers of neutralizing antibodies, IgM, IgG and IgA. Groups O/B showed a protective factor against the SARS-CoV-2 infection, but it was not associated to COVID-19 inpatients (versus COVID-19 convalescent plasma donors) suggesting that blood type is not associated to SARSCoV- 2 infection severity.