Late events after anti-CD19 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma.

Background: The short-term complications from chimeric antigen receptor T-cell therapy (CART) are well characterized, but the long-term complications still need to be further investigated. Therefore, herein, we will review the currently available literature published on the late adverse events following CART. Methods: We reviewed published data available from pivotal trials and real-world experiences with anti-CD19 CART (CART19) for adults with lymphoma. We defined late events as occurring or persisting beyond 1 month after CART infusion. We focused our literature review on the following late-event outcomes post-CART19: cytopenia, immune reconstitution, infections, and subsequent malignancies. Results: Grade 3-4 cytopenia beyond 30 days occurs in 30%-40% of patients and beyond 90 days in 3%-22% of patients and is usually managed with growth-factor and transfusion support, along with neutropenic prophylaxis. B-cell aplasia and hypogammaglobulinemia are expected on-target off-tumor effects of CART19, 44%-53% of patients have IgG < 400 mg/dL, and approximately 27%-38% of patients receive intravenous immunoglobulin (IVIG) replacement. Infections beyond the initial month from CART19 are not frequent and rarely severe, but they are more prevalent and severe when patients receive subsequent therapies post-CART19 for their underlying disease. Late neurotoxicity and neurocognitive impairment are uncommon, and other causes should be considered. T-cell lymphoma (TCL) after CART is an extremely rare event and not necessarily related to CAR transgene. Myeloid neoplasm is not rare post-CART, but unclear causality given heavily pretreated patient population is already at risk for therapy-related myeloid neoplasm. Conclusion: CART19 is associated with clinically significant long-term effects such as prolonged cytopenia, hypogammaglobulinemia, and infections that warrant clinical surveillance, but they are mostly manageable with a low risk of non-relapse mortality. The risk of subsequent malignancies post-CART19 seems low, and the relationship with CART19 and/or prior therapies is unclear; but regardless of the possible causality, this should not impact the current benefit-risk ratio of CART19 for relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).

Tuberculosis extrapulmonar: Presentación atípica de compromiso de la médula ósea / Extrapulmonary Tuberculosis: Unusual Presentation with Bone Marrow Involvement

RESUMEN La primera causa de muerte por enfermedad infecto-contagiosa a nivel mundial es atribuible a la infección por Mycobacterium tuberculosis. La tuberculosis extrapulmonar representa entre un 20 % y un 25 % de los casos de enfermedad tuberculosa. Frecuentemente, para arribar al diagnóstico de dichas localizaciones, se debe recurrir a pruebas diagnósticas invasivas Se presenta el caso de un paciente de 17 años de edad con compromiso extrapulmo nar de tuberculosis en médula ósea sin inmunocompromiso conocido, con síntomas de fiebre, astenia, pérdida de peso, tricitopenia y hepatoesplenomegalia, sin otros hallazgos clínicos significativos. Se arriba al diagnóstico por cultivo positivo para tuberculosis en material de punción/ biopsia de médula ósea. Luego de un mes de tratamiento con isoniacida, pirazinamida, etambutol y rifampicina evoluciona con registros febriles aún después de recibir antibióticos por infección urinaria por Klebsiella pneumoniae, por lo cual se inicia corticoterapia oral con buena respuesta. El paciente abandona el tratamiento luego de tres meses y medio por mala adherencia a este.

ABSTRACT The leading cause of death from a contagious infectious disease worldwide is attribut able to Mycobacterium tuberculosis infection. Extrapulmonary tuberculosis accounts for 20-25 % of cases of tuberculous disease. Frequently, in order to reach the diagnosis of these sites, invasive diagnostic tests have to be used. We present the case of a 17-year-old patient with extrapulmonary tuberculosis with bone marrow involvement. The patient wasn't immunocompromised, and had the following symptoms: fever, asthenia, weight loss, tricytopenia and hepatosplenomegaly, without other significant clinical findings. The diagnosis was reached by positive culture for tuberculosis in bone marrow puncture aspiration/biopsy material After one month of treatment with isoniazid, pyrazinamide, ethambutol and rifampicin, the patient evolved with fever episodes, even after having received antibiotics for urinary tract infection caused by Klebsiella pneumoniae. Thus, oral corticosteroid therapy was started, with good response. The patient discontinued treatment after three and a half months due to poor adherence.

Are accessory spleen screening and resection in refractory immune cytopenia an effective strategy or a waste of resources?

Splenectomy remains an effective treatment for refractory immune cytopenia (RIC), which encompasses immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA). Accessory spleens (AS) have been described without identifying specific risk factors. We retrospectively analyzed patients with RIC after splenectomy who underwent splenic scintigraphy (SS) at our institution. Seventy-one patients were included. Sixty-two patients had ITP, five had AIHA, and four had Evans syndrome. Seventy-five percent (n = 53) were women. Eleven patients (15.5%) had an AS detected by SS. A complete response (CR) to first-line steroids (odds ratio (OR) 5.75, 95% confidence interval (CI) 1.37-24.14, p = 0.017) and the absence of Howell-Jolly bodies (HJB) in peripheral blood smear (PBS) (OR 11.37, 95% CI 2.70-47.85, p = 0.001) were found to be risk factors. Patients with both elements had a higher rate of AS (83.3%) when compared to those with one or no factors (p < 0.001). Eight patients (73%) underwent an accessory splenectomy: seven (87.5%) achieved a CR, and none had perioperative complications. The presence of HJB in PBS changed from 25 to 87.5% after accessory splenectomy. We recommend the search for an AS via SS in patients with RIC due to ITP, who had a CR to corticosteroids and the absence of HJB in PBS. Accessory splenectomy is a safe and effective procedure.

Hemophagocytic lymphohistiocytosis: presentation and outcome of twenty-one patients at a single institution

ABSTRACT Introduction: Hemophagocytic lymphohistiocytosis comprises a systemic hyperactivation of macrophages that requires prompt recognition of symptoms and early treatment. Objective and Method: In this context, we described clinical and laboratory characteristics, therapeutic modality and outcome of 21 patients with HLH treated at a pediatric oncology hospital between January 2000 and February 2019. Results: HLH mainly affected females, fever was the most frequent clinical sign and hyperferritinemia was the most prevalent laboratory abnormality. All patients were admitted to the intensive care unit (ICU) at some point. Fifteen (71.4%) patients presented resolution criteria and eight (53.3%) of them presented reactivation. The mortality rate was 57.1% and the mean time between diagnosis and death was 9.98 months. The 5-year overall survival (OS) was 36.7%. We observed a significant difference in prognosis associated with reactivation of HLH. These patients demonstrated an estimated 5-year OS of 25%, while all patients that did not reactivate were alive until the end of the follow-up. Conclusion: In conclusion, HLH is a rare disease with a high mortality rate, especially in patients with disease reactivation and those with familial- or immunodeficiency-associated forms, which makes early recognition and genetic testing crucial for appropriate management and prompt SCT indication.

Hemophagocytic lymphohistiocytosis: presentation and outcome of twenty-one patients at a single institution.

INTRODUCTION: Hemophagocytic lymphohistiocytosis comprises a systemic hyperactivation of macrophages that requires prompt recognition of symptoms and early treatment. OBJECTIVE AND METHOD: In this context, we described clinical and laboratory characteristics, therapeutic modality and outcome of 21 patients with HLH treated at a pediatric oncology hospital between January 2000 and February 2019. RESULTS: HLH mainly affected females, fever was the most frequent clinical sign and hyperferritinemia was the most prevalent laboratory abnormality. All patients were admitted to the intensive care unit (ICU) at some point. Fifteen (71.4%) patients presented resolution criteria and eight (53.3%) of them presented reactivation. The mortality rate was 57.1% and the mean time between diagnosis and death was 9.98 months. The 5-year overall survival (OS) was 36.7%. We observed a significant difference in prognosis associated with reactivation of HLH. These patients demonstrated an estimated 5-year OS of 25%, while all patients that did not reactivate were alive until the end of the follow-up. CONCLUSION: In conclusion, HLH is a rare disease with a high mortality rate, especially in patients with disease reactivation and those with familial- or immunodeficiency-associated forms, which makes early recognition and genetic testing crucial for appropriate management and prompt SCT indication.

Autoinflammatory and autoimmune conditions at the crossroad of COVID-19.

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.

A Prospective Study of Hematologic Complications and Long-Term Survival of Italian Patients Affected by Shwachman-Diamond Syndrome.

OBJECTIVE: To describe the hematologic outcome and long-term survival of patients enrolled in the Shwachman-Diamond syndrome Italian Registry. STUDY DESIGN: A retrospective and prospective study of patients recorded in the Shwachman-Diamond syndrome Italian Registry. RESULTS: The study population included 121 patients, 69 males and 52 females, diagnosed between 1999 and 2018. All patients had the clinical diagnosis confirmed by mutational analysis on the SBDS gene. During the study period, the incidence of SDS was 1 in 153 000 births. The median age of patients with SDS at diagnosis was 1.3 years (range, 0-35.6 years). At the first hematologic assessment, severe neutropenia was present in 25.8%, thrombocytopenia in 25.5%, and anemia in 4.6% of patients. A normal karyotype was found in 40 of 79 patients, assessed whereas the most frequent cytogenetic abnormalities were isochromosome 7 and interstitial deletion of the long arm of chromosome 20. The cumulative incidence of severe neutropenia, thrombocytopenia, and anemia at 30 years of age were 59.9%, 66.8%, and 20.2%, respectively. The 20-year cumulative incidence of myelodysplastic syndrome/leukemia and of bone marrow failure/severe cytopenia was 9.8% and 9.9%, respectively. Fifteen of 121 patients (12.4%) underwent allogeneic stem cell transplantation. Fifteen patients (12.4%) died; the probability of overall survival at 10 and 20 years was 95.7% and 87.4%, respectively. CONCLUSIONS: Despite an improvement in survival, hematologic complications still cause death in patients with SDS. Further studies are needed to optimize type and modality of hematopoietic stem cell transplantation and to assess the long-term outcome in nontransplanted patients.

Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells.

CD19-targeted chimeric antigen receptor-modified T cell (CAR-T cell) therapy has shown excellent antitumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy remain unknown. Here we report late adverse events-defined as starting or persisting beyond 90 days after CAR-T cell infusion-in patients who survived at least 1 year after therapy. The median duration of follow-up was 28.1 months (range, 12.5 to 62.6 months). At last follow-up, 73% of patients were still alive and 24% were in ongoing complete remission (CR). The most common late adverse event was hypogammaglobulinemia (IgG <400 mg/dL or i.v immunoglobulinm (IVIG) replacement, observed in 67% of the patients with available data. Infection density was .55 infection/100 days at risk (2.08 per patient-year). The majority (80%) of the infections were treated in the outpatient setting, and 5% necessitated admission to the intensive care unit (ICU). Subsequent malignancies occurred in 15% of patients, including 5% with myelodysplastic syndrome (MDS). Among patients with ongoing CR and with no MDS, 16% experienced prolonged cytopenia requiring transfusions or growth factor support. Graft-versus-host disease occurred in 3 of 15 patients (20%) who had undergone previous allogeneic hematopoietic cell transplantation. Most of the late events observed in this cohort were not severe, and many could be related to previous or subsequent therapies, suggesting a safe long-term profile of CD19-targeted CAR-T cell immunotherapy.

Inmunodeficiencias primarias y citopenias / Primary immunodeficiencies and cytopenias

Introducción: La visión actual de las enfermedades por inmunodeficiencia primaria (IDP) incluye un número creciente de síndromes que están asociados con la desregulación inmune y la autoinmunidad como características predominantes. Las citopenias autoinmunes pueden ser el primer signo de desregulación que precede a la presentación clásica de inmunodeficiencia primaria, con infecciones recurrentes u oportunistas. El conocimiento de un espectro de enfermedades potencialmente involucradas (hematológicas, reumatológicas e inmunológicas) es crucial para la identificación de una cierta proporción de genotipos y fenotipos de otros diagnósticos descritos. También permitirá excluir desórdenes como lupus eritematoso sistémico, inmunodeficiencia variable común, síndrome linfoproliferativo autoinmune; así como realizar diagnósticos diferenciales noveles como la deficiencia de GATA2, deficiencia de CD27, deficiencia de sensibilidad a lipopolisacáridos, síndrome fosfoinositol-3-quinasa delta activada, inmunodeficiencia ligada a X con déficit de magnesio y otros. Objetivo: Proporcionar una sinopsis conceptual de la aparición de citopenias en las IDP con el propósito de actualizar el conocimiento actual sobre dicho tema y de aumentar la percepción, tanto de hematólogos como inmunólogos, en relación a la presentación de citopenias como manifestación de estas enfermedades. Métodos: Se revisaron artículos originales y de corte experimental publicados en la década 2009 - 2019, en algunas bases de datos de la Biblioteca Virtual de Salud (BVS) de Cuba. Conclusiones: Al igual que las formas benignas autolimitadas de citopenia autoimmune post o parainfecciosas, o la neutropenia autoimmune adquirida de la infancia, que generalmente ocurren independientemente de una IDP subyacente reconocida, muchas de las citopenias que acompañan a esta enfermedad (pero no todas) están mediadas por autoanticuerpos. Es esencial entonces, que los médicos valoren, ante la evidencia clara de citopenia, que esta puede ser autoinmune(AU)

Introduction: The current view of primary immunodeficiency diseases (IDP) includes an increasing number of syndromes that are associated with immune dysregulation and autoimmunity as predominant characteristics. Autoimmune cytopenias may be the first sign of dysregulation that precedes the classic presentation of primary immunodeficiency, with recurrent or opportunistic infections. The knowledge of a spectrum of potentially involved diseases (hematological, rheumatological and immunological) is crucial for the identification of a certain proportion of genotypes and phenotypes of other diagnoses described. It will also allow excluding disorders such as systemic lupus erythematosus, common variable immunodeficiency, autoimmune lymphoproliferative syndrome; as well as making novel differential diagnoses such as GATA2 deficiency, CD27 deficiency, lipopolysaccharide sensitivity deficiency, activated delta phosphoinositol-3-kinase syndrome, X-linked immunodeficiency with magnesium deficiency and others. Objective: This review provides a conceptual synopsis of the appearance of cytopenias in the IDPs with the purpose of updating current knowledge on this topic and increasing the perception, of both hematologists and immunologists, in relation to the presentation of cytopenias as manifestation of these diseases. Methodos: Original and experimental articles published in the 2009-2019 decade were reviewed in some databases of the Virtual Health Library (VHL) of Cuba. Conclusions: As the self-limited benign forms of post or parainfectious autoimmune cytopenia, or childhood acquired autoimmune neutropenia, which generally occur independently of a recognized underlying IDP, many of the cytopenias that accompany this disease (but not all) mediated by autoantibodies. It is essential, then, that doctors assess, given the clear evidence of cytopenia, that it may be autoimmune(AU)

Treatment of autoimmune hemolytic anemia: real world data from a reference center in Mexico.

BACKGROUND: Warm autoimmune hemolytic anemia (w-AIHA) is an uncommon disease with heterogeneous response to treatment. Steroids are the standard treatment at diagnosis, whereas rituximab has recently been recommended as the second-line therapy of choice. Our main objective was to document the response to treatment in patients with newly diagnosed w-AIHA, including the effectiveness of low-dose rituximab as frontline treatment and for refractory disease. METHODS: Patients with w-AIHA from 2002 to 2017 were included. Relapse-free survival (RFS), probability of maintained response (MR), and time-to-response were analyzed using the Kaplan-Meier method. Response was classified as complete, partial, and no response. RESULTS: We included 64 adults with w-AIHA (39 women and 25 men). The median age was 37 (16-77) years. Response rates to steroids alone were 76.7%, rituximab plus steroids, 100%; and cyclophosphamide, 80%. RFS with steroids at 6, 36, and 72 months was 86.3%, 65.1%, and 59.7%, respectively. Eighteen patients received rituximab at 100 mg/wk for 4 weeks plus high-dose dexamethasone as first-line therapy, with RFS at 6, 36, and 72 months of 92.3%, 58.7% and 44.1%, respectively. Eight patients refractory to several lines of therapy were treated with low-dose rituximab, and all achieved a response (three complete response and five partial response) at a median 16 days (95% confidence interval, 14.1-17.8), with a 75% probability of MR at 103 months; the mean MR was 81.93±18 months. CONCLUSION: Outcomes of w-AIHA treatment were considerably heterogeneous. Low rituximab doses plus high dexamethasone doses were effective for refractory disease.

Quantitative analysis of bone marrow in pancytopenic dogs / Análise quantitativa de medula óssea em cães pancitopênicos

The pancytopenia can be associated with intra and extra medullary disorders. When the etiology is not obvious, the examination of bone marrow is necessary. The study aims to report and discuss quantitative amendments in bone marrow and their causes in dogs with pancytopenia. Bone marrow aspirate was obtained from 65 dogs with pancytopenia over a period of 13 consecutive months for preparation of smears stained by Giemsa and observed in light microscopy. Five hundred cells differential count was held; and assessed myeloid:erythroid ratio, cellularity, megakaryocytes and direct parasitological examination. The data were evaluated by the Chi-square statistical test. Blood tests of 3120 canines with several clinical changes were analyzed to identify pancytopenia, which accounted for 167 (5.4%) dogs. Interpretation of quantitative characteristics was carried out from the bone marrow smear in 65 pancytopenic dogs and the etiology was established in 40 (61.5%) of these, which included infection by E. canis and L. chagasi, idiopathic aplastic anemia, chronic renal failure and co-infections. In 17 (26.2%) animals were not observed medullary changes. The most bone marrow change was observed myeloid and erythroid hypoplasia in 17 (26.2%) dogs, followed by myeloid and erythroid hyperplasia (24.6%). The myelogram association to the blood cell count allowed the identification of medullary findings and its participation on the occurrence of pancytopenia cases. The number of cases resulting from infectious diseases was 38 (58.5%) in canine assessed: significant number due to its endemic characteristic of the study region.

A pancitopenia pode estar associada a distúrbios intra e extra medulares. Quando a etiologia não é óbvia, o exame da medula óssea é necessário. Este estudo tem como objetivo relatar e discutir alterações quantitativas na medula óssea e suas causas em cães com pancitopenia. De 65 cães pancitopêncicos atendidos durante um período de 13 meses consecutivos, foram realizados aspirados de medula óssea, corados com Giemsa, e observados em microscopia de luz. Quinhentas células foram observadas para contagem diferencial, razão mieloide: eritróide, celularidade, megacariócitos e exame parasitológico direto. Os dados foram avaliados pelo teste estatístico Qui-quadrado. Hemograma de 3120 caninos com diversas alterações clínicas foram analisadas para identificar a pancitopenia, encontrada em 167 (5,4%) cães. A interpretação das características quantitativas foi realizada a partir do esfregaço de medula óssea em 65 cães pancitotopênicos e a etiologia foi estabelecida em 40 (61,5%), incluindo infecção por E. canis e L. chagasi, anemia aplástica idiopática, insuficiência renal crônica e co-infecções. Em 17 (26,2%) cães não foram observadas alterações medulares. A alteração de medula óssea mais observada foi a hipoplasia mielóide e eritróide em 17 (26.2%) cães, seguido pela hiperplasia mielóide e eritróide (24.6%). A associação do mielograma ao hemograma permitiu a identificação de achados medulares e sua participação na ocorrência de casos de pancitopenia. O número de casos resultantes de doenças infecciosas foi de 38 (58,5%) em caninos avaliados: número significativo devido à característica endêmica da região do estudo.

Quantitative analysis of bone marrow in pancytopenic dogs / Análise quantitativa de medula óssea em cães pancitopênicos

The pancytopenia can be associated with intra and extra medullary disorders. When the etiology is not obvious, the examination of bone marrow is necessary. The study aims to report and discuss quantitative amendments in bone marrow and their causes in dogs with pancytopenia. Bone marrow aspirate was obtained from 65 dogs with pancytopenia over a period of 13 consecutive months for preparation of smears stained by Giemsa and observed in light microscopy. Five hundred cells differential count was held; and assessed myeloid:erythroid ratio, cellularity, megakaryocytes and direct parasitological examination. The data were evaluated by the Chi-square statistical test. Blood tests of 3120 canines with several clinical changes were analyzed to identify pancytopenia, which accounted for 167 (5.4%) dogs. Interpretation of quantitative characteristics was carried out from the bone marrow smear in 65 pancytopenic dogs and the etiology was established in 40 (61.5%) of these, which included infection by E. canis and L. chagasi, idiopathic aplastic anemia, chronic renal failure and co-infections. In 17 (26.2%) animals were not observed medullary changes. The most bone marrow change was observed myeloid and erythroid hypoplasia in 17 (26.2%) dogs, followed by myeloid and erythroid hyperplasia (24.6%). The myelogram association to the blood cell count allowed the identification of medullary findings and its participation on the occurrence of pancytopenia cases. The number of cases resulting from infectious diseases was 38 (58.5%) in canine assessed: significant number due to its endemic characteristic of the study region.(AU)

A pancitopenia pode estar associada a distúrbios intra e extra medulares. Quando a etiologia não é óbvia, o exame da medula óssea é necessário. Este estudo tem como objetivo relatar e discutir alterações quantitativas na medula óssea e suas causas em cães com pancitopenia. De 65 cães pancitopêncicos atendidos durante um período de 13 meses consecutivos, foram realizados aspirados de medula óssea, corados com Giemsa, e observados em microscopia de luz. Quinhentas células foram observadas para contagem diferencial, razão mieloide: eritróide, celularidade, megacariócitos e exame parasitológico direto. Os dados foram avaliados pelo teste estatístico Qui-quadrado. Hemograma de 3120 caninos com diversas alterações clínicas foram analisadas para identificar a pancitopenia, encontrada em 167 (5,4%) cães. A interpretação das características quantitativas foi realizada a partir do esfregaço de medula óssea em 65 cães pancitotopênicos e a etiologia foi estabelecida em 40 (61,5%), incluindo infecção por E. canis e L. chagasi, anemia aplástica idiopática, insuficiência renal crônica e co-infecções. Em 17 (26,2%) cães não foram observadas alterações medulares. A alteração de medula óssea mais observada foi a hipoplasia mielóide e eritróide em 17 (26.2%) cães, seguido pela hiperplasia mielóide e eritróide (24.6%). A associação do mielograma ao hemograma permitiu a identificação de achados medulares e sua participação na ocorrência de casos de pancitopenia. O número de casos resultantes de doenças infecciosas foi de 38 (58,5%) em caninos avaliados: número significativo devido à característica endêmica da região do estudo.(AU)

Influence of TNF and IL6 gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematologic disorders characterized by cytopenia(s) and predisposition to leukemic progression. An immune dysregulation and an aberrant bone marrow microenvironment seem to be key elements in the physiopathological process of MDS. In order to evaluate a possible association between susceptibility and clinic-pathologic features, we genotyped 153 MDS patients for functional cytokine polymorphisms: TNF (-308 G/A), IFNG (+874 A/T and +875 CAn), IL6 (-174 G/C), and TGFB1 (+869 C/T and +915 G/C). The frequency of TNF and IL6 polymorphisms was different between patients and healthy controls (n = 131), suggesting a relatedness to MDS susceptibility in our population. Furthermore, the presence of each or both high-producing genotypes [TNF: p = 0.048, odds ratio (OR): 3.979; IL6: p = 0.001, OR: 6.835; both: p = 0.010, OR: 6.068] and thrombocytopenia at platelet counts of <50,000/µL (p = 0.004, OR: 4.857) were independently associated with an increased risk of manifesting a hemoglobin level of <8 g/dL at diagnosis. In particular, a severe bicytopenia was more frequently observed in patients with the TNF (high)_IL6 (high) combined genotype (p = 0.004, OR: 8.357), who consistently became transfusion dependent earlier (2.9 vs. 34.6 months; p = 0.001); and this likelihood was more evident in patients with lower bone marrow blast counts. The contribution of the remaining functional polymorphisms to the disease phenotype was less relevant. Our results demonstrate that TNF and IL6 gene polymorphisms, as underlying host features, are likely to play a key role in influencing the severity of the cytopenias in MDS and they may be instrumental for tailoring cytokine-target therapies.

Increased serum alkaline phosphatase in a FeLV-positive cat

Background: Feline Leukemia Virus (FeLV) is an oncogenic virus that usually invades bone marrow causing non-regenerative anemia and thrombocytopenia. In FeLV positive cats, the myeloid leukemia is characterized by intense proliferation of blast cells in a bone marrow with myeloid precursor predominance and several malignancies degree. The leukocyte alkaline phosphatase is found secondary granules of mature neutrophils of humans, horses and cows but not in dogs and cats, which demonstrate the enzyme activity in myeloblast and promyeloblasts cells. In this case is describing a FeLV-positive case with leukemic disorder accompanied by extremely high levels of serum alkaline phosphatase. Case: A 8-year-old castrated male Domestic Short Hair cat with a 3-month history of convulsions, pica, vomits, lethargy, hypodipsia and anorexia was examined and showed mild dehydration, severe jaundice and hyperpnoea. Laboratory results evidenced severe normocytic hypochromic non-regenerative anemia, moderated leukocytosis with severe degenerative neutrophil left shift, moderated lymphocytosis and severe thrombocytopenia. Serum biochemical profile showed mild hyperalbuminemia, moderated increment in alanine transaminase and severe increment in alkaline phosphatese. The cat was positive for ELISA point of care FeLV antigen and negative for FIV antibodies. Urinalysis revealed moderated bilirubinuria [...]

Increased serum alkaline phosphatase in a FeLV-positive cat

Background: Feline Leukemia Virus (FeLV) is an oncogenic virus that usually invades bone marrow causing non-regenerative anemia and thrombocytopenia. In FeLV positive cats, the myeloid leukemia is characterized by intense proliferation of blast cells in a bone marrow with myeloid precursor predominance and several malignancies degree. The leukocyte alkaline phosphatase is found secondary granules of mature neutrophils of humans, horses and cows but not in dogs and cats, which demonstrate the enzyme activity in myeloblast and promyeloblasts cells. In this case is describing a FeLV-positive case with leukemic disorder accompanied by extremely high levels of serum alkaline phosphatase. Case: A 8-year-old castrated male Domestic Short Hair cat with a 3-month history of convulsions, pica, vomits, lethargy, hypodipsia and anorexia was examined and showed mild dehydration, severe jaundice and hyperpnoea. Laboratory results evidenced severe normocytic hypochromic non-regenerative anemia, moderated leukocytosis with severe degenerative neutrophil left shift, moderated lymphocytosis and severe thrombocytopenia. Serum biochemical profile showed mild hyperalbuminemia, moderated increment in alanine transaminase and severe increment in alkaline phosphatese. The cat was positive for ELISA point of care FeLV antigen and negative for FIV antibodies. Urinalysis revealed moderated bilirubinuria [...](AU)

TET2 expression level and 5-hydroxymethylcytosine are decreased in refractory cytopenia of childhood.

Myelodysplastic syndromes (MDS) are myeloid malignancies characterized by ineffective hematopoiesis, dysplasia, peripheral cytopenia and increased risk of progression to acute myeloid leukemia. Refractory cytopenia of childhood (RCC) is the most common subtype of pediatric MDS and has overlapping clinical features with viral infections and autoimmune disorders. Mutations in TET2 gene are found in about 20-25% of adult MDS and are associated with a decrease in 5-hydroxymethylcytosine (5-hmC) content. TET2 deregulation and its malignant potential were reported in adult but not in pediatric MDS. We evaluated the gene expression and the presence of mutations in TET2 gene in 19 patients with RCC. TET2 expression level was correlated with 5-hmC amount in DNA and possible regulatory epigenetic mechanisms. One out of 19 pediatric patients with RCC was a carrier of a TET2 mutation. TET2 expression and 5-hmC levels were decreased in patients when compared to a disease-free group. Lower expression was not associated to the presence of mutation or with the status of promoter methylation, but a significant correlation with microRNA-22 expression was found. These findings suggested that TET2 downregulation and low levels of 5-hmC are inversely related to miR-22 expression. The existence of a regulatory loop between microRNA-22 and TET2 may play a role in MDS pathogenesis.

Síndrome de activación macrofágica idiopática en una mujer jóven / Idiopathic macrophage activation syndrome in a young woman

RESUMEN Se presenta el caso de una mujer de 27 años, con datos clínicos de síndrome de activación macrofágica (SAM), de etiología desconocida, con evolución tórpida y desfavorable que llega al fallecimiento. Se revisan los principales conceptos y características del SAM, haciendo énfasis en las actuales normas de consenso y en las variaciones en el tratamiento de acuerdo con las guías internacionales.

ABSTRACT We report the case of a 27 year old woman with clinical evidence of macrophage activation syndrome (MAS) of unknown etiology and unfavorable torpid comes to death. We review the main concepts and features of the SAM, the current emphasis on consensus standards and changes in treatment according to international guidelines.

Síndrome de ativação macrofágica secundária à infecção aguda pelo vírus Epstein-Barr: [relato de caso] / Macrophage activation syndrome triggered by Epstein-Barr virus: [case report]

A síndrome de ativação macrofágica (SAM) ou síndrome hemofagocítica secundária (reativa) consiste de uma rara, grave e potencialmente fatal complicação das doenças reumáticas crônicas, particularmente da artrite idiopática juvenil de início sistêmico, doença de Still do adulto e lúpus eritematoso sistêmico. É caracterizada pela excessiva ativação dos macrófagos, resultando febre, hepatoesplenomegalia, linfadenomegalia, envolvimento neurológico, graus variáveis de citopenias, hiperferritinemia, distúrbio hepático, coagulação intravascular e freqüente falência de múltiplos órgãos. Também ocorre em associação com neoplasias, imunodeficiências e variedade de agentes infecciosos virais (sobretudo do grupo do herpes), bacterianos e fúngicos. Relatamos um caso de SAM decorrente de infecção viral aguda pelo vírus Epstein-Barr tratado com corticóide oral

The macrophage activation syndrome (MAS) or secondary haemophagocytic syndrome (reactive) is an uncommon, severe and life-threatening complication of chronic rheumatic diseases, especially systemic onset juvenile idiopathic arthritis, adult-onset Still disease and systemic lupus eritematosus. It is characterized by the excessive activation of macrophages, resulting in fever, hepatoesplenomegaly, lymphadenopathy, neurological involvement, variable cytopenias, hyperferritinemia, liver disease, intravascular coagulation, often resulting in fatal multiple organ failure. Besides chronic rheumatic diseases, it is also seen in a heterogeneous group of diseases like neoplasms, imunodeficiencies and viruses (especially the herpes group), bacteria and fungi infections. We describe a case report of one patient with MAS triggered by Epstein-Barr virus infection treated with oral corticosteroid.