Single-center "Argentine" analysis of post-transplant lymphoproliferative disorders: incidence, histopathological characteristics and EBV status

ABSTRACT Introduction: Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations occurring after solid organ or bone marrow transplantation. The primary aims of our study were to characterize cumulative incidence of PTLDs, clinical and pathological features according to the Epstein-Barr virus (EBV) status and survival. Methods: This was a retrospective cohort study on adult and pediatric patients, from January 2001 to December 2017. The cumulative incidence of PTLD was calculated by analyzing all the patients transplanted at our hospital, based on the database of the Organ Donation and Ablation Authority of Argentina (INCUCAI). The Kaplan-Meier method was used to plot the survival. Results: Fifty-eight cases of biopsy-confirmed PTLD were identified and 12 cases of clinical data were incomplete and these patients were excluded. The median age at the time of the PTLD diagnosis was 17.5 years (interquartile range [IQR] 9 - 57). The median interval between transplant and PTLD diagnosis was 39 months (IQR 9 - 113). The most commonly transplanted organ was the liver (24 cases, 52.2%), followed by kidney (20 cases, 43.5%). The Epstein-Barr encoding region in situ hybridization (EBER ISH) was positive in 29 (69.8%) of the 43 evaluable biopsies. The PTLD cumulative incidence was 1.84% (95%CI 1.77 - 1.91) for solid organ and 0.84% (95%CI 0.48 - 1.2) for bone marrow transplant patients. The overall survival rate at 5 years was 0.77 (95%CI 0.61 - 0.87). Subgroups by the EBV EBER status, transplant type, PTLD subtype and age group (adult vs. pediatric) showed no statistically significant association with the overall survival. Conclusion: The PTLD incidence was similar to that of previous series and the EBER did not appear as a relevant factor in our patient survival.

EBER + extranodal NK/T lymphoma in patient with idiopathic CD4 lymphocytopenia / Linfoma T/NK EBER positivo en paciente con linfocitopenia CD4 idiopática

Abstract Idiopathic CD4 lymphocytopenia (ICL) not related to HIV is an infrequent and severe condition with no etiology defined until now. The concomitant presence of an underlying disease, especially an oncohematological process, could be related to the immune physiopathology and the development of the im munosuppressive state. On the other hand, Epstein Barr virus is a well-known oncogenic pathogen described in the development of several types of lymphoma which might be reactivated in the ICL. There is still no specific treatment for this syndrome, so the therapeutic scope for these patients is the treatment of opportunistic diseases and the administration of specific antimicrobials as prophylaxis. We present a patient with an uncommon asso ciation of an ICL and an extranodal T/NK lymphoma with detection of VEB nuclear RNA by in situ hybridization (EBER). Diagnosis was challenging which led the health team to carry out many studies over several months

Resumen La linfocitopenia CD4 idiopática (ICL) no relacionada al HIV es una condición grave e infrecuente sin una etiología aún definida. La presencia de una enfermedad subyacente, especialmente un proceso oncohematológico, podría tener relación en la fisiopatología del proceso inmunológico. Por otro lado, el virus Epstein Barr (VEB) es bien conocido por ser un patógeno oncogénico descrito en el desarrollo de diversos tipos de linfomas, el cual podría ser reactivado en estados de inmunosupresión severa. No existe aún un tratamiento específico para este síndro me, por lo que el objetivo terapéutico en estos pacientes radica en el manejo profiláctico y activo de las distintas enfermedades oportunistas ante las cuales son susceptibles. Se presenta un paciente con un déficit grave de linfocitos CD4 de causa idiopática, y un diagnóstico posterior de linfoma T/NK extraganglionar con detección de RNA nuclear de VEB por hibridización in situ (EBER), una asociación poco descrita en la literatura médica.

Ileítis como presentación de linfoma en síndrome de Wiskott-Aldrich / Ileitis as presentation of lymphoma in Wiskott-Aldrich syndrome

El síndrome de Wiskott-Aldrich (SWA) es un raro síndrome de inmunodeficiencia primaria ligado al cromosoma X que se asocia con aumento de incidencia de infecciones, trastornos autoinmunes y neoplasias. Se presenta el caso de un varón de 41 años con diagnóstico de síndrome de Wiskott-Aldrich y cuadro de ileítis como forma de presentación de un síndrome linfoproliferativo. La ileítis, en el contexto del paciente, representa un problema clínico dado el gran número de diagnósticos diferenciales (enfermedad inflamatoria intestinal, infecciones, neoplasias y enfermedades linfoproliferativas) por lo que suele requerir diagnóstico anatomopatológico y consideraciones particulares respecto al posterior tratamiento específico.

Wiskott-Aldrich syndrome is a rare X chromosome-linked primary immunodeficiency syndrome associated with an increased incidence of infections, autoimmune disorders and neoplasms. We present the case of a 41-year-old man with a diagnosis of Wiskott-Aldrich syndrome with ileitis as a form of presentation of a lymphoproliferative syndrome. The ileitis, in the context of the patient, represents a clinical challenge given the large number of differential diagnoses (inflammatory bowel disease, infections, neoplasms and lymphoproliferative diseases), so it usually requires anatomopathological diagnosis and particular considerations regarding the subsequent specific treatment.

Características clínicas y mortalidad de pacientes adultos con síndrome hemafagocítico, estudio de cohorte retrospectiva / Hemophagocytic lymphohistiocytosis: experience in 27 patients

Background: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation Aim: To describe the clinical characteristics, causes and survival associated with HLH. Material and Methods: Review of medical records of patients with HLH attended between 2004 and 2016. They were classified according to their probable cause in: associated with immunosuppression, cancer, post-infectious or idiopathic. Kaplan-Meier survival analysis was performed. Results: Twenty seven patients with HLH aged 18 to 87 years (59% men), were detected. Fourteen (52%) were secondary to immunosuppression, six (22%) were post-infectious, five (18%) were associated with cancer and two (7%) were of unknown cause. There were no significant differences in clinical or laboratory features between these etiologies. Within the immunosuppressed group, 12 (86%) were patients with oncologic or hematologic diseases or bone marrow transplantation. Associated cancers were mostly oncohematologic diseases. Thirty-day mortality was 53.4% (95% confidence intervals (CI) 32.7-70.3%), despite the treatment. Mortality was significantly associated with the presence of renal failure with a hazard ratio (HR) of 3.4 (95% CI of 1.2-9.9, p =0.025). Treatment of the underlying disease proved to be protective against mortality with an HR of 0.3 (95% CI 0.1 to 0.98, p = 0.046). Conclusions: The prognosis of HLH could be related to the treatment of the underlying disease. The study of the pathophysiology of this syndrome will allow a better understanding and treatment.

Función renal y nivel plasmático de dabigatrán en el valle, medido por un ensayo de trombina diluida / Renal function and plasma dabigatran level measured at trough by diluted thrombin time assay

El dabigatrán etexilato (inhibidor directo de trombina) es eficaz en la prevención tromboembólica en pacientes con fibrilación auricular. No requiere control rutinario de laboratorio, pero dada su eliminación renal, sería importante medirlo ante el deterioro de la función renal. Los objetivos del trabajo fueron verificar la calidad analítica del ensayo tiempo de trombina diluido para medición de la concentración plasmática (cc) de dabigatrán, correlacionar las cc con las pruebas básicas de coagulación tiempo de protrombina (TP) y tiempo de tromboplastina parcial activada (APTT) y evaluarlas de acuerdo al clearance de creatinina (CLCr). Se utilizaron muestras de plasma de 40 pacientes que recibían dabigatrán 150 (n = 19) o 110 (n = 21) mg/12 horas, colectadas 10-14 horas después de la última toma. Los ensayos de trombina diluida HemosIL DTI para la medición de dabigatrán, TP y APTT (IL), fueron realizados en coagulómetros fotoópticos ACL TOP 300 y 500 (IL). El DTI presentó coeficiente de variación intraensayo < 5.4% e interensayo < 6.0%, rango de linealidad 0-493 ng/ml; cc medidas en pacientes: mediana 83 (4-945) ng/ml. Individuos con CLCr en tercil inferior (< 46.1 ml/min) presentaron cc significativamente más elevadas, 308 (49-945), que los de tercilos medio, 72 (12-190), y superior, 60 (4-118) ng/ml. Las correlaciones cc vs. APTT o TP fueron moderadas, r2 = 0.59, -0.66, p < 0.0001, respectivamente. La prueba ensayada permitió cuantificar el nivel de dabigatrán plasmático tanto en pacientes con función renal normal como deteriorada, representando una herramienta útil en situaciones clínicas como deterioro de la función renal, pre cirugía o emergencias.

Dabigatran etexilate (direct thrombin inhibitor) is effective in preventing embolic stroke in patients with atrial fibrillation. It does not require laboratory control, but given the high renal elimination, its measurement in plasma is important in renal failure. The objectives of the study were to verify the analytical quality of the diluted thrombin time assay for measurement of dabigatran plasma concentration (cc), correlate cc with classic coagulation assays, prothrombin time (PT) and activated partial thromboplastin time (APTT), and evaluate them according to the creatinine clearance (CLCr). Forty plasma samples of patients (34 consecutive and 6 suspected of drug accumulation) receiving dabigatran at 150 (n = 19) or 110 (n = 21) mg/12 hours were collected. Blood samples were drawn at 10-14 hours of the last intake. Dabigatran concentration was determined by diluted thrombin time (HemosIl DTI, Instrumentation Laboratory (IL). PT and APTT (IL) were performed on two fotooptical coagulometers, ACL TOP 300 and 500 (IL). DTI presented intra-assay coefficient of variation < 5.4% and inter-assay < 6%, linearity range 0-493 ng/ml. Patients´ cc: median 83 (4-945) ng/ml. Individuals with CLCr in the lowest tertile (22.6-46.1 ml/min) showed significantly higher median cc: 308 (49-945), compared to the average 72 (12-190) and highest tertile, 60 (4-118) ng/ml. Correlation between cc and APTT or PT were moderate, r2 = 0.59 and -0.66, p < 0.0001, respectively. DTI test allowed us to quantify plasma dabigatran levels, both in patients with normal or altered renal function, representing a useful tool in clinical situations such as renal failure, pre surgery or emergencies.

Dabigatran en plasma: tiempos de trombina diluido, Ecarin y veneno de víbora de Russell diluido / Plasma dabigatran: diluted thrombin time, Ecarin and diluted Russell Viper Venom Time / Dabigatrana em plasma: tempos de trombina diluído, Ecarin e veneno de víbora de Russell diluído

Los objetivos del trabajo fueron verificar la calidad analítica del ensayo tiempo de trombina diluido (DTI) para medición de la concentración plasmática (cc) de dabigatran comparando dos coagulómetros de detección foto-óptica, comparar los resultados con el tiempo de Ecarin (ECT) y correlacionar las cc con las pruebas básicas de coagulación Tiempo de protrombina (TP), APTT y Tiempo de trombina (TT), y tiempo de veneno de víbora de Russell con fosfolípidos concentrados (DRVVTC). Se tomaron 43 muestras de plasma en el valle (10-14 h de la última toma) de 40 pacientes que recibían dabigatran. DTI y ECT presentaron (%) repetitividad <5,4% y <7,5%, CV interensayo <6% y <9%, respectivamente, en el protocolo EP15A2, aceptables para un Error Total permitido (TEa) <15%. Las cc medidas en pacientes fueron: mediana 83 (4-945) ng/mL. La comparación de equipos ACL TOP 300 y 500 dio resultados equivalentes por procedimiento alternativo de comparación de métodos. La comparación ECT vs. DTI fue satisfactoria por regresión de Deming (pendiente 1,143, ordenada al origen -19,33). Las correlaciones de cc vs. APTT, TP y DRVVTC fueron moderadas y no lineales tendiendo a plateau a cc>350 ng/mL, r2 0,59, 0,66 y 0,59, respectivamente. El TT fue extremadamente sensible: >120 s a cc 50 ng/mL. DTI presentó un buen desempeño analítico y permitió cuantificar dabigatran plasmático a cc bajas y altas en ambos equipos utilizados. ECT presentó resultados comparables a DTI. Se verifica una correlación moderada entre cc de dabigatran y las pruebas clásicas y DRVVTC, pudiendo ser estimadores de cc a partir de los 50 ng/mL.

The aims of the study were to verify the analytical performance of Dilute Thrombin Time (DTI) test to measure plasma dabigatran concentration (cc) in two photo-optical coagulometers, compare Ecarin clotting Time (ECT) and DTI results, and correlate cc with classical coagulation tests: prothrombin time (PT), APTT, thrombin time (TT) and diluted Russell Viper Venom Time tests with high phospholipid concentration (DRVVTC). Forty three plasma samples from 40 patients taking dabigatran were drown at through (10-14 hs.since last dose). DTI and ECT showed repetitivity (%) <5.4% and <7.5%, interassay CV <6% and <9%, respectively, following EP15A2 protocol, acceptable considering a Allowed Total Error (TEa)<15%. Patients` cc: median 83 (4-945) ng/mL. The comparison between ACL TOP 300 and 500 coagulometers showed equivalent results by using the alternative method comparison test. ECT vs. DTI: acceptable by Deming`s regression (slope 1.143, Y insert -19.33). cc vs. APTT, TP and DRVVTC: nonlinear and moderate correlations with plateau reached at cc >350 ng/mL, r2 0.59, 0.66 y 0.59, respectively. TT is extremely prolonged at cc >50 ng/mL. In conclusion: DTI showed a good analytical performance in both coagulometers. ECT showed comparable results to DTI. We verified that dabigatran cc presented moderate correlations with PT, APTT and DRVVTC, and that these tests could only qualitative estimate cc >50 ng/mL.

Os objetivos do trabalho foram verificar a qualidade analítica do ensaio tempo de trombina diluído (DTI) para medição da concentração plasmática (cc) de dabigatrana, comparando dois coagulômetros de detecção foto-óptica, comparar os resultados com o tempo de Ecarina (ECT) e correlacionar as cc com os testes básicos de coagulação Tempo de protrombina (TP), APTT e Tempo de trombina (TT), e tempo de veneno de víbora de Russell com fosfolipídios concentrados (DRVVTC). Foram tomadas 43 amostras de plasma no vale (10-14 h. da última toma) de 40 pacientes que recebiam dabigatrana. DTI e ECT apresentaram (%) repetitividade <5,4% e <7,5%, CV interensaio <6% e <9%, respectivamente, no protocolo EP15A2, aceitáveis para um Erro Total permitido (TEa) <15%. Cc medidas em pacientes: mediana 83 (4-945) ng/mL. Comparação de equipamentos ACL TOP 300 e 500: resultados equivalentes por procedimento alternativo de comparação de métodos. Comparação ECT vs. DTI: satisfatória por regressão de Deming (pendente 1,143, ordenada à origem -19,33). Correlações cc vs. APTT, TP e DRVVTC: moderadas e não lineares tendendo a plateau a cc>350 ng/mL, r2 0,59; 0,66 e 0,59, respectivamente. O TT é extremamente sensível: >120 s a cc 50 ng/mL. DTI apresentou um bom desempenho analítico e permitiu quantificar dabigatrana plasmática a cc baixas e altas em ambos os equipamentos utilizados. ECT apresentou resultados comparáveis com DTI. Verifica-se uma correlação moderada entre cc de dabigatrana e os testes clássicos e DRVVTC, podendo ser estimadores de cc a partir dos 50 ng/mL.

Variables condicionantes del tratamiento en pacientes añosos con leucemia mieloide aguda: Experiencia institucional / Treatment conditioning variables in elderly patients with acute myeloid leukemia. An institutional experience

Los mayores de 60 años con leucemia mieloide aguda (LMA) tienen peor pronóstico que el resto de los pacientes. En la literatura se expresan diferentes factores que podrían condicionar su supervivencia. Se propuso determinar cuáles fueron los principales determinantes de supervivencia global en nuestra población; y como objetivo secundario cuáles estaban vinculados con mortalidad temprana, entendida la misma como muerte dentro de las ocho semanas de iniciado el tratamiento. Para ello se diseñó un estudio de cohorte retrospectivo que incluyó 133 pacientes no tratados previamente. El análisis ajustado a covariables demostró que las variables de mayor peso para determinar supervivencia global fueron el recuento leucocitario ≥ 30 000 al diagnóstico [HR ajustado 2.19 (1.06-4.53), p = 0.03)] y el estado general (ECOG) 3 o 4 [HRa 4.63 (1.69-12.68), p < 0.001)]. En cuanto a mortalidad relacionada al tratamiento, el estado general (ECOG) 3-4 mostró ser la única variable que mantuvo su poder estadístico en el análisis multivariado con OR ajustado (ORa) 12.40 (IC 1.12-137.17, p = 0.04). El mal resultado inherente a los pacientes añosos con diagnóstico de LMA no se entiende por completo aún. Probablemente la mejor forma de evaluarlos debería tener en cuenta no solo la edad, sino también resultados de laboratorio, de estudios genéticos y moleculares, utilizando índices específicos de comorbilidad, estado general y alguna evaluación geriátrica de fragilidad. Este estudio identificó que la leucocitosis y el mal estado general fueron los factores que mostraron un mayor poder en la predicción de la mortalidad.

Patients over 60 years old with acute myeloid leukemia (AML) have a worse prognosis due to several factors that determine the therapeutic outcome. The main predictors of mortality in patients with AML reported in the literature were analyzed in our population. The primary objective was to analyze overall survival. The secondary objective was to determine treatment-related mortality, defined as death within eight weeks of starting treatment. It was designed as a retrospective study. A total of 133 treatment naive patients were included, from January 1991 to August 2014. The adjusted analysis showed that the most important variables to determine overall survival were the WBC count ≥ 30 000 at diagnosis [adjusted HR 2.19 (1.06-4.53), p = 0.03)] and the Performance Status (ECOG) 3 or 4 [aHR 4.63 (1.69-12.68), p < 0.001)]. Performance Status 3-4 was the only variable that conditioned treatment related mortality, showing in the univariate analysis an OR 5.44 (CI 1.93-15.28, p < 0.001). It was also the only variable that kept its statistical power in the multivariate analysis adjusted OR (aOR) 12.40 (IC 1.12-137.17, p = 0.04). The inherent poor outcome in elderly patients diagnosed with AML is not fully understood. The best way of assessing these elderly patients should probably include not only age but the best way of assessing these elderly patients should probably include not only age but laboratory, genetic and molecular studies. Especially designed comorbidity and fragility indices should be included, along with functional status. Leukocytosis and poor quality of life were identified as the most powerfull factors for predicting mortality in our study.