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Abstract: Posttransplant cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PTCy in HLA-identical HSCT is less explored. We conducted a retrospective study of 107 consecutive patients undergoing an HLA-identical sibling (10/10) HSCT in 2 centers in Spain, 50 with GVHD prophylaxis with methotrexate–cyclosporin A (MTX-CsA) and 57 using a PTCy-based regimen with additional immunosuppression. Graft source was unmanipulated mobilized peripheral blood stem cells (PBSC) in most patients (97 patients, 91%). Cumulative incidences of grade II to IV and III to IV acute GVHD at 100 days were lower in the PTCy group (22.6% vs 52.2%, P = .0015; 8.8% vs 24.4%, P = .016), without statistically significant differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (16.7% vs 26%, P = .306). At 2 years, no statistically significant differences were observed in OS (78% vs 56%, P = .088), EFS (62.5% vs 48%, P = .054), relapse (28% vs 27%, P = .47), and NRM (8.8% vs 24%, P = .054). The composite endpoint of GVHD and relapse-free survival (GRFS) was favorable for the PTCy group (24% vs 48%, P = .011), PTCy being the sole independent factor identified in the multivariate analysis for this endpoint. In this study, PTCy combination with additional immunosuppression using mostly PBSCs grafts showed a reduction of acute GVHD rate and an impact on GRFS, with safety results comparable with those obtained with MTX-CsA. Further prospective studies are needed to confirm these observations..

Abstract: Despite considerable advances in our understanding of the pathophysiology of graft-versus-host disease (GVHD), its prediction remains unresolved and depends mainly on clinical data. The aim of this study is to build a predictive model based on clinical variables and cytokine gene polymorphism for predicting acute GVHD (aGVHD) and chronic GVHD (cGVHD) from the analysis of a large cohort of HLA-identical sibling donor allogeneic stem cell transplant (allo-SCT) patients. A total of 25 SNPs in 12 cytokine genes were evaluated in 509 patients. Data were analyzed using a linear regression model and the least absolute shrinkage and selection operator (LASSO). The statistical model was constructed by randomly selecting 85% of cases (training set), and the predictive ability was confirmed based on the remaining 15% of cases (test set). Models including clinical and genetic variables (CG-M) predicted severe aGVHD significantly better than models including only clinical variables (C-M) or only genetic variables (G-M). For grades 3-4 aGVHD, the correct classification rates (CCR1) were: 100% for CG-M, 88% for G-M, and 50% for C-M. On the other hand, CG-M and G-M predicted extensive cGVHD better than C-M (CCR1: 80% vs. 66.7%, respectively). A risk score was calculated based on LASSO multivariate analyses. It was able to correctly stratify patients who developed grades 3-4 aGVHD (P < .001) and extensive cGVHD (P < .001). The novel predictive models proposed here improve the prediction of severe GVHD after allo-SCT. This approach could facilitate personalized risk-adapted clinical management of patients undergoing allo-SCT.

Abstract: We retrospectively compared the clinical outcomes of adults with acute leukemia who received single-unit umbilical cord blood (UCB) transplantation (sUCBT) (n = 135) or stem cell transplant using coinfusion of a UCB graft with CD34+ cells from a third-party donor (Haplo-Cord) (n = 72) at different institutions within the Grupo Español de Trasplante Hematopoyético. In multivariable analysis, patients in the Haplo-Cord group showed more rapid neutrophil (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.5-3.3; P < .001) and platelet recovery (HR, 1.6; 95% CI, 1.2-2.3; P = .015) and lower incidence of chronic graft-versus-host disease (GVHD) (relative risk, 0.5; 95% CI, 0.3-0.8; P = .01). Nonrelapse mortality, relapse, disease-free survival (DFS), and GVHD/relapse-free survival were similar in the 2 groups. Regarding disease-specific outcomes, DFS in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients was not significantly different; however, a significantly higher relapse rate was found in patients with AML treated with Haplo-Cord (HR, 2.3; 95% CI, 1-5.4; P = .04). Our study confirms that Haplo-Cord was an effective strategy to accelerate neutrophil and platelet recovery and shows that, in the context of specific treatment platforms, sUCBT and Haplo-Cord offer similar long-term outcomes.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a curative procedure for several hematological malignancies. Haploidentical HSCT (haplo-HSCT) using high-dose post-transplantation cyclophosphamide (PTCy) makes transplantation possible for patients with no HLA-matched sibling donor. However, this treatment can cause complications, mainly infection, graft-vs.-host disease (GVHD), and conditioning-related toxicity. In recent years, different biomarkers in the form of tissue-specific proteins have been investigated; these may help us to predict complications of allo-HSCT. In this study we explored two such biomarkers, suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (REG3α), in the largest series reported of T cell–replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed. ST2 and REG3α levels at day +15 were not associated with post-transplant complications. ST2 levels at day +30 were higher in patients with grade II-IV acute GVHD, mainly those who received reduced intensity conditioning (RIC; median 2,503 vs. 1,830 ng/ml; p = 0.04). Of note, patients with higher plasma ST2 levels at day +30 also presented a higher incidence of non-relapse mortality (HR, 7.9; p = 0.004) and lower 2-year overall survival (25 vs. 44 months; p = 0.02) than patients with lower levels. Patients with REG3α levels higher than 1,989 pg/ml at day +30 presented a higher incidence of acute gastrointestinal GVHD in the whole cohort (HR, 8.37; p = 0.003) and in the RIC cohort (HR 6.59; p = 0.01). These data suggest that measurement of ST2 and REG3α might be useful for the prognosis and prediction of complications in patients undergoing haplo-HSCT with PTCy.

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics.

The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients.

High-dose chemotherapy with autologous peripheral blood stem cell rescue has been reported as feasible and effective in HIV-associated lymphoma. Although a sufficient number of stem cells seems achievable in most patients, there are cases of stem cell harvest failure. The aim of this study was to describe the mobilization policies used in HIV-associated lymphoma, evaluate the failure rate and identify factors influencing mobilization results. We analyzed 155 patients who underwent attempted stem cell mobilization at 10 European centers from 2000–2012. One hundred and twenty patients had non-Hodgkin lymphoma and 35 Hodgkin lymphoma; 31% had complete remission, 57% chemosensitive disease, 10% refractory disease, 2% untested relapse. Patients were mobilized with chemotherapy + G-CSF (86%) or G-CSF alone (14%); 73% of patients collected >2 and 48% >5 × 106 CD34+ cells/kg. Low CD4+ count and refractory disease were associated with mobilization failure. Low CD4+ count, low platelet count and mobilization with G-CSF correlated with lower probability to achieve >5 × 106 CD34+ cells/kg, whereas cyclophosphamide ≥3 g/m2 + G-CSF predicted higher collections. Circulating CD34+ cells and CD34/WBC ratio were strongly associated with collection result. HIV infection alone should not preclude an attempt to obtain stem cells in candidates for autologous transplant as the results are comparable to the HIV-negative population.

Pascual Balsalobre, data manager del Servicio de Hematología del Hospital Gregorio Marañón y del Registro Europeo de Trasplante Hemopoyético, reflexiona sobre el papel de la Enfermería en los equipos multidisciplinares de investigación. Curriculum: Diplomado en Enfermería, Master en Drogodependencias y SIDA, Título Superior en Ciencias de la Salud (Enfermería) y Bachelor of Nursing. Trabaja como data manager en el Servicio de Hematología de la Unidad de Trasplante de Médula Ósea del Hospital General Universitario Gregorio Marañón de Madrid y del Registro Europeo de Trasplante Hemopoyético de Londres.

El trasplante de progenitores hemopoyéticos (TPH) es una terapia asociada a complicaciones que generan malestar y que son potencialmente mortales (toxicidad, enfermedad injerto contra huesped, infecciones, recaída de la enfermedad etc). Objetivo: Explorar las condiciones en las que mueren los pacientes trasplantados en nuestra institución. Metodología: Análisis descriptivo y retrospectivo. Sujetos de estudio: Adultos con TPH en el HGU Gregorio Marañón que murieron entre Octubre de 2000 y Septiembre de 2003. Resultados: 32 pacientes (60% hombres) fueron incluidos. Tipo de transplante: Auto en 13 (40%) y alo en 19 (60%). La Causa de muerte fue progresión de la enfermedad en el 50% y mortalidad relacionada con el procedimiento en el otro 50%. La mediana de supervivencia fue de 5 meses (rango 0,5-39,5). El 78% de los pacientes murió hospitalizado y el resto (22%) en casa. Seis (24%) de los pacientes que murieron en el hospital fueron ingresados para un manejo paliativo. Dolor, disnea y ansiedad fueron los síntomas mas frecuentes, y el 23,5% de los pacientes murió sin un control óptimo de la sintomatología. Comentarios sobre la sintomatología durante la última semana de vida aparecieron en 15 de 16 registros de Enfermería y en 6 de 16 registros médicos. Conclusiones: Una elevada proporción de nuestros pacientes murieron en el hospital pero ninguno en la Unidad de Cuidados Paliativos. En la mayoría de los casos, a pesar de que un adecuado tratamiento fue prescrito, los síntomas no fueron completamente controlados. Las referencias a la situación sintomática de los pacientes son recogidas esencialmente en los registros de Enfermería. Abstract Stem cell transplantation is a therapeutic procedure associated with potentially fatal complications (toxicity, graft versus host disease, infections, relapse/progression, etc). Aim: To explore the conditions in which patients transplanted in our institution die. Methods. Descriptive and retrospective analysis of the clinical chart and MED-A forms from adult patients who were transplanted in our hospital and died between October 2000 and September 2003. Results: 32 patients (60% males) were included. Type of transplant: Auto 13 (40%), allo 19 (60%). Cause of death: 50% progression, 50% transplant related mortality. Median of survival was 5 months (range 0,5-39,5). Regarding place of death, 78% of patients died within the hospital and other 22% died at home. Six (24%) of patients dying within the hospital were admitted for palliative management. Pain, disnea and anxiety were the most frequent symptoms and 23,5% of patients died with an insufficient symptom control. Comments regarding the symptomatology in the last week of life were recorded in 15 of 16 nursing charts and in 6 of 16 physician charts. Conclusions: A high proportion of our patients died within the hospital but none in the Palliative Care Unit. In most of cases, despite an appropriate treatment, symptoms were not completely controlled. Most of comments regarding symptomatology of patients were recorded in Nursing charts. Centro de Trabajo: 30th Annual Meeting of the European Group for Blood and Marrow Transplantation, 20th Meeting of the EBMT Nurses Group and 3rd Meeting of the EBMT Data Management Group. Barcelona. 28-31 Marzo 2004 Fecha del Trabajo: 01/05/2004 Palabra Clave: Trasplante de progenitores hemopoyéticos, muerte, cuidados paliativos, Enfermería Key Words: Stem Cell transplantation, death, palliative care, Nursing

Giving up health recommendations and care against medical advice is a setback that may happen in daily health work. In a pilot study made at the Department of Infectious Diseases in Hospital Gregorio Marañón (Madrid, Spain), during the first five months in 1998, the incidence of leaving against medical advice was 12,3 times higher than the mean in that hospital (7,03% vs 0,57%). Patients involved in this kind of event were drug abusers with acute infectious problems in a HIV primary infection or a multiple drug dependency. 42% of this patients returned to the hospital in the next 15 days. The research group thought out to study this problem under this hypothesis: Leaving against medical advice, besides having harmful consequences for the patient and the public health, produces an increase in the cost and the stay of the patient in hospital.The main objective of the research was to set up the economic the deviation in the cost/stay of a group of patients that had left against medical advice or in a regular process. It is a prospective and observational study. We studied 284 drug abusers staying in the Department of Infectious Diseases between Oct, 1st, 1999 and Sept, 30th, 2000. The research variables were: 1. Sociodemographic: Initials, , age, sex, and history number. 2. Clinical: Leaving medical diagnosis, returning medical diagnosis. 3. Administrative: Group of Related Diagnosis (GRD), admission date, leaving date, returning date and estimated cost of the episode. All episodes were grouped by kind of leaving and GRD. The cost/stay was calculated adjusted to GRD, and the deviations inside GRD were analyzed in the regular leaving group and the leaving against medical advice group.Results: Around 90% admission episodes were grouped in 6 GRD: 714 (47.92%), 541 (8.85%), 709 (8.85%), 710 (7,81%), 101 (7,29%) y 715 (7,29%). The Pneumonia in HIV (GRD 714) caused the majority of the admissions. Global deviation adjusted to cost/stay was 29,44% (more expensive in the leaving against medical advice group).

El abandono de las recomendaciones y los cuidados sanitarios en contra del consejo sanitario es una contrariedad que eventualmente ocurre en el ejercicio del profesional sanitario. En un estudio piloto realizado en la unidad de Enfermedades Infecciosas del HGU Gregorio Marañón durante los cinco primeros meses de 1998, la incidencia de Altas en Contra de la Opinión Clínica (ACOC) fue 12,3 veces superior a la media hospitalaria (7,03% vs 0,57%). Los pacientes implicados en este tipo de evento eran toxicómanos activos, que sufrían procesos infecciosos agudos sobre la base de la infección por VIH y/o una politoxicomanía, y el 42% de ellos volvían al hospital en un plazo inferior a 15 días. El equipo investigador se planteó estudiar este problema bajo la siguiente hipótesis de trabajo: El Alta en Contra de la Opinión Clínica, además de suponer consecuencias nocivas para el propio paciente y la salud pública, supone un encarecimiento del coste/estancia del paciente. El Objetivo principal de este trabajo es establecer la desviación económica en el coste/estancia entre el grupo de pacientes toxicómanos activos con ACOC y Alta Normal (AN). Se trata de un estudio observacional y prospectivo. Los sujetos de estudio son 284 toxicómanos activos ingresados en la citada unidad entre el 1-10-99 y el 30-9-00. Las Variables de estudio recogidas son: 1. Sociodemográficas: Iniciales, edad, sexo y nº de historia. 2. Clínicas: Diagnóstico médico al alta, diagnóstico médico al reingreso. 3. Administrativas: Grupo de diagnósticos relacionados (GDR), fecha de ingreso, fecha de alta, fecha de reingreso, tipo de reingreso y coste estimado del episodio. Todos los episodios se agruparon por tipo de alta y GDR. Posteriormente se calculó el coste/estancia corregido por GDR, procediéndose al análisis de las desviaciones intra-GDR para los grupos de AN y ACOC. Resultados: En torno al 90% de los episodios de ingreso fueron agrupados en 6 GDR: 714 (47.92%), 541 (8.85%), 709 (8.85%), 710 (7,81%), 101 (7,29%) y 715 (7,29%). La neumonía en VIH+ (GRD 714) fue el motivo de ingreso más importante. La desviación global ponderada en el coste/estancia corregido fue del 29,44% (más caro en el grupo con ACOC). Abstract Giving up health recommendations and care against medical advice is a setback that may happen in daily health work. In a pilot study made at the Department of Infectious Diseases in Hospital Gregorio Marañón (Madrid, Spain), during the first five months in 1998, the incidence of leaving against medical advice was 12,3 times higher than the mean in that hospital (7,03% vs 0,57%). Patients involved in this kind of event were drug abusers with acute infectious problems in a HIV primary infection or a multiple drug dependency. 42% of this patients returned to the hospital in the next 15 days. The research group thought out to study this problem under this hypothesis: Leaving against medical advice, besides having harmful consequences for the patient and the public health, produces an increase in the cost and the stay of the patient in hospital. The main objective of the research was to set up the economic the deviation in the cost/stay of a group of patients that had left against medical advice or in a regular process. It is a prospective and observational study. We studied 284 drug abusers staying in the Department of Infectious Diseases between Oct, 1st, 1999 and Sept, 30th, 2000. The research variables were: 1. Sociodemographic: Initials, , age, sex, and history number. 2. Clinical: Leaving medical diagnosis, returning medical diagnosis. 3. Administrative: Group of Related Diagnosis (GRD), admission date, leaving date, returning date and estimated cost of the episode. All episodes were grouped by kind of leaving and GRD. The cost/stay was calculated adjusted to GRD, and the deviations inside GRD were analyzed in the regular leaving group and the leaving against medical advice group. Results: Around 90% admission episodes were grouped in 6 GRD: 714 (47.92%), 541 (8.85%), 709 (8.85%), 710 (7,81%), 101 (7,29%) y 715 (7,29%). The Pneumonia in HIV (GRD 714) caused the majority of the admissions. Global deviation adjusted to cost/stay was 29,44% (more expensive in the leaving against medical advice group). Palabra Clave: ACOC, alta voluntaria, alta por fuga, enfermos infecciosos, toxicómano, gestión sanitaria Key Words: Living AMA, discharges AMA, infectious patients, drug abuser, hospital financial management

We carried out a longitudinal study to analyze the immune recovery of four patients with aggressive HIV-associated lymphoma (HIVLy) treated with highly active antiretroviral therapy (HAART) and high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ASCT). We also studied three control non-HIV-infected patients with lymphoma (HIV−Ly) and six HIV patients on HAART without lymphoma (HIVLy−). After 12 months of follow-up, the HIV HIVLypatients reached the pre-ASCT CD4levels, despite a transient decrease after the ASCT. All ASCT patients (HIVLyand HIV−Ly) showed an increase in CD4, CD4CD45RO, and CD4CD28T cellsμl. Although HIVLypatients had values of CD4, CD4CD45RO, and CD4 CD28T cellsμl lower than the HIV−Lypatients, their recovery rate over the 12 months after ASCT appeared to be better. HIVLypatients had higher pre-ASCT plasma IL-7 levels than HIV−Ly, however, these values decreased after ASCT. All ASCT patients showed a slight increase of TCR rearrangement excision circles (TRECs) and they did not have a different pattern of TREC evolution. We could not find differences between HIVLypatients 12 months after ASCT and HIVLy−in DNA-HIV (copies106cell). Overall, HIVLypatients showed an appropriate immune reconstitution 12 months after ASCT, and, interestingly, they had an amount of DNA-HIV copies similar to HIVLy−control patients in their CD4cells. [ABSTRACT FROM AUTHOR]