RESUMEN

Letermovir (LTV), recently approved for the prophylaxis of human cytomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has been shown to decrease the rate of infection in the first months post-transplantation. The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. We studied HCMV infection and HCMV-specific T cell reconstitution in 2 matched groups of HSCT recipients, those treated with LTV prophylaxis (n = 30; LTV group) and those receiving preemptive therapy (n = 31; PET group). We analyzed the rates of graft-versus-host disease (GVHD), neutropenia, baseline disease recurrence, and overall survival in the 2 groups. Clinically significant infections necessitating preemptive therapy showed a similar rate in the 2 groups (PET: 21 of 31 [68%]; LTV: 17 of 30 [57%]; P = .434) but occurred significantly later (after prophylaxis discontinuation) in the LTV group. There was no between-group difference in peak HCMV DNAemia level (P = .232). HCMV-specific T cell recovery was delayed by approximately 100 days in the LTV group. HCMV-specific CD4 and CD8 T cell counts were significantly lower in the LTV group at days 120 to 360 and days 90 to 120, respectively. A lower rate of chronic GVHD (P = .024) was seen in the LTV group. Time to engraftment, rate of disease relapse, and 1-year survival were not different between the 2 groups, whereas trends toward a lower rate of neutropenia (P = .124) and a higher rate of acute GVHD grade III-IV (P = .103) were observed in the LTV group. Because LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, immunologic and virologic monitoring should be implemented after discontinuation of prophylaxis. The potential effect of LTV prophylaxis in reducing chronic GVHD should be evaluated in prospective studies.

Asunto(s)

Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Acetatos , Citomegalovirus , Infecciones por Citomegalovirus/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Recurrencia Local de Neoplasia , Estudios Prospectivos , Quinazolinas

RESUMEN

Human cytomegalovirus (HCMV) infection is one of the major causes of mortality and morbidity after allo-hematopoietic stem cell transplantation (HSCT). Antiviral therapies are associated with toxicity and high economic burden. The aim of this retrospective study was to identify allo-HSCT HCMV-seropositive recipients at low risk of clinically significant HCMV infection who could avoid antiviral therapies. Sixty adult patients who underwent allo-HSCT were clustered in two groups: i) 22 (37%) spontaneously controlling HCMV reactivation (Controllers); ii) 38 (63%) developing clinically significant HCMV infection and receiving pre-emptive therapy (Non-Controllers). We analyzed several patient baseline characteristics, total/HCMV-specific CD4+ and CD8+ T-cell counts and their cytokine production (IFNγ, TNFα, IL2). Controllers presented a higher number of total/HCMV-specific CD4+ and CD8+ T-cells (P=0.001 and P=0.017 for total CD4+ and CD8+ T-cells respectively; P<0.001 for HCMV-specific T-cells) and a lower percentage of mono-functional IFNγ-producing HCMV-specific CD8+ T-cells (P=0.002). In bi-variable models, the prognostic impact of the percentage of mono-functional HCMV-specific CD8+ T-cells on treatment-free survival, adjusted for total/HCMVspecific CD4+ and CD8+ T-cells, was confirmed. An HCMV-seronegative donor was the only baseline characteristic associated with a clinically significant infection. These data, when confirmed by a larger prospective study, may provide information for guiding the personalized management of HCMV infection in allo-HSCT recipients.

Asunto(s)

Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Linfocitos T CD8-positivos , Citocinas , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Prospectivos , Estudios Retrospectivos

RESUMEN

We report a randomized study comparing fludarabine in combination with busulfan (FB) or thiotepa (FT), as conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis. The primary study endpoint was progression-free survival (PFS). Sixty patients were enrolled with a median age of 56 years and an intermediate-2 or high-risk score in 65%, according to the Dynamic International Prognostic Staging System (DIPSS). Donors were HLA-identical sibling (n = 25), matched unrelated (n = 25) or single allele mismatched unrelated (n = 10). With a median follow-up of 22 months (range, 1 to 68 months), outcomes at 2 years after HSCT in the FB arm versus the FT arm were as follows: PFS, 43% versus 55% (P = .28); overall survival (OS), 54% versus 70% (P = .17); relapse/progression, 36% versus 24% (P = .24); nonrelapse mortality (NRM), 21% in both arms (P = .99); and graft failure, 14% versus 10% (P = .96). A better PFS was observed in patients with intermediate-1 DIPSS score (P = .03). Both neutrophil engraftment and platelet engraftment were significantly influenced by previous splenectomy (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.16 to 4.51; P = .02) and splenomegaly at transplantation (HR, 0.51; 95% CI, 0.27 to 0.94; P = .03). In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen.

Asunto(s)

Busulfano/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Mielofibrosis Primaria/terapia , Tiotepa/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Adulto , Donantes de Sangre , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/mortalidad , Pronóstico , Recurrencia , Análisis de Supervivencia , Acondicionamiento Pretrasplante/normas , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico

RESUMEN

BACKGROUND: Gram-negative bacteremia (GNB) is a major cause of illness and death after hematopoietic stem cell transplantation (HSCT), and updated epidemiological investigation is advisable. METHODS: We prospectively evaluated the epidemiology of pre-engraftment GNB in 1118 allogeneic HSCTs (allo-HSCTs) and 1625 autologous HSCTs (auto-HSCTs) among 54 transplant centers during 2014 (SIGNB-GITMO-AMCLI study). Using logistic regression methods. we identified risk factors for GNB and evaluated the impact of GNB on the 4-month overall-survival after transplant. RESULTS: The cumulative incidence of pre-engraftment GNB was 17.3% in allo-HSCT and 9% in auto-HSCT. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most common isolates. By multivariate analysis, variables associated with GNB were a diagnosis of acute leukemia, a transplant from a HLA-mismatched donor and from cord blood, older age, and duration of severe neutropenia in allo-HSCT, and a diagnosis of lymphoma, older age, and no antibacterial prophylaxis in auto-HSCT. A pretransplant infection by a resistant pathogen was significantly associated with an increased risk of posttransplant infection by the same microorganism in allo-HSCT. Colonization by resistant gram-negative bacteria was significantly associated with an increased rate of infection by the same pathogen in both transplant procedures. GNB was independently associated with increased mortality at 4 months both in allo-HSCT (hazard ratio, 2.13; 95% confidence interval, 1.45-3.13; P <.001) and auto-HSCT (2.43; 1.22-4.84; P = .01). CONCLUSIONS: Pre-engraftment GNB is an independent factor associated with increased mortality rate at 4 months after auto-HSCT and allo-HSCT. Previous infectious history and colonization monitoring represent major indicators of GNB. CLINICAL TRIALS REGISTRATION: NCT02088840.

Asunto(s)

Bacteriemia/epidemiología , Bacterias Gramnegativas/aislamiento & purificación , Infecciones por Bacterias Gramnegativas/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante/efectos adversos , Adolescente , Adulto , Factores de Edad , Anciano , Bacteriemia/etiología , Bacteriemia/microbiología , Bacteriemia/mortalidad , Niño , Preescolar , Farmacorresistencia Bacteriana Múltiple , Escherichia coli/aislamiento & purificación , Femenino , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Incidencia , Lactante , Italia/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Trasplante Autólogo , Trasplante Homólogo , Adulto Joven

RESUMEN

An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with ≥10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DLI strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mielomonocítica Crónica/terapia , Síndromes Mielodisplásicos/terapia , Guías de Práctica Clínica como Asunto , Humanos , Factores de Riesgo , Acondicionamiento Pretrasplante , Trasplante Homólogo

RESUMEN

BACKGROUND: Neurological complications (NC) after hematopoietic stem cell transplantation (HSCT) are rare events. The evolution of transplant procedures has resulted in improved survival and has allowed elderly patients or those with comorbidity to receive an HSCT. The risk of NC in these patients has still not been well defined. Therefore, we carried out an observational study to estimate the occurrence and identify the risks associated with NC. METHODS: The study cohort included 452 adult-allogeneic HSCT recipients, transplanted from 1997 to 2012. The median follow up was 1.3 year (0-15.7). A myeloablative regimen was used in 307 patients. Two hundred patients were grafted from matched unrelated donor (MUD), of these, 129 (64.5%) received an in vivo T-cell depletion. RESULTS: Out of 452 patients, 30 (6.6%) developed NC. Infections were the most frequent causes of NC (30%). Overall survival decreased in patients developing NC (P < 0.001). Univariate survival regression on the cumulative incidence of NC identified period of transplant, linear trend between 4-year periods (1997-2012) (P < 0.001), MUD (P < 0.001), and recipient's age (P = 0.034) as significant risk factors. In multivariate analysis, period of transplant (P < 0.001) and MUD (P = 0.004) remained significant independent risk factors. Matched unrelated donor recipients showed a 3.8-fold elevated risk of developing NC. CONCLUSIONS: Analysis highlights a temporal trend of incidence of NC that progressively increased over time and confirms a strong association between donor type and risk of NC. Our observations suggest that, although relatively uncommon, NC after allo-HSCT, may become more frequent due to the improved overall survival in recent years.

Asunto(s)

Enfermedades del Sistema Nervioso Central/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Adulto , Factores de Edad , Anciano , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/mortalidad , Infecciones del Sistema Nervioso Central/epidemiología , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Incidencia , Italia/epidemiología , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Agonistas Mieloablativos/uso terapéutico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del Tratamiento , Donante no Emparentado , Adulto Joven

RESUMEN

PURPOSE: The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. PATIENTS AND METHODS: We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT. RESULTS: Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%. CONCLUSION: Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.

Asunto(s)

Síndromes Mielodisplásicos , Humanos , Pronóstico

RESUMEN

BACKGROUND: The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. METHODS: We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. FINDINGS: Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). INTERPRETATION: In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. FUNDING: Agenzia Italiana del Farmaco.

Asunto(s)

Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Busulfano/administración & dosificación , Ciclofosfamida/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/cirugía , Acondicionamiento Pretrasplante , Vidarabina/análogos & derivados , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Vidarabina/administración & dosificación

RESUMEN

The relative contribution of human cytomegalovirus (HMCV)-specific CD4(+) and CD8(+) T cells to the control of HCMV infection in hematopoietic stem cell transplant (HSCT) recipients is still controversial. HCMV reactivation and HCMV-specific CD4(+) and CD8(+) T cell reconstitution were monitored for 1 year in 63 HCMV-seropositive patients receiving HSCT. HCMV reactivation was detected in all but 2 patients. In 20 of 63 (31.7%) patients (group 1) HCMV infection resolved spontaneously, whereas 32 of 63 (50.8%) patients (group 2) controlled the infection after a single short-course of pre-emptive therapy and the remaining 9 (14.3%) patients (group 3) suffered from relapsing episodes of HCMV infection, requiring multiple courses of antiviral therapy. The kinetics and magnitude of HCMV-specific CD8(+) T cell reconstitution were comparable among the 3 groups, but HCMV-specific CD4(+) T cells were lower in number in patients requiring antiviral treatment. HCMV-seronegative donors, as well as unrelated donors (receiving antithymocyte globulin) and acute graft-versus-host disease (GVHD) were associated with both delayed HCMV-specific CD4(+) T cell reconstitution and severity of infection. Conversely, these risk factors had no impact on HCMV-specific CD8(+) T cells. Eight patients with previous GVHD suffered from HCMV gastrointestinal disease, although in the presence of HCMV-specific CD4(+) and CD8(+) systemic immunity and undetectable HCMV DNA in blood. Reconstitution of systemic HCMV-specific CD4(+) T cell immunity is required for control of HCMV reactivation in adult HSCT recipients, but it may not be sufficient to prevent late-onset organ localization in patients with GVHD. HCMV-specific CD8(+) T cells contribute to control of HCMV infection, but only after HCMV-specific CD4(+) T cell reconstitution.

Asunto(s)

Antineoplásicos/uso terapéutico , Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por Citomegalovirus/tratamiento farmacológico , Neoplasias Hematológicas/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas , Adulto , Anciano , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/virología , Proliferación Celular , Enfermedad Crónica , Citomegalovirus/inmunología , Citomegalovirus/patogenicidad , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/mortalidad , Infecciones por Citomegalovirus/patología , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Activación Viral

RESUMEN

High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long-term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long-term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients treated with a program of anthracycline-based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R-COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl-2 negative. TRM was 0%. The 5-year PFS was 54% and the 5-year OS was 83%. After a median f-up of 6.7 years (range 1.5-13.6), 54% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Linfoma Folicular/terapia , Adulto , Anciano , Antraciclinas/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Ciclofosfamida/administración & dosificación , Femenino , Expresión Génica , Humanos , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Prednisona/administración & dosificación , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-bcl-2/deficiencia , Proteínas Proto-Oncogénicas c-bcl-2/genética , Recurrencia , Rituximab , Análisis de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento , Vincristina/administración & dosificación

RESUMEN

Acquired chromosomal abnormalities are important prognostic factors in patients with myelodysplastic syndromes treated with supportive care and with disease-modifying therapeutic interventions, including allogeneic hematopoietic stem cell transplantation. To assess the prognostic impact of cytogenetic characteristics after hematopoietic stem cell transplantation accurately, we investigated a homogeneous group of 523 patients with primary myelodysplastic syndromes who have received stem cells from human leukocyte antigen-identical siblings. Overall survival at five years from transplantation in good, intermediate, and poor cytogenetic risk groups according to the International Prognostic Scoring System was 48%, 45% and 30%, respectively (P<0.01). Both the disease status (complete remission vs. not in complete remission) and the morphological classification at transplant in the untreated patients were significantly associated with probability of overall survival and relapse-free survival (P<0.01). The cytogenetic risk groups have no prognostic impact in untreated patients with refractory anemia ± ringed sideroblasts (P=0.90). However, combining the good and intermediate cytogenetic risk groups and comparing them to the poor-risk group showed within the other three disease-status-at-transplant groups a hazard ratio of 1.86 (95%CI: 1.41-2.45). In conclusion, this study shows that, in a large series of patients with primary myelodysplastic syndromes, poor-risk cytogenetics as defined by the standard International Prognostic Scoring System is associated with a relatively poor survival after allogeneic stem cell transplantation from human leukocyte antigen-identical siblings except in patients who are transplanted in refractory anemia/refractory anemia with ringed sideroblasts stage before progression to higher myelodysplastic syndrome stages.

Asunto(s)

Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/terapia , Hermanos , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del Tratamiento , Adulto Joven

Asunto(s)

Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes Mielodisplásicos/terapia , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Femenino , Humanos , Masculino

RESUMEN

Approximately one-third of patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (HSCT) are cured by this treatment. Treatment failure may be due to transplant complications or relapse. To identify predictive factors for transplantation outcome, we studied 519 patients with MDS or oligoblastic acute myeloid leukemia (AML, <30% marrow blasts) who received an allogeneic HSCT and were reported to the Gruppo Italiano Trapianto di Midollo Osseo registry between 2000 and 2011. Univariate and multivariate survival analyses were performed using Cox proportional hazards regression. High-risk category, as defined by the revised International Prognostic Scoring System (IPSS-R), and monosomal karyotype were independently associated with relapse and lower overall survival after transplantation. On the other hand, older recipient age and high hematopoietic cell transplantation-comorbidity index (HCT-CI) were independent predictors of nonrelapse mortality. Accounting for various combinations of patient's age, IPSS-R category, monosomal karyotype, and HCT-CI, the 5-year probability of survival after allogeneic HSCT ranged from 0% to 94%. This study indicates that IPSS-R risk category and monosomal karyotype are important factors predicting transplantation failure both in MDS and oligoblastic AML. In addition, it reinforces the concept that allogeneic HSCT offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos/cirugía , Adolescente , Adulto , Anciano , Aloinjertos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Recurrencia , Factores de Riesgo , Resultado del Tratamiento , Adulto Joven

Asunto(s)

Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/cirugía , Femenino , Humanos , Masculino

RESUMEN

The effect of minor H antigen mismatching on the occurrence of graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) after HLA-matched hematopoietic stem cell transplantation (HSCT) has mainly been demonstrated in single-center studies. Yet, the International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 20 laboratories of the IHIW, the roles of 10 autosomal and 10 Y chromosome-encoded minor H antigens were investigated on GvHD and relapse incidence in 639 HLA-identical related donor (IRD) and 210 HLA-matched unrelated donor (MUD) HSCT recipients. Donor and recipient DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, and HY. The correlations with the primary outcomes GvHD (acute or chronic GvHD), survival, and relapse were statistically analyzed. The results of these multicenter analyses show that none of the HLA class I-restricted HY antigens were found to be associated with any of the primary outcomes. Interestingly, of the HLA class II-restricted HY antigens analyzed, HLA-DQ5 positive recipients showed a significantly increased GvHD-free survival in female-to-male HSCT compared with male-to-female HSCT (P = .013). Yet, analysis of the overall gender effect, thus independent of the known HY antigens, between the gender groups demonstrated an increased GvHD incidence in the female-to-male transplantations (P < .005) and a decreased GvHD-free survival in the female-to-male transplantations (P < .001). Of all autosomally encoded minor H antigens, only mismatching for the broadly expressed minor H antigen HA-8 increased the GvHD incidence in IRD HSCT (Hazard ratio [HR] = 5.28, P < .005), but not in MUD HSCT. Most striking was the influence of hematopoietic restricted minor H antigens on GvL as mismatching for hematopoietic minor H antigens correlated with lower relapse rates (P = .078), higher relapse-free survival (P = .029), and higher overall survival (P = .032) in recipients with GvHD, but not in those without GvHD. In conclusion, the significant GvHD effect of the broadly expressed minor H antigen HA-8 favors matching for HA-8 in IRD, but not in MUD, patient/donor pairs. The GvHD-GvL association demonstrating a significant lower relapse in hematopoietic minor H antigen mismatched patient/donor pairs underlines their clinical applicability for adoptive immunotherapy, enhancing the GvL effect in a GvHD controllable manner.

Asunto(s)

Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Histocompatibilidad/inmunología , Antígenos de Histocompatibilidad Menor/inmunología , Adulto , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Prueba de Histocompatibilidad , Humanos , Masculino , Donante no Emparentado

RESUMEN

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Estudios de Cohortes , Femenino , Humanos , Masculino , Cadenas de Markov , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/mortalidad , Riesgo , Análisis de Supervivencia , Factores de Tiempo , Trasplante Homólogo

RESUMEN

In 54 adult stem cell transplant recipients, the presence and persistence of human rhinoviruses (including the novel lineage C) were evaluated by molecular detection and phylogenetic analysis, independently from respiratory symptoms. In the same group of patients, the presence of other coinfecting respiratory pathogens, including the novel enterovirus 109, was also evaluated.

Asunto(s)

Infecciones por Enterovirus/diagnóstico , Enterovirus/genética , Pulmón/metabolismo , Infecciones por Picornaviridae/diagnóstico , Complicaciones Posoperatorias/diagnóstico , ARN Viral/análisis , Rhinovirus/genética , Trasplante de Células Madre , Adulto , Coinfección/diagnóstico , Coinfección/etiología , Infecciones por Enterovirus/etiología , Estudios de Seguimiento , Genotipo , Humanos , Pulmón/virología , Patología Molecular , Filogenia , Infecciones por Picornaviridae/etiología , Estudios Retrospectivos

RESUMEN

BACKGROUND: Human cytomegalovirus (HCMV) infection of the central nervous system (CNS) is a rare but life threatening condition which may follow hematopoietic stem cell transplantation. Diagnosis, monitoring and treatment approaches rely on anecdotal reports. CASE PRESENTATIONS: The different outcomes of HCMV CNS disease in an adult and a pediatric T-cell depleted hematopoietic stem cell transplant (HSCT) recipient are reported. In the first case, HCMV encephalitis emerged in the context of simultaneous impairment of the T- and B-cell immunity. Antiviral treatment only reduced viral load in peripheral blood and the patient died. In the second case, an HCMV radiculopathy was observed and antiviral treatment was adjusted on the basis of intrathecal drug level. In addition, donor HCMV-specific cytotoxic T lymphocytes (CTLs) were infused. Viral load in the CNS decreased and the patient recovered from the acute event. In neither case were drug-resistant HCMV variants observed in blood or CNS samples. CONCLUSIONS: T-cell depleted HSCT appears a predisposing condition for CNS HCMV infection since never observed in other HSCT recipients at our center in the last 15 years. Intensive diagnostic approaches and timely aggressive combination treatments might improve clinical outcome in these patients.

Asunto(s)

Antivirales/administración & dosificación , Infecciones por Citomegalovirus/patología , Encefalitis Viral/patología , Trasplante de Células Madre Hematopoyéticas , Radiculopatía/patología , Traslado Adoptivo , Sangre/virología , Líquido Cefalorraquídeo/virología , Preescolar , Infecciones por Citomegalovirus/tratamiento farmacológico , Encefalitis Viral/tratamiento farmacológico , Resultado Fatal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiculopatía/tratamiento farmacológico , Linfocitos T Citotóxicos/inmunología , Resultado del Tratamiento , Carga Viral

RESUMEN

BACKGROUND: A novel human enterovirus (HEV) type within the species HEV-C, named EV109, was discovered from cases of respiratory illness in Nicaragua in September 2010. The aim of this study, was to retrospectively examine the presence and the role of EV109 in respiratory samples from two patients populations; infants below the age of 2 years, hospitalized for acute respiratory diseases (ARDs) and adult hematopoietic stem cell transplantation recipients. RESULTS: A total of 1149 nasopharingeal aspirates were collected and tested for the presence of EV109 by reverse transcription-PCR (RT-PCR). In positive samples, the presence of the most common respiratory viruses was also assayed and clinical symptoms were evaluated. Samples from 2 of the 974 infants tested positive for EV109 RNA (0.2%) and belonged to patients with lower ARDs; co-infection with other viral pathogens under study was observed in both cases. In transplant recipients, one out of the 175 samples analyzed, from a patients with upper respiratory simptoms tested positive for HEV 109 in the absence of co-infecting viruses. Sequence analysis of amplified EV109 genomic regions, showed only a few nucleotide differences when compared with the Nicaraguan strains. CONCLUSIONS: Overall these results indicate that HEV109 variants have circulated and differentiated in different lineages worldwide. Although more cases and larger studies are needed, HEV109 infection may be associated to ARDs both in infants and in hematopoietic stem cell transplantation recipients. If these preliminary observations will be confirmed, improved molecular methods with a wider panel of potential pathogens will be useful for monitoring these categories of patients.

Asunto(s)

Infecciones por Enterovirus/epidemiología , Infecciones por Enterovirus/patología , Enterovirus/clasificación , Enterovirus/genética , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/patología , Análisis por Conglomerados , Enterovirus/aislamiento & purificación , Infecciones por Enterovirus/virología , Genotipo , Humanos , Lactante , Masculino , Epidemiología Molecular , Datos de Secuencia Molecular , Nasofaringe/virología , Nicaragua/epidemiología , Filogenia , ARN Viral/genética , Infecciones del Sistema Respiratorio/virología , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Trasplante de Células Madre/efectos adversos , Trasplante