RESUMEN
High dose-intensive or infusional intermediate-dose immunochemotherapy is highly effective treatment for Burkitt lymphoma irrespective of human immunodeficiency virus (HIV) infection. However, toxicities of these regimens are relevant, especially in older adults and elderly patients. The prospective multicenter BURKIMAB14 trial included four to six blocks of immunochemotherapy according to stage (localized: 1 and 2 non-bulky; advanced: 2 bulky, 3, 4) and age, with dose reduction in patients >55 years old. Dose-intensity of chemotherapy was reduced in patients ≤55 years old after achieving complete metabolic response (CMR). Their outcomes were compared with those of similar patients included in the former BURKIMAB08 trial, in which there was no dose reduction. CMR was attained in 86 of 107 (80%) patients (17/19 in localized stages and 69/88 in advanced stages). Patients from the BURKIMAB14 trial ≤55 years old showed similar overall survival (OS), fewer infections and cytopenias than patients from the BURKIMAB08 trial. Patients >55 years old had a significantly higher treatment- related mortality despite dose reduction of chemotherapy. With a median follow-up of 3.61 years the 4-year OS probability was 73% (range, 63-81%). Age (≤55 vs. >55 years) and stage (localized vs. advanced) had prognostic significance. No significant differences in OS were observed in HIV-positive versus HIV-negative patients. The results of BURKIMAB14 are similar to those of other dose-intensive immunochemotherapy trials. Age >55 years and advanced stage, but not HIV infection, were associated with poor survival. Dose reduction of chemotherapy in young adults in CMR is safe and does not impact outcomes (clinicaltrials gov. Identifier: NCT05049473).
Asunto(s)
Linfoma de Burkitt , Infecciones por VIH , Leucemia , Humanos , Adulto Joven , Anciano , Persona de Mediana Edad , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Reducción Gradual de Medicamentos , Estudios de Factibilidad , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Rituximab/uso terapéuticoRESUMEN
A single nucleotide polymorphism (SNP), 3 kbp upstream of the IL28B gene (rs12979860; C/T), has been shown to influence the dynamics of cytomegalovirus (CMV) replication in allogeneic stem cell transplant recipients (Allo-SCT). We investigated whether this SNP had any effect on the dynamics of CMV-specific T-cell immunity in these patients. CMV pp65/IE-1 IFN-γ CD8+ and CD4+ T cells were enumerated by flow cytometry in 85 patients with no prior CMV DNAemia (group A) and in 57 after the onset of CMV DNAemia (group B). Donor IL28B genotype was determined by real-time PCR and plasma levels of IL-28B were quantitated by ELISA. CMV-specific T-cell counts and plasma IL-28B levels in patients in group A were not significantly different among the IL28B genotype groups. Patients harboring the donor IL28B T/T genotype appeared to expand CMV-specific IFN-γ CD8+ cells to a higher level in response to viral replication than their C/T and C/C counterparts. Fewer patients in the T/T group received pre-emptive antiviral therapy (P = 0.05). Overall, a significant inverse correlation was observed between median IL-28B levels measured prior to the CMV DNAemia onset and the level of CMV-specific CD8+ T cells enumerated after detection of CMV DNAemia (σ = -0.471; P = 0.013). In summary, the data suggested that the protective effect attributed to the rs12979860 SNP minor T allele could be mediated, at least in part, by eliciting robust CMV-specific T-cell responses. J. Med. Virol. 89:685-695, 2017. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Citomegalovirus/inmunología , Interleucinas/genética , Polimorfismo de Nucleótido Simple , Linfocitos T/inmunología , Receptores de Trasplantes , Adolescente , Adulto , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Técnicas de Genotipaje , Humanos , Interferón gamma/análisis , Interferones , Interleucinas/sangre , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Trasplante de Células Madre , Trasplante Homólogo , Adulto JovenRESUMEN
Allogeneic stem cell transplantation (allo-HCT) represents the most effective immunotherapy for acute myeloid leukemia (AML) and myeloid malignancies. However, disease relapse remains the most common cause of treatment failure. By performing a second allo-HCT, durable remission can be achieved in some patients. However, a second allo-HCT is of no benefit for the majority of patients, so this approach requires further understanding. We present a retrospective cohort of 116 patients diagnosed with AML, myelodysplastic syndromes, and myeloproliferative disorders who consecutively underwent a second allo-HCT for disease relapse. The median age was 38 years (range, 4 to 69 years). Sixty-three patients were alive at last follow-up. The median follow-up of the whole cohort was 193 days (range, 2 to 6724 days) and the median follow-up of survivors was 1628 days (range, 52 to 5518 days). Overall survival (OS) at 5 years was 32% (SE ± 4.7%). Multivariate analysis identified active disease status (P < .001) and second allo-HCT < 430 days (the median of the time to second transplantation) after the first transplantation (P < .001) as factors for poor prognosis, whereas the use of an HLA-identical sibling donor for the second allo-HCT was identified as a good prognostic factor (P < .05) for OS. The use of myeloablative conditioning (P = .01), active disease (P = .02), and a donor other than an HLA-identical sibling (others versus HLA-identical siblings) (P = .009) were factors statistically significant for nonrelapse mortality in multivariate analysis. Time to second transplantation was statistically significant (P = .001) in the relapse multivariate analysis, whereas multivariate analysis identified active disease status (P < .001) and time to second transplantation (P < .001) as poor prognosis factors for disease-free survival. This study confirms active disease and early relapse as dismal prognostic factors for a second allo-HCT. Using a different donor at second allo-HCT did not appear to change outcome, but using an HLA-identical sibling donor for a second transplantation appears to be associated with better survival. Further studies are warranted.
Asunto(s)
Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Hermanos , Donantes de Tejidos , Adolescente , Adulto , Anciano , Aloinjertos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The role of Natural killer (NK) cells in the control of cytomegalovirus (CMV) infection in allogeneic stem cell transplant recipients has not been precisely characterized. The current study is aimed at investigating the potential role of NK cells expressing the activating receptor NKG2C in affording protection against the development of CMV DNAemia in patients exhibiting detectable CMV-specific CD8(+) T-cell responses early following transplantation. A total of 61 nonconsecutive patients were included in the study. Peripheral levels of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK cells and CMV pp65/IE-1-specific IFN-γ-producing CD8(+) T-cells were enumerated by flow cytometry at days +30 and +60 after transplant. Neither the absolute number of NKG2C(+) NK cells, nor that of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK-cell subsets at day 30 differed significantly between patients with or without subsequent CMV DNAemia. No significant correlation was found between levels of both NKG2C(+) NK-cell populations and the peak CMV DNA load within subsequent episodes of CMV DNAemia. The data indicate that enumeration of NKG2C(+) NK cells early after transplant is unlikely to be helpful in identifying those patients at highest risk of developing CMV DNAemia. Moreover, the data do not support a direct implication of NKG2C(+) NK cells in preventing the development of CMV DNAemia.
Asunto(s)
Infecciones por Citomegalovirus/inmunología , Citomegalovirus/aislamiento & purificación , ADN Viral/sangre , Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/análisis , Adulto , Linfocitos T CD8-positivos/inmunología , Citomegalovirus/genética , Infecciones por Citomegalovirus/virología , Femenino , Humanos , Células Asesinas Naturales/virología , Recuento de Linfocitos , Masculino , Carga Viral , ViremiaRESUMEN
Single nucleotide polymorphisms (SNPs) in genes involved in the activation or regulation of innate and adaptive immune responses may modulate the susceptibility to and the natural history of certain chronic viral infections. The current study aimed to investigate whether donor and recipient SNPs in the chemokine receptor 5 (rs1800023), monocyte chemoattractant protein 1 (rs13900), interleukin-10 (rs1878672), and Toll-like receptor 9 (rs352140) genes would exert any influence on the rate of incidence and features of CMV DNAemia in the allogeneic stem cell transplantation setting. This was a retrospective observational multicenter study. The cohort consisted of 102 non-consecutive allogeneic stem cell transplant recipients. SNP genotyping was performed by allele-specific real-time PCR. CMV surveillance was performed by the pp65 antigenemia assay/and or by real-time PCR. Seventy-three patients developed CMV DNAemia within the first 100 days after transplantation (71.5%). Neither donor nor recipient SNPs were associated significantly with the rate of incidence of active CMV infection, nor with the need for pre-emptive antiviral therapy. Both the duration of CMV DNAemia and the plasma CMV DNA peak load during episodes were significantly higher in patients harboring the donor (but not the recipient) chemokine receptor 5 A/A genotype, than in their A/G and G/G counterparts (P = 0.022 and P = 0.045, respectively). The data reported suggest that SNPs in chemokine receptor 5 may influence the dynamics of CMV infection in the Allo-SCT setting.
Asunto(s)
Quimiocina CCL2/genética , Infecciones por Citomegalovirus/epidemiología , Interleucina-10/genética , Receptores CCR5/genética , Trasplante de Células Madre/efectos adversos , Receptor Toll-Like 9/genética , Trasplante Homólogo/efectos adversos , Adolescente , Adulto , Anciano , Infecciones por Citomegalovirus/genética , ADN Viral/sangre , Femenino , Estudios de Asociación Genética , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Donantes de Tejidos , Receptores de Trasplantes , Viremia/epidemiología , Viremia/genética , Adulto JovenAsunto(s)
Interferón-alfa/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Rituximab/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
The role of natural killer (NK) cells in affording protection against human cytomegalovirus (CMV) in allogeneic stem cell transplant recipients is largely unknown. The current study was aimed at determining whether NKG2C+ NK cells confer protection from CMV DNAemia early following transplantation in patients lacking mono and polyfunctional CMV pp65 and IE-1-specific CD4+ and CD8+ T-cell responses, as measured by flow cytometry for intracellular cytokine staining. Fourteen out of the 36 patients included in this study developed CMV DNAemia between days +30 and +60 after transplant. Three patients did so after day +60. Peripheral blood levels of CD56(bright) CD16(-/low) and CD56(dim) CD16+ NKG2C+ NK cells measured at day +30 and at day +60 in patients who had or had not subsequent CMV DNAemia did not differ significantly. In addition, no significant correlation was found between CD56(bright) CD16(-/low) (σ = -0.229; P = 0.39) and CD56(dim) CD16+ (σ = -0.285; P = 0.28) NKG2C+ NK-cell levels and initial plasma CMV DNA loads. In summary, the data presented do not support a direct implication of NKG2C+ NK cells in preventing the development of CMV DNAemia or modulating the magnitude of CMV replication at early stages during episodes of CMV DNAemia in allogeneic stem cell transplant patients with unreconstituted CMV-specific T-cell responses.
Asunto(s)
Infecciones por Citomegalovirus/prevención & control , ADN Viral/sangre , Células Asesinas Naturales/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/análisis , Trasplante de Células Madre/efectos adversos , Trasplante Homólogo/efectos adversos , Viremia/prevención & control , Estudios de Cohortes , Infecciones por Citomegalovirus/inmunología , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Células Asesinas Naturales/química , Masculino , Carga Viral , Viremia/inmunologíaRESUMEN
UNLABELLED: The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue to appear. In this trial we evaluated the feasibility, safety and efficacy of rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine followed by consolidation with (90)Y-ibritumomab tiuxetan. Patients received six cycles followed by a single dose of (90)Y-ibritumomab tiuxetan. Thirty patients were enrolled; their median age was 59 years. Twenty-four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60-93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation therapy. In the intent-to-treat population, failure-free, progression-free and overall survival rates at 4 years were 40% (95% confidence interval 20.4-59.6), 52% (95% confidence interval 32.4-71.6) and 81% (95% confidence interval 67.28-94.72), respectively. For patients who received consolidation, failure-free and overall survival rates were 55% (95% confidence interval 31.48-78.52) and 87% (95% confidence interval 70-100), respectively. Hematologic toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3-4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with a median duration of 5 and 12 weeks, respectively. Six (20%) patients died, three due to secondary malignancies (myelodysplastic syndrome and bladder and rectum carcinomas). In conclusion, in our experience, rituximab-hyperCVAD alternated with rituximab-methotrexate-cytarabine and followed by consolidation with (90)Y-ibritumomab tiuxetan was efficacious although less feasible than expected. The unacceptable toxicity observed, especially secondary malignancies, advise against the use of this strategy. TRIAL REGISTRATION: clinical.gov identifier: NCT2005-004400-37.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/epidemiología , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Linfoma de Células del Manto/diagnóstico , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Rituximab , Resultado del TratamientoRESUMEN
Thymidine phosphorylase (TYMP), an enzyme involved in nucleotide synthesis, has been implicated in critical biological processes such as DNA replication, protection against mutations, and tissue repair. In this work, we retrospectively evaluated the influence of a polymorphism in the TYMP gene (rs112723255; G/A) upon the outcome of 448 patients subjected to allogeneic stem cell transplantation (allo-SCT) from an human leukocyte antigen (HLA)-identical sibling donor. The TYMP genotype of patients correlated with overall survival-carriers of the minor allele (A) being at an increased risk of dying after transplantation (hazard ratio, HR = 1.9; P = 0.004). This effect was mostly due to differences in transplant toxicity-related mortality (HR = 2.5; P = 0.029). In addition, the TYMP genotype of donors was associated with the risk of chronic graft-versus-host disease (GVHD)-carriers of the minor allele being at an increased risk of developing this complication ([HR] = 1.7; P = 0.039). The impact of such polymorphism on the risk of chronic GVHD is limited to patients transplanted in early stage disease (HR = 2.2; P = 0.019). The combination of a donor harboring the minor allele with a patient homozygous for the major allele was associated with the highest risk of chronic GVHD (HR = 2.8; P = 0.008). These findings provide the first evidence of the significant impact of the TYMP genotype upon the clinical outcome of patients treated with HLA-identical sibling allo-SCT.
Asunto(s)
Genotipo , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Polimorfismo Genético , Hermanos , Trasplante de Células Madre , Timidina Fosforilasa/genética , Adolescente , Adulto , Anciano , Alelos , Niño , Preescolar , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Prueba de Histocompatibilidad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Trasplante HomólogoRESUMEN
PURPOSE: To describe the contrast-enhanced ultrasound (CEUS) features of liver and biliary lesions related to hepatic artery thrombosis in adult patients with orthotopic liver transplantation. METHODS: Gray-scale ultrasound (US), Doppler US, and CEUS using a hexafluoride-based US contrast media were performed on a series of eight patients with liver transplantation and hepatic artery thrombosis. RESULTS: Six of the cases presented infarctions, seen as parenchymal geographic areas of lack of enhancement. Biliary necrosis, seen as nonenhancing periportal cuff, was seen in one case. Infected biloma, seen as a nonenhancing hilar collection, was present in two cases. Infarction and biloma coexisted in one patient. Two abscesses were seen as a late complication in one case. One of them was seen as a typical necrotic abscess with a central nonenhancing area and peripheral rim enhancement higher than the surrounding liver. The other one was seen as a partially liquefied abscess. CONCLUSION: CEUS was useful to diagnose lesions related to hepatic artery thrombosis in liver transplantation. It enabled distinguishing between them and to define their size and extension better than conventional gray-scale US.
Asunto(s)
Medios de Contraste , Hepatopatías/diagnóstico por imagen , Trasplante de Hígado , Trombosis/diagnóstico por imagen , Absceso/diagnóstico por imagen , Adulto , Femenino , Arteria Hepática/diagnóstico por imagen , Humanos , Aumento de la Imagen/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Infarto/diagnóstico por imagen , Hígado/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Necrosis/diagnóstico por imagen , Complicaciones Posoperatorias/diagnóstico por imagen , Estudios Retrospectivos , Ultrasonografía Doppler en Color/métodosRESUMEN
BACKGROUND: CPX-351 is approved for the treatment of therapy related acute myeloid leukemia (t-AML) and AML with myelodysplastic related changes (MRC-AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real-life patients. METHODS: Retrospective analysis of AML patients treated with CPX-351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry. RESULTS: Median age of 79 patients treated with CPX-351 was 67 years old (interquartile range 62-71), 53 were MRC-AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX-351 was 52%, 60-days mortality 18%, measurable residual disease <0.1% in 54% (12 out of 22) of them. Stem cell transplant (SCT) was performed in 27 patients (34%), median OS was 10.3 months, and 3-year relapse incidence was 50%. Using PSM, we obtained two comparable cohorts treated with CPX-351 (n = 52) or IC (n = 99), without significant differences in CR/CRi (60% vs. 54%) and median OS (10.3 months vs. 9.1 months), although more patients were bridged to SCT in the CPX-351 group (35% vs. 12%). The results were confirmed when only 3 + 7 patients were included in the historical cohort. In multivariable analyses, SCT was associated with better OS (HR 0.33 95% CI: 0.18-0.59), p < 0.001. CONCLUSION: Larger post-authorization studies may provide evidence of the clinical benefits of CPX-351 for AML in the real-life setting.
Asunto(s)
Citarabina , Leucemia Mieloide Aguda , Humanos , Anciano , Estudios Retrospectivos , Citarabina/uso terapéutico , Inducción de RemisiónRESUMEN
BACKGROUND: Solid-organ transplant (SOT) recipients are considered to be at increased risk for toxoplasmosis. However, risk factors for this infection have not been assessed. The aim of this study was to determine the risk factors, clinical features, and outcomes of toxoplasmosis in SOT recipients. METHODS: A multicenter, matched case-control study (1:2 ratio) was conducted between 2000 and 2009. Control subjects were matched for center, transplant type, and timing. Cases were identified from the hospitals' microbiology and transplantation program databases. Logistic regression was performed to identify independent risk factors. RESULTS: Twenty-two cases (0.14%) of toxoplasmosis were identified among 15 800 SOTs performed in 11 Spanish hospitals, including 12 heart, 6 kidney, and 4 liver recipients. Diagnosis was made by seroconversion (n = 17), histopathologic examination (n = 5), polymerase chain reaction (n = 2), and autopsy (n = 2). In a comparison of case patients with 44 matched control subjects, a negative serostatus prior to transplantation was the only independent risk factor for toxoplasmosis (odds ratio, 15.12 [95% confidence interval, 2.37-96.31]; P = .004). The median time to diagnosis following transplantation was 92 days. Primary infection occurred in 18 (81.8%) cases. Manifestations included pneumonitis (n = 7), myocarditis (n = 5), brain abscesses (n = 5), chorioretinitis (n = 3), lymph node enlargement (n = 2), hepatosplenomegaly (n = 2), and meningitis (n =1). Five patients (22.7%) had disseminated disease. Crude mortality rate was 13.6% (3 of 22 patients). CONCLUSIONS: Although uncommon, toxoplasmosis in SOT patients causes substantial morbidity and mortality. Seronegative recipients are at high risk for developing toxoplasmosis and should be given prophylaxis and receive careful follow-up.
Asunto(s)
Trasplante de Órganos/efectos adversos , Toxoplasmosis/etiología , Toxoplasmosis/patología , Adolescente , Adulto , Anciano , Antiinfecciosos/uso terapéutico , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prednisona/farmacología , Factores de Riesgo , Adulto JovenRESUMEN
Immune mechanisms involved in control of cytomegalovirus (CMV) infection in the allogeneic stem cell transplantation setting have not been fully disclosed. CMV pp65 and IE-1-specific CD8(+) T cells expressing IFN-γ, TNF-α, and CD107a, alone or in combination, and NKG2C(+) NK cells were prospectively enumerated during 13 episodes of CMV DNAemia. The expansion of monofunctional and polyfunctional CD8(+) T cells was associated with CMV DNAemia clearance. The size and functional diversity of the expanding CD8(+) T-cell population was greater in self-resolved episodes than in episodes treated with antivirals. These differences were related to the magnitude of expansion of cognate antigen IFN-γ CD4(+) T cells. The resolution of CMV DNAemia was associated frequently with a marked expansion of both CD56(dim) /CD16(+) NK cells and NKG2C(+) CD56(bright) /CD16(-) NK cells. The data lend support to the role of polyfunctional CD8(+) T cells in controlling CMV replication in the allogeneic stem cell transplantation setting, and suggest that NKG2C(+) NK cells may be involved critically in the resolution of CMV DNAemia episodes.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Citomegalovirus/inmunología , Células Asesinas Naturales/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/inmunología , Trasplante de Células Madre , Adulto , Antígeno CD56/metabolismo , Linfocitos T CD8-positivos/virología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , ADN Viral/sangre , Femenino , Humanos , Interferón gamma/metabolismo , Células Asesinas Naturales/virología , Proteína 1 de la Membrana Asociada a los Lisosomas/metabolismo , Masculino , Persona de Mediana Edad , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Fosfoproteínas/inmunología , Receptores de IgG/metabolismo , Trasplante Homólogo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas de la Matriz Viral/inmunología , Adulto JovenRESUMEN
BACKGROUND: Although Hodgkin's lymphoma is a highly curable disease with modern chemotherapy protocols, some patients are primary refractory or relapse after first-line chemotherapy or even after high-dose therapy and autologous stem cell transplantation. We investigated the potential role of allogeneic stem cell transplantation in this setting. DESIGN AND METHODS: In this phase II study 92 patients with relapsed Hodgkin's lymphoma and an HLA-identical sibling, a matched unrelated donor or a one antigen mismatched, unrelated donor were treated with salvage chemotherapy followed by reduced intensity allogeneic transplantation. Fourteen patients showed refractory disease and died from progressive lymphoma with a median overall survival after trial entry of 10 months (range, 6-17). Seventy-eight patients proceeded to allograft (unrelated donors, n=23). Fifty were allografted in complete or partial remission and 28 in stable disease. Fludarabine (150 mg/m(2) iv) and melphalan (140 mg/m(2) iv) were used as the conditioning regimen. Anti-thymocyte globulin was additionally used as graft-versus-host-disease prophylaxis for recipients of grafts from unrelated donors. RESULTS: The non-relapse mortality rate was 8% at 100 days and 15% at 1 year. Relapse was the major cause of failure. The progression-free survival rate was 47% at 1 year and 18% at 4 years from trial entry. For the allografted population, the progression-free survival rate was 48% at 1 year and 24% at 4 years. Chronic graft-versus-host disease was associated with a lower incidence of relapse. Patients allografted in complete remission had a significantly better outcome. The overall survival rate was 71% at 1 year and 43% at 4 years. CONCLUSIONS: Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin's lymphoma. The reduced intensity conditioning approach significantly reduced non-relapse mortality; the high relapse rate represents the major remaining challenge in this setting. The HDR-Allo trial was registered in the European Clinical Trials Database (EUDRACT, https://eudract.ema.europa.eu/) with number 02-0036.
Asunto(s)
Enfermedad de Hodgkin/cirugía , Trasplante de Células Madre/métodos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Europa (Continente) , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Prevención Secundaria , Trasplante de Células Madre/mortalidad , Tasa de Supervivencia , Acondicionamiento Pretrasplante/mortalidad , Trasplante Homólogo/mortalidad , Adulto JovenRESUMEN
The coexistence of skin-limited Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD) is an exceptional finding. The association of lymphomas and histiocytosis is also infrequent. We report the case of a 68-year-old man which presented an exceptional association of cutaneous LCH and RDD and splenic marginal zone lymphoma. He was stable for few years. Suddenly, the patient was admitted into Hematology Department with a remarkable enlargement of spleen and liver without enlargement of lymphadenopathies or skin lesions flare. He died 24 h later despite treatment with systemic chemotherapy combined with prednisone. Pre-mortem biopsy showed infiltration with histiocytic sarcoma. We think that a transdifferentiation phenomenon could explain our case, although we could not show a clonal relationship between the cutaneous and the liver diseases. We also want to pay attention to the fact that a fast transformation to a more aggressive disease can occur long time after the presentation of the first lesion, a problem that stresses the importance of performing a close and permanent follow-up of these patients.
Asunto(s)
Sarcoma Histiocítico/complicaciones , Histiocitosis de Células de Langerhans/complicaciones , Histiocitosis Sinusal/complicaciones , Neoplasias Hepáticas/complicaciones , Linfoma de Células B de la Zona Marginal/complicaciones , Neoplasias Primarias Secundarias , Neoplasias del Bazo/complicaciones , Anciano , Resultado Fatal , Sarcoma Histiocítico/patología , Histiocitosis de Células de Langerhans/patología , Histiocitosis Sinusal/patología , Humanos , Neoplasias Hepáticas/patología , Linfoma de Células B de la Zona Marginal/patología , Masculino , Neoplasias del Bazo/patologíaRESUMEN
High Grade B Cell Lymphoma, NOS, and High Grade B Cell Lymphoma with Dual Hit or Triple Hit have been recently recategorized in the 2016 revision of the WHO classification of lymphoid neoplasms. In this study we have characterized the genetic, histopathological, and clinical features of a series of this type of lymphoid neoplasia (17 HGBCL NOS and 53 HGBCL DH/TH).HGBCL NOS showed better response to first line treatment than HGBCL with DH/TH but no significant differences in PFS or OS were found between the two categories. Survival analysis in the whole cohort of cases found that only the presence of BCL2 translocation was significantly associated with PFS. Other clinical features such as IPI, LDH or stage were equivalent in both categories. Furthermore, both high grade and DLBCL morphological patterns showed equivalent PFS and OS in this set of High grade BCL NOS/DH/TH.Key pointsBCL2 translocation in High Grade B Cell Lymphoma NOS and High Grade B Cell Lymphoma with DH/TH is associated with reduced progression free survival.Both high grade and DLBCL morphological patterns showed equivalent outcome regarding PFS and OS in HGBCL.
Asunto(s)
Linfoma de Células B Grandes Difuso , Estudios de Cohortes , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Translocación GenéticaRESUMEN
Human herpesvirus-6 (HHV-6) may enhance cytomegalovirus (CMV) replication in allogeneic stem cell transplant (allo-SCT) recipients either through direct or indirect mechanisms. Definitive evidence supporting this hypothesis are lacking. We investigated the effect of HHV-6 replication on active CMV infection in 68 allo-SCT recipients. Analysis of plasma HHV-6 and CMV DNAemia was performed by real-time PCR. Enumeration of pp65 and IE-1 CMV-specific IFNgamma CD8(+) and CD4(+)T cells was performed by intracellular cytokine staining. HHV-6 DNAemia occurred in 39.8% of patients, and was significantly associated with subsequent CMV DNAemia in univariate (P=.01), but not in multivariate analysis (P=.65). The peak of HHV-6 DNAemia was not predictive of the development of CMV DNAemia. Timing and kinetics of active CMV infection were comparable in patients either with or without a preceding episode of HHV-6 DNAemia. The occurrence of HHV-6 DNAemia had no impact on CMV-specific T cell immunity reconstitution early after transplant. The receipt of a graft from an HLA-mismatched donor was independently associated with HHV-6 (P=.009) and CMV reactivation (P=.04). The data favor the hypothesis that a state of severe immunosuppression leads to HHV-6 and CMV coactivation, but argue against a role of HHV-6 in predisposing to the development of CMV DNAemia or influencing the course of active CMV infection.
Asunto(s)
Infecciones por Citomegalovirus/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpesvirus Humano 6/fisiología , Replicación Viral , Adolescente , Adulto , Anciano , Infecciones por Citomegalovirus/virología , ADN Viral/sangre , Femenino , Humanos , Terapia de Inmunosupresión/efectos adversos , Masculino , Persona de Mediana Edad , Infecciones por Roseolovirus/complicaciones , Trasplante Homólogo , Activación Viral , Adulto JovenRESUMEN
Adults with high-risk acute lymphoblastic leukemia (HR-ALL) have a poor outcome with standard chemotherapy and usually undergo unrelated stem cell transplantation (SCT) if a matched sibling donor is not available. We analyzed the outcome of adult patients with unrelated SCT for HR-ALL and studied the possible effect of the hematopoietic stem cell source of the transplant. A total of 149 adult patients (median age, 29 years, range, 15-59 years) with HR-ALL underwent unrelated SCT in 13 Spanish institutions between 2000 and 2007. Patients in first complete remission (CR1) at transplantation had at least one adverse prognostic factor (advanced age, adverse cytogenetics, hyperleukocytosis, or slow response to induction therapy). ALL was in CR1 in 81 patients (54%), in second CR (CR2) in 37 patients (25%), in third CR (CR3) in 11 patients (7%), and with overt disease in 20 patients (13%). The hematopoietic source was unrelated cord blood (UCB) in 62 patients and an unrelated donor (UD) in 87 patients. The patients undergoing UCB-SCT and UD-SCT were comparable in terms of the main clinical and biological features of ALL, except for a higher frequency of patients with more overt disease in the UCB-SCT group. There was no statistically significant difference in overall survival (OS) or disease-free survival (DFS) at 5 years between the 2 groups. Treatment-related mortality (TRM) was significantly lower in the UCB-SCT group (P = .021). The probability of relapse at 1 year was 17% (95% confidence interval [CI], 7%-27%) for the UD-SCT group and 27% (95% CI, 14%-40%) for the UCB-SCT group (P = .088), respectively. Only disease status at transplantation (CR1, 41% [95% CI, 18%-64%] vs CR2, 51% [95% CI, 17%-85%] vs advanced disease, 66% [95% CI, 46%-86%]; P = .001) and the absence of chronic graft-versus-host disease (74% [95% CI, 46%-100%] vs 33% [95% CI, 17%-49%]; P = .034) were significant factors for relapse. All unrelated transplantation modalities were associated with high treatment-related mortality for adult HR-ALL patients without a sibling donor. UCB-SCT and UD-SCT were found to be equivalent options. Disease status at transplantation and chronic GVHD were the main factors influencing relapse in both transplantation modalities.
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Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Supervivencia sin Enfermedad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Donadores Vivos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Sobrevivientes , Resultado del Tratamiento , Adulto JovenRESUMEN
The dynamics of CMV pp65 and IE-1-specific IFNgamma-producing CD8(+) (IFNgamma CD8(+)) and CD4(+) (IFNgamma CD4(+)) T cells and CMV DNAemia were assessed in 19 pre-emptively treated episodes of active CMV infection. Peripheral counts of IFNgamma CD8(+) and IFNgamma CD4(+) T cells inversely correlated with CMV DNAemia levels (P = <0.001 and P = 0.003, respectively). A threshold value of 1.3 cells/microl predicting CMV DNAemia clearance was established for IFNgamma CD8(+) T cells (PPV, 100%; NPV, 93%) and for IFNgamma CD4(+) T cells (PPV, 100%; NPV, 75%). Undetectable T-cell responses were usually observed at the time of initiation of pre-emptive therapy. Either a rapid (within 7 days) or a delayed (median 31 days) expansion of both T-cell populations concomitant with CMV DNAemia clearance was observed in 5 and 8 episodes, respectively. An inconsistent or a lack of expansion of both T-cell subsets was related to a persistent CMV DNAemia. Robust and maintained CMV-specific T-cell responses after CMV DNAemia clearance and cessation of antiviral therapy were associated with a null incidence of relapsing infections at least during the following month. Data obtained in the present study may be helpful in the design of therapeutic strategies for the management of active CMV infections in the allo-SCT recipient.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por Citomegalovirus/diagnóstico , Citomegalovirus/inmunología , Fosfoproteínas/sangre , Trasplante de Células Madre , Proteínas de la Matriz Viral/sangre , Adolescente , Adulto , Anciano , Citomegalovirus/genética , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/inmunología , ADN Viral/sangre , Determinación de Punto Final/métodos , Femenino , Humanos , Proteínas Inmediatas-Precoces/inmunología , Interferón gamma/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Especificidad del Receptor de Antígeno de Linfocitos T , Trasplante HomólogoRESUMEN
The remission rate with plasma exchange (PE) in thrombotic thrombocytopenic purpura (TTP) exceeds 80%, but the disease relapses in up to 20-30% of the cases. Clinical characteristics and response to treatment of relapsed TTP are not well defined. The objective of the present study was to compare the clinical and biological characteristics at presentation and the response to treatment between de novo and relapsed TTP. For such purpose, a total of 102 episodes of idiopathic TTP (70 de novo and 32 relapses) included in a recent multicentric prospective cohort study were analysed. All patients were homogeneously treated with daily PE and costicosteroids. In comparison with de novo TTP, episodes of relapsed TTP showed a higher Hb level (median, 122 g/l versus 91 g/l, p < 0.001) and lower serum lactate dehydrogenase (2.2- versus 4.5-fold above the upper limit of normality, p < 0.001). Neurological symptoms and fever were less frequently observed in patients with relapsed TTP than in patients with de novo TTP. Patients with relapsed TTP needed fewer PE sessions (five versus ten, p = 0.02) and a smaller volume of plasma (221 ml/kg versus 468 ml/kg, p = 0.004) to achieve remission than those with de novo TTP. There was no significant difference in the rate of recrudescence under treatment, the need of complementary treatments or the frequency of refractoriness to PE therapy. In conclusion, relapsed TTP has a milder clinical profile and responds more easily to PE than de novo TTP.