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ABSTRACT: There is a paucity of information on how to select the most appropriate unrelated donor (UD) in hematopoietic stem cell transplantation (HSCT) using posttransplant cyclophosphamide (PTCy). We retrospectively analyzed the characteristics of 10/10 matched UDs (MUDs) and 9/10 mismatched UDs (MMUDs) that may affect transplant outcomes in patients with acute myeloid leukemia (AML) in first or second complete remission (CR1 or CR2). The primary end point was leukemia-free survival (LFS). Overall, 1011 patients were included with a median age of 54 years (range, 18-77). Donors had a median age of 29 years (range, 18-64); 304 (30%) were females, of which 150 (15% of the whole group) were donors to male recipients, and 621 (61%) were MUDs; 522 (52%) had negative cytomegalovirus (CMV-neg) serostatus, of which 189 (19%) were used for CMV-neg recipients. Donor age older than 30 years had a negative impact on relapse (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.06-1.8), LFS (HR, 1.4; 95% CI, 1.12-1.74), overall survival (HR 1.45; 95% CI, 1.14-1.85) and graft-versus-host disease (GVHD) free, relapse-free survival (HR, 1.29; 95% CI, 1.07-1.56). In addition, CMV-neg donors for CMV-neg recipients were associated with improved LFS (HR, 0.74; 95% CI, 0.55-0.99). The use of MMUD and female donors for male recipients did not significantly impact any transplant outcomes. For patients undergoing HSCT from a UD with PTCy for AML, donor age <30 years significantly improves survival. In this context, donor age might be prioritized over HLA match considerations. In addition, CMV-neg donors are preferable for CMV-neg recipients. However, further research is needed to validate and refine these recommendations.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Donante no Emparentado , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Adolescente , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Estudios Retrospectivos , Adulto Joven , Prueba de Histocompatibilidad , Ciclofosfamida/uso terapéutico , Factores de Edad , Enfermedad Injerto contra Huésped/etiología , Antígenos HLA/inmunología , Supervivencia sin EnfermedadRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented burden on healthcare systems around the world and a severe global socioeconomic crisis, with more than 750 million confirmed cases and at least 7 million deaths reported by 31st December 2023. The DEFI-VID19 study (ClinicalTrials.gov NCT04335201), a phase II, single-arm, multicenter, open-label trial was designed in mid-2020 to assess the safety and efficacy of defibrotide in treating patients with COVID-19 pneumonia. Defibrotide was administered at a dose of 25 mg/kg/d intravenously, divided into four daily doses over a planned 14-day period for patients with COVID-19 pneumonia receiving non-invasive ventilation. The primary endpoint was Respiratory Failure Free Survival (RFFS); Overall Survival (OS), the number of post-recovery days, and adverse events were the secondary endpoints. For comparison, a contemporaneous control cohort receiving standard of care only was retrospectively selected by applying the eligibility criteria of the DEFI-VID19 trial. To adjust for the imbalance between the two cohorts in terms of baseline variable distributions, an outcome regression analysis was conducted. In adjusted analysis, patients receiving defibrotide reported a trend towards higher RFFS (HR=0.71[0.95CI: 0.34 to 1.29, P= .138]) and OS (HR=0.78[0.95CI: 0.33 to 1.53, P= .248]) and showed a significantly increased number of post-recovery days (difference in means: 3.61[ 0.95CI: 0.97 to 6.26, P= .0037]). Despite concomitant thromboprophylaxis with low molecular weight heparin, the safety profile of defibrotide proved to be favorable. Taken together, our findings suggest that defibrotide may represent a valuable addition to the COVID-19 therapeutic options.
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After allogeneic hematopoietic stem cell transplantation (HSCT), the emergence of circulating cytomegalovirus (CMV)- specific T cells correlates with protection from CMV reactivation, an important risk factor for non-relapse mortality. However, functional assays measuring CMV-specific cells are time-consuming and often inaccurate at early time-points. We report the results of a prospective single-center, non-interventional study that identified the enumeration of Dextramerpositive CMV-specific lymphocytes as a reliable and early predictor of viral reactivation. We longitudinally monitored 75 consecutive patients for 1 year after allogeneic HSCT (n=630 samples). The presence of ≥0.5 CMV-specific CD8+ cells/mL at day +45 was an independent protective factor from subsequent clinically relevant reactivation in univariate (P<0.01) and multivariate (P<0.05) analyses. Dextramer quantification correlated with functional assays measuring interferon-γ production, and allowed earlier identification of high-risk patients. In mismatched transplants, the comparative analysis of lymphocytes restricted by shared, donor- and host-specific HLA revealed the dominant role of thymic-independent CMV-specific reconstitution. Shared and donor-restricted CMV-specific T cells reconstituted with similar kinetics in recipients of CMV-seropositive donors, while donor-restricted T-cell reconstitution from CMV-seronegative grafts was impaired, indicating that in primary immunological responses the emergence of viral-specific T cells is largely sustained by antigen encounter on host infected cells rather than by cross-priming/presentation by non-infected donor-derived antigen-presenting cells. Multiparametric flow cytometry and high-dimensional analysis showed that shared-restricted CMV-specific lymphocytes display a more differentiated phenotype and increased persistence than donor-restricted counterparts. In this study, monitoring CMV-specific cells by Dextramer assay after allogeneic HSCT shed light on mechanisms of immune reconstitution and enabled risk stratification of patients, which could improve the clinical management of post-transplant CMV reactivations.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Humanos , Citomegalovirus/fisiología , Linfocitos T , Infecciones por Citomegalovirus/etiología , Estudios Prospectivos , Trasplante Homólogo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Antígenos HLA , Linfocitos T CD8-positivosRESUMEN
X-linked chronic granulomatous disease is a rare disease caused by mutations in the CYBB gene. While more extensive knowledge is available on genetics, pathogenesis, and possible therapeutic options, mitochondrial activity and its implications on patient monitoring are still not well-characterized. We have developed a novel protocol to study mitochondrial activity on whole blood of XCGD patients before and after transplantation, as well as on XCGD carriers. Here we present results of these analyses and of the restoration of mitochondrial activity in hyperinflamed X-linked Chronic Granulomatous Disease after hematopoietic stem cell transplantation. Moreover, we show a strong direct correlation between mitochondrial activity, chimerism, and DHR monitored before and after transplantation and in XCGD carriers. In conclusion, based on these findings, we suggest testing this new ready-to-use marker to better characterize patients before and after treatment and to investigate disease expression in carriers.
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Enfermedad Granulomatosa Crónica , Trasplante de Células Madre Hematopoyéticas , Humanos , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/terapia , Quimerismo , Fagocitos , HeterocigotoRESUMEN
Letermovir (LMV) inhibits HCMV replication by binding to components of the HCMV-terminase complex showing a potential role in prevention of HCMV-related complications in allogenic hematopoietic stem cell transplant recipients (allo-HSCTRs). However, little is known about breakthrough HCMV infection and the relevance of HCMV DNAemia during prophylaxis. We reported the results of a multicenter prospective study involving five Italian centers in the management of HCMV DNAemia in 75 adult HCMV-seropositive allo-HSCTRs undergoing LMV prophylaxis. The aim of the present study was to characterize the presence of real HCMV reactivation during LMV prophylaxis. Then, the presence of circulating infectious HCMV particles was determined by virus isolation and degradation of free-floating viral DNA. This report provides the first evidence that during LMV prophylaxis the clinical relevance of HCMV DNAemia should be critically considered.
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Antivirales , Citomegalovirus , Acetatos , Antivirales/uso terapéutico , Citomegalovirus/genética , ADN Viral/genética , Estudios Prospectivos , Quinazolinas , Células MadreRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before allo-HSCT has not been established. We conducted a Phase II study to evaluate the tolerability and efficacy of clofarabine and treosulfan as conditioning regimen before allo-HSCT. The primary objective was to evaluate the cumulative incidence of nonrelapse mortality (NRM) on day +100. Forty-four patients (36 with acute myelogenous leukemia, 5 with acute lymphoblastic leukemia, 3 with myelodysplastic syndromes) were enrolled. The median patient age was 47 years, and the median duration of follow-up was 27 months. The conditioning regimen was based on clofarabine 40 mg/m2 (days -6 to -2) and treosulfan 14 g/m2 (days -6 to -4). Allogeneic hematopoietic stem cells were derived from a sibling (nâ¯=â¯22) or a well-matched unrelated donor (nâ¯=â¯22). Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, rituximab, cyclosporine, and a short-course of methotrexate. The regimen allowed for rapid engraftment and a 100-day NRM of 18%, due mainly to bacterial infections. The incidences of grade II-IV acute GVHD and chronic GVHD were 16% and 19%, respectively. The rates of overall survival (OS), progression-free survival, and relapse at 2 years were 51%, 31%, and 50%, respectively. Significantly different outcomes were observed between patients with low-intermediate and patients with high-very high Disease Risk Index (DRI) scores (1-year OS, 78% and 24%, respectively). Our findings show that the use of treosulfan and clofarabine as a conditioning regimen for allo-HSCT is feasible, with a 78% 1-year OS in patients with a low-intermediate DRI score. However, 1-year NRM was 18%, and despite the intensified conditioning regimen, relapse incidence remains a major issue in patients with poor prognostic risk factors.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Clofarabina , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Persona de Mediana Edad , Acondicionamiento PretrasplanteRESUMEN
Incidence and outcome of infections after allogeneic hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis are largely unknown. Study aims were to estimate the incidence of pre-engraftment bloodstream infections (PE-BSIs) and viral infections (VIs; cytomegalovirus [CMV], adenovirus [ADV], human herpes virus 6 [HHV6], and BK-polyomavirus hemorrhagic-cystitis [BKPyV-HC]), their predictive factors, and infection-related mortality (IRM) after HSCT with PT-Cy. We analyzed 235 patients: 62%, 21%, and 17% received haploidentical (haplo), matched-unrelated donor (MUD), and matched-related donor, respectively. Overall, 72 patients had 77 PE-BSI episodes at a median time of 13 days after HSCT: cumulative incidence function (CIF) at 28 days was 32%, without differences among donor types (P = .988). By multivariate analysis, CIF of PE-BSI was higher in patients with severe neutropenia before HSCT (adjusted hazard ratio [AHR] = 2.90) and in multidrug-resistant Gram-negative bacteria rectal carriers (AHR = 2.68). IRM at 30 days was 5%, without differences by donor type (P = .106). Overall, 208 patients experienced ≥1 VIs (first occurrence among CMV, HHV6, ADV, BKPyV-HC) at a median time of 20 days after HSCT: CIF at 90 days was 91%, significantly higher in MUD and haplo (P = .0089). By multivariate analysis, also acute GVHD grade ≥2 (AHR = 1.32) and host/donor CMV-serology mismatch (positive/positive versus negative/negative: AHR = 2.95, positive/negative versus negative/negative: AHR = 2.41, negative/positive versus negative/negative: AHR = 2.35) affected VIs occurrence. IRM at 180 days was 8%, without differences among donor types (P = .106). In conclusion, study results did not show a significant impact of donor type on PE-BSI incidence; conversely, MUD and haploidentical transplants retained a higher occurrence of VIs in the early phase after HSCT.
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Cistitis , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Donante no EmparentadoRESUMEN
The use of posttransplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis has revolutionized haploidentical hematopoietic stem cell transplantation (HSCT), allowing safe infusion of unmanipulated T cell-replete grafts. PT-Cy selectively eliminates proliferating alloreactive T cells, but whether and how it affects natural killer (NK) cells and their alloreactivity is largely unknown. Here we characterized NK cell dynamics in 17 patients who received unmanipulated haploidentical grafts, containing high numbers of mature NK cells, according to PT-Cy-based protocols in 2 independent centers. In both series, we documented robust proliferation of donor-derived NK cells immediately after HSCT. After infusion of Cy, a marked reduction of proliferating NK cells was evident, suggesting selective purging of dividing cells. Supporting this hypothesis, proliferating NK cells did not express aldehyde dehydrogenase and were killed by Cy in vitro. After ablation of mature NK cells, starting from day 15 after HSCT and favored by the high levels of interleukin-15 present in patients' sera, immature NK cells (CD62L+NKG2A+KIR-) became highly prevalent, possibly directly stemming from infused hematopoietic stem cells. Importantly, also putatively alloreactive single KIR+ NK cells were eliminated by PT-Cy and were thus decreased in numbers and antileukemic potential at day 30 after HSCT. As a consequence, in an extended series of 99 haplo-HSCT with PT-Cy, we found no significant difference in progression-free survival between patients with or without predicted NK alloreactivity (42% vs 52% at 1 year, P = NS). Our data suggest that the majority of mature NK cells infused with unmanipulated grafts are lost upon PT-Cy administration, blunting NK cell alloreactivity in this transplantation setting.
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Ciclofosfamida/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunosupresores/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Adulto , Anciano , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Células Asesinas Naturales/citología , Células Asesinas Naturales/trasplante , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Multidrug-resistant Gram-negative bacteria (MDR-GNB) are an emerging cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Three-hundred forty-eight consecutive patients transplanted at our hospital from July 2012 to January 2016 were screened for a pretransplant MDR-GNB colonization and evaluated for clinical outcomes. A pretransplant MDR-GNB colonization was found in 16.9% of allo-HSCT and in 9.6% of auto-HSCT recipients. Both in auto- and in allo-HSCT, carriers of a MDR-GNB showed no significant differences in overall survival (OS), transplant-related mortality (TRM), or infection-related mortality (IRM) compared with noncarriers. OS at 2 years for carriers compared with noncarriers was 85% versus 81% (P = .262) in auto-HSCT and 50% versus 43% (P = .091) in allo-HSCT. TRM at 2 years was 14% versus 5% (P = .405) in auto-HSCT and 31% versus 25% (P = .301) in allo-HSCT. IRM at 2 years was 14% versus 2% (P = .142) in auto-HSCT and 23% versus 14% (P = .304) in allo-HSCT. In multivariate analysis, only grade III to IV acute graft-versus-host disease was an independent factor for reduced OS (P < .001) and increased TRM (P < .001) and IRM (P < .001). During the first year after transplant, we collected 73 GNB bloodstream infectious (BSI) episodes in 54 patients, 42.4% of which sustained by a MDR-GNB. Rectal swabs positivity associated with the pathogen causing subsequent MDR-GNB BSI episodes in 13 of 31 (41.9%). Overall, OS at 4 months from MDR-GNB BSI episode onset was of 67.9%, with a 14-day attributed mortality of 12.9%, not being significantly different between carriers and noncarriers (P = .207). We conclude that in this extended single-center experience, a pretransplant MDR-GNB colonization did not significantly influence OS, TRM, and IRM both in auto- and allo-HSCT settings and that MDR-GNB attributed mortality can be controlled in carriers when an early pre-emptive antimicrobial therapy is started in case of neutropenic fever.
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Bacteriemia/etiología , Farmacorresistencia Bacteriana Múltiple/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Autólogo/efectos adversos , Trasplante Homólogo/efectos adversos , Adulto , Anciano , Bacteriemia/patología , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo/métodos , Trasplante Homólogo/métodos , Adulto JovenAsunto(s)
Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped/diagnóstico , Trasplante de Células Madre Hematopoyéticas , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/microbiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Pronóstico , Receptores de Trasplantes , Trasplante Homólogo/efectos adversosRESUMEN
Hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA) is a severe complication whose pathophysiology is unknown. We describe 6 patients in which the disease was associated with complement regulatory gene abnormalities received from their respective donors. It is suggested that mutated and transplanted monocyte-derived cells are responsible for production of abnormal proteins, complement dysregulation, and, ultimately, for the disease. This observation might have important drawbacks as far as HSCT-TMA pathophysiology and treatment are concerned.
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Proteínas del Sistema Complemento/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Mutación , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/genética , Adolescente , Anemia de Diamond-Blackfan/inmunología , Anemia de Diamond-Blackfan/patología , Anemia de Diamond-Blackfan/terapia , Anemia de Células Falciformes/inmunología , Anemia de Células Falciformes/patología , Anemia de Células Falciformes/terapia , Proteínas del Sistema Complemento/inmunología , Expresión Génica , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Persona de Mediana Edad , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/inmunología , Donantes de Tejidos , Trasplante Homólogo , Adulto JovenRESUMEN
Infection-related mortality (IRM) is a substantial component of nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). No scores have been developed to predict IRM before transplantation. Pretransplantation clinical and biochemical data were collected from a study cohort of 607 adult patients undergoing allo-HSCT between January 2009 and February 2017. In a training set of 273 patients, multivariate analysis revealed that age >60 years (P = .003), cytomegalovirus host/donor serostatus different from negative/negative (P < .001), pretransplantation IgA level <1.11 g/L (P = .004), and pretransplantation IgM level <.305 g/L (P = .028) were independent predictors of increased IRM. Based on these results, we developed and subsequently validated a 3-tiered weighted prognostic index for IRM in a retrospective set of patients (n = 219) and a prospective set of patients (n = 115). Patients were assigned to 3 different IRM risk classes based on this index score. The score significantly predicted IRM in the training set, retrospective validation set, and prospective validation set (P < .001, .044, and .011, respectively). In the training set, 100-day IRM was 5% for the low-risk group, 11% for the intermediate-riak group, and 16% for the high-risk groups. In the retrospective validation set, the respective 100-day IRM values were 7%, 17%, and 28%, and in the prospective set, they were 0%, 5%, and 7%. This score predicted also overall survival (P < .001 in the training set, P < 041 in the retrospective validation set, and P < .023 in the prospective validation set). Because pretransplantation levels of IgA/IgM can be modulated by the supplementation of enriched immunoglobulins, these results suggest the possibility of prophylactic interventional studies to improve transplantation outcomes.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones/mortalidad , Adolescente , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Inmunoglobulinas/uso terapéutico , Infecciones/etiología , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Factores de Riesgo , Aprendizaje Automático Supervisado , Trasplante Homólogo , Adulto JovenRESUMEN
BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for patients with acute myeloid leukemia (AML). However, post-HCT relapse and regimen-related toxicity remain significant barriers to long-term survival. In recent years, new conditioning regimens have been explored to improve transplantation outcomes in patients with AML. Treosulfan combines a potent immunosuppressive and antileukemic effect with a low toxicity profile. METHODS: To investigate the role of treosulfan-based conditioning, the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party performed a registry analysis of 520 adult patients with AML who received treosulfan-based conditioning and underwent HCT between 2000 and 2012, including 225 patients in first complete remission, 107 in second or later complete remission, and 188 with active/advanced disease 188 (88 with primary refractory disease). The median patient age was 57 years (range, 20-73 years). Donors were human leukocyte antigen-identical siblings (n = 187), unrelated donors (n = 235), or mismatched related donors (n = 98). Conditioning regimens included treosulfan (42 g/m2 [n = 396], 36 g/m2 [n = 109], or 30 g/ m2 [n = 15]) with fludarabine or alkylating agents followed by infusion of hematopoietic stem cells (bone marrow, n = 52; peripheral blood, n = 468). RESULTS: At a median follow-up of 61 months, the 5-year overall survival, leukemia-free survival, relapse incidence, and nonrelapse mortality rates were 38%, 33%, 42%, and 25%, respectively. The incidence of grade II-IV acute and chronic graft-versus-host disease was 24% (grade III-V, 11%) and 38%, respectively. Only 11 patients (2%) developed veno-occlusive disease, with two deaths (0.4%) from veno-occlusive disease. CONCLUSIONS: Treosulfan-based conditioning regimens provide an acceptable long-term survival with favorable nonrelapse mortality and a very low risk of veno-occlusive disease. Further studies are needed to optimize the treosulfan-based conditioning regimen for patients with AML. Cancer 2017;123:2671-79. © 2017 American Cancer Society.
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Antineoplásicos Alquilantes/uso terapéutico , Busulfano/análogos & derivados , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapéutico , Sistema de Registros , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Alquilantes/uso terapéutico , Busulfano/uso terapéutico , Causas de Muerte , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Adulto JovenRESUMEN
Memory stem T cells (TSCM) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked TSCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived TSCM are highly enriched early after HSCT. We showed at the antigen-specific and clonal level that TSCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of TSCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting TSCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT.
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Trasplante de Células Madre Hematopoyéticas , Memoria Inmunológica , Linfopoyesis , Linfocitos T/inmunología , Linfocitos T/fisiología , Adulto , Donantes de Sangre , Diferenciación Celular/inmunología , Proliferación Celular , Haplotipos , Humanos , Memoria Inmunológica/inmunología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Trasplante HomólogoRESUMEN
Reduced-toxicity conditioning with fludarabine and treosulfan is a dose-intensive regimen with enhanced anti-leukemia effect and acceptable toxicity in AML/MDS. HLA-C regulates natural-killer (NK) cell function by inhibiting Killer immunoglobulin-like receptors (KIR) and is divided into C1 and C2 epitopes. The missing-ligand theory suggests that missing recipient KIR ligands drives NK-alloreactivity after SCT, in the absence of HLA-mismatch by activating unlicensed donor NK cells. We analyzed SCT outcomes in 203 patients with AML/MDS, median age 58 years, given SCT from matched-siblings (n = 97) or matched-unrelated donors (n = 106), using two treosulfan doses (total 36 or 42 g/m2 ). 34% expressed one HLA-C group 1 allele (C1C1), 19% one HLA-C group 2 allele (C2C2), and 48% both KIR ligands (C1C2). Median follow-up was 48 months. 5-year relapse, nonrelapse mortality (NRM) and leukemia-free survival (LFS) rates were 38%, 27%, and 36%, respectively. Relapse rates were 43%, 45%, and 26% in patients expressing C1C1, C1C2, and C2C2 ligands, respectively (P = .03). Multivariate-analysis identified chemo-refractory disease (HR 3.1, P = .003), poor cytogenetics (HR 1.7, P = .08), female donor to male recipient (HR 0.4, P = .01) and C2C2 ligands (HR 0.4, P = .04) as independent factors predicting relapse. HLA-C ligands were not associated with GVHD or NRM. LFS was 33%, 30%, and 46%, respectively (P = .07). Chemorefractory disease (HR 3.1, P = .0004) and C2C2 group ligand (HR 0.6, P = .06) independently predicted LFS. Treosulfan dose did not predict any SCT outcome. In conclusion, missing HLA-C group 1 ligand is associated with reduced relapse risk, similar NRM and improved LFS, after HLA-matched SCT with treosulfan conditioning in AML/MDS.
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Busulfano/análogos & derivados , Antígenos HLA-C/genética , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adulto , Anciano , Busulfano/administración & dosificación , Busulfano/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Ligandos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Receptores KIR/genética , Recurrencia , Estudios Retrospectivos , Hermanos , Donante no Emparentado , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Adulto JovenRESUMEN
Human herpesvirus 6 (HHV-6) is increasingly recognized as a potentially life-threatening pathogen in allogeneic hematopoietic stem cell transplantation (alloSCT). We retrospectively evaluated 54 adult patients who developed positivity to HHV-6 after alloSCT. The median time from alloSCT to HHV-6 reactivation was 34 days. HHV-6 was present in plasma samples from 31 patients, in bone marrow (BM) of 9 patients, in bronchoalveolar lavage fluid and liver or gut biopsy specimens from 33 patients, and in cerebrospinal fluid of 7 patients. Twenty-nine patients developed acute graft-versus-host disease (GVHD), mainly grade III-IV, and 15 had concomitant cytomegalovirus reactivation. The median absolute CD3+ lymphocyte count was 207 cells/µL. We reported the following clinical manifestations: fever in 43 patients, skin rash in 22, hepatitis in 19, diarrhea in 24, encephalitis in 10, BM suppression in 18, and delayed engraftment in 11. Antiviral pharmacologic treatment was administered to 37 patients; nonetheless, the mortality rate was relatively high in this population (overall survival [OS] at 1 year, 38% ± 7%). A better OS was significantly associated with a CD3+ cell count ≥200/µL at the time of HHV-6 reactivation (P = .0002). OS was also positively affected by the absence of acute GVHD grade III-IV (P = .03) and by complete disease remission (P = .03), but was not significantly influenced by steroid administration, time after alloSCT, type of antiviral prophylaxis, plasma viral load, or organ involvement. Although HHV-6 detection typically occurred early after alloSCT, better T cell immune reconstitution seems to have the potential to improve clinical outcomes. Our findings provide new insight into the interplay between HHV-6 and the transplanted immune system.
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Herpesvirus Humano 6/fisiología , Infecciones por Roseolovirus/etiología , Trasplante Haploidéntico/efectos adversos , Adulto , Anciano , Antivirales/uso terapéutico , Citomegalovirus , Exantema Súbito/virología , Femenino , Supervivencia de Injerto/inmunología , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 6/inmunología , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Esteroides/uso terapéutico , Análisis de Supervivencia , Trasplante Haploidéntico/mortalidad , Resultado del Tratamiento , Activación Viral , Virosis/tratamiento farmacológico , Virosis/etiología , Virosis/mortalidad , Adulto JovenRESUMEN
Allogeneic transplantation is the only potentially curative strategy for myelofibrosis, even in the era of new drugs that so far only mitigate symptoms. The choice to proceed to allogeneic transplantation is based on several variables including age, disease phase, degree of splenomegaly, donor availability, comorbidities and iron overload. These factors, along with conditioning regimen and time to transplantation, may influence the outcome of ASCT. We report 14 patients affected by myelofibrosis with a median age of 57 years (range, 41-76) receiving a treosulfan-fludarabine based reduced toxicity conditioning. Patients (pts) received a stem cell transplantation from an HLA identical (n = 10) or matched unrelated donor (n = 4). All pts had a complete myeloablation followed by engraftment and in 12 out of 13 evaluated pts donor chimerism was 100% at 1 month. In most cases a reduction of splenomegaly and a reduction (or resolution) of bone marrow fibrosis was observed. After a median follow-up of 39 months (range, 3-106), the 3-year probability of overall survival and disease free survival was 54 +/- 14% and 46 +/- 14%, respectively. The cumulative incidence of non-relapse mortality at 2 years was 39 +/- 15%. Causes of non-relapse mortality were: infection (n = 2), GvHD (n = 2) and haemorrhage (n = 1). We can conclude that a treosulfan and fludarabine based conditioning has a potent myeloablative and anti-disease activity although non-relapse mortality remains high in this challenging clinical setting. Copyright © 2014 John Wiley & Sons, Ltd.
Asunto(s)
Busulfano/análogos & derivados , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/terapia , Trasplante de Células Madre , Acondicionamiento Pretrasplante/métodos , Donante no Emparentado , Anciano , Aloinjertos , Busulfano/administración & dosificación , Busulfano/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Acondicionamiento Pretrasplante/efectos adversos , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell transplantation (HSCT) for FLT3-ITD-positive acute myeloid leukemia (AML), and available therapies are largely unsatisfactory. In this study, we retrospectively collected data on the off-label use of the tyrosine kinase inhibitor sorafenib, either alone or in association with hypomethylating agents and adoptive immunotherapy, in 13 patients with post-transplantation FLT3-ITD-positive AML relapses. Hematological response was documented in 12 of 13 patients (92%), and five of 13 (38%) achieved complete bone marrow remission. Treatment was overall manageable in the outpatient setting, although all patients experienced significant adverse events, especially severe cytopenias (requiring a donor stem cell boost in five patients) and typical hand-foot syndrome. None of the patients developed graft-vs.-host disease following sorafenib alone, whereas this was frequently observed when this was given in association with donor T-cell infusions. Six patients are alive and in remission at the last follow-up, and four could be bridged to a second allogeneic HSCT, configuring a 65 ± 14% overall survival at 100 d from relapse. Taken together, our data suggest that sorafenib might represent a valid treatment option for patients with FLT3-ITD-positive post-transplantation relapses, manageable also in combination with other therapeutic strategies.