RESUMEN
BACKGROUND: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia. METHODS: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months. RESULTS: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome. CONCLUSIONS: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).
Asunto(s)
Anemia Aplásica/terapia , Suero Antilinfocítico/uso terapéutico , Benzoatos/uso terapéutico , Ciclosporina/uso terapéutico , Hidrazinas/uso terapéutico , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Pirazoles/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/genética , Suero Antilinfocítico/efectos adversos , Benzoatos/efectos adversos , Ciclosporina/efectos adversos , Quimioterapia Combinada , Femenino , Humanos , Hidrazinas/efectos adversos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos , Pirazoles/efectos adversos , Receptores de Trombopoyetina/agonistas , Inducción de Remisión , Adulto JovenRESUMEN
Idiopathic aplastic anemia (AA) has 2 key characteristics: an autoimmune response against hematopoietic stem/progenitor cells and regulatory T-cells (Tregs) deficiency. We have previously demonstrated reduction in a specific subpopulation of Treg in AA, which predicts response to immunosuppression. The aims of the present study were to define mechanisms of Treg subpopulation imbalance and identify potential for therapeutic intervention. We have identified 2 mechanisms that lead to skewed Treg composition in AA: first, FasL-mediated apoptosis on ligand interaction; and, second, relative interleukin-2 (IL-2) deprivation. We have shown that IL-2 augmentation can overcome these mechanisms. Interestingly, when high concentrations of IL-2 were used for in vitro Treg expansion cultures, AA Tregs were able to expand. The expanded populations expressed a high level of p-BCL-2, which makes them resistant to apoptosis. Using a xenograft mouse model, the function and stability of expanded AA Tregs were tested. We have shown that these Tregs were able to suppress the macroscopic clinical features and tissue manifestations of T-cell-mediated graft-versus-host disease. These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions. Supplementation of ex vivo expansion cultures of Tregs with high concentrations of IL-2 or delivery of IL-2 directly to patients could improve clinical outcomes in addition to standard immunosuppressive therapy.
Asunto(s)
Anemia Aplásica/inmunología , Apoptosis/efectos de los fármacos , Proteína Ligando Fas/farmacología , Interleucina-2/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Anemia Aplásica/patología , Animales , Apoptosis/inmunología , Células Cultivadas , Femenino , Humanos , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/patología , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Interleucina-2/deficiencia , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Linfocitos T Reguladores/fisiologíaRESUMEN
AIMS/OBJECTIVES: To explore the impact of Human Leucocyte Antigen (HLA)-A and B epitope-matched platelets on the outcome of platelet transfusions in alloimmunised patients with aplastic anaemia (AA). The relevance of HLA-C epitope mismatches was also investigated. BACKGROUND: Patients who become immunologically refractory (IR) to random platelet transfusions can experience an adequate rise in platelet count through the provision of HLA-compatible platelets using an antigen-matching algorithm. This approach has been shown to be effective in patients with a low calculated reaction frequency, but it is not always successful in highly sensitised patients. The use of HLA epitopes-selected platelets has been suggested as an alternative to the antigen matching approach. METHODS: The effect of HLA epitope matching (both Eplets and Triplets) on the outcome of platelet transfusion was analysed in 37 highly immunised AA patients previously transfused with HLA-A and B antigen-matched platelets. Epitope matching was determined using the HLAMatchmaker programme. The outcome of the transfusions was assessed by the platelet count increments (PCIs) obtained 1 and 24 hours post-transfusions. RESULTS: HLA-A and B epitope matching was equivalent to HLA antigen matching in raising platelet counts. There was no significant difference in PCI when HLA-C epitope mismatches were considered. In addition, transfusions with fewer than two antigen mismatches resulted in significantly higher PCIs compared to transfusions with more than two antigen mismatches. CONCLUSIONS: HLA epitope-matched platelet provision may represent a clinically effective transfusion strategy for patients IR to random platelet transfusions. Further prospective studies are required.
Asunto(s)
Anemia Aplásica , Epítopos , Antígenos HLA-A , Antígenos HLA-B , Isoanticuerpos , Transfusión de Plaquetas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia Aplásica/sangre , Anemia Aplásica/inmunología , Anemia Aplásica/terapia , Niño , Epítopos/sangre , Epítopos/inmunología , Femenino , Antígenos HLA-A/sangre , Antígenos HLA-A/inmunología , Antígenos HLA-B/sangre , Antígenos HLA-B/inmunología , Humanos , Isoanticuerpos/biosíntesis , Isoanticuerpos/inmunología , Masculino , Persona de Mediana EdadRESUMEN
The improved success of HLA-matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia (SAA) in recent decades has had an impact on the indications for and timing of this treatment modality. In the absence of a matched sibling donor (MSD), historically MUD HSCT was reserved as an option after failure to respond to at least 2 courses of immunosuppressive therapy (IST) in adults with SAA, but with improved outcomes over time, it is now considered following failure to respond to 1 course of IST. Recent national and international studies and guidelines now recommend upfront MUD HSCT as an option for children for whom an MUD is readily available, because outcomes are similar to those for MSD HSCT. Fludarabine-based conditioning and the use of in vivo T cell depletion with antithymocyte globulin or alemtuzumab has been associated with a reported overall survival (OS) of >85% in adult patients undergoing MUD HSCT. However, the recent introduction of eltrombopag for patients with SAA has transformed the treatment landscape, and there is currently much interest in its use with IST as upfront treatment, which showed a high response rate in an early-phase study. The risks of HSCT, especially graft-versus-host disease (GVHD), need to be carefully balanced against the concerns of IST, namely relapse and later clonal evolution to myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). In the absence of a current prospective randomized trial comparing these 2 approaches, in this review we examine the evidence supporting consideration of early MUD HSCT in adults with SAA who would have been considered for MSD HSCT but who lack a MSD and for whom an MUD is readily available, especially using an irradiation-free conditioning regimen, with a low risk of GVHD, as another treatment option. This option may be offered to patients to provide them with an informed choice, with the aim of curing disease rather than achieving freedom from disease, relapse-free survival, or OS. Furthermore, understanding the immune signature for the response to IST and the immunologic responses to somatic mutations and clonal progression to MDS/AML may help define the future indications for upfront HSCT and a more precise medical approach to therapy.
Asunto(s)
Anemia Aplásica , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Donante no Emparentado , Adulto , Anemia Aplásica/mortalidad , Anemia Aplásica/terapia , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/terapia , HumanosRESUMEN
We report on 499 patients with severe aplastic anemia aged ≥ 50years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (nâ¯=â¯275, 55%) or HLA-matched (8/8) unrelated donors (nâ¯=â¯187, 37%) between 2005 and 2016. The median age at HCT was 57.8 years; 16% of patients were 65 to 77years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90% (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.03 to 1.92; Pâ¯=â¯.03) and after unrelated donor transplantation (HR, 1.47; 95% CI, 1 to 2.16; Pâ¯=â¯.05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66% (range, 57% to 75%) and 57% (range, 47% to 76%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57% (range, 48% to 67%) and 48% (range, 36% to 59%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65years or older (subdistribution HR [sHR], 1.7; 95% confidence interval, 1.07 to 2.72; Pâ¯=â¯.026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI)â¯+â¯methotrexate (sHR, .52; 95% CI, .33 to .81; Pâ¯=â¯.004) and CNI alone or with other agents (sHR, .27; 95% CI, .14 to .53; P < .001) compared with CNIâ¯+â¯mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Factores de Edad , Anciano , Anemia Aplásica/mortalidad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Premedicación/métodos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in vitro expandability for potential clinical use. Using mass cytometry and an unbiased multidimensional analytical approach, we identified 2 specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene expression, expandability, and function. Treg B predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4, and CD45RO within FOXP3(hi), CD127(lo) Tregs), expresses the interleukin-2 (IL-2)/STAT5 pathway and cell-cycle commitment genes. Furthermore, in vitro-expanded Tregs become functional and take on the characteristics of Treg B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2-sensitive and expandable in vitro, suggesting novel therapeutic approaches such as low-dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration.
Asunto(s)
Anemia Aplásica/inmunología , Anemia Aplásica/terapia , Memoria Inmunológica , Terapia de Inmunosupresión/métodos , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Femenino , Factores de Transcripción Forkhead/inmunología , Humanos , Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-7/inmunología , Antígenos Comunes de Leucocito/inmunología , Masculino , Persona de Mediana Edad , Receptores CCR4/inmunología , Factor de Transcripción STAT5/inmunología , Receptor fas/inmunologíaRESUMEN
Prevention of graft-versus-host disease (GVHD) is paramount for allogeneic hematopoietic stem cell transplantation (HSCT) to treat nonmalignant diseases. We previously reported that allogeneic HSCT for severe aplastic anemia (SAA) using the fludarabine, cyclophosphamide, and alemtuzumab (Campath-1H) (FCC) regimen is associated with a very low risk of GVHD and excellent clinical outcomes. We now report a single-center study of 45 patients with longer follow-up and investigation of lymphocyte recovery. Overall survival (OS) was 93%, and event-free survival (EFS) was 90.7%. Acute and chronic GVHD each occurred in 6 patients (13.3%), and only 1 case was severe. Mixed T cell chimerism was frequent and persisted after cessation of immunosuppression. T cells were extensively depleted, representing only 11.3% of lymphocytes at day 30 and rising to 43.8% by 1 year, but still significantly below normal levels (67.2%; P = .018), and deficiency persisted after immunosuppressive therapy (IST) withdrawal. Depletion of CD4 T cells was particularly profound, causing inversion of the normal CD4:CD8 T cell ratio. T cell subset composition was also abnormal, with memory and effector T cells predominating for at least 6 months after FCC HSCT. Analysis of T cell subset chimerism showed that CD4 T cells were predominantly donor-derived at 1 year, whereas recipient-derived CD8 T cells shaped mixed chimerism with a notable contribution of recipient effector CD8 T cells. The prolonged mixed T cell chimerism after IST withdrawal and low incidence of GVHD indicates the establishment of mutual tolerance, but the low incidence of viral disease suggests maintenance of antiviral immunity. Our study shows that despite the abnormal T cell profile after allogeneic HSCT for SAA using the FCC regimen, this regimen is conducive to an excellent clinical outcome.
Asunto(s)
Alemtuzumab/farmacología , Anemia Aplásica/terapia , Linfocitos T CD8-positivos/inmunología , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Adolescente , Adulto , Supervivencia Celular , Femenino , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Subgrupos de Linfocitos T/inmunología , Quimera por Trasplante , Resultado del Tratamiento , Irradiación Corporal Total , Adulto JovenRESUMEN
The distinction between acquired aplastic anemia (AA) and hypocellular myelodysplastic syndrome (hMDS) is often difficult, especially nonsevere AA. We postulated that somatic mutations are present in a subset of AA, and predict malignant transformation. From our database, we identified 150 AA patients with no morphological evidence of MDS, who had stored bone marrow (BM) and constitutional DNA. We excluded Fanconi anemia, mutations of telomere maintenance, and a family history of BM failure (BMF) or cancer. The initial cohort of 57 patients was screened for 835 known genes associated with BMF and myeloid cancer; a second cohort of 93 patients was screened for mutations in ASXL1, DNMT3A, BCOR, TET2, and MPL. Somatic mutations were detected in 19% of AA, and included ASXL1 (n = 12), DNMT3A (n = 8) and BCOR (n = 6). Patients with somatic mutations had a longer disease duration (37 vs 8 months, P < .04), and shorter telomere lengths (median length, 0.9 vs 1.1, P < .001), compared with patients without mutations. Somatic mutations in AA patients with a disease duration of >6 months were associated with a 40% risk of transformation to MDS (P < .0002). Nearly one-fifth of AA patients harbor mutations in genes typically seen in myeloid malignancies that predicted for later transformation to MDS.
Asunto(s)
Anemia Aplásica/genética , Transformación Celular Neoplásica/genética , Mutación , Síndromes Mielodisplásicos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia Aplásica/patología , Niño , Estudios de Cohortes , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Cariotipo , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Telómero/genética , Adulto JovenAsunto(s)
Betacoronavirus , Inactivadores del Complemento/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Hemoglobinuria Paroxística/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Adulto , COVID-19 , Activación de Complemento/efectos de los fármacos , Inactivadores del Complemento/farmacología , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Femenino , Hemoglobinuria Paroxística/complicaciones , Hemoglobinuria Paroxística/inmunología , Hemólisis/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , SARS-CoV-2RESUMEN
Refractory aplastic anemia (AA) is defined as a lack of response to first-line immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporin and is manifested as persistence of severe cytopenias at 6 months after IST. Although supportive care is critical for AA patients, it is of paramount importance for refractory disease in view of the longer duration of pancytopenia and susceptibility to life-threatening infections due to IST. Improvements in supportive care have largely contributed to better outcome over the past 2 decades, with 5-year overall survival reaching 57% during 2002 to 2008 for patients with AA unresponsive to initial IST. Exclusion of hypocellular myelodysplastic syndrome and constitutional BM failure masquerading as apparent idiopathic AA should be done in conjunction with centers of excellence. Hematopoietic stem cell transplantation is indicated if refractory AA patients are fit and have a suitably matched donor, either a sibling (>40-50 years) or unrelated donor. Patients lacking a fully matched donor should be considered for a second course of antithymocyte globulin plus cyclosporin, although response in the refractory setting is only â¼30% to 35%. Response may also occur with alemtuzumab or the thrombopoietin mimetic eltrombopag in refractory AA. The emerging data for alternate donor (cord or haploidentical) transplantation in AA has provided additional therapeutic choices to consider in refractory disease.
Asunto(s)
Anemia Aplásica/terapia , Anemia Refractaria/terapia , Suero Antilinfocítico/uso terapéutico , Transfusión Sanguínea , Trasplante de Células Madre de Sangre del Cordón Umbilical , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunosupresores/uso terapéutico , Control de Infecciones , Resultado del Tratamiento , Donante no EmparentadoRESUMEN
Although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for patients with Fanconi anemia (FA), published series mostly refer to single-center experience with limited numbers of patients. We analyzed results in 795 patients with FA who underwent first HSCT between May 1972 and January 2010. With a 6-year median follow-up, overall survival was 49% at 20 years (95% confidence interval, 38-65 years). Better outcome was observed for patients transplanted before the age of 10 years, before clonal evolution (ie, myelodysplastic syndrome or acute myeloid leukemia), from a matched family donor, after a conditioning regimen without irradiation, the latter including fludarabine. Chronic graft-versus-host disease and secondary malignancy were deleterious when considered as time-dependent covariates. Age more than 10 years at time of HSCT, clonal evolution as an indication for transplantation, peripheral blood as source of stem cells, and chronic graft-versus-host disease were found to be independently associated with the risk for secondary malignancy. Changes in transplant protocols have significantly improved the outcome of patients with FA, who should be transplanted at a young age, with bone marrow as the source of stem cells.
Asunto(s)
Anemia de Fanconi/mortalidad , Anemia de Fanconi/terapia , Trasplante de Células Madre Hematopoyéticas/mortalidad , Adolescente , Adulto , Anciano , Niño , Preescolar , Europa (Continente) , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Trasplante Homólogo , Adulto JovenRESUMEN
We have analyzed 1448 patients with acquired aplastic anemia grafted between 2005 and 2009, and compared outcome of identical sibling (n=940) versus unrelated donor (n=508) transplants. When compared to the latter, sibling transplants were less likely to be performed beyond 180 days from diagnosis (39% vs. 85%), to have a cytomegalovirus negative donor/recipient status (15% vs. 23%), to receive antithymocyte globulin in the conditioning (52% vs. 61%), and more frequently received marrow as a stem cell source (60% vs. 52%). Unrelated donor grafts had significantly more acute grade II-IV (25% vs. 13%) and significantly more chronic graft-versus-host disease (26% vs. 14%). In multivariate analysis, the risk of death of unrelated donor grafts was higher, but not significantly higher, compared to a sibling donor (P=0.16). The strongest negative predictor of survival was the use of peripheral blood as a stem cell source (P<0.00001), followed by an interval of diagnosis to transplant of 180 days or more (P=0.0005), patient age 20 years or over (P=0.0005), no antithymocyte globulin in the conditioning (P=0.003), and donor/recipient cytomegalovirus sero-status, other than negative/negative (P=0.04). In conclusion, in multivariate analysis, the outcome of unrelated donor transplants for acquired aplastic anemia, is currently not statistically inferior when compared to sibling transplants, although patients are at greater risk of acute and chronic graft-versus-host disease. The use of peripheral blood grafts remains the strongest negative predictor of survival.
Asunto(s)
Anemia Aplásica/mortalidad , Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas , Hermanos , Donante no Emparentado , Anemia Aplásica/epidemiología , Europa (Continente)/epidemiología , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Antígenos HLA/genética , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Masculino , Factores de Riesgo , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a potential cure for patients with myelodysplastic syndrome (MDS) who are ineligible for standard-intensity regimens. Previously published data from our institution suggest excellent outcomes at 1 yr using a uniform fludarabine, busulfan, and alemtuzumab-based regimen. Here we report long-term follow-up of 192 patients with MDS and acute myelogenous leukemia (AML) secondary to MDS (MDS-AML) transplanted with this protocol, using sibling (n = 45) or matched unrelated (n = 147) donors. The median age of the cohort was 57 yr (range, 21 to 72 yr), and median follow-up was 4.5 yr (range, 0.1 to 10.6 yr). The 5-yr overall survival (OS), event-free survival, and nonrelapse mortality were 44%, 33%, and 26% respectively. The incidence of de novo chronic graft-versus-host disease (GVHD) was low at 19%, illustrating the efficacy of alemtuzumab for GVHD prophylaxis. Conversely, the 5-yr relapse rate was 51%. For younger patients (age <50 yr), the 5-yr OS and relapse rates were 58% and 39%, respectively. On multivariate analysis, advanced age predicted significantly worse outcomes, with patients age >60 yr having a 5-yr OS of 15% and relapse rate of 66%. Patients receiving preemptive donor lymphocyte infusions had an impressive 5-yr OS of 67%, suggesting that this protocol may lend itself to the incorporation of immunotherapeutic strategies. Overall, these data demonstrate good 5-yr OS for patients with MDS and MDS-AML undergoing alemtuzumab-based RIC-HSCT. The low rate of chronic GVHD is encouraging, and comparative studies with other RIC protocols are warranted.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapéutico , Síndromes Mielodisplásicos/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Alemtuzumab , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Transfusión de Linfocitos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/mortalidad , Recurrencia , Hermanos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Donante no EmparentadoRESUMEN
New transplant approaches are urgently needed for patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor (UD) or who have failed UD or cord blood transplant. Patients with refractory SAA are at risk of later clonal evolution to myelodysplastic syndrome and acute leukemia. We report our pilot findings with haploidentical hematopoietic stem cell transplantation (haploHSCT) using uniform reduced-intensity conditioning with postgraft high-dose cyclophosphamide in 8 patients with refractory SAA or patients who rejected a prior UD or cord blood transplant. Six of 8 patients engrafted. Graft failure was associated with donor-directed HLA antibodies, despite intensive pre-HSCT desensitization with plasma exchange and rituximab. There was only 1 case of grade II skin graft-versus-host disease. We show that haploHSCT can successfully rescue refractory SAA patients who lack donor-directed HLA antibodies but not in the presence of donor-directed HLA antibodies. This novel protocol for haploHSCT for SAA has been adopted by the European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party for a future noninterventional, observational study to further evaluate its efficacy.
Asunto(s)
Anemia Aplásica/terapia , Anemia Refractaria/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Donantes de Tejidos , Trasplante Homólogo , Adulto JovenAsunto(s)
Adenosina Desaminasa/deficiencia , Trastornos de Fallo de la Médula Ósea/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Linfopenia/genética , Mutación , Neutropenia/genética , Adenosina Desaminasa/sangre , Adenosina Desaminasa/genética , Adulto , Secuencia de Aminoácidos , Trastornos de Fallo de la Médula Ósea/sangre , Trastornos de Fallo de la Médula Ósea/enzimología , Trastornos de Fallo de la Médula Ósea/patología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos y Proteínas de Señalización Intercelular/genética , Linfopenia/sangre , Linfopenia/enzimología , Persona de Mediana Edad , Neutropenia/sangre , Neutropenia/enzimología , LinajeAsunto(s)
Anemia Aplásica/diagnóstico , Anemia Aplásica/tratamiento farmacológico , Benzoatos/uso terapéutico , Hidrazinas/uso terapéutico , Pirazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Anemia Aplásica/etiología , Benzoatos/administración & dosificación , Benzoatos/efectos adversos , Biomarcadores , Biopsia , Médula Ósea/patología , Humanos , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Terapia Molecular Dirigida , Pronóstico , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Resultado del TratamientoRESUMEN
Relapse occurs in 30%-50% of recipients of T cell-depleted (TCD) reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Despite limited published supportive data, donor lymphocyte infusion (DLI) is used preemptively (pDLI) to improve donor chimerism and prevent relapse, and therapeutically (tDLI) after disease recurrence. We evaluated the efficacy and toxicity of pDLI and tDLI in 113 patients after TCD (alemtuzumab, n = 99; antithymocyte globulin, n = 14) RIC HSCT for AML or MDS. Recipients of pDLI (n = 62) had an estimated 5-year overall survival (OS) of 80% and an event-free survival of 65%. More than one-half (52%; n = 32) of the patients received pDLI within 6 months post-HSCT; despite this, the 5-year incidence of graft-versus-host disease was only 31% (95% confidence interval [CI], 19%-43%). Recipients of tDLI (n = 51) had an estimated 5-year OS of 40% and a 5-year relapse/progression rate of 69% (95% CI, 54%-81%). Recipients of tDLI at >6 months post-HSCT had a significantly superior 5-year OS after tDLI compared with those treated earlier (P = .008). The cumulative incidence of graft-versus-host disease at 5 years after tDLI was 45% (95% CI, 23%-65%). We demonstrate that pDLI safely promotes durable remission after TCD RIC HSCT for AML or MDS, and that tDLI salvages patients after late relapse with greater efficacy.