RESUMO
During the phase of proliferation needed for hematopoietic reconstitution following transplantation, hematopoietic stem/progenitor cells (HSPC) must express genes involved in stem cell self-renewal. We investigated the expression of genes relevant for self-renewal and expansion of HSPC (operationally defined as CD34+ cells) in steady state and after transplantation. Specifically, we evaluated the expression of ninety-one genes that were analyzed by real-time PCR in CD34+ cells isolated from (i) 12 samples from umbilical cord blood (UCB); (ii) 15 samples from bone marrow healthy donors; (iii) 13 samples from bone marrow after umbilical cord blood transplant (UCBT); and (iv) 29 samples from patients after transplantation with adult hematopoietic cells. The results show that transplanted CD34+ cells from adult cells acquire an asset very different from transplanted CD34+ cells from cord blood. Multivariate machine learning analysis (MMLA) showed that four specific gene signatures can be obtained by comparing the four types of CD34+ cells. In several, but not all cases, transplanted HSPC from UCB overexpress reprogramming genes. However, these remarkable changes do not alter the commitment to hematopoietic lineage. Overall, these results reveal undisclosed aspects of transplantation biology.
RESUMO
BACKGROUND: Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. METHODS: We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. RESULTS: After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). CONCLUSIONS: The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).
Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/uso terapêutico , Linfócitos T/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Taxa de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
PURPOSE: To analyze ocular surface parameters in patients before hematopoietic stem cell transplantation (HSCT) and to correlate them with hematological characteristics. METHODS: This is a retrospective analysis of prospectively collected data from 203 patients undergoing HSCT. Demographic data and hematological parameters (disorder type and stage) were collected from clinical charts. Ocular surface parameters (ocular surface disease index; Schirmer test I; tear film break-up time; corneal esthesiometry; and corneal and conjunctival staining) were analyzed the day before beginning the conditioning treatment for HSCT preparation. RESULTS: A high prevalence of dry eye (DE) was found: 116 patients (57.2%) were diagnosed as not suffering from DE, whereas 87 patients (42.8%) were diagnosed as having DE. Of these, 26 were classified as dry eye workshot (DEWS) severity score 1, 46 as DEWS score 2, and 15 as DEWS score 3. Tear film break-up time was found to be the only parameter statistically worse in the chronic lymphoproliferative disorder group compared with the stem cell malignancy group. Older age [odds ratio (OR) 1.03], female sex (OR 2.03), advanced stage of hematological disease (OR 1.4), and previous auto- or allo-HSCT (OR 1.9) showed a significant positive association in predicting DE onset before transplantation. CONCLUSIONS: DE was already present in a significant number of patients suffering from hematological disease before HSCT. Some hematological parameters seemed to influence this percentage. These results highlight the role of ocular surface examination by an ophthalmologist in hematological patients before HSCT, with the aim of diagnosing and, if necessary, treating DE patients early.
Assuntos
Síndromes do Olho Seco/diagnóstico , Transplante de Células-Tronco Hematopoéticas , Transtornos Linfoproliferativos/diagnóstico , Adolescente , Adulto , Idoso , Doença Crônica , Síndromes do Olho Seco/epidemiologia , Fluorofotometria , Humanos , Transtornos Linfoproliferativos/terapia , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Estudos Retrospectivos , Inquéritos e Questionários , Transplante Homólogo , Adulto JovemRESUMO
PURPOSE: In acute myeloid leukemia (AML), alloreactive natural killer (NK) cells are crucial mediators of immune responses after haploidentical stem cell transplantation. Allogeneic NK cell infusions have been adoptively transferred with promising clinical results. We aimed at determining whether the composition of NK graft in terms of frequency of alloreactive NK cells influence the clinical response in a group of elderly AML patients undergoing NK immunotherapy. EXPERIMENTAL DESIGN: Seventeen AML patients, in first complete remission (CR; median age 64 years, range 53-73) received NK cells from haploidentical KIR-ligand-mismatched donors after fludarabine/cyclophosphamide chemotherapy, followed by IL2. To correlate donor NK cell activity with clinical response, donor NK cells were assessed before and after infusion. RESULTS: Toxicity was moderate, although 1 patient died due to bacterial pneumonia and was censored for clinical follow-up. With a median follow-up of 22.5 months (range, 6-68 months), 9 of 16 evaluable patients (0.56) are alive disease-free, whereas 7 of 16 (0.44) relapsed with a median time to relapse of 9 months (range, 3-51 months). All patients treated with molecular disease achieved molecular CR. A significantly higher number of donor alloreactive NK cell clones was observed in responders over nonresponders. The infusion of higher number of alloreactive NK cells was associated with prolonged disease-free survival (0.81 vs. 0.14, respectively;P= 0.03). CONCLUSIONS: Infusion of purified NK cells is feasible in elderly AML patients as post-CR consolidation strategy. The clinical efficacy of adoptively transferred haploidentical NK cells may be improved by infusing high numbers of alloreactive NK cells.
Assuntos
Imunoterapia , Isoantígenos/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Doadores de Tecidos , Fatores Etários , Idoso , Terapia Combinada , Feminino , Genótipo , Haplótipos , Teste de Histocompatibilidade , Humanos , Imunofenotipagem , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Células Matadoras Naturais/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Receptores KIR3DL1/genética , Receptores KIR3DL1/metabolismo , Recidiva , Resultado do TratamentoRESUMO
Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Histiocitose de Células de Langerhans/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histiocitose de Células de Langerhans/mortalidade , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
We have recently reported on the outcome of autologous transplantation in the rare myelomas (IgD, IgE, IgM, and nonsecretory [NS]) but there is no real information on the outcome of these conditions after allogeneic transplantation. We used the European Group for Blood and Marrow Transplantation myeloma database to compare the outcomes after allogeneic transplantation of 1354 common myelomas (IgG, IgA, and light chain myeloma) with the outcome in 26 IgD myelomas and 52 NS myelomas. There was little difference between common and the IgD and NS myeloma patients with respect to prognostic factors although the IgD group had a higher beta 2 microglobulin at diagnosis, shorter time to transplantation, and more T cell depletion. IgD and NS patients had a significantly greater achievement of complete remission at conditioning but this did not translate into equivalent progression-free survival and overall survival for the IgD patients although the NS outcome was very similar to that of common myeloma. The PFS and OS of IgD, common, and NS myelomas appear similar after allogeneic transplantation, despite a tendency for higher early relapse rate in IgD myeloma. Allogeneic transplantation may, therefore, be an option to investigate in prospective observational studies.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoglobulina D/sangue , Mieloma Múltiplo/terapia , Agonistas Mieloablativos/uso terapêutico , Adulto , Idoso , Europa (Continente) , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Humanos , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/classificação , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Recidiva , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Linfócitos T/imunologia , Linfócitos T/patologia , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Microglobulina beta-2/sangue , Microglobulina beta-2/imunologiaRESUMO
This document updates and expands the recommendations on primary prophylaxis of invasive fungal diseases (IFD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, published in 2009 by the Gruppo Italiano Trapianto Midollo Osseo (GITMO). A consensus process was undertaken to describe and evaluate current information and practice regarding risk stratification and primary antifungal prophylaxis during the pre-engraftment and postengraftment phases after allo-HSCT. The revised recommendations were based on the evaluation of recent literature including a large, prospective, multicenter epidemiological study of allo-HSCT recipients conducted among the GITMO transplantation centers during the period of 2008 to 2010. It is intended as a guide for the identification of types and phases of transplantation at low, standard, and high risk for IFD, according to the underlying disease, transplantation, and post-transplantation factors. The risk stratification was the critical determinant of the primary antifungal approach for allo-HSCT recipients.
Assuntos
Antifúngicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Micoses/prevenção & controle , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Consenso , Humanos , ItáliaRESUMO
Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP-IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP-IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs.
Assuntos
Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Micoses/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Lactente , Itália/epidemiologia , Pessoa de Meia-Idade , Micoses/etiologia , Estudos Prospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Busulfan liver metabolism depends on glutathione, a crucial mediator of cellular and systemic stress. Here we investigated 40 polymorphisms at 27 loci involved in hepatic glutathione homeostasis, with the aim of testing their impact on the clinical outcome of 185 busulfan-conditioned allogeneic transplants. GSTA2 S112T serine allele homozygosity is an independent prognostic factor for poorer survival (RR=2.388), for increased any time- and 100-day transplant-related mortality (RR=4.912 and RR=5.185, respectively). The genotype also predicts a wider busulfan area under the concentration-time curve (1214.36 ± 570.06 vs. 838.10 ± 282.40 mMol*min) and higher post-transplant bilirubin serum levels (3.280 ± 0.422 vs. 1.874+0.197 mg/dL). In vitro, busulfan elicits pro-inflammatory activation (increased NF-KappaB activity and interleukin-8 expression) in human hepatoma cells. At the same time, the drug down-regulates a variety of genes involved in bilirubin liver clearance: constitutive androstane receptor, multidrug resistance-associated protein, solute carrier organic anion transporters, and even GSTA2. It is worthy of note that GSTA2 also acts as an intra-hepatic bilirubin binding protein. These data underline the prognostic value of GSTA2 genetic variability in busulfan-conditioned allotransplants and suggest a patho-physiological model in which busulfan-induced inflammation leads to the impairment of post-transplant bilirubin metabolism.
Assuntos
Bilirrubina/sangue , Bussulfano/farmacocinética , Glutationa Transferase/genética , Transplante de Células-Tronco Hematopoéticas , Isoenzimas/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Genótipo , Glutationa Transferase/metabolismo , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mediadores da Inflamação/metabolismo , Isoenzimas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Cancer stem cell survival relies on the activation of inflammatory pathways, which is speculatively triggered by cell autonomous mechanisms or by microenvironmental stimuli. Here, we observed that hypoxic bone marrow stroma-derived transforming growth factor-ß 1 promotes the growth of human breast cancer stem cells as mammospheres. The ensuing Slug-dependent serine 139 phosphorylation of the DNA damage sensor H2AX in breast cancer stem cells induces tumor necrosis factor-α and IL-8 mRNAs, whose stability is enhanced by cytoplasmic ß-catenin. ß-Catenin also up-regulates and binds miR-221, reducing the stability of the miR-221 targets Rad51 and ERα mRNAs. Our data show that the Slug/ß-catenin-dependent activation of DNA damage signaling triggered by the hypoxic microenvironment sustains the proinflammatory phenotype of breast cancer stem cells.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Inflamação/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/genética , Neoplasias da Mama/genética , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Citocinas/genética , Citocinas/metabolismo , Dano ao DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Inflamação/genética , Células MCF-7 , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Modelos Biológicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Transcrição da Família Snail , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Fator de Crescimento Transformador beta1/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
To evaluate trends in allografting from unrelated donors, we conducted a study on 196 consecutive myeloma patients transplanted between 2000 and 2009 in Italy. Twenty-eight percent, 37%, and 35%, respectively, received myeloablative, reduced-intensity, and nonmyeloablative conditioning. In these 3 cohorts, 1-year and 5-year transplantation-related mortalities were 28.8% and 37.0%, 20.3% and 31.3%, and 25.0% and 30.3%, respectively (P = .745). Median overall survival (OS) and event-free survival from transplantation for the 3 cohorts were 29 and 10 months, 11 and 6 months, and 32 and 13 months, respectively (P = .039 and P = .049). Overall cumulative incidences of acute and chronic graft-versus-host-disease (GVHD) were 46.1% and 51.1%. By Cox multivariate analyses, chronic GVHD was significantly associated with longer OS (hazard ratio [HR], .51; P = .009), whereas the use of peripheral blood stem cells was borderline significant (HR, .55; P = .051). Better response posttransplantation was associated with longer event-free survival (HR, 2.13 to 4.25; P < .001). Acute GVHD was associated with poorer OS (HR, 2.53; P = .001). This analysis showed a strong association of acute and chronic GVHD and depth of response posttransplantation with clinical outcomes. Long-term disease control remains challenging regardless of the conditioning. In the light of these results, prospective trials may be designed to better define the role of allografting from unrelated donors in myeloma.
Assuntos
Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Agonistas Mieloablativos/uso terapêutico , Sistema de Registros , Condicionamento Pré-Transplante/métodos , Doadores não Relacionados , Doença Aguda , Adulto , Idoso , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
The monitoring of minimal residual disease (MRD) through low sensitivity real-time (RT) polymerase chain reaction (PCR) analysis of BCR-ABL transcripts allows early detection of chronic myeloid leukemia (CML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT). The introduction of more sensitive techniques, such as RT quantitative (Q)-PCR, may lead to an overestimation of the risk of CML relapse. In this study, we reviewed the results of peripheral blood RT Q-PCR in CML patients who underwent allogeneic HSCT from 1983 to 2007. In our laboratory, RT Q-PCR analysis was routinely performed since 2002. Eighty-seven of 189 patients had available RT Q-PCR data; 63 patients had at least 3 RT Q-PCR analyses assessable. Fifty-two of 63 patients (83%) had, at least once, detectable transcript levels, but with an BCR-ABL/ABL ratio <.1% defined as Assuntos
Proteínas de Fusão bcr-abl/genética
, Transplante de Células-Tronco Hematopoéticas/métodos
, Leucemia Mielogênica Crônica BCR-ABL Positiva/genética
, Leucemia Mielogênica Crônica BCR-ABL Positiva/cirurgia
, Adulto
, Feminino
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Neoplasia Residual
, RNA Mensageiro/genética
, Transplante Homólogo
, Adulto Jovem
RESUMO
By using GRADE system we updated the guidelines for management of CLL issued in 2006 from SIE, SIES and GITMO group. We recommended fludarabine, cyclophosphamide, rituximab (FCR) in younger and selected older patients with a good fitness status, no unfavourable genetics (deletion 17p and/or p53 mutations), and a less toxic treatment in nonfit and elderly patients. In patients without unfavourable genetics, relapsed after 24 months the same initial treatment including rituximab can be considered. In patients with unfavourable genetics, refractory or relapsed within 24 months from a prior fludarabine-based treatment, allogeneic SCT or experimental treatments should be given.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , HumanosRESUMO
Thirteen patients with acute myeloid leukemia, 5 with active disease, 2 in molecular relapse, and 6 in morphologic complete remission (CR; median age, 62 years; range, 53-73 years) received highly purified CD56(+)CD3(-) natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor-ligand mismatched donors after fludarabine/cyclophosphamide immunosuppressive chemotherapy, followed by IL-2. The median number of infused NK cells was 2.74 × 10(6)/Kg. T cells were < 10(5)/Kg. No NK cell-related toxicity, including GVHD, was observed. One of the 5 patients with active disease achieved transient CR, whereas 4 of 5 patients had no clinical benefit. Both patients in molecular relapse achieved CR that lasted for 9 and 4 months, respectively. Three of 6 patients in CR are disease free after 34, 32, and 18 months. After infusion, donor NK cells were found in the peripheral blood of all evaluable patients (peak value on day 10). They were also detected in BM in some cases. Donor-versus-recipient alloreactive NK cells were shown in vivo by the detection of donor-derived NK clones that killed recipient's targets. Adoptively transferred NK cells were alloreactive against recipient's cells, including leukemia. In conclusion, infusion of purified NK cells is feasible in elderly patients with high-risk acute myeloid leukemia. This trial was registered at www.clinicaltrial.gov as NCT00799799.
Assuntos
Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/administração & dosagem , Imunoterapia Adotiva/métodos , Células Matadoras Naturais , Leucemia Mieloide Aguda , Receptores KIR/análise , Antígenos CD/análise , Antígenos CD/biossíntese , Separação Celular , Ciclofosfamida/administração & dosagem , Citometria de Fluxo , Teste de Histocompatibilidade , Humanos , Imunofenotipagem , Interleucina-2/biossíntese , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Leucaférese , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Fatores de Risco , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
The importance of donor-recipient human leukocyte antigen (HLA)-DPB1 matching for the clinical outcome of unrelated hematopoietic stem cell transplantation (HSCT) is controversial. We have previously described an algorithm for nonpermissive HLA-DPB1 disparities involving HLA-DPB1*0901,*1001,*1701,*0301,*1401,*4501, based on T-cell alloreactivity patterns. By revisiting the immunogenicity of HLA-DPB1*02, a modified algorithm was developed and retrospectively tested in 621 unrelated HSCTs facilitated through the Italian Registry for oncohematologic adult patients. The modified algorithm proved to be markedly more predictive of outcome than the original one, with significantly higher Kaplan-Meier probabilities of 2-year survival in permissive compared with nonpermissive transplantations (55% vs 39%, P = .005). This was the result of increased adjusted hazards of nonrelapse mortality (hazard ratio [HR] = 1.74; confidence interval [CI], 1.19-2.53; P = .004) but not of relapse (HR = 1.02; CI, 0.73-1.42; P = .92). The increase in the hazards of overall mortality by nonpermissive HLA-DPB1 disparity was similar in 10 of 10 (HR = 2.12; CI, 1.23-3.64; P = .006) and 9 of 10 allele-matched transplantations (HR = 2.21; CI, 1.28-3.80; P = .004), both in early-stage and in advanced-stage disease. These data call for revisiting current HLA matching strategies for unrelated HSCT, suggesting that searches should be directed up-front toward identification of HLA-DPB1 permissive, 10 of 10 or 9 of 10 matched donors.
Assuntos
Algoritmos , Seleção do Doador/métodos , Antígenos HLA-DR , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Doadores de Tecidos , Adulto , Intervalo Livre de Doença , Feminino , Cadeias HLA-DRB1 , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Recidiva , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Transplante HomólogoRESUMO
A case of osteomyelitis caused by multidrug-resistant Pseudomonas aeruginosa is reported in a patient who underwent allogeneic bone marrow transplantation for acute lymphoblastic leukaemia. The patient was successfully treated by prolonged administration of a full dose of colistin and tigecycline, and surgical curettage with the positioning of resorbable calcium sulfate pellets loaded with colistin.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Colistina/uso terapêutico , Minociclina/análogos & derivados , Osteomielite/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Adulto , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Feminino , Humanos , Minociclina/uso terapêutico , Osteomielite/complicações , Osteomielite/microbiologia , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Tigeciclina , Transplante HomólogoRESUMO
BACKGROUND AND OBJECTIVES: Peripheral blood stem cells (PBSC) following reduced intensity conditioning (RIC) are being increasingly used for allogeneic transplantation in multiple myeloma. The purpose of this study was to compare outcome of patients transplanted with either PBSC or bone marrow (BM) following RIC or myeloablative conditioning (MAC). DESIGN AND METHODS: Data from 1,667 patients who had received an allogeneic identical sibling donor transplant for multiple myeloma from 1994 to 2003 were analyzed. Comparisons were made between results of PBSC and BM transplants after conditioning with RIC or MAC. RESULTS: The engraftment rate was faster with PBSC than with BM (median: 14 and 18 days for neutrophils and 15 and 25 days for platelets respectively) irrespectively of whether RIC or MAC was used. The incidence of acute graft-versus-host disease (GVHD) did not differ significantly between the groups while chronic GVHD was more prevalent in PBSC recipients irrespectively of whether they had RIC or MAC. Non-relapse mortality did not differ between PBSC and BM recipients, but was significantly higher in those treated with MAC than in those given RIC irrespectively of the cell source. The relapse/progression rate did not differ between PBSC and BM recipients, but was significantly higher in those given RIC, irrespectively of the cell source. There was no significant difference in overall or progression-free survival between patients given PBSC or BM transplants. INTERPRETATION AND CONCLUSIONS: Although transplantation of PBSC is associated with faster engraftment and more frequent chronic GVHD, overall survival, non-relapse mortality, relapse/progression and progression-free survival are similar to those following BM transplants. However both PBSC and BM transplants are associated with lower non-relapse mortality, lower response rate and higher relapse/progression if RIC is used instead of MAC.
Assuntos
Transplante de Medula Óssea/métodos , Histocompatibilidade , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Doadores de Tecidos , Adolescente , Adulto , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Estudos Retrospectivos , Irmãos , Transplante Homólogo , Resultado do TratamentoRESUMO
Host antigen-presenting cells (APCs) have been shown to induce acute graft-versus-host disease (aGVHD) in experimental models. In this study, we investigated whether pretransplantation blood levels of host APCs, such as plasmacytoid and myeloid dendritic cells and monocytes, correlate with the development of aGVHD. A total of 89 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched related (n = 48) or unrelated (n = 41) donors were enrolled in the study. Blood samples were analyzed by flow cytometry before initiating the conditioning regimen. In related donor transplants, patient-donor sex mismatch and monocyte levels significantly correlated with aGVHD grade II-IV in both univariate and multivariate analyses. Similar results were not observed in recipients of matched unrelated transplants, possibly due to use of antithymocyte globulin (ATG) or differences in graft source in these patients. In conclusion, pretransplantation recipient monocyte levels are relevant to the development of GVHD in HSCT from related donors.