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2.
J Clin Invest ; 134(14)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38833312

RESUMO

BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/µL at hour +1 or greater than 224.5 CAR+EVs/µL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).


Assuntos
Antígenos CD19 , Vesículas Extracelulares , Imunoterapia Adotiva , Linfoma de Células B , Humanos , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Antígenos CD19/imunologia , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Linfoma de Células B/sangue , Adulto , Idoso , Receptores de Antígenos Quiméricos/imunologia , Estudos Prospectivos
3.
Cells ; 13(8)2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38667272

RESUMO

Clonal hematopoiesis of indeterminate potential (CHIP) refers to the phenomenon where a hematopoietic stem cell acquires fitness-increasing mutation(s), resulting in its clonal expansion. CHIP is frequently observed in multiple myeloma (MM) patients, and it is associated with a worse outcome. High-throughput amplicon-based single-cell DNA sequencing was performed on circulating CD34+ cells collected from twelve MM patients before autologous stem cell transplantation (ASCT). Moreover, in four MM patients, longitudinal samples either before or post-ASCT were collected. Single-cell sequencing and data analysis were assessed using the MissionBio Tapestri® platform, with a targeted panel of 20 leukemia-associated genes. We detected CHIP pathogenic mutations in 6/12 patients (50%) at the time of transplant. The most frequently mutated genes were TET2, EZH2, KIT, DNMT3A, and ASXL1. In two patients, we observed co-occurring mutations involving an epigenetic modifier (i.e., DNMT3A) and/or a gene involved in splicing machinery (i.e., SF3B1) and/or a tyrosine kinase receptor (i.e., KIT) in the same clone. Longitudinal analysis of paired samples revealed a positive selection of mutant high-fitness clones over time, regardless of their affinity with a major or minor sub-clone. Copy number analysis of the panel of all genes did not show any numerical alterations present in stem cell compartment. Moreover, we observed a tendency of CHIP-positive patients to achieve a suboptimal response to therapy compared to those without. A sub-clone dynamic of high-fitness mutations over time was confirmed.


Assuntos
Hematopoiese Clonal , Mieloma Múltiplo , Mutação , Análise de Célula Única , Humanos , Mieloma Múltiplo/genética , Análise de Célula Única/métodos , Mutação/genética , Masculino , Pessoa de Meia-Idade , Feminino , Hematopoiese Clonal/genética , Idoso , Transplante de Células-Tronco Hematopoéticas , Análise de Sequência de DNA/métodos , Adulto , Evolução Clonal/genética
4.
Curr Opin Hematol ; 30(1): 14-21, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36539361

RESUMO

PURPOSE OF REVIEW: Several studies showed that age alone should not be used as an arbitrary parameter to exclude patients from allogeneic hematopoietic cell transplantation (HCT). The accessibility to allogeneic HCT programs for older patients with hematological diseases is growing up constantly. The Center for International Blood and Marrow Transplant Research has recently shown that over 30% of allogeneic HCT recipients are at least 60 years old and that nearly 4% are aged 70 or more. Historically, the use of allogeneic HCT among elderly patients has been limited by age restrictions, reflecting physicians' concerns regarding prohibitive transplant-related mortality and HCT-associated morbidity. RECENT FINDINGS: The introduction of reduced intensity/toxicity conditioning regimens has allowed transplant Centers to carry out allogeneic HCT on patients previously considered not ideal candidates. The integration of specific risk scores could lead to better capture mental and physical frailties of older patients. Older adults less frequently have available medically fit siblings, able to donate, so, unrelated donors, familial haploidentical donors or umbilical cord blood grafts could potentially abrogate such a difficulty, allowing the curative potential of allogeneic HCT. SUMMARY: The appropriate assessing of allogeneic HCT feasibility for elderly patients should be the resonate application of different clinical and biological principles.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Idoso , Humanos , Pessoa de Meia-Idade , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fatores de Risco , Doadores não Relacionados , Condicionamento Pré-Transplante
5.
Front Oncol ; 12: 1066285, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36530990

RESUMO

Disease relapse represents by far the most frequent cause of hematopoietic cell transplantation (HCT) failure. Patients with acute leukemia suffering relapse after HCT have limited conventional treatment options with little possibility of cure and represent, de facto, suitable candidates for the evaluation of novel cellular and biological-based therapies. Donor lymphocyte infusions (DLI) has been one of the first cellular therapies adopted to treat post HCT relapse of acute leukemia patients and still now, it is widely adopted in preemptive and prophylactic settings, with renewed interest for manipulated cellular products such as NK-DLI. The acquisition of novel biological insights into pathobiology of leukemia relapse are translating into the clinic, with novel combinations of target therapies and novel agents, helping delineate new therapeutical landscapes. Hypomethylating agents alone or in combination with novel drugs demonstrated their efficacy in pre-clinical models and controlled trials. FLT3 inhibitors represent an essential therapeutical instrument incorporated in post-transplant maintenance strategies. The Holy grail of allogeneic transplantation lies in the separation of graft-vs.-host disease from graft vs. tumor effects and after more than five decades, is still the most ambitious goal to reach and many ways to accomplish are on their way.

6.
Front Immunol ; 13: 994731, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36275688

RESUMO

Background: T cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T cells. Case presentation: We report on a patient affected by refractory Diffuse Large B-cell Lymphoma who was resistant to CAR T-cell therapy and to two cycles post CAR-T of pembrolizumab (PBZ) due to the evolution into a B-cell Hodgkin-like lymphoma. Owing to the CD30 expression and the Hodgkin-like phenotype, the patient was ultimately treated with Brentuximab-Vedotin and finally underwent remission. Upon PBZ treatment, 100% of circulating CAR-T+ cells showed a persistent CD8+ senescent/exhausted phenotype, while an increase in the percentage of senescent cells was found in the non-CAR CD8+ T cells compartment. Conclusions: PBZ is not able to reinvigorate exhausted CAR+ T cells and to confer durable clinical response. We hypothesize that the phenomenon is due to the senescent phenotype of CAR+ T cells, which did not allow PBZ-induced reactivation and proliferative rescue. The phenomenon, together with the loss of CAR-T target CD19 and the shift of non-CAR CD8+ T cells towards a senescent phenotype likely contributed to set up an immune landscape with poor antitumor capacity.


Assuntos
Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Antígenos CD19 , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos de Linfócitos T , Linfócitos T CD8-Positivos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Terapia Baseada em Transplante de Células e Tecidos
7.
Front Oncol ; 12: 901132, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35992847

RESUMO

In chronic myeloid leukemia (CML), Aurora kinase A and Polo like kinase 1 (PLK1), two serine-threonine kinases involved in the maintenance of genomic stability by preserving a functional G2/M checkpoint, have been implicated in BCR::ABL1-independent resistance to the tyrosine kinase inhibitor (TKI) imatinib mesylate and in leukemic stem cell (LSC) persistence. It can be speculated that the observed deregulated activity of Aurora A and Plk1 enhances DNA damage, promoting the occurrence of additional genomic alterations contributing to TKI resistance and ultimately driving progression from chronic phase to blast crisis (BC). In this study, we propose a new therapeutic strategy based on the combination of Aurora kinase A or PLK1 inhibition with danusertib or volasertib, respectively, and WEE1 inhibition with AZD1775. Danusertib and volasertib used as single drugs induced apoptosis and G2/M-phase arrest, associated with accumulation of phospho-WEE1. Subsequent addition of the WEE1 inhibitor AZD1775 in combination significantly enhanced the induction of apoptotic cell death in TKI-sensitive and -resistant cell lines as compared to both danusertib and volasertib alone and to the simultaneous combination. This schedule indeed induced a significant increase of the DNA double-strand break marker γH2AX, forcing the cells through successive replication cycles ultimately resulting in apoptosis. Finally, combination of danusertib or volasertib+AZD1775 significantly reduced the clonogenic potential of CD34+ CML progenitors from BC patients. Our results may have implications for the development of innovative therapeutic approaches aimed to improve the outcomes of patients with multi-TKI-resistant or BC CML.

8.
Front Immunol ; 13: 1058739, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36713433

RESUMO

Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Rabbit anti-T lymphocyte globulin (ATLG) in addition to calcineurin inhibitors and antimetabolites is a suitable strategy to prevent GVHD in several transplant settings. Randomized studies already demonstrated its efficacy in terms of GVHD prevention, although the effect on relapse remains the major concern for a wider use. Tailoring of ATLG dose on host characteristics is expected to minimize its side effects (immunological reconstitution, relapse, and infections). Here, day -6 to day +15 pharmacokinetics of active ATLG serum level was first assayed in an explorative cohort of 23 patients by testing the ability of the polyclonal serum to bind antigens on human leukocytes. Significantly lower levels of serum active ATLG were found in the patients who developed GVHD (ATLG_AUCCD45: 241.52 ± 152.16 vs. 766.63 +/- 283.52 (µg*day)/ml, p = 1.46e-5). Consistent results were obtained when the ATLG binding capacity was assessed on CD3+ and CD3+/CD4+ T lymphocytes (ATLG_AUCCD3: 335.83 ± 208.15 vs. 903.54 ± 378.78 (µg*day)/ml, p = 1.92e-4; ATLG_AUCCD4: 317.75 ± 170.70 vs. 910.54 ± 353.35 (µg*day)/ml, p = 3.78e-5. Concomitantly, at pre-infusion time points, increased concentrations of CD69+ extracellular vesicles (EVs) were found in patients who developed GVHD (mean fold 9.01 ± 1.33; p = 2.12e-5). Consistent results were obtained in a validation cohort of 12 additional ATLG-treated HSCT patients. Serum CD69+ EVs were mainly represented in the nano (i.e. 100 nm in diameter) EV compartment and expressed the leukocyte marker CD45, the EV markers CD9 and CD63, and CD103, a marker of tissue-resident memory T cells. The latter are expected to set up a host pro-inflammatory cell compartment that can survive in the recipient for years after conditioning regimen and contribute to GVHD pathogenesis. In summary, high levels of CD69+ EVs are significantly correlated with an increased risk of GVHD, and they may be proposed as a tool to tailor ATLG dose for personalized GVHD prevention.


Assuntos
Vesículas Extracelulares , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Humanos , Coelhos , Soro Antilinfocitário/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Anticorpos/uso terapêutico , Linfócitos , Recidiva
10.
Front Immunol ; 12: 804988, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35173709

RESUMO

Recently, many reports were published supporting the clinical use of adoptively transferred natural killer (NK) cells as a therapeutic tool against cancer, including acute myeloid leukemia (AML). Our group demonstrated promising clinical response using adoptive immunotherapy with donor-derived alloreactive KIR-ligand-mismatched NK cells in AML patients. Moreover, the antileukemic effect was correlated with the dose of infused alloreactive NK cells ("functional NK cell dose"). Herein, we update the results of our previous study on a cohort of adult AML patients (median age at enrollment 64) in first morphological complete remission (CR), not eligible for allogeneic stem cell transplantation. After an extended median follow-up of 55.5 months, 8/16 evaluable patients (50%) are still off-therapy and alive disease-free. Overall survival (OS) and disease-free survival (DFS) are related with the dose of infused alloreactive NK cells (≥2 × 105/kg).


Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Idoso , Feminino , Antígenos de Histocompatibilidade/imunologia , Teste de Histocompatibilidade , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
11.
Bone Marrow Transplant ; 55(5): 946-954, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31768009

RESUMO

Plerixafor inhibits CXCR4, thus inducing the mobilization of hematopoietic stem/progenitor cells in lymphoma and multiple myeloma (MM) patients eligible for autologous stem cell transplantation (ASCT). However, the kinetics of plerixafor-induced mobilization of lymphocyte subsets is poorly known. Here, we evaluated the graft content, the engraftment, and the immunological reconstitution of MM patients receiving plerixafor. Thirty-seven patients undergoing one or tandem ASCT were enrolled. After mobilization with cyclophosphamide plus G-CSF, plerixafor was added at hematological recovery regardless of CD34+ cell count. We evaluated the number of CD34+, CD34+/CD38-, CD3+, CD4+, CD8+, CD19+, CD56+/CD3-, CD4+/CD25+/FOXP3+, and CD138+/CD38+ cells on each apheresis. Hematological and immunological recovery were determined at 30 days, 3, 6, 9, and 12 months after ASCT. Overall, 34/37 patients mobilized a median of 10.1 × 106 CD34+ cells/Kg (IQ 7.7-13.4). Patients with <20/µL CD34+ cells at plerixafor administration (18/33) had a significantly higher CD34+ cell fold increase, but not a higher absolute number, than 16/33 patients with ≥20/µL CD34+ cells. A similar CD34+ and immune graft composition was reported. A higher number of CD3+ and CD8+ cells/µL was observed at 3 months after first ASCT (p < 0.05) in the group with ≥20 CD34+ cells/µL. Thus, in MM patients, the timing of plerixafor administration influences immunological recovery.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Mieloma Múltiplo , Benzilaminas , Ciclamos , Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas , Humanos , Mieloma Múltiplo/terapia , Transplante Autólogo
12.
Bone Marrow Transplant ; 54(5): 717-725, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30232415

RESUMO

Umbilical Cord Blood (UCB) represents a valid option for patients with hematopoietic malignancies lacking an HLA matched donor. To overcome the limitation of the low stem cell dose of UCB, the intrabone (IB) route has been proposed. We report the results of a prospective study on a poor-prognosis cohort of 23 patients receiving intrabone single UCB transplant (Clinicaltrials.gov NCT00886522). Cumulative incidence of hematological recovery at day 90 was 82 ± 9% (ANC > 0.5 × 109/L) and 70 ± 10% (platelet > 50 × 109/L) and correlated with CD34 + cells in the graft. NRM was 20 ± 9%. No severe aGVHD and only one extensive cGVHD occurred, with fast immune reconstitution. To test the hypothesis that the direct IB injection could affect the expression of stem cells regulatory pathways, CD34 + cells from BM aspirates at day + 10, + 20, + 30, processed in hypoxic conditions mimicking the BM-microenvironment (7%pO2), were studied for the expression of c-Mpl, Notch1 and CXCR4. We found that the expression of c-Mpl in CD34 + cells at day + 10 significantly correlated with hematological recovery. In conclusion, IB-UCB transplant success is associated with low incidence of GVHD and high-speed platelet recovery; intrabone route may preserve full hematopoietic stemness by direct delivery of UCB stem cells into the hypoxic HSC niche.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro/sangue , Neoplasias Hematológicas , Hematopoese , Recuperação de Função Fisiológica , Células-Tronco , Adolescente , Adulto , Contagem de Células , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
13.
Biol Blood Marrow Transplant ; 24(12): 2450-2458, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30026107

RESUMO

Chronic graft-versus-host disease (cGVHD) is a major complication after stem cell transplantation (HSCT). Several randomized studies already demonstrated that anti-T lymphoglobulin (ATLG) is effective in preventing GVHD after myeloablative unrelated and HLA-identical sibling transplants. However, the issue of doses and the potential increase of relapses still remain unsolved. Here we report data on 190 patients with acute leukemia and myelodysplastic syndrome who underwent an unrelated HSCT with low-dose ATLG (15 to 30 mg/kg) given at an earlier timing (days -6 to -2). HSCT was performed from HLA 10/10 (n = 62, 33%), 9/10 (n = 91, 48%), 8/10 (n = 30, 16%), and <8/10 (n = 7, 4%) identical unrelated donor. Peripheral blood was the stem cell source in 42% (n = 80). Median follow-up was 51 months. Grades II to IV and III to IV acute GVHD were 26% and 9%, respectively, and 2-year overall and moderate to severe cGVHD were 23% and 14%, respectively. The 3-year incidences of relapse and nonrelapse mortality were 26% and 18%, respectively. The rates of 3-year overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 60%, 56% and 44%, respectively. Factors such as younger donor, good performance status, and early disease were associated with better outcome in terms of OS, DFS, and GRFS. Our data indicate that doses of ATLG lower that those used in randomized clinical trials can be used for GVHD prevention, even in the adult setting, without clear increases in relapse and infections; these findings need to be further validated by a prospective randomized study.


Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Soro Antilinfocitário/farmacologia , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Estudos Retrospectivos , Doadores não Relacionados , Adulto Jovem
14.
Clin Cancer Res ; 22(8): 1914-21, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26787753

RESUMO

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 Tratamento
15.
Dig Liver Dis ; 47(12): 1059-66, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26427587

RESUMO

BACKGROUND: Bone marrow stem/progenitor cells seem to be effective in liver regeneration after tissue injury. AIM: To evaluate the feasibility and safety of the mobilization and reinfusion of CD133+ stem/progenitor cells in patients with end-stage liver disease. METHODS: Autologous CD133+ stem/progenitor cells, mobilized with granulocyte-colony stimulating factor, were collected by leukapheresis and reinfused at increasing doses through the hepatic artery starting from 5×10(4)/kg up to 1×10(6)/kg. RESULTS: 16 subjects with Model for End-stage Liver Disease (MELD) score between 17 and 25 were enrolled, 14 mobilized an adequate number of CD133+ stem/progenitor cells and 12 were reinfused. No severe adverse events related to the procedure were reported. MELD score significantly worsened during mobilization in Child Turcotte Pugh-C patients. A significant improvement of liver function was observed 2 months after reinfusion (MELD 19.5 vs. 16; P=0.045). Overall, 5 patients underwent liver transplantation within 12 months from reinfusion and 2 died because of progressive liver failure. CONCLUSIONS: CD133+ stem/progenitor cells reinfusion in patients with end-stage liver disease is feasible and safe. A worsening of liver function was observed during mobilization in Child Turcotte Pugh-C patients. The temporary improvement of MELD score after reinfusion suggests that stem cells therapy may be a "bridge to transplant" approach for these patients.


Assuntos
Antígenos CD , Doença Hepática Terminal/terapia , Glicoproteínas , Transplante de Células-Tronco Hematopoéticas , Peptídeos , Células-Tronco/citologia , Antígeno AC133 , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Humanos , Itália , Leucaférese , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
16.
Haematologica ; 99(1): 172-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24056816

RESUMO

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 Jovem
18.
Blood ; 118(12): 3273-9, 2011 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-21791425

RESUMO

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 & derivados
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