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Memory T selected cells (CD45RA-/RO+) as donor lymphocyte infusion are less capable of producing alloreactivity and graft versus host disease (GvHD) compared with naïve T cells. The objective of this study was to evaluate the safety and efficacy of high-dose memory (CD45RA-/RO+) donor lymphocyte infusion (mDLI) after allogeneic hematopoietic cell transplantation (HCT). Indications for mDLI were "as needed" and "as prophylactic regimen." Sixty-one children diagnosed with malignant (82%) and non-malignant diseases (18%) received 241 mDLIs. Patients received a median of three infusions (range 1â13) of mDLI with a median infused dose of 1.35 × 107/kg CD45RO+ containing 8.96 × 106/kg CD3+CD45RO+ and 3.81 × 103/kg CD3+CD45RA+. De novo GvHD developed in 7 patients following 4% of the mDLI infusions. Among patients with GvHD before mDLI, this condition worsened following 6 infusions (11%) in the 3 patients with grade II-IV acute GvHD. A decrease in cytomegalovirus viral load followed 65% of mDLI infusions. Two-year overall survival (OS) for the total cohort was 64% (95% CI 57%â72%). For patients receiving prophylactic mDLI, the two-year non-relapse mortality was 10% (95% CI 9%â11%). In summary, high-dose mDLI is feasible and safe, with a relatively low risk of severe GvHD even in patients with active GvHD. Importantly, mDLI was associated with positive effects, including enhanced control of CMV viremia.
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BACKGROUND AIMS: There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)-hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA- memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment. METHODS: Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 106/kg CD45RA- memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2-specific response within the CD45RA- memory T cells and the most frequent human leukocyte antigen typing in the Spanish population. RESULTS: We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events. CONCLUSIONS: Adoptive cell therapy with off-the-shelf CD45RA- memory T cells containing SAR-CoV-2-specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia. TRIAL REGISTRATION: NCT04578210.
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COVID-19 , Linfopenia , Humanos , SARS-CoV-2 , COVID-19/terapia , Células T de Memória , Resultado do Tratamento , Linfopenia/terapia , AntiviraisRESUMO
BACKGROUND AIMS: We have previously demonstrated the safety and feasibility of adoptive cell therapy with CD45RA- memory T cells containing severe acute respiratory syndrome coronavirus 2-specific T cells for patients with coronavirus disease 2019 from an unvaccinated donor who was chosen based on human leukocyte antigen compatibility and cellular response. In this study, we examined the durability of cellular and humoral immunity within CD45RA- memory T cells and the effect of dexamethasone, the current standard of care treatment, and interleukin-15, a cytokine critically involved in T-cell maintenance and survival. METHODS: We performed a longitudinal analysis from previously severe acute respiratory syndrome coronavirus 2-infected and infection-naïve individuals covering 21 months from infection and 10 months after full vaccination with the BNT162b2 Pfizer/BioNTech vaccine. RESULTS: We observed that cellular responses are maintained over time. Humoral responses increased after vaccination but were gradually lost. In addition, dexamethasone did not alter cell functionality or proliferation of CD45RA- T cells, and interleukin-15 increased the memory T-cell activation state, regulatory T cell expression, and interferon gamma release. CONCLUSIONS: Our results suggest that the best donors for adoptive cell therapy would be recovered individuals and 2 months after vaccination, although further studies with larger cohorts would be needed to confirm this finding. Dexamethasone did not affect the characteristics of the memory T cells at a concentration used in the clinical practice and IL-15 showed a positive effect on SARS-CoV-2-specific CD45RA- T cells.
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COVID-19 , Interferon gama , Humanos , Interferon gama/metabolismo , Interleucina-15 , Células T de Memória , Seleção do Doador , Vacina BNT162 , COVID-19/terapia , SARS-CoV-2 , Tratamento Farmacológico da COVID-19 , Antígenos Comuns de Leucócito/metabolismo , Fenótipo , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Proliferação de Células , Anticorpos Antivirais , VacinaçãoRESUMO
COVID-19 disease is the manifestation of syndrome coronavirus 2 (SARS-CoV-2) infection, which is causing a worldwide pandemic. This disease can lead to multiple and different symptoms, being lymphopenia associated with severity one of the most persistent. Natural killer cells (NK cells) are part of the innate immune system, being fighting against virus-infected cells one of their key roles. In this study, we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2-specific-like NK population in the blood of convalescent donors. CD57+ NKG2C+ phenotype in SARS-CoV-2 convalescent donors indicates the presence of 'memory'/activated NK cells as it has been shown for cytomegalovirus infections. Although the existence of this population is donor dependent, its expression may be crucial for the specific response against SARS-CoV-2, so that, it gives us a tool for selecting the best donors to produce off-the-shelf living drug for cell therapy to treat COVID-19 patients under the RELEASE clinical trial (NCT04578210).
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Transferência Adotiva , Doadores de Sangue , COVID-19/imunologia , Convalescença , Memória Imunológica , Células Matadoras Naturais/imunologia , SARS-CoV-2/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.
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Hematopoiese Clonal , Mieloma Múltiplo/patologia , Síndromes Mielodisplásicas/etiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Feminino , Citometria de Fluxo/métodos , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Mutação , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante Autólogo , Microambiente TumoralRESUMO
PURPOSE: Use of adoptive immunotherapy with virus-specific T cells (VST) in patients with inborn errors of immunity prior to hematopoietic stem cell transplantation (HSCT) has been reported in few patients. We report our experience, reviewing all the cases previously reported. METHODS: We report four children with inborn errors of immunity who received VST infusion in a pre-HSCT setting in two reference centers in Spain and review all inborn errors of immunity cases previously reported. RESULTS: Taking into account our four cases, nine children have been reported to receive VST prior to HSCT to date: 3 severe combined immunodeficiency, 2 CTPS1 deficiency, 1 dyskeratosis congenital, 1 ORAI1 deficiency, 1 Rothmund-Thomson syndrome, and 1 combined immunodeficiency without confirmed genetic defect. In four patients, immunotherapy resulted in clinical improvement, allowing to proceed to HSCT. In these cases, the infusion was started closely to viral diagnosis [mean time 28 days (IQR; 17-52 days)], and the VST was followed shortly thereafter by HSCT [mean time 28 days (IQR; 10-99 days)]. Viremia was controlled after HSCT in two cases (performed 7 and 36 days after the infusion). Multiple infusions were required in many cases. Five out of nine patients died before receiving HSCT. These patients presented with a prolonged and uncontrolled infection before VST administration [mean time from viral diagnosis to VST infusion was 176 days (IQR; 54-1687)]. CONCLUSIONS: In patients with inborn errors of immunity, the efficacy of VST for treating disseminated viral infections in pre-transplant settings seems to have a limited efficacy. However, this therapy could be used in a pre-emptive setting before severe viral disease occurs or closely to HSCT.
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Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/terapia , Imunoterapia Adotiva/métodos , Cuidados Pré-Operatórios , Linfócitos T/imunologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/diagnóstico , Imunoterapia Adotiva/efeitos adversos , Cuidados Pré-Operatórios/métodos , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T/metabolismo , Falha de Tratamento , Resultado do Tratamento , Viroses/etiologiaRESUMO
BACKGROUND: Naïve T-cell-depleted grafts have been employed as an ex vivo T-cell depletion (TCD) platform to prevent graft-versus-host disease (GvHD) and improve immune reconstitution by providing rapid donor memory T-cell reconstitution after allogenic hematopoietic stem cell transplantation (allo-HSCT). CD45RA- memory T cells confer protection against viruses such as cytomegalovirus, Epstein-Barr virus, and adenovirus; however, reports have shown an unexpectedly high incidence of human herpesvirus (HHV)-6B encephalitis among pediatric allo-HSCT patients. METHODS: We report the first 18 consecutive allo-HSCT, 16 haplo-HSCT, and two human leukocyte antigen-matched related donors implanted with naïve TCD grafts. All donors were administered three cell products: first, a CD34+ stem cell product; second, a CD45RA+ TCD graft, followed by an adoptive natural killer (NK) cell infusion within 10 days after HSCT. The study's primary endpoint was the incidence of HHV-6B encephalitis. RESULTS: Engraftment was achieved in 94.5% of cases; 2-year overall survival, event-free survival, and GvHD/relapse-free survival were 87.2% (95% CI 78.6-95.8), 67.3% (95% CI 53.1-81.5), and 64% (95% CI 50.5-78.1), respectively. HHV-6B reactivation occurred in 7 of the haplo-HSCT patients, six of who received a cell infusion with an NK/CD4 ratio <2. None of the patients developed encephalitis. CONCLUSIONS: In this clinical study, we show that early adoptive NK cell infusion after a 45RA+ TCD allo-HSCT graft is safe and can prevent HHV-6B encephalitis. We recommend infusing adoptive NK cells after allo-HSCT using CD45RA+ TCD grafts.
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Encefalite/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 6/isolamento & purificação , Células Matadoras Naturais/transplante , Depleção Linfocítica , Infecções por Roseolovirus/prevenção & controle , Adolescente , Transferência Adotiva/métodos , Criança , Pré-Escolar , Encefalite/imunologia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Herpesvirus Humano 6/imunologia , Humanos , Lactente , Células Matadoras Naturais/imunologia , Masculino , Infecções por Roseolovirus/imunologia , Linfócitos T/imunologia , Transplante Homólogo/métodosRESUMO
SF3B1 is a highly mutated gene in myelodysplastic syndrome (MDS) patients, related to a specific subtype and parameters of good prognosis in MDS without excess blasts. More than 40% of MDS patients carry at least two myeloid-related gene mutations but little is known about the impact of concurrent mutations on the outcome of MDS patients. In applying next-generation sequencing (NGS) with a 117 myeloid gene custom panel, we analyzed the co-occurrence of SF3B1 with other mutations to reveal their clinical, biological, and prognostic implications in very low/low- and intermediate-risk MDS patients. Mutations in addition to those of SF3B1 were present in 80.4% of patients (median of 2 additional mutations/patient, range 0-5). The most frequently mutated genes were as follows: TET2 (39.2%), DNMT3A (25.5%), SRSF2 (10.8%), CDH23 (5.9%), and ASXL1, CUX1, and KMT2D (4.9% each). The presence of at least two mutations concomitant with that of SF3B1 had an adverse impact on survival compared with those with the SF3B1 mutation and fewer than two additional mutations (median of 54 vs. 87 months, respectively: p = 0.007). The co-occurrence of SF3B1 mutations with specific genes is also linked to a dismal prognosis: SRSF2 mutations were associated with shorter overall survival (OS) than SRSF2wt (median, 27 vs. 75 months, respectively; p = 0.001), concomitant IDH2 mutations (median OS, 11 [mut] vs. 75 [wt] months; p = 0.001), BCOR mutations (median OS, 11 [mut] vs. 71 [wt] months; p = 0.036), and NUP98 and STAG2 mutations (median OS, 27 and 11 vs. 71 months, respectively; p = 0.008 and p = 0.002). Mutations in CHIP genes (TET2, DNMT3A) did not significantly affect the clinical features or outcome. Our results suggest that a more comprehensive NGS study in low-risk MDS SF3B1mut patients is essential for a better prognostic evaluation.
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Síndromes Mielodisplásicas/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Dioxigenases , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Prognóstico , Proteínas Proto-Oncogênicas/genéticaRESUMO
The iron chelator deferasirox is widely used in patients with iron overload. Patients with low-grade myelodysplastic syndromes (MDS) get transfusion dependency and need to be treated with deferasirox to avoid iron overload. Moreover, in some patients an increase in both erythroid and platelets have been observed after deferasirox therapy. However, the mechanisms involved in these clinical findings are poorly understood. The aim of this work was to analyze, in patients treated with deferasirox, the changes in the gene-expression profile after receiving the treatment. A total of 15 patients with the diagnosis of low-grade MDS were studied. Microarrays were carried out in RNA from peripheral blood before and after 14 weeks of deferasirox therapy. Changes in 1457 genes and 54 miRNAs were observed: deferasirox induced the downregulation of genes related to the Nf kB pathway leading of an overall inactivation of this pathway. In addition, the iron chelator also downregulated gamma interferon. Altogether these changes could be related to the improvement of erythroid response observed in these patients after therapy. Moreover, the inhibition of NFE2L2/NRF2, which was predicted in silico, could be playing a critical role in the reduction of reactive oxygen species (ROS). Of note, miR-125b, overexpressed after deferasirox treatment, could be involved in the reduced inflammation and increased hematopoiesis observed in the patients after treatment. In summary this study shows, for the first time, the mechanisms that could be governing deferasirox impact in vivo.
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Deferasirox/uso terapêutico , Eritropoese/efeitos dos fármacos , Perfilação da Expressão Gênica , Quelantes de Ferro/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Transcriptoma/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Deferasirox/efeitos adversos , Eritropoese/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Humanos , Quelantes de Ferro/efeitos adversos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Análise de Sequência com Séries de Oligonucleotídeos , Farmacogenética , Resultado do TratamentoRESUMO
Background: Treatment-free remission (TFR)-that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response-is an emerging treatment goal in chronic myeloid leukemia (CML). Objective: To evaluate TFR after discontinuation of second-line nilotinib therapy. Design: Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905). Setting: 63 centers in 18 countries. Patients: Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR. Interventions: Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment. Measurements: Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point). Results: 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation. Limitation: The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment. Conclusion: TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib. Primary Funding Source: Novartis Pharmaceuticals Corporation.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Indução de Remissão , Resultado do TratamentoRESUMO
The CD45RA T cell depletion (TCD) method has been used to deplete naive T cells, preventing graft-versus-host disease (GVHD) but preserving memory cells, providing immediate functional T cells with anti-infection, antileukemia, and antirejection effects. We describe a series of 25 consecutive high-risk patients with leukemia who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with CD45RA TCD. Each patient received 2 cell products: 1 created by CD34 positive selection and the other through CD45RA depletion from the CD34 negative fraction by a CliniMACS device. CD45RA-depleted haplo-HSCT was well tolerated, with rapid engraftment and low risk of severe acute GVHD and chronic GVHD. Although this treatment achieved a good control of viral reactivations, such as cytomegalovirus and adenovirus, we observed an unexpectedly high rate of limbic encephalitis due to human herpesvirus-6 (HHV-6; 8 cases). Characteristically, the infection appeared early in almost all patients, just after the engraftment. Although no patient died from encephalitis, 1 patient showed neuropsychological sequelae, and another experienced secondary graft failure just after the HHV-6 reactivation.
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Encefalite Viral/etiologia , Herpesvirus Humano 6/patogenicidade , Linfócitos T/metabolismo , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Pré-Escolar , Encefalite Viral/patologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Incidência , MasculinoRESUMO
BACKGROUND: Cancer immunotherapy involving natural killer (NK) cells has gained interest. Here we report two methods to obtain interleukin (IL)-15-activated NK cells for clinical use. STUDY DESIGN AND METHODS: IL-15-activated NK cell products were obtained after 1) enrichment from healthy haploidentical donors' peripheral blood mononuclear cells (PBMNCs) collected by nonmobilized apheresis by a two-step magnetic procedure, depletion of CD3+ cells followed by selection of CD56+ cells and ex vivo overnight stimulation with IL-15 (NKIL15); and 2) expansion using the K562-mb15-41BBL cell line (NKAE), from autologous PBMNCs from patients with multiple myeloma or expansion from healthy haploidentical PBMNCs obtained from whole blood using the same previous cell line. We analyzed the NK cell recovery and expansion, T cell depletion, phenotype, cytotoxicity, safety, and genomic stability of two good manufacturing practices (GMP)-grade IL-15-activated NK cell products. RESULTS: The number of NK cells obtained from NKIL15 cell and NKAE cell products was similar; however, there were significantly fewer T cells in the NKIL15 cell product. The haploidentical NKAE cell product contained more T cells than the autologous NKAE cell product. The surface expression of the activating receptors CD69, CD25, natural killer group-2 member D receptor, NKp44, NKp46, NKp30, and DNA accessory molecule 1 was up regulated in both NK cell products. NKIL15 cell and NKAE cell products had significantly higher lytic activity than unstimulated NK cells and showed no lytic activity against PBMNCs from healthy donors. No genetic alterations or potential oncogenic effects were found. CONCLUSION: Different GMP-grade procedures can be used to obtain large numbers of highly IL-15-activated NK cells with extremely low T cell content for clinical use.
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Técnicas de Cultura de Células/métodos , Imunoterapia Adotiva/métodos , Interleucina-15/farmacologia , Células Matadoras Naturais/citologia , Neoplasias/terapia , Doadores de Sangue , Humanos , Células K562 , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Contagem de Linfócitos , Métodos , Linfócitos T/citologiaRESUMO
Myelodysplastic syndromes (MDS) are the commonest hematologic malignancies in the elderly. Since many patients with MDS actually die from age-related ailments, the very disease burden of MDS remains largely unknown. This registry-based study was aimed at investigating the excess mortality attributable to MDS. We analyzed 7,408 adult patients diagnosed with primary MDS from 1980 to 2014. Excess mortality was estimated by comparing the patients' survival with that expected in the matched general population. Median age of patients was 74 years, 58% were males, and 65% belonged to the lower risk categories of the Revised International Prognostic Scoring System (IPSS-R). Excess mortality accounted for three-fourths of the all-cause mortality and was mainly driven by factors unrelated to leukemic transformation. Excess mortality increased with the IPSS-R risk category [Incidence rate ratio (IRR): 2.1, 95% CI: 1.9-2.3; P < .001]. Older age and male sex retained an independent association with higher excess mortality after discounting demographic effects. Excess mortality increased in the most recent periods just in the higher risk IPSS-R categories (IRR: 1.2; 95% CI: 1.1-1.3 when comparing periods 2007-14, 2000-06, and 1980-99). In conclusion, MDS carry a significant excess mortality, even in the lower risk categories, that is mainly driven by factors unrelated to leukemic transformation, and increases with older age, male sex, and poorer risk categories. Excess mortality has increased in recent years in the higher risk patients, which might be ascribed to a parallel increase in age-related comorbidities. Our results claim for more comprehensive treatment strategies for patients with MDS. Am. J. Hematol. 92:149-154, 2017. © 2016 Wiley Periodicals, Inc.
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Síndromes Mielodisplásicas/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Mortalidade/tendências , Prognóstico , Fatores Sexuais , Espanha , Análise de SobrevidaRESUMO
The International Prognostic Scoring System and its revised form (IPSS-R) are the most widely used indices for prognostic assessment of patients with myelodysplastic syndromes (MDS), but can only partially account for the observed variation in patient outcomes. This study aimed to evaluate the relative contribution of patient condition and mutational status in peripheral blood when added to the IPSS-R, for estimating overall survival and the risk of leukemic transformation in patients with MDS. A prospective cohort (2006-2015) of 200 consecutive patients with MDS were included in the study series and categorized according to the IPSS-R. Patients were further stratified according to patient condition (assessed using the multidimensional Lee index for older adults) and genetic mutations (peripheral blood samples screened using next-generation sequencing). The change in likelihood-ratio was tested in Cox models after adding individual covariates. The addition of the Lee index to the IPSS-R significantly improved prediction of overall survival [hazard ratio (HR) 3.02, 95% confidence interval (CI) 1.96-4.66, P < 0.001), and mutational analysis significantly improved prediction of leukemic evolution (HR 2.64, 1.56-4.46, P < 0.001). Non-leukemic death was strongly linked to patient condition (HR 2.71, 1.72-4.25, P < 0.001), but not to IPSS-R score (P = 0.35) or mutational status (P = 0.75). Adjustment for exposure to disease-modifying therapy, evaluated as a time-dependent covariate, had no effect on the proposed model's predictive ability. In conclusion, patient condition, assessed by the multidimensional Lee index and patient mutational status can improve the prediction of clinical outcomes of patients with MDS already stratified by IPSS-R.
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Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Taxa de Sobrevida , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Espanha/epidemiologiaRESUMO
This study aimed to evaluate the evolution of iron overload, assessed by serum ferritin (SF), in transfusion-dependent lower risk patients with myelodysplastic syndrome (MDS), as well as to describe the occurrence of organ complications, and to analyze its relationship with iron chelation therapy. This observational retrospective study was conducted from March 2010 to March 2011 in 47 Spanish hospitals. A total of 263 patients with lower risk MDS (International Prognostic Scoring System [IPSS] low/intermediate-1 risk or Spanish Prognostic Index [SPI] 0-1 risk), transfusion-dependent, and who had received ≥10 packed red blood cells (PRBC) were included. At MDS diagnosis, patients received a mean of 2.8 ± 3.9 PRBC/month, and 8.7% of patients showed SF ≥1000 µg/L. Over the course of the disease, patients received a mean of 83.4 ± 83.3 PRBC, and 36.1% of patients presented SF ≥2500 µg/L. Cardiac, hepatic, endocrine, or arthropathy complications appeared/worsened in 20.2, 11.4, 9.9, and 3.8% of patients, respectively. According to investigator, iron overload was a main cause of hepatic (70.0%) and endocrine (26.9%) complications. A total of 96 (36.5%) patients received iron chelation therapy for ≥6 months, being deferasirox the most frequent first chelation treatment (71.9%). Chelation-treated patients showed longer overall survival (p < 0.001), leukemia-free survival (p = 0.007), and cardiac event-free survival (p = 0.017) than non-chelated patients. In multivariable analyses, age (p = 0.011), IPSS (p < 0.001), and chelation treatment (p = 0.015) were predictors for overall survival; IPSS (p = 0.014) and transfusion frequency (p = 0.001) for leukemia-free survival; and chelation treatment (p = 0.040) and Sorror comorbidity index (p = 0.039) for cardiac event-free survival. In conclusion, these results confirm the potential survival benefit of iron chelation therapy and provide additional evidence on the deleterious effect of iron overload in lower risk MDS patients.
Assuntos
Terapia por Quelação/métodos , Sobrecarga de Ferro/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Ferritinas/sangue , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/mortalidade , Estudos RetrospectivosRESUMO
The impact of lenalidomide treatment on long-term outcomes of patients with lower risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)) is unclear. This study used time-dependent multivariate methodology to analyse the influence of lenalidomide therapy on overall survival (OS) and acute myeloblastic leukaemia (AML) progression in 215 patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk and del(5q). There were significant differences in several relevant characteristics at presentation between patients receiving (n = 86) or not receiving lenalidomide (n = 129). The 5-year time-dependent probabilities of OS and progression to AML were 62% and 31% for patients receiving lenalidomide and 42% and 25% for patients not receiving lenalidomide; differences were not statistically significant in multivariate analysis that included all variables independently associated with those outcomes (OS, P = 0·45; risk of AML, P = 0·31, respectively). Achievement of RBC transfusion independency (P = 0·069) or cytogenetic response (P = 0·021) after lenalidomide was associated with longer OS in multivariate analysis. These data clearly show that response to lenalidomide results in a substantial clinical benefit in lower risk MDS patients with del(5q). Lenalidomide treatment does not appear to increase AML risk in this population of patients.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Avaliação de Medicamentos/métodos , Transfusão de Eritrócitos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Lenalidomida , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/genética , Prognóstico , Estudos Retrospectivos , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 < 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residual disease by multiparameter flow cytometry at day +100 after HDT/ASCT (hazard ratio 8.0; P = .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citometria de Fluxo , Mieloma Múltiplo/terapia , Neoplasia Residual/diagnóstico , Neoplasia Residual/etiologia , Transplante de Células-Tronco/efeitos adversos , Idoso , Terapia Combinada , Análise Citogenética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Neoplasia Residual/mortalidade , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
Interleukin-6 (IL-6) may play an important role in the pathophysiology of anemia of inflammation associated with myelodysplastic syndrome (MDS). This double-blind, placebo-controlled, phase 2 study assessed the efficacy and safety of siltuximab, a chimeric anti-IL-6 monoclonal antibody, in patients with low- and intermediate-1-risk MDS who require transfusions for MDS anemia. Patients were randomized in a 2:1 ratio to siltuximab 15 mg kg(-1) every 4 weeks + best supportive care (BSC) or placebo + BSC for 12 weeks. The primary endpoint was reduction in red blood cell (RBC) transfusions to treat MDS anemia, defined as ≥50% relative decrease and ≥2-unit absolute decrease in RBC transfusions. Fifty and 26 patients were randomized to the siltuximab and placebo groups, respectively. The study did not meet its prespecified hypothesis, with six (12%) patients in the siltuximab group and one (3.8%) in the placebo group having reductions in RBC transfusions (P = 0.271). At the time of the planned futility analysis, the prespecified cutoff criteria were not met, and the study was terminated early due to lack of efficacy. No unexpected safety findings were observed. In conclusion, compared to placebo, treatment with siltuximab did not reduce RBC transfusions in transfusion-dependent patients with low- and intermediate-1-risk MDS. Future studies might explore siltuximab in patients with less iron overload and with elevated IL-6 levels and/or using higher doses for MDS.
Assuntos
Anemia Refratária/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Assistência ao Paciente/métodos , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/etiologia , Anemia Refratária/imunologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Terapia Combinada , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Transfusão de Eritrócitos/estatística & dados numéricos , Feminino , Hemoglobinas/análise , Humanos , Interleucina-6/imunologia , Masculino , Futilidade Médica , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/imunologiaRESUMO
In the latest recommendations for the management of chronic-phase chronic myeloid leukemia suboptimal responses have been reclassified as "warning responses." In contrast to previous recommendations current guidance advises close monitoring without changing therapy. We have identified 198 patients treated with first-line imatinib, with a warning response after 12 months of treatment (patients with a complete cytogenetic response but no major molecular response [MMR]). One hundred and forty-six patients remained on imatinib, while 52 patients changed treatment to a second generation tyrosine kinase inhibitor (2GTKI). Changing therapy did not correlate with an increase in overall survival or progression-free survival. Nevertheless, a significant improvement was observed in the probability of a MMR: 24% vs. 42% by 12 months and 43% vs. 64% by 24 months (P = 0.002); as well as the probability of achieving a deep molecular responses (MR(4.5) ): 1% vs. 17% and 7% vs. 23% by 12 and 24 months, respectively (P = <0.001) .The treatment change to 2GTKI remained safe; however, we have observed a 19% of treatment discontinuation due to side effects. We have observed an improvement of molecular responses after changing treatment to 2GTKI in patients with late suboptimal response treated with imatinib first line. However, these benefits were not correlated with an improvement of progression free survival or overall survival.
Assuntos
Benzamidas/uso terapêutico , Biomarcadores Tumorais/sangue , Substituição de Medicamentos , Proteínas de Fusão bcr-abl/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Conduta Expectante , Benzamidas/farmacologia , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Estudos Multicêntricos como Assunto , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Resultado do TratamentoRESUMO
Cytogenetic aberrations identified by metaphase cytogenetics (MC) have diagnostic, prognostic, and therapeutic implications in myelodysplastic syndromes (MDS). However, in some MDS patients MC study is unsuccesful. Single nucleotide polymorphism array (SNP-A) based karyotyping could be helpful in these cases. We performed SNP-A in 62 samples from bone marrow or peripheral blood of primary MDS with an unsuccessful MC study. SNP-A analysis enabled the detection of aberrations in 31 (50%) patients. We used the copy number alteration information to apply the International Prognostic Scoring System (IPSS) and we observed differences in survival between the low/intermediate-1 and intermediate-2/high risk patients. We also saw differences in survival between very low/low/intermediate and the high/very high patients when we applied the revised IPSS (IPSS-R). In conclusion, SNP-A can be used successfully in PB samples and the identification of CNA by SNP-A improve the diagnostic and prognostic evaluation of this group of MDS patients.