RESUMO
BACKGROUND: There are no studies assessing the evolution and patterns of genetic studies performed at diagnosis in acute myeloid leukemia (AML) patients. Such studies could help to identify potential gaps in our present diagnostic practices, especially in the context of increasingly complex procedures and classifications. METHODS: The REALMOL study (NCT05541224) evaluated the evolution, patterns, and clinical impact of performing main genetic and molecular studies performed at diagnosis in 7285 adult AML patients included in the PETHEMA AML registry (NCT02607059) between 2000 and 2021. RESULTS: Screening rates increased for all tests across different time periods (2000-2007, 2008-2016, and 2017-2021) and was the most influential factor for NPM1, FLT3-ITD, and next-generation sequencing (NGS) determinations: NPM1 testing increased from 28.9% to 72.8% and 95.2% (p < .001), whereas FLT3-ITD testing increased from 38.1% to 74.1% and 95.9% (p < .0001). NGS testing was not performed between 2000-2007 and only reached 3.5% in 2008-2016, but significantly increased to 72% in 2017-2021 (p < .001). Treatment decision was the most influential factor to perform karyotype (odds ratio [OR], 6.057; 95% confidence interval [CI], 4.702-7.802), and fluorescence in situ hybridation (OR, 2.273; 95% CI, 1.901-2.719) studies. Patients ≥70 years old or with an Eastern Cooperative Oncology Group ≥2 were less likely to undergo these diagnostic procedures. Performing genetic studies were associated with a favorable impact on overall survival, especially in patients who received intensive chemotherapy. CONCLUSIONS: This unique study provides relevant information about the evolving landscape of genetic and molecular diagnosis for adult AML patients in real-world setting, highlighting the increased complexity of genetic diagnosis over the past 2 decades.
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B-cell maturation antigen (BCMA) is the lead antigen for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). A challenge is inter- and intra-patient heterogeneity in BCMA expression on MM cells and BCMA downmodulation under therapeutic pressure. Accordingly, there is a desire to augment and sustain BCMA expression on MM cells in patients that receive BCMA-CAR T-cell therapy. We used all-trans retinoic acid (ATRA) to augment BCMA expression on MM cells and to increase the efficacy of BCMA-CAR T cells in pre-clinical models. We show that ATRA treatment leads to an increase in BCMA transcripts by quantitative reverse transcription polymerase chain reaction and an increase in BCMA protein expression by flow cytometry in MM cell lines and primary MM cells. Analyses with super-resolution microscopy confirmed increased BCMA protein expression and revealed an even distribution of non-clustered BCMA molecules on the MM cell membrane after ATRA treatment. The enhanced BCMA expression on MM cells after ATRA treatment led to enhanced cytolysis, cytokine secretion and proliferation of BCMA-CAR T cells in vitro, and increased efficacy of BCMA-CAR T-cell therapy in a murine xenograft model of MM in vivo (NSG/MM.1S). Combination treatment of MM cells with ATRA and the γ- secretase inhibitor crenigacestat further enhanced BCMA expression and the efficacy of BCMA-CAR T-cell therapy in vitro and in vivo. Taken together, the data show that ATRA treatment leads to enhanced BCMA expression on MM cells and consecutively, enhanced reactivity of BCMA-CAR T cells. The data support the clinical evaluation of ATRA in combination with BCMA-CAR T-cell therapy and potentially, other BCMA-directed immunotherapies.
Assuntos
Secretases da Proteína Precursora do Amiloide , Imunoterapia Adotiva , Mieloma Múltiplo , Tretinoína , Animais , Humanos , Camundongos , Antígeno de Maturação de Linfócitos B , Mieloma Múltiplo/terapia , Linfócitos T , Tretinoína/farmacologia , Receptores de Antígenos QuiméricosRESUMO
Hematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, during the daytime, derepressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via ß3-adrenergic receptor. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes.
Assuntos
Movimento Celular , Colinérgicos/farmacologia , Ritmo Circadiano , Células-Tronco Hematopoéticas/fisiologia , Leucócitos/fisiologia , Sistema Nervoso Parassimpático/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/fisiologia , Adesão Celular , Células Cultivadas , Quimiotaxia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Feminino , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Adrenérgicos beta 2 , Receptores Adrenérgicos beta 3/fisiologia , Receptores Acoplados a Proteínas G/fisiologiaRESUMO
Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group. This cooperative nationwide strategy provides advanced molecular diagnostic for acute myeloid leukemia patients of the PETHEMA group.
Assuntos
Leucemia Mieloide Aguda , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , RecidivaRESUMO
This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.
Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Citarabina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Análise de Sobrevida , Resultado do TratamentoAssuntos
Proteínas Estimuladoras de Ligação a CCAAT , Leucemia Mieloide Aguda , Mutação , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Estimuladoras de Ligação a CCAAT/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Prognóstico , Sistema de Registros , Espanha/epidemiologiaRESUMO
BACKGROUND: The development of new noninvasive approaches for the diagnosis of human platelet antigen (HPA)-1 fetomaternal incompatibility has become of great interest. These approaches allow determination of whether the fetus is incompatible or not with the mother and a decision on antenatal therapy to avoid fetal or neonatal alloimmune thrombocytopenia (FNAIT). The objective of this work was to perform rapid, noninvasive prenatal test for HPA-1ab fetal antigen detection after the detection of an HPA-1-homozygous mother by using plasma cell-free DNA (cfDNA). STUDY DESIGN AND METHODS: The HPA-1 genotypes of 142 pregnant women and 17 nonpregnant controls were retrospectively determined by high-resolution melting (HRM) polymerase chain reaction (PCR). Coamplification at lower denaturation temperature (COLD) HRM PCR was performed to determine the fetal genotype analyzing cfDNA from all HPA-1bb pregnant women. RESULTS: After the HRM analysis, the following genotypes were identified: HPA-1aa (71.13%), HPA-1bb (2.8%), and HPA-1ab (26.06%). Four HPA-1bb-homozygous pregnant women were carrying an incompatible fetus. Plasma samples from these mothers were analyzed by HRM COLD-PCR. Homozygous HPA-1bb pregnant women carrying an HPA-1ab-heterozygous fetus did not group with either the HPA-1ab or the HPA-1bb controls. Thus, COLD-PCR analysis allows the detection of HPA-1ab-heterozygous fetuses carried by homozygous mothers during first weeks of pregnancy. CONCLUSION: The fetal genotype from HPA-1bb-homozygous women was detected by a noninvasive prenatal test as soon as 12 weeks of gestation.
Assuntos
Antígenos de Plaquetas Humanas/sangue , Ácidos Nucleicos Livres/análise , Histocompatibilidade Materno-Fetal/genética , Programas de Rastreamento/métodos , Diagnóstico Pré-Natal/métodos , Adolescente , Adulto , Antígenos de Plaquetas Humanas/imunologia , Estudos de Casos e Controles , Feminino , Genótipo , Homozigoto , Humanos , Integrina beta3 , Reação em Cadeia da Polimerase/métodos , Gravidez , Trombocitopenia Neonatal Aloimune/diagnóstico , Trombocitopenia Neonatal Aloimune/prevenção & controle , Adulto JovemRESUMO
Programmed death 1 (PD-1) activation triggers an immune checkpoint resulting in inhibition of T cells that leads to peripheral tolerance. Some PD-1 polymorphisms have been described and associated with the development of autoimmune diseases or cancer predisposition, but there are few data concerning the relevance of such polymorphisms on the clinical outcome after allogeneic hematopoietic stem cell transplant (alloHSCT). We analyzed the distribution of the SNPs PD-1.1G/A (rs36084323) and PD-1.3G/A (rs11568821) genotypes of the donor in a cohort of 1485 alloHSCT from HLA-identical sibling donors. We found an increased risk of grades II to IV graft-versus-host disease (GvHD) in patients receiving grafts from donors homozygous for the G allele at the rs36084323 SNP (P = 0.033; hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.1 to 4.8) and also from donors homozygous for the A allele at the rs11568821 position (P < 0.001; HR 4.5, 95%CI 2.0 to 10.1). In contrast, the PD-1 genotype of the donor did not show association with overall survival or relapse incidence. These results suggest that the PD-1 genotype of the donor plays an important role for the development of acute GvHD after alloHSCT from HLA-identical sibling donors.
Assuntos
Genótipo , Doença Enxerto-Hospedeiro , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas , Polimorfismo Genético , Receptor de Morte Celular Programada 1/genética , Irmãos , Doença Aguda , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/imunologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Vitamin D is a steroid-like hormone which acts by binding to vitamin D receptor (VDR). It plays a main role in the calcium homeostasis and metabolism. In addition, vitamin D display other important effects called "non-classical actions." Among them, vitamin D regulates immune cells function and hematopoietic cells differentiation and proliferation. Based on these effects, it is currently being evaluated for the treatment of hematologic malignancies. In addition, vitamin D levels have been correlated with patients' outcome after allogeneic stem cell transplantation, where it might regulate immune response and, accordingly, might influence the risk of graft-versus-host disease. Here, we present recent advances regarding its clinical applications both in the treatment of hematologic malignancies and in the transplant setting.
Assuntos
Neoplasias Hematológicas/terapia , Hematopoese , Leucemia/terapia , Síndromes Mielodisplásicas/terapia , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Imunidade Adaptativa/efeitos dos fármacos , Animais , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/metabolismo , Hematopoese/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Leucemia/imunologia , Leucemia/metabolismo , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/metabolismo , Receptores de Calcitriol/imunologia , Receptores de Calcitriol/metabolismo , Transplante de Células-Tronco/métodos , Vitamina D/imunologia , Vitamina D/metabolismo , Vitaminas/imunologia , Vitaminas/metabolismoRESUMO
Minor histocompatibility antigen (miHA) mismatches have been related to graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, but this association remains controversial due to the lack of consistency in the results obtained by different groups. The CTLA-4 genotype of the donor has been reported to be relevant in the appearance of acute GVHD. We explored the effect of the donor's CTLA-4 genotype in the incidence of acute GVHD associated with HA-1, HA-8, or H-Y miHA mismatches in a large cohort of 1295 patients receiving an allogeneic transplant from an HLA-identical sibling donor. The incidence of acute GVHD was higher if the donor and recipient were mismatched for HA-1, HA-8, or H-Y, but only when the donor had the CTLA-4 rs231775 AA genotype (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.27 to 3.75; P = .005; HR, 2.11, 95% CI, 1.06 to 4.18; P = .033; and HR, 1.50; 95% CI, 1.05 to 2.15; P = .025, respectively). In contrast, this increased risk of developing acute GVHD was not found when the donor presented the CTLA-4 rs231775 AG or GG genotypes. We conclude that the immune response to specific miHA mismatches is modulated by the CTLA-4 genotype of the donor.
Assuntos
Antígeno CTLA-4/genética , Imunidade , Antígenos de Histocompatibilidade Menor/imunologia , Doadores de Tecidos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Genótipo , Doença Enxerto-Hospedeiro/imunologia , Histocompatibilidade/imunologia , Humanos , Lactente , Pessoa de Meia-Idade , Adulto JovemRESUMO
There is at present little data to guide the choice of conditioning for patients with lymphoma undergoing reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). In this study, we compared the outcomes of patients undergoing RIC SCT who received fludarabine and melphalan (FluMel), the standard RIC regimen used by the Spanish Group of Transplantation, and fludarabine and busulfan (FluBu), the standard RIC regimen used by the Dana-Farber Cancer Institute/Brigham and Women's Hospital. We analyzed 136 patients undergoing RIC SCT for lymphoma with either FluBu (n = 61) or FluMel (n = 75) conditioning between 2007 and 2014. Median follow-up was 36 months. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 13% with FluBu and 36% with FluMel (P = .002). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 3.3% with FluBu and 31% with FluMel (P < .0001). The cumulative incidence of relapse at 1 year was 29% with FluBu and 10% with FluMel (P = .08). The 3-year disease-free survival rate was 47% with FluBu and 36% with FluMel (P = .24), and the 3-year overall survival rate was 62% with FluBu and 48% with FluMel (P = .01). In multivariable analysis, FluMel was associated with a higher risk of acute grades II to IV GVHD (HR, 7.45; 95% CI, 2.30 to 24.17; P = .001) and higher risk of NRM (HR, 4.87; 95% CI, 1.36 to 17.44; P = .015). The type of conditioning was not significantly associated with relapse or disease-free survival in multivariable models. However, conditioning regimen was the only factor significantly associated with overall survival: FluMel conditioning was associated with a hazard ratio for death of 2.78 (95% CI, 1.23 to 6.27; P = .014) compared with FluBu. In conclusion, the use of FluBu as conditioning for patients undergoing SCT for lymphoma was associated with a lower risk of acute GVHD and NRM and improved overall survival when compared with FluMel in our retrospective study. These results confirm the differences between these RIC regimens in terms of toxicity and efficacy and support the need for comparative prospective studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Condicionamento Pré-Transplante/mortalidade , Condicionamento Pré-Transplante/métodos , Adulto , Bussulfano/uso terapêutico , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfoma/mortalidade , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Taxa de Sobrevida , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide Aguda/mortalidade , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Humanos , Lactente , Recém-Nascido , Cooperação Internacional , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Razão de Chances , Análise de Sobrevida , Transplante HomólogoRESUMO
This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy followed by panobinostat maintenance in elderly patients with newly diagnosed acute myeloid leukemia. Patients with prior history of myelodysplastic syndrome were excluded and 38 evaluable patients were included in the study (median age: 71 years; range: 65-83). Study patients received an induction with idarubicin (8 mg/m(2) iv days 1-3) plus cytarabine (100 mg/m(2) iv days 1-7) plus panobinostat po at escalating doses (days 8, 10, 12, 15, 17 and 19) that could be repeated in non-responding patients. Patients achieving complete remission received a consolidation cycle with the same schema, followed by panobinostat maintenance (40 mg po 3 days/week) every other week until progression. Thirty-one patients were treated at the maximum tolerated dose of panobinostat in the combination (10 mg) with good tolerability. Complete remission rate was 64% with a time to relapse of 17.0 months (12.8-21.1). Median overall survival for the whole series was 17 months (5.5-28.4). Moreover, in 4 of 5 patients with persistent minimal residual disease before maintenance, panobinostat monotherapy reduced its levels, with complete negativization in two of them. Maintenance phase was well tolerated. The most frequent adverse events were thrombocytopenia (25% grades 3/4), and gastrointestinal toxicity, asthenia and anorexia (mainly grades 1/2). Five patients required dose reduction during this phase, but only one discontinued therapy due to toxicity. These results suggest that panobinostat is one of the first novel agents with activity in elderly acute myeloid leukemia patients, and suggest further investigation is warranted, particularly in the context of maintenance therapy. This trial is registered at clinicaltrials.gov identifier: 00840346.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Idarubicina/administração & dosagem , Indóis/administração & dosagem , Quimioterapia de Indução , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Quimioterapia de Manutenção , Masculino , Dose Máxima Tolerável , Neoplasia Residual , Panobinostat , Prognóstico , Recidiva , Resultado do TratamentoRESUMO
The study of monocyte activation and differentiation has great applications in sepsis, chronic inflammatory diseases, and cancer studies. However, despite the existence of well-established protocols for monocyte purification from human blood, the isolation of murine monocytes that can be subsequently activated has not yet been fully optimized. Here we evaluate a recently developed commercial procedure for obtaining monocytes from the bone marrow based on immunomagnetic depletion of non-monocytic cells. Moreover, we compare the advantages and disadvantages of this approach relative to other existing procedures. We found that monocytes isolates generated using this technique had equal purity to those attained via depletion from peripheral blood; however, higher yields were achieved. Furthermore, isolates from this technique have lower levels of macrophage contamination than those reported in samples generated by culturing bone marrow extracts with macrophage colony-stimulating factor (M-CSF). In addition, we demonstrate that the purified monocytes are sensitive to lipopolysaccharide (LPS)-mediated activation and, therefore, are useful for studies aimed at elucidating the molecular mechanisms involved in monocyte activation and differentiation.
Assuntos
Células da Medula Óssea , Separação Celular , Monócitos/citologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacosRESUMO
The use of PET in patients with marginal zone B cell lymphoma (MZL) is controversial because of variability of fluorodeoxyglucose (FDG) avidity. We analyzed 40 PET/CT in 25 consecutive patients to compare its performance with CT at staging and as a first-line response assessment. Sensitivity of PET/CT and CT was 96 and 76%. Mean standard uptake value was 6.1, 6.9 and 3.4 (p = 0.3) in nodal, extranodal and splenic subtypes, respectively. Of 17 patients (extranodal: n = 9; nodal: n = 6; splenic subtype: n = 2) with both imaging tests available at diagnosis, 8 (47%) had more involved areas with PET/CT than with CT, 75% of which were extranodal lesions. PET/CT resulted in upstaging of five patients although treatment of only two of them was changed. Responses of 15 patients with post-treatment PET/CT were the following: 9 negative and 6 positive of which 3 were isolated residual lesions. Progression was documented in two of these three patients. Response was also assessed by CT in 11 patients. Discrepancies were found in three: Two were in complete remission by CT while PET/CT detected localized residual disease; another patient was in partial remission by CT, whereas PET/CT showed only one positive lesion. Two of these three patients relapsed. Patients with negative post-treatment PET/CT did not relapse. With a median follow-up of 50 months (10-152 months), 3-year overall survival was 100 and 80% for patients with negative and positive post-treatment PET/CT (p = 0.2). Three-year disease-free survival was 86%; the negative predictive value (NPV) was 100%, and the positive predictive value (PPV) was 83.3%. Although a larger number of patients will be required to further confirm these data, we can conclude that PET/CT is a useful imaging tool for both staging and response assessment in patients with nodal and extranodal MZL as a result of its high sensitivity, NPV and PPV.
Assuntos
Fluordesoxiglucose F18/uso terapêutico , Linfoma de Zona Marginal Tipo Células B/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) is an effective treatment for patients with lymphomas. However, failure to reach the minimum threshold of hematopoietic stem cells to proceed to ASCT may occur, even with the most effective strategies currently available. STUDY DESIGN AND METHODS: We report on 33 patients diagnosed with lymphoma who had at least one prior mobilization failure and received cytarabine at a dose of 400 mg/m(2) /day intravenously × 3 days plus granulocyte-colony-stimulating factor (G-CSF) 10 to 12 µg/kg/day as mobilization regimen. The median number of previous lines of chemotherapy was three. RESULTS: Thirty-two of 33 patients (96.8%) reached the target CD34+ cell dose (>2 × 10(6) /kg). The mean (range) number of apheresis procedures was 1.8 (1-3) with 4.69 × 10(6) (1.5 × 10(6) -6.8 × 10(6) )/kg CD34+ cells obtained. All but one patient received chemomobilization in the outpatient department. Severe infections or treatment-related mortality were not observed. All patients that received ASCT (31/33) engrafted without requiring G-CSF during the posttransplant period. CONCLUSION: This study shows that cytarabine at intermediate doses plus G-CSF in patients diagnosed with lymphoma who had a prior mobilization failure is a feasible and effective mobilization regimen.
Assuntos
Citarabina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Linfoma não Hodgkin/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Contagem de Células , Terapia Combinada , Citarabina/farmacologia , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/sangue , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/terapia , Humanos , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/radioterapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Autólogo , Resultado do TratamentoRESUMO
UNLABELLED: Burkitt lymphoma (BL) is highly FDG-avid even though its usefulness in the management of these patients is still controversial. AIM: We analyzed the role of positron emission tomography/computerized tomography (PET/CT) in staging newly diagnosed patients with BL and evaluating disease after first-line chemotherapy. METHODS: Fifty-two PET/CTs were performed in 32 patients (20 at diagnosis, 27 after treatment, five to monitor residual disease). Involved areas were retrospectively compared with those observed in contrast-enhanced CT. RESULTS: Discrepancies were found in 64.7% of patients for whom results of both tests at diagnosis were available (n = 17), most of them involving extranodal sites. Regarding response assessment, discrepancies were observed in 38% of patients with both tests (5/13): residual masses detected by CT with negative PET/CT. Of 27 patients with post-treatment PET/CT, 22 were in complete remission whereas one true-positive and four false-positive lesions (two nodal and two extranodal) were detected. With a median follow-up of 27 months, 22 patients with negative PET/CT did not relapse. Thus, negative predictive value (NPV) was 100%. With respect to positive predictive value (PPV), one of five patients with positive assays after treatment died due to progression while the remaining four had false-positive lesions. Nevertheless, for these four patients, mean SUVmax at nodal sites was 4.1 vs. 14.9 at diagnosis, while mean SUVmax at extranodal sites was 3.8 vs. 12.1. Thus, with a cutoff value for SUVmax < 66% of that observed at diagnosis, PPV was also 100%. CONCLUSION: More accurate staging can be achieved using PET/CT. NPV reaches 100%, and using a ΔSUV < 66%, a high PPV is also observed.
Assuntos
Linfoma de Burkitt/diagnóstico , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/mortalidade , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Post-transplantation cyclophosphamide (PTCy) has emerged as a promising approach for preventing graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is a lack of studies examining the impact of this GVHD prophylaxis when different donor types are used in patients with Hodgkin lymphoma (HL). This study compared the outcomes of patients with HL undergoing HSCT from HLA-matched donors, including matched sibling donors (MSDs) and matched unrelated donors (MUDs), and haploidentical donors, using PTCy as the GVHD prophylaxis approach in all cohorts. We retrospectively compared outcomes of allo-HSCT from 166 HLA-matched donors (96 sibling and 70 unrelated donors) and 694 haploidentical donors using PTCy-based GVHD prophylaxis in patients with HL registered in the European Society for Blood and Marrow Transplantation database from 2010 to 2020. Compared to HLA-matched HSCT, haploidentical donor HSCT was associated with a significantly lower rate of platelet engraftment (86% versus 94%; P < .001) and a higher rate of grade II-IV acute GVHD (34% versus 24%; Pâ¯=â¯.01). The 2-year cumulative incidence of nonrelapse mortality (NRM) was significantly lower in the HLA-matched cohort compared to the haploidentical cohort (10% versus 18%; Pâ¯=â¯.02), resulting in a higher overall survival (OS) rate (82% versus 70%; Pâ¯=â¯.002). There were no significant differences between the 2 cohorts in terms of relapse, progression-free survival, or GVHD-free relapse-free survival. In multivariable analysis, haploidentical HSCT was associated with an increased risk of grade II-IV acute GVHD and NRM and worse OS compared to HLA-matched HSCT. Our findings suggest that in the context of PTCy-based GVHD prophylaxis, transplantation from HLA-matched donors appears to be a more favorable option compared to haploidentical HSCT.
Assuntos
Doença Enxerto-Hospedeiro , Doença de Hodgkin , Linfoma , Humanos , Doença de Hodgkin/tratamento farmacológico , Estudos Retrospectivos , Medula Óssea , Recidiva Local de Neoplasia/complicações , Ciclofosfamida/uso terapêutico , Linfoma/complicações , Linfoma/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Doadores não RelacionadosRESUMO
ABSTRACT: Studies comparing the efficacy of posttransplant cyclophosphamide (PTCy) to conventional calcineurin inhibitor (CNI)-based graft-versus-host disease (GVHD) prophylaxis regimens in patients with Hodgkin lymphoma (HL) are scarce. This study aimed to compare the outcomes of patients with HL undergoing hematopoietic stem cell transplantation (HSCT) from HLA-matched donors who received GVHD prophylaxis with either PTCy- or conventional CNI-based regimens, using data reported in the European Society for Blood and Marrow Transplantation database between January 2015 and December 2022. Among the cohort, 270 recipients received conventional CNI-based prophylaxis and 176 received PTCy prophylaxis. Notably, PTCy prophylaxis was associated with delayed hematopoietic recovery but also with a lower risk of chronic (25% vs 43%; P < .001) and extensive chronic GVHD (13% vs 28%; P = .003) compared with the CNI-based cohort. The 2-year cumulative incidence of nonrelapse mortality and relapse was 11% vs 17% (P = .12) and 17% vs 30% (P = .007) for PTCy- and CNI-based, respectively. Moreover, the 2-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) were all significantly better in the PTCy group compared with the CNI-based group: 85% vs 72% (P = .005), 72% vs 53% (P < .001), and 59% vs 31% (P < .001), respectively. In multivariable analysis, PTCy was associated with a lower risk of chronic and extensive chronic GVHD, reduced relapse, and better OS, PFS, and GRFS than the CNI-based platform. Our findings suggest that PTCy as GVHD prophylaxis offers more favorable outcomes than conventional CNI-based prophylaxis in adult patients with HL undergoing HSCT from HLA-matched donors.