RESUMO
BACKGROUND: Salvage autologous hematopoietic stem cell transplantation (autoHSCT) may be used to treat relapse of multiple myeloma occurring after previous autoHSCT. When insufficient number of hematopoietic stem cells was stored from the initial harvest, remobilization of stem cells is necessary. PURPOSE: The analysis of stem cell remobilization after previous autoHSCT. PATIENTS AND METHODS: Fifty-eight patients, 60% males, median 59 years, were included. Median time interval between autoHSCT and remobilization was 42 months. The first remobilization was performed mostly after chemotherapy: cyclophosphamide (33%), cytarabine (43%), and etoposide (19%). RESULTS: The first remobilization was successful in 67% patients. About 19% patients required plerixafor rescue, among whom it allowed for successful harvesting in 14%. Use of cyclophosphamide, cytarabine, and etoposide allowed for successful remobilization in 53%, 84%, and 55% patients, respectively. Patients treated with cytarabine had the highest yield of CD34+ cells (median 7.5 × 106 /kg vs 5.8 and 2.4 for etoposide and cyclophosphamide, P = .001). Higher percentage of patients was able to collect ≥2 × 106 CD34+ cells/kg during one leukapheresis after cytarabine (76% vs 21% for cyclophosphamide vs 36% for etoposide, P = .001). Cytarabine use was associated with lower risk of remobilization failure OR = 0.217, P = .02. Toxicity comprised mostly hematological toxicity (thrombocytopenia and neutropenia). One patient succumbed to septic shock. CONCLUSION: Remobilization after previous autoHSCT is feasible only in a proportion of patients. Cytarabine is associated with the highest rate of successful mobilization and the highest yield of mobilized CD34+ cells. The toxicity requires careful surveillance of these patients.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Adulto , Idoso , Ciclofosfamida/uso terapêutico , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Transplante AutólogoRESUMO
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole potential cure for paroxysmal nocturnal hemoglobinuria (PNH); however, the data on its utility in PNH are limited. This retrospective analysis of patients with PNH who underwent allo-HSCT in 11 Polish centers between 2002 and 2016 comprised 78 patients with PHN, including 27 with classic PNH (cPNH) and 51 with bone marrow failure-associated PNH (BMF/PNH). The cohort was 59% male, with a median age of 29 years (range, 12 to 65 years). There was a history of thrombosis in 12% and a history of hemolysis in 81%, and 92% required erythrocyte transfusions before undergoing allo-HSCT. No patient received eculizumab, and 26% received immunosuppressive treatment. The median time from diagnosis to allo-HSCT was 12 months (range, 1 to 127 months). Almost all patients (94%) received reduced-toxicity conditioning, 66% with treosulfan. The stem cell source was peripheral blood in 72% and an identical sibling donor in 24%. Engraftment occurred in 96% of the patients. With a median follow-up of 5.1 years in patients with cPNH and 3.2 years in patients with BMF/PNH, 3-year overall survival (OS) was 88.9% in the former and 85.1% in the latter (P = not significant [NS]). The 3-year OS for patients with/without thrombosis was 50%/92% (P = NS) in the cPNH group and 83.3%/85.3% (P = NS) in the BMF/PNH group. The 3-year OS for in the BMF/PNH patients with/without hemolysis was 93.9%/62.9% (hazard ratio, .13; P = .016). No other factors impacted OS. After allo-HSCT, the frequency of the PNH clone was reduced to 0%, <1%, and <2.4% in 48%, 48%, and 4% of cPNH patients and in 84%, 11%, and 5% of BMF/PNH patients, respectively. The frequency of acute graft-versus-host disease (GVHD) grade II-IV was 23%, and the cumulative 1-year incidence of extensive chronic GVHD was 10.8% in the BMF/PNH group and 3.7% in the cPNH group. Allo-HSCT is a valid option for PNH patients, effectively eliminating the PNH clone with satisfactory overall survival and acceptable toxicity. Reduced-toxicity conditioning with treosulfan is effective and safe in patients with cPNH and BMF/PNH.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística , Leucemia , Adolescente , Adulto , Idoso , Criança , Feminino , Hemoglobinúria Paroxística/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Polônia , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento , Adulto JovemAssuntos
Anemia Aplástica , Vacinas contra COVID-19 , COVID-19 , Hemoglobinúria Paroxística , Humanos , Anemia Aplástica/complicações , Anemia Aplástica/terapia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/terapia , VacinaçãoRESUMO
OBJECTIVE: MicroRNAs engaged in angiogenesis and hematopoiesis can influence hematopoietic stem cells (HSCs) homing after transplantation by targeting bone marrow niche microenvironment. This study aimed to examine the kinetics of miRNA-15a, miRNA-16, miRNA-126, miRNA-146a, and miRNA-223 in autologous HSC transplantation settings. METHODS: The study comprised of 51 patients with hematological malignancies (42 multiple myeloma, 9 lymphoma). Samples were taken at four time points: before conditioning, after chemotherapy but prior to autologous HSC transplantation (day 0), on day +7, and +14 days after HSCT. The miRNA levels were evaluated by the real-time PCR method. RESULTS: A significant, steady decline of all tested microRNAs in the course of transplantation, as compared to the baseline, was found. The study revealed that higher levels of miRNA-15a, miRNA-16, miRNA-126, and miRNA-146a on day 0 correlated with longer time to engraftment. Additionally, a positive correlation between the levels of miRNA-15a, miRNA-146a, and miRNA-223 assessed on day +7 and the time to engraftment was observed. CONCLUSIONS: In conclusion, all investigated microRNAs changed significantly in the course of transplantation. Our results suggest that the miRNAs may participate in hematopoietic recovery in the early post-transplant period and influence engraftment efficiency after HSCT.
Assuntos
Expressão Gênica , Sobrevivência de Enxerto/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , MicroRNAs/genética , Adulto , Idoso , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Transplante Autólogo , Resultado do TratamentoRESUMO
As a site of complicated interactions among cytokines, bone marrow niche has been the subject of many scientific studies, mainly in the context of the proteins influencing damage or recovery of endothelium after allogeneic hematopoietic stem cell transplantation (HSCT). In this study, we aimed at exploring mutual correlations of bone marrow niche cytokines involved in the homing and mobilization of hematopoietic stem cells, as well as in angiogenesis. The aim of our study was to evaluate levels of cytokines: VEGF, angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), and matrix metalloproteinase 9 (MMP-9) during autologous HSCT and to examine their influence on hematological recovery. Forty-three patients with hematological malignancies (33 multiple myeloma, 10 lymphoma) were enrolled in the study. Plasma samples were taken at five time points: before conditioning treatment (BC), on transplantation day (0) and 7 (+7), 14 (+14), and 21 (+21) days after HSCT. The cytokine levels were evaluated by ELISA method. Our study revealed decreased levels of VEGF, ANGPT1, and MMP-9 in the early post-transplant period as compared to the baseline (BC). ANGPT2 was decreased after conditioning treatment, but tended to increase from day +7. On day +7, positive correlations between ANGPT1 level as well as MMP-9 and the time to engraftment were observed. As opposite to ANGPT1, negative correlation between ANGPT2 level on day +7 after HSCT and the time to hematological recovery was noticed. Our study suggests that investigated cytokines are an important part of bone marrow environment and significantly influence the time to engraftment after HSCT.
Assuntos
Angiopoietina-1/biossíntese , Angiopoietina-2/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Linfoma , Metaloproteinase 9 da Matriz/biossíntese , Mieloma Múltiplo , Proteínas de Neoplasias/biossíntese , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adulto , Idoso , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/terapia , Humanos , Linfoma/sangue , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/terapiaRESUMO
OBJECTIVES: The epidemiology of myelodysplastic syndromes (MDS) differs among countries. Here, we present the first epidemiological indices determined for Poland. METHODS: Twenty-one haematological centres participated in the study. Patients diagnosed with MDS and acute myeloid leukaemia (AML) with 20-29% blasts were enrolled. Data collection was conducted for strictly predefined period. RESULTS: The overall crude incidence rate for all MDS subtypes was 1.95 (95% CI, 1.81-2.09) per 100 000 person-years: 2.46 (95% CI, 2.24-2.69) for males and 1.47 (95% CI, 1.31-1.65) for females; after excluding AML cases, the indices were as follows: 2.35 (95% CI, 2.08-2.66) for males and 1.27 (95% CI, 1.08-1.5) for females. Prevalence rate was 6.2 per 100 000 persons (95% CI, 5.96-6.45), that is 6.86 (95% CI, 6.49-7.24) for males and 5.58 (95% CI, 5.26-5.92) for females. Both incidence and prevalence increased with increasing age. The most frequently diagnosed MDS subtype was refractory cytopenia with multilineage dysplasia (RCMD), responsible for 30.3% of all newly diagnosed MDSs. CONCLUSIONS: RCMD is the most frequent MDS subtype in Poland. Incidence and prevalence indices are lower than those reported for other populations, which probably results from inadequate diagnosis of potential cases of this disease.
Assuntos
Erros de Diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Vigilância da População , Prevalência , Fatores Sexuais , Adulto JovemRESUMO
INTRODUCTION: Thrombocytapheresis is an alternative treatment beneficial in rare circumstances, when cytoreductive agents are contraindicated, drug therapy gave no response or the expected response would be too slow. Here we present a case of a pregnant woman who underwent 5 thrombocytaphereses using Spectra Optia device to reduce circulating platelets (PLT) count and prepare for Cesarian section. PATIENT CHARACTERISTICS AND PERFORMED TREATMENT: A 39-year-old woman with diagnosed chronic myeloid leukemia (CML) was treated with interferon because of too high PLT count. The treatment was well tolerated but the effect was not satisfactory (PLT count remained high). Because of high risk of bleeding during childbirth, the healthcare providers decided to perform thrombocytapheresis to reduce circulating PLT count below 1000×10E3/µl, and to prepare the patient for a planned Cesarean section. The results are presented as mean±SD. RESULTS: Five therapeutic aphereses procedures were performed, with a Spectra Optia device (TerumoBCT). A mean of 1.3±0.3 total blood volume was processed and we observed a mean PLT drop of 42.3±17.7%. Each apheresis procedure resulted in a PLT level ≤1000×10E3/µl. PLT CE1 was high 50.6±2.6% and reproducible. The white blood cell (WBC) loss was low (18.5%±11.0%). No adverse effects were observed. CONCLUSION: Therapeutic platelet depletion using the Spectra Optia™ Apheresis System can be effective and safe during pregnancy. Thrombocytapheresis procedures were reproducible and Spectra Optia system successfully adjusted settings to each procedure conditions. Thrombocytapheresis seems to be a viable and safe option even in pregnant women.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Plaquetoferese/instrumentação , Complicações Hematológicas na Gravidez/terapia , Adulto , Cesárea , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Contagem de Plaquetas , Plaquetoferese/métodos , Gravidez , Complicações Hematológicas na Gravidez/sangueRESUMO
Epidemiological studies on myelodysplastic syndromes (MDS) in Middle-Eastern Europe are scarce. No data about the demographic, clinical, and laboratory features of Polish MDS patients have been published. The aim of this study was to assess the epidemiological data and toxic exposure of Polish MDS patients and their association with hematological parameters and clinical outcomes. For 15 months, 966 living MDS patients were enrolled at 24 centers (12 university and 12 community hospitals). Follow-up was conducted for the next 55 months. The percentage of patients older than 80 years (16%) was between the values for Eastern and Western countries. In patients younger than 55 years, a female predominance was observed (male/female ratio 0.70:1 vs. 1.29:1; p < 0.001). Female patients had higher platelet counts (160 × 109/l vs. 111 × 109/l; p < 0.001). Patients exposed to chemicals were younger than patients without such exposure; their median age at MDS diagnosis was 66 vs. 70 years (p = 0.037). Smokers had significantly lower hemoglobin concentrations (8.6 vs. 9.1 g/dl; p = 0.032) and lower platelet counts (99 × 109/l vs. 137 × 109/l; p < 0.001) than nonsmokers. We provide the first description of the characteristics of Polish MDS patients. Females predominated in the group aged <60 years and they had higher platelet counts. The course of the disease is affected by toxic exposure and smoking.
Assuntos
Anemia/etiologia , Síndromes Mielodisplásicas/epidemiologia , Fumar/efeitos adversos , Trombocitopenia/etiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Hospitais Comunitários , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/fisiopatologia , Polônia/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Risco , Fatores Sexuais , Adulto JovemRESUMO
The bone marrow niche functions are modulated by complicated cytokines network. The aim of our study was to evaluate the levels of VCAM-1, VEGF, MMP-9 and SDF during mobilization of CD34+ cells in patients with hematological malignancies. Thirty four patients were enrolled to the study (19F, 15 M) at median age of 57 years. The group consisted of patients with multiple myeloma (26) and lymphoma (8). The mobilization procedures comprised chemotherapy and then G-CSF. Blood samples were collected before chemotherapy (N = 34) and on the day of the first apheresis (N = 26). Cytokines were evaluated with ELISA assay. We observed significant increase in VCAM-1 levels during mobilization. On contrary, VEGF and SDF levels decreased during mobilization procedure. The levels of MMP-9 were stable during mobilization. We divided patients according to baseline cytokines levels below and above median into "low" and "high" expressors. The group of VEGF "low" expressors had longer median time of G-CSF treatment before first apheresis than 'high' expressors. Baseline VEGF levels correlated adversely with duration of G-CSF treatment before first apheresis. Patients were also divided according to median cytokines levels at apheresis into "low" and "high" expressors. "High" VCAM-1 expressors had higher CD34+in peripheral blood as well as higher CD34+numbers collected during first apheresis than "low" expressors. In conclusion, the levels of niche cytokines change significantly during mobilization in patients with hematopoietic malignancies. Baseline VEGF can influence timing of mobilization. Higher VCAM-1 corresponds with higher mobilization efficacy.
Assuntos
Remoção de Componentes Sanguíneos/métodos , Citocinas/metabolismo , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/terapia , Células-Tronco Hematopoéticas/citologia , Nicho de Células-Tronco/imunologia , Adulto , Idoso , Antígenos CD34/metabolismo , Antineoplásicos/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Fator Estimulador de Colônias de Granulócitos/metabolismo , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Humanos , Cinética , Linfoma/sangue , Linfoma/terapia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/terapia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
In the last decade, peripheral blood was the main source of hematopoietic stem cells (HSC) for autologous and allogeneic transplantation. The exact mechanisms of HSC mobilization are still not clear and the efficacy of the procedure is hardly predictable. Ligand-receptor interactions of adhesion molecules, such as SDF1/CXCR4, VLA4/VCAM-1, or CD44/osteopontin, play an important role in homing of HSC in the hematopoietic niche. There is some evidence that disruption of the ligand-receptor complex leads to the egress of HSCs to the peripheral blood. The aim of the present study was the evaluation of constitutive polymorphism of genes encoding cytokines and receptors present in the HSC niche and their impact on the efficacy of mobilization of HSCs in patients with hematological malignancies. We enrolled 110 patients (60 females and 50 males) in the study. The median age of the patients was 55 (range, 22 to 69) years. The group consisted of patients with multiple myeloma (n = 74), non-Hodgkin lymphoma (n = 19), Hodgkin lymphoma (n = 15), or acute myeloid leukemia (n = 2). The mobilization procedures comprised chemotherapy and subsequent granulocyte-colony stimulating factor (G-CSF) at a dose of 10 µg/kg daily. The poor mobilizers group was defined according to Italian National Bone Marrow Transplant Registry criteria: patients with peak CD34(+) in the peripheral blood < 20/µL or total yield < 2 × 10(6) CD34(+) cells/kg body weight in maximum 3 aphereses. Genotyping was performed using standard PCR-based assays. The group of patients (N = 108) who achieved minimal threshold for collections (CD34(+) at least 10/µL) proceeded to apheresis. The median total yield of CD34(+) in this group was 5.6 × 10(6) cells/kg body weight, whereas the median number of cells collected during the first apheresis was 3.3 × 10(6) cells/kg body weight. Median number of days of G-CSF treatment before first apheresis was 10. Fifteen patients fulfilled the criteria for poor mobilizer. The group of poor mobilizers had higher frequency of TT genotype in rs13347 (CD44) gene (CC+ CT versus TT P = .047). Patients homozygous for T allele had a lower total yield of CD34(+) cells/kg body weight than the group with allele C (median, 3.7 × 10(6)/kg versus 5.8 × 10(6)/kg; P = .019) and a lower number of CD34(+) cells gathered during first apheresis (.95 × 10(6)/kg versus 3.3 × 10(6)/kg, P = .04). Multivariate logistic regression analysis revealed that the CD44 TT genotype was the only factor associated with 5-fold higher risk of poor mobilization (P = .037). Polymorphic variants of CXCR4 and VCAM-1 did not significantly influence the efficacy of HSCs mobilization in our group of patients. In conclusion, our results indicate that among investigated single nucleotide polymorphisms (SNPs), only CD44 rs13347 has an impact on the efficacy of HSCs mobilization in patients with hematologic malignancies. CD44 SNPs analysis may be helpful for predicting the poor mobilizers population who may benefit from newer modalities using adhesion molecules inhibitors.
Assuntos
Antígenos CD34/biossíntese , Neoplasias Hematológicas/genética , Mobilização de Células-Tronco Hematopoéticas/métodos , Receptores de Hialuronatos/genética , Adulto , Idoso , Antígenos CD34/sangue , Remoção de Componentes Sanguíneos/métodos , Feminino , Genótipo , Neoplasias Hematológicas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores CXCR4/genética , Molécula 1 de Adesão de Célula Vascular/genética , Adulto JovemRESUMO
Acquired aplastic anemia (AA) is an immune-mediated bone marrow (BM) failure where marrow disruption is driven by a cytotoxic T-cell-mediated autoimmune attack against hematopoietic stem cells. The key diagnostic challenge in children, but also in adults, is to exclude the possible underlying congenital condition and myelodysplasia. The choice of treatment options, either allogeneic hematopoietic cell transplantation (alloHCT) or immunosuppressive therapy (IST), depends on the patient's age, comorbidities, and access to a suitable donor and effective therapeutic agents. Since 2022, horse antithymocyte globulin (hATG) has been available again in Europe and is recommended for IST as a more effective option than rabbit ATG. Therefore, an update on immunosuppressive strategies is warranted. Despite an improved response to the new immunosuppression protocols with hATG and eltrombopag, some patients are not cured or remain at risk of aplasia relapse or clonal evolution and require postponed alloHCT. The transplantation field has evolved, becoming safer and more accessible. Upfront alloHCT from unrelated donors is becoming a tempting option. With the use of posttransplant cyclophosphamide, haploidentical HCT offers promising outcomes also in AA. In this paper, we present the state of the art in the management of severe AA for pediatric and adult patients based on the available guidelines and recently published studies.
Assuntos
Anemia Aplástica , Transplante de Células-Tronco Hematopoéticas , Humanos , Anemia Aplástica/terapia , Anemia Aplástica/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Criança , Imunoterapia/métodos , Soro Antilinfocitário/uso terapêutico , Imunossupressores/uso terapêutico , Resultado do Tratamento , AnimaisRESUMO
Salvage autologous hematopoietic cell transplantation (auto-HCT) may be used to treat relapse of plasma cell myeloma occurring after previous auto-HCT. When an insufficient number of hematopoietic stem cells have been stored from the initial harvest, remobilization is necessary. Here, we aimed to analyze the efficacy and safety of different doses of cytarabine (total 800 vs. 1600 vs. 2400 mg/m2) for remobilization. Sixty-five patients, 55% male, with a median age at remobilization 63 years, were included. Remobilization was performed with cytarabine_800 in 7, cytarabine_1600 in 36, and cytarabine_2400 in 22 patients. Plerixafor rescue was used in 25% of patients receiving cytarabine_1600 and 27% of those receiving cytarabine_2400. Patients administered cytarabine_800 were not rescued with plerixafor. Remobilization was successful in 80% of patients (57% cytarabine_800; 86% cytarabine_1600; 77% cytarabine_2400; p = 0.199). The yield of collected CD34+ cells did not differ between the different cytarabine doses (p = 0.495). Patients receiving cytarabine_2400 were at the highest risk of developing severe cytopenias, requiring blood product support, or having blood-stream infections. One patient died of septic shock after cytarabine_2400. In summary, remobilization with cytarabine is feasible in most patients. All doses of cytarabine allow for successful remobilization. Cytarabine_2400 is associated with higher toxicity; therefore, lower doses (800 or 1600 mg/m2) seem to be preferable.
RESUMO
In neoplastic disorders, endothelial cells take part in tumor progression and also influence the recovery of hematopoiesis after high-dose chemotherapy. Measurements of circulating endothelial cells (CEC), their subsets and kinetics were taken in patients with lymphoid malignancies (37 multiple myeloma, ten lymphoma) during autologous hematopoietic stem cell transplantation (HSCT). CEC were evaluated by four-color flow cytometry at different time points. Additionally levels of angiopoietins 1 and 2 were evaluated by ELISA assay. The baseline number of CECs and their subsets in patients were higher than in the control group. The median CEC number dropped significantly after transplantation (from 9.5/µL to 6.2/µL, p < 0.001). Apoptosis of CECs 24 h after chemotherapy was enhanced in comparison to baseline values (median apoptotic CEC number 4.15/µL vs 3.1/µL; p < 0,001). The time for neutrophil engraftment was shorter for patients with a low apoptotic CEC count at baseline as compared to those with a high apoptotic CEC count (median time to engraftment 13 vs. 16 days respectively, p = 0.04). We observed an adverse correlation of progenitor CEC numbers measured 1 h after transplantation with the time to neutrophil engraftment (r = -0.49, p = 0.008). We also found a negative correlation between the number of CECs originating from microvessels measured 1 h after transplantation, and the time to neutrophil engraftment (r = -0.39, p = 0.04). Baseline angiopoietins 1 and 2 concentration did not influence the post-transplant regeneration time. CEC numbers significantly change during autologous HSCT. Our results suggest that progenitor CECs and CECs derived from microvessels both take part in successful engraftment.
Assuntos
Apoptose/fisiologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/cirurgia , Adulto , Idoso , Feminino , Citometria de Fluxo/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Cinética , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Circulating endothelial cells (CECs) in patients with hematological malignancies are assessed as a noninvasive marker of angiogenesis. The aim of this study was to evaluate the numbers of CECs and their subsets during mobilization of hematopoietic stem cells. PATIENTS AND METHODS: Thirty-eight patients were enrolled to the study (19 females and 19 males) at median age of 56.5 years. The group consisted of patients with multiple myeloma (26), lymphoma (10), and acute myeloid leukemia (2). Blood samples were collected before chemotherapy (0), 1 day after chemotherapy (Cht+1), on the day G-CSF commenced (G0), after 1 day of G-CSF (G+1), and on the day of the first apheresis. CECs were evaluated by four-color flow cytometry. Circulating progenitor cells were defined as CD45-/CD34+/CD31+/CD133+. Apoptotic CECs (ApoCECs) were defined as CD146+/AnnexinV+. RESULTS: Median (Me) CECs number was 10.5/µl and it decreased after chemotherapy (Me = 8.3/µl, P < 0.001 when compared with baseline). Based on the number of aphereses needed to obtain 2 × 10(6)/kg CD34+ cells, patients were divided into "highly efficient" (one apheresis) and "poorly efficient" mobilizers (two or more aphereses). Median ApoCEC at Day G+1 was lower in highly efficient than in poorly efficient mobilizers (Me = 3.1/µl vs. Me = 5.1/µl, P = 0.02). ApoCEC at Day G+1 correlated with the number of aphereses (r = 0.48, P = 0.03). In multivariate analysis, ApoCEC at Day G+1 was an independent factor for successful mobilization during one apheresis. CONCLUSIONS: CECs and their subsets change significantly during mobilization of HSCs. ApoCECs measured at the time of G-CSF commencement can predict the efficacy of HSC collection.
Assuntos
Células Endoteliais/citologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Antígeno AC133 , Adulto , Idoso , Anexina A5/metabolismo , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Apoptose , Remoção de Componentes Sanguíneos , Estudos de Casos e Controles , Separação Celular , Feminino , Citometria de Fluxo , Glicoproteínas/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Leucemia Mieloide Aguda/terapia , Antígenos Comuns de Leucócito/metabolismo , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Neovascularização Patológica , Peptídeos/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Fatores de Tempo , Adulto JovemRESUMO
Mobilization of CD34+ cells is a key element in the therapy of patients with multiple myeloma (MM) undergoing autologous stem cell transplantation. The use of chemotherapy and the granulocyte colony-stimulating factor can significantly affect the expression of inflammation-related proteins and the migration of hematopoietic stem cells. We assessed the mRNA expression of selected proteins involved in the inflammatory landscape in patients with MM (n = 71). The study aimed to evaluate C-C motif chemokine ligands 3, 4, 5 (CCL3, CCL4, CCL5), leukocyte cell-derived chemotaxin 2 (LECT2), tumor necrosis factor (TNF), and formyl peptide receptor 2 (FPR2) levels in the course of mobilization and their role in the CD34+ collection efficacy. mRNA expression from peripheral blood (PB) plasma was evaluated by Reverse transcription polymerase chain reaction. We observed a deep decline in CCL3, CCL4, LECT2, and TNF mRNA expression on the day of the first apheresis (day A) compared with that at baseline. A negative correlation was observed between CCL3, FPR2, LECT2, TNF level, and the CD34+ cells count in PB on day A, and the number of CD34+ cells obtained at first apheresis. Our results indicate that the investigated mRNAs significantly alter and may regulate the migration of CD34+ cells during mobilization. Moreover, in the case of FPR2 and LECT2, the results obtained in patients differed from the murine models.
Assuntos
Remoção de Componentes Sanguíneos , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Animais , Camundongos , Mobilização de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/tratamento farmacológico , Transplante Autólogo , Antígenos CD34 , Fator Estimulador de Colônias de Granulócitos , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
Sirtuins are involved in the fate of hematopoietic stem cells (HSCs), including their metabolism, stress response, differentiation, migration, and apoptosis. The aim of this study was to explore SIRT1-7 expression during HSC mobilization. The study included 50 patients with lymphoproliferative disorders (39 multiple myeloma, 11 lymphoma). Samples were taken before mobilization (day 0) and on the day of first apheresis (day A). The sirtuin expression was evaluated by the Droplet Digital PCR (ddPCR) method. A significant increase of the SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7 levels measured at day A as compared to baseline was observed. The study revealed a positive correlation between SIRT5, SIRT6, and SIRT7 expression and the CD34+ peak value in peripheral blood and the number of CD34+ cells collected on day A. Patients from the SIRT7 "high expressors" group collected more CD34+ cells on day A than "low expressors". Upregulated expressions of SIRT3 and SIRT7 on the day of first apheresis were observed in patients in complete remission status (CR) as compared to the non-CR group. Our results suggest that the investigated sirtuins may influence the HSC migration and hematopoietic landscape during mobilization. SIRT5, SIRT6, and SIRT7 may be associated with the efficacy of HSC mobilization.
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Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.
Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Mielofibrose Primária , Trombocitemia Essencial , Trombose , Adulto , Criança , Humanos , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/epidemiologia , Policitemia Vera/complicações , Mielofibrose Primária/genética , Estudos Prospectivos , Trombose/etiologia , Adulto JovemRESUMO
Recent developments in the field of targeted therapy have led to the discovery of a new drug, plerixafor, that is a specific inhibitor of the CXCR4 receptor. Plerixafor acts in concert with granulocyte colony-stimulating factor (G-CSF) to increase the number of stem cells circulating in the peripheral blood (PB). Therefore, it has been applied in the field of hematopoietic stem cell mobilization. We analyzed retrospectively data regarding stem cell mobilization with plerixafor in a cohort of 61 patients suffering from multiple myeloma (N = 23), non-Hodgkin's lymphoma (N = 20), or Hodgkin's lymphoma (N = 18). At least one previous mobilization attempt had failed in 83.6% of these patients, whereas 16.4% were predicted to be poor mobilizers. The median number of CD34+ cells in the PB after the first administration of plerixafor was 22/µL (range of 0-121). In total, 85.2% of the patients proceeded to cell collection, and a median of two (range of 0-4) aphereses were performed. A minimum of 2.0 × 10(6) CD34+ cells per kilogram of the patient's body weight (cells/kg b.w.) was collected from 65.6% of patients, and the median number of cells collected was 2.67 × 10(6) CD34+ cells/kg b.w. (0-8.0). Of the patients, 55.7% had already undergone autologous stem cell transplantation, and the median time to neutrophil and platelet reconstitution was 12 and 14 days, respectively. Cases of late graft failure were not observed. We identified the diagnosis of non-Hodgkin's lymphoma and previous radiotherapy as independent factors that contributed to failure of mobilization. The current report demonstrates the satisfactory efficacy of plerixafor plus G-CSF for stem cell mobilization in heavily pre-treated poor or predicted poor mobilizers.
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Ensaios de Uso Compassivo , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Receptores CXCR4/antagonistas & inibidores , Adulto , Idoso , Antígenos CD34/sangue , Benzilaminas , Estudos de Coortes , Ciclamos , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Doença de Hodgkin/sangue , Doença de Hodgkin/terapia , Humanos , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/terapia , Polônia , Estudos Retrospectivos , Transplante Autólogo , Adulto JovemRESUMO
microRNAs play an important role in the regulation of gene expression, cell fate, hematopoiesis, and may influence the efficacy of CD34+ cell mobilization. The present study examines the role of hsa-miR-15a-5p, hsa-miR-16-5p, hsa-miR-34a-5p, hsa-miR-126-3p, hsa-miR-146a-5p, hsa-miR-155-5p, and hsa-miR-223-3p in the course of hematopoietic stem cell mobilization. The numbers of CD34+ cells collected in patients with hematological malignancies (39 multiple myelomas, 11 lymphomas) were determined during mobilization for an autologous hematopoietic stem cell transplantation. The miRNA level was evaluated by RT-PCR. Compared to baseline, a significant decline in hsa-miR-15a-5p, hsa-miR-16-5p, hsa-miR-126-3p, hsa-miR-146a-5p, and hsa-miR-155-5p was observed on the day of the first apheresis (day A). An increase was observed only in the expression of hsa-miR-34a-5p. On day A, a negative correlation was found between hsa-miR-15a-5p and hsa-miR-146a-5p levels and the number of CD34+ cells in peripheral blood. A negative correlation was observed between hsa-miR-146a-5p and the number of collected CD34+ cells after the first apheresis. Good mobilizers, defined according to GITMO criteria, demonstrated a lower hsa-miR-146a-5p level on day A than poor mobilizers. Patients from the hsa-miR-146a-5p "low expressors" collected more CD34+ cells than "high expressors". Our results suggest that the investigated miRNAs, especially hsa-miR-146a-5p, may influence the efficacy of HSC mobilization.
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INTRODUCTION: The misbalance between a family of inhibitor of apoptosis proteins (IAP), regulated by the nuclear factor kappa B (NF-κB) and their natural antagonist second mitochondrial-derived activator of caspases/direct IAP binding protein with low pI (Smac/DIABLO) are important to biology of acute myeloid leukemia (AML). MATERIAL AND METHODS: The aim of the study was to assess NF-κB and Smac/DIABLO proteins expression in blasts of 109 newly diagnosed AML patients using the multicolor flow cytometry and evaluate their influence on AML patients outcome. RESULTS: Expression of NF-κB and of Smac/DIABLO proteins were found in 95% and 98% of the patients, respectively. A negative correlation between Smac/DIABLO and NF-κB was observed. Age < 60 years old as well as higher Smac/DIABLO expression were associated with a higher probability of complete response achievement in the multivariate analysis. Longer overall survival (OS) in the univariate and multivariate analyses was influenced by age < 60 years old, a favorable or intermediate-risk karyotype and high Smac/DIABLO expression. Additionally, in the survival analysis of the subgroups, the patients aged < 60 years old, with high Smac/DIABLO expression, lower NF-κB expression and < 50% of bone marrow blasts who were treated with standard treatment had better OS. CONCLUSIONS: Lower NF-κB and higher Smac/DIABLO expression may influence AML patients outcome.