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Studies on asparaginase enzyme activity (AEA) monitoring in Chinese patients receiving PEG-asparaginase remain limited. We monitored AEA in paediatric patients diagnosed with acute lymphoblastic leukaemia (ALL) and treated according to the Chinese Children's Cancer Group study protocols, CCCG-ALL-2015/CCCG-ALL-2020 protocols. We measured the AEA at days 7 ± 1 and 14 ± 1 and analysed their association with patient characteristics and PEG-asparaginase-related adverse effects (AEs). We measured 2147 samples from 329 patients. Mean AEA levels (interquartile range) were 931 iu/L (654-1174 iu/L) at day 7 ± 1 and 664 iu/L (463-860 iu/L) at day 14 ± 1. The AEA levels were higher in younger children and increased with the cumulative dose numbers. PEG-asparaginase inactivation rate was 19.1%, and the silent inactivation (SI) rate was 12.5%. Nine patients were identified with allergic-like reactions. Hypofibrinogenaemia, hypertriglyceridaemia, pancreatitis and thrombosis were associated with older age, whereas hypoglycaemia was associated with younger age. The risk of hypertriglyceridaemia and hypoglycaemia increased with cumulative dose numbers of PEG-asparaginase. Except for hypofibrinogenaemia, elevated AEA levels did not increase the risk of PEG-asparaginase-related AEs. Drug monitoring can be utilized as guidance for treatment decision-making. Individualizing asparaginase doses do not reduce toxicities. The treatment target of PEG-asparaginase remains to achieve sustained and adequate activity.
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Asparaginasa , Polietilenglicoles , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Asparaginasa/administración & dosificación , Asparaginasa/efectos adversos , China , Pueblos del Este de Asia , Pancreatitis/inducido químicamente , Polietilenglicoles/efectos adversos , Polietilenglicoles/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
BACKGROUND: The predictive importance of IKZF1del in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has shown variability across different studies. Thus, the optimal treatment approach for children with IKZF1del BCP-ALL remains contentious, with the ongoing debate surrounding the use of IKZF1del-based high-risk stratification versus a minimal residual disease (MRD)-guided protocol. METHODS: IKZF1 status was reliably determined in 804 patients using multiplex ligation-dependent probe amplification (MLPA) data obtained from four hospitals in Fujian, a province of China. In the Chinese Children Leukemia Group (CCLG)-ALL 2008 cohort, IKZF1 status was included in the risk assignment, with all IKZF1del patients receiving a high-risk regimen. Conversely, in the Chinese Children's Cancer Group (CCCG)-ALL 2015 cohort, IKZF1del was not incorporated into the risk assignment, and patients were treated based on an MRD-guided risk stratification protocol. RESULTS: IKZF1del was found in 86 patients (86/804, 10.7%) overall and in 30 (30/46, 65.2%) BCR::ABL1-positive patients. Overall, IKZF1del was a poor prognostic predictor for patients, though the significance diminished upon age adjustment, white blood cell (WBC) count at diagnosis, treatment group, and MRD status. In the CCLG-ALL 2008 cohort, IKZF1del conferred a notably lower 5-year overall survival (OS) and event-free survival (EFS) and a significantly higher 5-year cumulative incidence of relapse (CIR) than IKZF1wt. In the CCLG-ALL 2015 cohort, IKZF1del conferred a lower 5-year OS and EFS and a higher 5-year CIR than IKZF1wt, but the differences were insignificant. The IKZF1del patients treated with higher intensity chemotherapy (CCLG-ALL 2008 high-risk regimen) had a markedly lower 5-year OS and EFS compared with those treated with the MRD-guided protocol (CCCG-ALL 2015 protocol). Furthermore, patients treated with the CCLG-ALL 2008 high-risk regimen experienced a higher frequency of serious adverse events (SAEs), especially infection-related SAEs, compared with those treated with the CCCG-ALL 2015 MRD-guided protocol. CONCLUSIONS: The prognostic effect of IKZF1del may vary in different protocols. Compared with higher intensity chemotherapy, the MRD-guided protocol may be a more effective approach to treating BCP-ALL with IKZF1del in children.
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Factor de Transcripción Ikaros , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Factor de Transcripción Ikaros/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Femenino , Niño , Pronóstico , Preescolar , Neoplasia Residual/genética , Lactante , Adolescente , China/epidemiología , Eliminación de GenAsunto(s)
Anemia Aplásica , Trasplante de Células Madre Hematopoyéticas , Sistema de Registros , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Anemia Aplásica/terapia , Anemia Aplásica/mortalidad , Anemia Aplásica/diagnóstico , Anciano , Masculino , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , China/epidemiología , Pueblos del Este de AsiaRESUMEN
BACKGROUND: This Phase 3 randomized, double-blind study evaluated the efficacy and safety of plerixafor plus granulocyte-colony-stimulating factor for the mobilization of hematopoietic stem cells in Chinese patients with non-Hodgkin's lymphoma. STUDY DESIGN AND METHODS: Adults (ages 18-75 years) with non-Hodgkin's lymphoma in first or second complete or partial remission, without previous hematopoietic stem cell mobilization or autologous transplant, were included. Patients received granulocyte-colony-stimulating factor 10 µg/kg/day from Days 1 through 4 before they were randomized (1:1) to receive either plerixafor 0.24 mg/kg/day or placebo subcutaneously on Days 4 through 7 plus continued granulocyte-colony-stimulating factor on Days 5 through 8. Apheresis began on Day 5 and continued for no more than 4 days. The primary endpoint was collection of 5 × 106 CD34+ cells/kg or greater over no more than 4 days of apheresis. Other endpoints included the collection of 2 × 106 CD34+ cells/kg or greater and safety. RESULTS: Overall, 101 patients were enrolled, and 50 were randomized to each group. More patients in the plerixafor group achieved 5 × 106 CD34+ cells/kg or greater (62 vs. 20%; p < 0.0001) or 2 × 106 CD34+ cells/kg or greater (88 vs. 66%) and underwent transplantation (88 vs. 68%) compared with those in the placebo group. The most common plerixafor-related adverse events were nausea (7.8%) and diarrhea (3.9%). CONCLUSION: Plerixafor plus granulocyte-colony-stimulating factor is superior to placebo plus granulocyte-colony-stimulating factor for the mobilization of CD34+ cells for autologous transplantation and is generally well tolerated in Chinese patients with non-Hodgkin's lymphoma.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/farmacología , Linfoma no Hodgkin/terapia , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencilaminas , China , Terapia Combinada , Ciclamas , Método Doble Ciego , Sinergismo Farmacológico , Enfermedades Gastrointestinales/inducido químicamente , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Movilización de Célula Madre Hematopoyética/efectos adversos , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/efectos adversos , Humanos , Hipopotasemia/inducido químicamente , Linfoma no Hodgkin/tratamiento farmacológico , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/inducido químicamente , Trasplante de Células Madre de Sangre Periférica , Inducción de Remisión , Trasplante Autólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system with demyelination, axon damage, and paralysis. Induction of mixed chimerism with allogeneic donors has been shown to not cause graft-versus-host disease (GVHD) in animal models and humans. We have reported that induction of MHC-mismatched mixed chimerism can cure autoimmunity in autoimmune NOD mice, but this approach has not yet been tested in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). Here, we report that MHC-mismatched mixed chimerism with C57BL/6 (H-2(b)) donor in SJL/J (H-2(s)) EAE recipients eliminates clinical symptoms and prevents relapse. This cure is demonstrated by not only disappearance of clinical signs but also reversal of autoimmunity; elimination of infiltrating T, B, and macrophage cells in the spinal cord; and regeneration of myelin sheath. The reversal of autoimmunity is associated with a marked reduction of autoreactivity of CD4(+) T cells and significant increase in the percentage of Foxp3(+) Treg among host-type CD4(+) T cells in the spleen and lymph nodes. The latter is associated with a marked reduction of the percentage of host-type CD4(+)CD8(+) thymocytes and an increase of Treg percentage among the CD4(+)CD8(+) and CD4(+)CD8(-) thymocytes. Thymectomy leads to loss of prevention of EAE relapse by induction of mixed chimerism, although there is a dramatic expansion of host-type Treg cells in the lymph nodes. These results indicate that induction of MHC-mismatched mixed chimerism can restore thymic negative selection of autoreactive CD4(+) T cells, augment production of Foxp3(+) Treg, and cure EAE.
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Encefalomielitis Autoinmune Experimental/inmunología , Complejo Mayor de Histocompatibilidad/inmunología , Linfocitos T Reguladores/inmunología , Timo/inmunología , Quimera por Trasplante/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/terapia , Femenino , Citometría de Flujo , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Ratones Endogámicos C57BL , Ratones Endogámicos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Recurrencia , Linfocitos T Reguladores/metabolismo , Timocitos/inmunología , Trasplante HomólogoRESUMEN
There are several reports describing population pharmacokinetic (popPK) models of busulfan (BU). However, limited information is available in Chinese hematopoietic stem cell transplantation (HSCT) patients. The present study aimed to establish a popPK model of intravenous BU in Chinese HSCT patients for individualized drug therapy. The popPK model of BU was developed from a total of 284 concentration-time points from 53 patients. The effects of demographic and biochemical covariates were investigated by nonlinear mixed effect model (NONMEM) software. Plots, visual predictive check (VPC), bootstrap and normalized prediction distribution error (NPDE) were performed to determine the stability and the reliability of the final model. A one-compartment model with first-order elimination process was confirmed as the final structural model for BU. For a typical patient whose body surface area (BSA) is 1.7 m2 , the population typical values of CL and Vd were 11.86 L/h, and 48.2 L, respectively. The result suggested BSA showed significant influence on CL and Vd (P<.001). Plots revealed the final model was performing a goodness fit. The steady rate verified by bootstrap was 100%, relative deviation was less than 4.00%, estimated value of final model was in the 95% confidence interval (CI). The VPC results showed the observed values were almost all positioned within the 5th and 95th CIs. The mean and variance of the NPDE were 0.0363 (Wilcoxon signed-rank test, 0.298) and 0.877 (Fisher variance test, 0.134; SW test of normality, 0.108), respectively. The global adjusted P value was 0.305, which indicated that the prediction of the BU popPK model was adequate. A physician-friendly Microsoft Excel-base tool was implemented using the final popPK model for designing individualized dosing regimens.
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Pueblo Asiatico , Busulfano/administración & dosificación , Busulfano/sangre , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Administración Intravenosa , Adolescente , Adulto , Pueblo Asiatico/genética , Niño , Femenino , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Adulto JovenRESUMEN
We reported previously that anti-CD3 mAb treatment before hematopoietic cell transplantation (HCT) prevented graft-versus-host disease (GVHD) and preserved graft-versus-leukemia (GVL) effects in mice. These effects were associated with downregulated donor T cell expression of tissue-specific homing and chemokine receptors, marked reduction of donor T cell migration into GVHD target tissues, and deletion of CD103(+) dendritic cells (DCs) in mesenteric lymph nodes (MLN). MLN CD103(+) DCs and peripheral lymph node (PLN) DCs include CCR7(+) and CCR7(-) subsets, but the role of these DC subsets in regulating donor T cell expression of homing and chemokine receptors remain unclear. Here, we show that recipient CCR7(+), but not CCR7(-), DCs in MLN induced donor T cell expression of gut-specific homing and chemokine receptors in a retinoid acid-dependent manner. CCR7 regulated activated DC migration from tissue to draining lymph node, but it was not required for the ability of DCs to induce donor T cell expression of tissue-specific homing and chemokine receptors. Finally, anti-CD3 treatment depleted CCR7(+) but not CCR7(-) DCs by inducing sequential expansion and apoptosis of CCR7(+) DCs in MLN and PLN. Apoptosis of CCR7(+) DCs was associated with DC upregulation of Fas expression and natural killer cell but not T, B, or dendritic cell upregulation of FasL expression in the lymph nodes. These results suggest that depletion of CCR7(+) host-type DCs, with subsequent inhibition of donor T cell migration into GVHD target tissues, can be an effective approach in prevention of acute GVHD and preservation of GVL effects.
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Células Dendríticas/inmunología , Receptores CCR7/inmunología , Linfocitos T/inmunología , Linfocitos T/trasplante , Acondicionamiento Pretrasplante/métodos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Complejo CD3/inmunología , Movimiento Celular/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Quimiocina/inmunología , Donantes de Tejidos , Trasplante Homólogo , Tropismo/inmunologíaRESUMEN
Background: Extensive research has been conducted on the correlation between adipose tissue and the risk of malignant lymphoma. Despite numerous observational studies exploring this connection, uncertainty remains regarding a causal relationship between adipose tissue and malignant lymphoma. Methods: The increase or decrease in adipose tissue was represented by the height of BMI. The BMI and malignant lymphoma genome-wide association studies (GWAS) used a summary dataset from the OPEN GWAS website. Single-nucleotide polymorphisms (SNPs) that met the criteria of P <5e-8 and LD of r2 = 0.001 in the BMI GWAS were chosen as genetic instrumental variants (IVs). Proxy SNPs with LD of r2 > 0.8 were identified, while palindromic and outlier SNPs were excluded. Mendelian randomization (MR) analysis used five methods, including inverse-variance weighted (IVW) model, weighted median (WM), MR-Egger, simple mode, and weighted mode. Sensitivity assessments included Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis. Participants randomly selected by the National Center for Health Statistics (NHANSE) and newly diagnosed HL patients at Fujian Medical University Union Hospital were used for external validation. Results: The results of the MR analysis strongly supported the causal link between BMI and Hodgkin's lymphoma (HL). The research demonstrated that individuals with lower BMI face a significantly increased risk of developing HL, with a 91.65% higher risk (ORIVW = 0.0835, 95% CI 0.0147 - 0.4733, P = 0.005). No signs of horizontal or directional pleiotropy were observed in the MR studies. The validation results aligned with the results from the MR analysis (OR = 0.871, 95% CI 0.826 - 0.918, P< 0.001). And there was no causal relationship between BMI and non-Hodgkin's lymphoma (NHL). Conclusions: The MR analysis study demonstrated a direct correlation between lower BMI and HL. This suggested that a decrease in adipose tissue increases the risk of developing HL. Nevertheless, further research is essential to grasp the underlying mechanism of this causal association comprehensively.
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Tejido Adiposo , Índice de Masa Corporal , Estudio de Asociación del Genoma Completo , Enfermedad de Hodgkin , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad de Hodgkin/genética , Predisposición Genética a la Enfermedad , Femenino , Masculino , Factores de Riesgo , Adulto , Persona de Mediana EdadRESUMEN
Background: Autologous stem cell transplantation (ASCT) is a potentially curative strategy for relapse or refractory(r/r) aggressive lymphoma. However, a proportion of lymphoma patients who are at high risk of mobilization failure fail to mobilize stem cells and cannot proceed to ASCT. The aim of this study is to explore the efficacy and safety of Etoposide combined with Cytarabine (EA) plus G-CSF mobilization in poor mobilizers (PMs) with r/r aggressive lymphoma. Methods: This retrospective study analyzed the outcomes of chemo-mobilization based on EA (Etoposide 0.1 g/m2, qd d1~3; AraC 0.5 g/m2, q12h d1~3) in 98 patients with r/r aggressive lymphoma. Of these, 39 patients met the criteria for predicted PMs as proposed by the Gruppo Italiano Trapianto di Midollo Osseo working group. Results: Of the 39 PMs, 38(97.4%) patents harvested adequate mobilization (≥2×106 CD34+ cells/kg), while 31(79.5%) patients achieved optimal mobilization (≥5×106 CD34+ cells/kg). Overall, the mean number of CD34+ cells/kg collected was 17.99(range: 1.08~83.07) ×106 with an average of 1.4 apheresis sessions, and the number was 15.86(range: 0.37~83.07) ×106 for the first apheresis, respectively. A single apheresis procedure was sufficient to reach the target yield of adequate mobilization in 35(89.7%) PMs, while 76.9% of PMs achieved optimal collection within two apheresis sessions. We observed acceptable hematological toxicity and antibiotic usage exposure in 26 patients with a mean duration of 3.6 days. No grade 4 infection or mobilization-related mortality was recorded. Most patients underwent ASCT and achieved successful hematopoietic recovery with prompt engraftment duration, except for one NK/T-cell lymphoma patient who succumbed to severe septicemia after receiving conditioning chemotherapy. Conclusion: Our findings indicate that EA plus G-CSF is an effective and tolerable CD34+ stem cell mobilization strategy for patients with r/r lymphoma, including those predicted to be PMs. This regimen could be an option for patients with r/r lymphoma, particularly those undergoing mobilization for salvage ASCT therapy.
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Citarabina , Etopósido , Factor Estimulante de Colonias de Granulocitos , Movilización de Célula Madre Hematopoyética , Linfoma , Humanos , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Citarabina/administración & dosificación , Citarabina/uso terapéutico , Masculino , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Adulto , Persona de Mediana Edad , Linfoma/terapia , Linfoma/mortalidad , Linfoma/tratamiento farmacológico , Estudios Retrospectivos , Anciano , Adulto Joven , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recurrencia , Resultado del Tratamiento , AdolescenteRESUMEN
BACKGROUND: Diagnostic challenges exist for CMV pneumonia in post-hematopoietic stem cell transplantation (post-HSCT) patients, despite early-phase radiographic changes. OBJECTIVE: The study aims to employ a deep learning model distinguishing CMV pneumonia from COVID-19 pneumonia, community-acquired pneumonia, and normal lungs post-HSCT. METHODS: Initially, 6 neural network models were pre-trained with COVID-19 pneumonia, community-acquired pneumonia, and normal lung CT images from Kaggle's COVID multiclass dataset (Dataset A), then Dataset A was combined with the CMV pneumonia images from our center, forming Dataset B. We use a few-shot transfer learning strategy to fine-tune the pre-trained models and evaluate model performance in Dataset B. RESULTS: 34 cases of CMV pneumonia were found between January 2018 and December 2022 post-HSCT. Dataset A contained 1681 images of each subgroup from Kaggle. Combined with Dataset A, Dataset B was initially formed by 98 images of CMV pneumonia and normal lung. The optimal model (Xception) achieved an accuracy of 0.9034. Precision, recall, and F1-score all reached 0.9091, with an AUC of 0.9668 in the test set of Dataset B. CONCLUSIONS: This framework demonstrates the deep learning model's ability to distinguish rare pneumonia types utilizing a small volume of CT images, facilitating early detection of CMV pneumonia post-HSCT.
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Relapse remains the main cause of treatment failure in patients with myeloid malignancies even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We observed a particularly low incidence of relapse in patients prepared with fludarabine, busulfan and melphalan in our previous study and this multicenter retrospective analysis aimed to confirm the feasibility of the regimen and to identify the potential prognostic factors. This study was performed using registry data from adults patients with myeloid malignancies who underwent their first allo-HSCT following fludarabine(≥100 mg/m2), busulfan (≥3.2 mg/kg) and melphalan (≥100 mg/m2) based conditioning at nine transplantation centers in China between Jan. 2020 and Mar. 2022. A total of 221 consecutive patients (AML n = 171, MDS-IB-1 or 2 n = 44, CMML n = 6) with median age of 46 were enrolled in this study. The median follow-up was 507 days for survivors. The 2-year NRM, CIR, OS and DFS were 10.6% ± 2.2%, 14.8% ± 3.3%, 79.4% ± 3.7% and 74.6% ± 3.7%, respectively. In multivariate analyses, high HCT-CI (≥3) was the only independent factor for higher NRM [hazard ratio (HR), 2.96; 95% confidence interval (CI), 1.11 to 7.90; p = 0.030] and ECOG score ≥2 was the only independent factor for inferior OS (HR, 2.43; 95%CI, 1.15 to 5.16; p = 0.020) and DFS (HR, 2.12; 95%CI, 1.13 to 4.02; p = 0.020). AML diagnosis and positive measurable residual disease (MRD) at transplantation were predictors for higher CIR (HR = 7.92, 95%CI 1.05-60.03, p = 0.045; HR = 3.64, 95%CI 1.40-9.44, p = 0.008; respectively), while post-transplantation cyclophosphamide based graft-versus-host disease prophylaxis was associated with lower CIR (HR = 0.24 95%CI 0.11-0.54, p = 0.001). The intensity of conditioning regimen did not impact CIR, NRM, DFS and OS. These results supported that double alkylating agents of busulfan and melphalan based conditioning regimens were associated with low relapse rate and acceptable NRM in adult patients with myeloid malignancies. The optimal dose remained to be confirmed by further prospective studies.
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Between 2020 and 2021, 31,525 hematopoietic stem cell transplantations (HSCTs) were reported to the Chinese Blood and Marrow Transplantation Registry Group throughout mainland China. In this report, we describe the activity and current trends for HSCT in China during the SARS-CoV-2 pandemic. In 2020, a total of 13,415 cases of HSCT were reported from 166 transplantation teams, and 75% (10,042 cases) were allogeneic HSCTs. In 2021, a total of 18,110 cases of HSCT were reported from 174 transplantation teams, and 70% (12,744 cases) were allogeneic HSCTs. Haploidentical donor (HID) transplantation accounted for 63% (7977 cases) of allogeneic HSCTs in 2021. The most common indications for allogeneic HSCT for malignant disease were acute myeloid leukemia (37%) and acute lymphoblastic leukemia (23%), and the largest proportion of nonmalignant disease comprised aplastic anemia (13%). The peripheral blood stem cell source accounted for 41% of HIDs and 75% of matched sibling donors. The BuCy-based regimen (57%) was the most popular conditioning regimen for allogeneic HSCT, followed by the BuFlu-based regimen (28%) and total body irradiation-based regimen (11%). This survey provides comprehensive information about the current activities and might benefit clinical physicians' decision planning for HSCT.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Humanos , SARS-CoV-2 , Médula Ósea , Pueblos del Este de Asia , Pandemias , COVID-19/epidemiología , Sistema de RegistrosRESUMEN
Hepatitis-associated aplastic anemia (HAAA) is a life-threatening hematologic disorder characterized by bone marrow failure. Allogeneic hematopoietic stem cell transplantation (HSCT) is the first-line treatment for HAAA. Severe infection and complications in patients with very severe aplastic anemia are the challenges to the efficacy of HSCT. We report a rare case of successful transplantation with HLA-matched peripheral hematopoietic stem cells for a 15-year-old girl suffering from HAAA with multidrug-resistant bacterial and fungal infections. Through effectively controlling infection and optimal timing of transplantation by adjusting the conditioning regimen, the allo-HSCT was successfully performed for the patient. Updated data of following-up 26 months after transplantation showed that the patient was still in complete remission with a good quality of life. This case provided a reference for treating severely infected patients with HAAA before HSCT.
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BACKGROUND: Efficient mobilization of CD34+ hematopoietic stem cells plays a vital role in successful autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM), especially in cases with high-risk cytogenetic recommended for tandem ASCT. However, the optimal mobilization strategy remains a matter of debate in the era of lenalidomide. The combination of etoposide with Cytarabine plus G-CSF as a novel mobilization regimen in MM has not been reported previously. METHODS: This research retrospectively studied mobilization efficacy and safety using etoposide combined with Cytarabine (etoposide 50-100 mg/m2, qd d1-3; AraC 0.5 g/m2, q12h d1~3) plus G-CSF (5 µg/kg/day, from d5 until the day of apheresis) in 128 patients with MM. 70(54.7%) patients received lenalidomide-based induction regimens treatment. RESULTS: A median of 27.75×106 CD34+ cells/kg was collected in the first apheresis, and 28.23×106 CD34+ cells/kg were collected overall. Of the 128 patients, all achieved adequate collection (≥2×106 CD34+ cells/kg), 121(94.5%) achieved optimal collection for single ASCT (≥5×106 CD34+ cells/kg), and 114(89.1%) harvested optimal collection for tandem ASCT (≥10×106 CD34+ cells/kg). In particular, the target yield of optimal collection for tandem ASCT was reached in 82.8% (106/128) by a single apheresis procedure. 14 patients obtained deeper response post mobilization. In multivariate analysis, cycles of prior chemotherapy independently affected the optimal achievement of CD34+ cells (p=0.004, OR 0.695, 95% CI 0.544~0.888). Previous lenalidomide exposure did not significantly impair CD34+ cells collection. Although 68% episodes of antibiotic usage were observed, no severe infection or treatment-related mortality occurred. CONCLUSION: Stem cell mobilization with Etoposide + Cytarabine plus G-CSF was highly efficient and safe in patients with MM, which could be considered in high-risk MM patients who were referred for tandem ASCT.
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Host dendritic cells (DCs) play a critical role in initiating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL), and separation of GVL from GVHD remains a major challenge in the treatment of hematologic malignancies by allogeneic hematopoietic cell transplantation (HCT). Here, we show that preconditioning with anti-CD3 monoclonal antibody before conditioning with total body irradiation (TBI) prevents GVHD but retains GVL in a HCT model of major histocompatibility complex (MHC)-mismatched C57BL/6 donor to BALB/c host. Prevention of GVHD is associated with inhibition of donor T-cell expression of homing and chemokine receptors, and inhibition of GVHD target tissue expression of chemokines. Furthermore, inhibition of donor T-cell expression of gut homing alpha4beta7 and chemokine receptor (CCR)9 by anti-CD3 preconditioning results from a reduction of CD103(+) DCs in draining mesenteric lymph nodes (LNs), which is associated with down-regulation of DC expression of CCR7, a receptor required for tissue DC migration to draining LNs. These results indicate that anti-CD3 preconditioning reduces not only tissue release of chemokines but also prevents tissue DC migration to draining LNs and subsequently reduces the capacity of DCs of draining LNs to imprint donor T-cell tissue tropism. Therefore, modulation of host DCs by anti-CD3 preconditioning before HCT represents a new approach for separating GVL from GVHD.
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Anticuerpos/inmunología , Complejo CD3/inmunología , Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Leucemia/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Animales , Antígenos CD/inmunología , Donantes de Sangre , Diferenciación Celular , Movimiento Celular , Células Cultivadas , Quimiocinas/metabolismo , Regulación hacia Abajo , Trasplante de Células Madre Hematopoyéticas , Cadenas alfa de Integrinas/inmunología , Leucemia/patología , Leucemia/cirugía , Ratones , Receptores de Quimiocina/inmunología , Linfocitos T/metabolismo , Acondicionamiento Pretrasplante , Trasplante Homólogo , Regulación hacia Arriba , Irradiación Corporal TotalRESUMEN
In allogeneic hematopoietic cell transplantation (HCT), donor T cell-mediated graft versus host leukemia (GVL) and graft versus autoimmune (GVA) activity play critical roles in treatment of hematological malignancies and refractory autoimmune diseases. However, graft versus host disease (GVHD), which sometimes can be fatal, remains a major obstacle in classical HCT, where recipients are conditioned with total body irradiation or high-dose chemotherapy. We previously reported that anti-CD3 conditioning allows donor CD8(+) T cells to facilitate engraftment and mediate GVL without causing GVHD. However, the clinical application of this radiation-free and GVHD preventative conditioning regimen is hindered by the cytokine storm syndrome triggered by anti-CD3 and the high-dose donor bone marrow (BM) cells required for induction of chimerism. Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are known to induce apoptosis of cancer cells and reduce production of proinflammatory cytokines by nonmalignant cells. Here, we report that SAHA inhibits the proliferative and cytotoxic activity of anti-CD3-activated T cells. Administration of low-dose SAHA reduces cytokine production and ameliorates the cytokine storm syndrome triggered by anti-CD3. Conditioning with anti-CD3 and SAHA allows induction of chimerism with lower doses of donor BM cells in old nonautoimmune and autoimmune lupus mice. In addition, conditioning with anti-CD3 and SAHA allows donor CD8(+) T cell-mediated GVA activity to reverse lupus glomerulonephritis without causing GVHD. These results indicate that conditioning with anti-CD3 and HDAC inhibitors represent a radiation-free and GVHD-preventative regimen with clinical application potential.
Asunto(s)
Complejo CD3/inmunología , Quimerismo/efectos de los fármacos , Citocinas/inmunología , Trasplante de Células Madre Hematopoyéticas , Ácidos Hidroxámicos/farmacología , Nefritis Lúpica/inmunología , Acondicionamiento Pretrasplante , Envejecimiento/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimerismo/inducido químicamente , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Femenino , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/administración & dosificación , Nefritis Lúpica/patología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Linfocitos T/efectos de los fármacos , Linfocitos T/patología , VorinostatRESUMEN
Allogeneic haploidentical HSCT (haplo-HSCT) and unrelated umbilical cord blood transplantation(UCBT)are used in patients lacking HLA-identical sibling or unrelated donors. With myeloablative condition and GVHD prophylaxis of using low-dose ATG and post-transplantation cyclophosphamide (PTCY), we conducted a prospective clinical trial. Of eligible 122 patients from February 2015 to December 2019 in the study, 113 patients were involved. Forty-eight patients were in the group of sequential haplo-cord transplantation (haplo-cord HSCT), and 65 patients were in the group of single UCBT. The primary endpoint of 2-year disease-free survival (DFS) was no statistical difference between groups (64.1 vs. 56.5%), p>0.05. The analysis of subgroup patients with relapsed/refractory showed haplo-cord HSCT was associated with better OS (HR 0.348, 95% CI, 0.175-0.691; p=0.0025), DFS (HR 0.402, 95% CI, 0.208-0.779; p=0.0069), and GRFS (HR 0.235, 95% CI, 0.120-0.457, p<0.0001) compared to the single cord group. The 2-year's probability in OS, DFS, and GRFS was 64.9 vs. 31.6%, 64.5 vs. 31.6%, and 60.8 vs. 15.0% in the haplo-cord group and single cord group, respectively. III-IV acute GVHD 8.3 vs. 6.2%, chronic GVHD 25.8 vs. 13.7%, and extensive chronic GVHD 5.3 vs. 1.8% were shown in corresponding group, p>0.05. The patients engrafted persistently with UCB showed better survival outcomes. Our sequential Haplo-cord HSCT with ATG/PTCY improved the survival of patients and might be an alternative transplantation approach for patients with relapsed/refractory hematologic malignancies.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Niño , Resistencia a Medicamentos , Femenino , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Análisis de Supervivencia , Trasplante Haploidéntico , Adulto JovenRESUMEN
BACKGROUND: There were few studies on real-world data about autologous hematopoietic stem cell transplantation (auto-HSCT) or allogeneic HSCT (allo-HSCT) in peripheral T-cell lymphoma (PTCL). This study aimed to investigate the clinical outcomes of patients who received auto-HSCT or allo-HSCT in China. METHODS: From July 2007 to June 2017, a total of 128 patients who received auto-HSCT (nâ =â72) or allo-HSCT (nâ =â56) at eight medical centers across China were included in this study. We retrospectively collected their demographic and clinical data and compared the clinical outcomes between groups. RESULTS: Patients receiving allo-HSCT were more likely to be diagnosed with stage III or IV disease (95% vs. 82%, Pâ=â0.027), bone marrow involvement (42% vs. 15%, Pâ=â0.001), chemotherapy-resistant disease (41% vs. 8%, Pâ=â0.001), and progression disease (32% vs. 4%, Pâ<â0.001) at transplantation than those receiving auto-HSCT. With a median follow-up of 30 (2-143) months, 3-year overall survival (OS) and progression-free survival (PFS) in the auto-HSCT group were 70%(48/63) and 59%(42/63), respectively. Three-year OS and PFS for allo-HSCT recipients were 46%(27/54) and 44%(29/54), respectively. There was no difference in relapse rate (34%[17/63] in auto-HSCT vs. 29%[15/54] in allo-HSCT, Pâ=â0.840). Three-year non-relapse mortality rate in auto-HSCT recipients was 6%(4/63) compared with 27%(14/54) for allo-HSCT recipients (Pâ=â0.004). Subanalyses showed that patients with lower prognostic index scores for PTCL (PIT) who received auto-HSCT in an upfront setting had a better outcome than patients with higher PIT scores (3-year OS: 85% vs. 40%, Pâ=â0.003). Patients with complete remission (CR) undergoing auto-HSCT had better survival (3-year OS: 88% vs. 48% in allo-HSCT, Pâ=â0.008). For patients beyond CR, the outcome of patients who received allo-HSCT was similar to that in the atuo-HSCT group (3-year OS: 51% vs. 46%, Pâ=â0.300). CONCLUSIONS: Our study provided real-world data about auto-HSCT and allo-HSCT in China. Auto-HSCT seemed to be associated with better survival for patients in good condition (lower PIT score and/or better disease control). For patients possessing unfavorable characteristics, the survival of patients receiving allo-HSCT group was similar to that in the auto-HSCT group.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma de Células T Periférico , China , Humanos , Linfoma de Células T Periférico/terapia , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Trasplante Autólogo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Several clinical trials have compared the safety and efficacy of umbilical cord blood transplantation (UCBT) with haploidentical transplantation (HIT) in patients with hematological malignancies. To obtain more reliable evidence, we performed a systematic review and meta-analysis. Seven studies were included and there was a combined total of 102 children and 1311 adults undergoing UCBT, along with 94 children and 915 adults undergoing HIT. Pooled comparisons of studies of UCBT and HIT in children found that the incidence of chronic graft-versus-host disease (GVHD) and disease-free survival (DFS) at 2 years (RR 0.34, 95% CI (0.03, 4.53), P=0.41; HR 0.51, 95% CI (0.23, 1.09), P=0.08) were not statistically different. For adults, although the incidence of grade II-IV acute GVHD differ (RR 1.17, 95% CI (1.02, 1.34), P=0.02), but it indicates a very small difference between the groups as the RR is barely above 1. On the other hand, although the incidence of grade III-IV acute GVHD did not differ (RR 1.51, 95% CI (0.78, 2.92), P=0.22), but there is a tendency of higher risk for the UCBT. And the incidence of chronic GVHD did not differ (RR 1.05, 95% CI (0.82, 1.34), P=0.71). There was no difference in relapse, non-relapse mortality (NRM) and DFS at 2 years (HR 0.92, 95% CI (0.74, 1.13), P=0.42; HR 0.87, 95% CI (0.49, 1.52) P=0.62 and HR 0.74 95% CI (0.39, 1.43), P=0.37). In conclusion, UCBT and HIT could be considered as equally effective option for adult patients without HLA-matched donors.
RESUMEN
Bloodstream infection (BSI) caused by multidrug-resistant (MDR) bacteria or extensively drug-resistant (XDR) bacteria is a global threat. However, an effective treatment regimen is still controversial and inadequate due to the rapid deterioration caused by the bacteria. In immunocompromised and neutropenic patients, MDR-BSI is an emergency, which causes treatment-related mortality. In this study, four agranulocytosis patients with hematologic malignancies after HSCT receiving treatment for carbapenem-resistant Enterobacteriaceae- (CRE-) BSI were included. Conventional treatment using two to three combined antibiotics was administered in the first and second patients. Combination treatment using four drugs, polymyxin B, high-dose tigecycline, fosfomycin, and double-dose carbapenem, was administered in the third and fourth patients. None of the patients receiving conventional treatment survived. Both patients receiving combination treatment using four drugs survived. Therefore, four-drug combination therapy may be needed in CRE-BSI patients who experienced severe agranulocytosis after HSCT. The efficacy of the four-drug combination treatment for CRE-BSI patients as well as the adverse effects need to be further studied.