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1.
Am J Hematol ; 99(1): 48-56, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37853951

RESUMEN

ZAP70 has a prognostic value in chronic lymphocytic leukemia (CLL), through altered B-cell receptor signaling, which is important in CLL pathogenesis. A good correlation between ZAP70 expression in CLL cells and the occurrence of autoimmune phenomena has been reported. Yet, the great majority of CLL-associated autoimmune cytopenia is due to polyclonal immunoglobulin (Ig) G synthesized by nonmalignant B cells, and this phenomenon is poorly understood. Here, we show, using flow cytometry, that a substantial percentage of CD5- nonmalignant B cells from CLL patients expresses ZAP70 compared with CD5- B cells from healthy subjects. This ZAP70 expression in normal B cells from CLL patients was also evidenced by the detection of ZAP70 mRNA at single-cell level with polyclonal Ig heavy- and light-chain gene transcripts. ZAP70+ normal B cells belong to various B-cell subsets and their presence in the naïve B-cell subset suggests that ZAP70 expression may occur during early B-cell development in CLL patients and potentially before malignant transformation. The presence of ZAP70+ normal B cells is associated with autoimmune cytopenia in CLL patients in our cohort of patients, and recombinant antibodies produced from these ZAP70+ nonmalignant B cells were frequently autoreactive including anti-platelet reactivity. These results provide a better understanding of the implication of ZAP70 in CLL leukemogenesis and the mechanisms of autoimmune complications of CLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Autoinmunidad , Linfocitos B , Citometría de Flujo , Pronóstico , Proteína Tirosina Quinasa ZAP-70/genética , Proteína Tirosina Quinasa ZAP-70/metabolismo
2.
J Med Genet ; 59(4): 377-384, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-33737400

RESUMEN

INTRODUCTION: This study aims to define the phenotypic and molecular spectrum of the two clinical forms of ß-galactosidase (ß-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB). METHODS: Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed. RESULTS: The clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1 gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group. CONCLUSION: This study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.


Asunto(s)
Gangliosidosis GM1 , Mucopolisacaridosis IV , Femenino , Gangliósido G(M1) , Gangliosidosis GM1/genética , Humanos , Mucopolisacaridosis IV/genética , Mutación , Embarazo , beta-Galactosidasa/genética
3.
Int J Mol Sci ; 24(11)2023 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-37298503

RESUMEN

Ex vivo monitored human CD34+ stem cells (SCs) injected into myocardium scar tissue have shown real benefits for the recovery of patients with myocardial infarctions. They have been used previously in clinical trials with hopeful results and are expected to be promising for cardiac regenerative medicine following severe acute myocardial infarctions. However, some debates on their potential efficacy in cardiac regenerative therapies remain to be clarified. To elucidate the levels of CD34+ SC implication and contribution in cardiac regeneration, better identification of the main regulators, pathways, and genes involved in their potential cardiovascular differentiation and paracrine secretion needs to be determined. We first developed a protocol thought to commit human CD34+ SCs purified from cord blood toward an early cardiovascular lineage. Then, by using a microarray-based approach, we followed their gene expression during differentiation. We compared the transcriptome of undifferentiated CD34+ cells to those induced at two stages of differentiation (i.e., day three and day fourteen), with human cardiomyocyte progenitor cells (CMPCs), as well as cardiomyocytes as controls. Interestingly, in the treated cells, we observed an increase in the expressions of the main regulators usually present in cardiovascular cells. We identified cell surface markers of the cardiac mesoderm, such as kinase insert domain receptor (KDR) and the cardiogenic surface receptor Frizzled 4 (FZD4), induced in the differentiated cells in comparison to undifferentiated CD34+ cells. The Wnt and TGF-ß pathways appeared to be involved in this activation. This study underlined the real capacity of effectively stimulated CD34+ SCs to express cardiac markers and, once induced, allowed the identification of markers that are known to be involved in vascular and early cardiogenesis, demonstrating their potential priming towards cardiovascular cells. These findings could complement their paracrine positive effects known in cell therapy for heart disease and may help improve the efficacy and safety of using ex vivo expanded CD34+ SCs.


Asunto(s)
Infarto del Miocardio , Células Madre , Humanos , Células Madre/metabolismo , Miocardio/metabolismo , Antígenos CD34/metabolismo , Miocitos Cardíacos/metabolismo , Infarto del Miocardio/metabolismo , Diferenciación Celular/fisiología , Moléculas de Adhesión Celular/metabolismo , Receptores Frizzled/metabolismo
4.
Int J Mol Sci ; 24(23)2023 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-38068992

RESUMEN

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease characterized by the presence of the BCR-ABL fusion gene, which results from the Philadelphia chromosome. Since the introduction of tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM), the clinical outcomes for patients with CML have improved significantly. However, IM resistance remains the major clinical challenge for many patients, underlining the need to develop new drugs for the treatment of CML. The basis of CML cell resistance to this drug is unclear, but the appearance of additional genetic alterations in leukemic stem cells (LSCs) is the most common cause of patient relapse. However, several groups have identified a rare subpopulation of CD34+ stem cells in adult patients that is present mainly in the bone marrow and is more immature and pluripotent; these cells are also known as very small embryonic-like stem cells (VSELs). The uncontrolled proliferation and a compromised differentiation possibly initiate their transformation to leukemic VSELs (LVSELs). Their nature and possible involvement in carcinogenesis suggest that they cannot be completely eradicated with IM treatment. In this study, we demonstrated that cells from CML patients with the VSELs phenotype (LVSELs) similarly harbor the fusion protein BCR-ABL and are less sensitive to apoptosis than leukemic HSCs after IM treatment. Thus, IM induces apoptosis and reduces the proliferation and mRNA expression of Ki67 more efficiently in LHSCs than in leukemic LVSELs. Finally, we found that the expression levels of some miRNAs are affected in LVSELs. In addition to the tumor suppressor miR-451, both miR-126 and miR-21, known to be responsible for LSC leukemia-initiating capacity, quiescence, and growth, appear to be involved in IM insensitivity of LVSELs CML cell population. Targeting IM-resistant CML leukemic stem cells by acting via the miRNA pathways may represent a promising therapeutic option.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , MicroARNs , Adulto , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/metabolismo , Resistencia a Antineoplásicos/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , MicroARNs/metabolismo , Apoptosis , Células Madre/metabolismo , Células Madre Neoplásicas/metabolismo
5.
J Hepatol ; 76(3): 568-576, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34748893

RESUMEN

BACKGROUND & AIMS: Ferroportin disease is a rare genetic iron overload disorder which may be underdiagnosed, with recent data suggesting it occurs at a higher prevalence than suspected. Costs and the lack of defined criteria to prompt genetic testing preclude large-scale molecular screening. Hence, we aimed to develop a readily available scoring system to promote and enhance ferroportin disease screening. METHODS: Our derivation cohort included probands tested for ferroportin disease from 2008 to 2016 in our rare disease network. Data were prospectively recorded. Univariate and multivariate logistic regression were used to determine significant criteria, and odds ratios were used to build a weighted score. A cut-off value was defined using a ROC curve with a predefined aim of 90% sensitivity. An independent cohort was used for cross validation. RESULTS: Our derivation cohort included 1,306 patients. Mean age was 55±14 years, ferritin 1,351±1,357 µg/L, and liver iron concentration (LIC) 166±77 µmol/g. Pathogenic variants (n = 32) were identified in 71 patients. In multivariate analysis: female sex, younger age, higher ferritin, higher LIC and the absence of hypertension or diabetes were significantly associated with the diagnosis of ferroportin disease (AUROC in whole derivation cohort 0.83 [0.78-0.88]). The weighted score was based on sex, age, the presence of hypertension or diabetes, ferritin level and LIC. An AUROC of 0.83 (0.77-0.88) was obtained in the derivation cohort without missing values. Using 9.5 as a cut-off, sensitivity was 93.6 (91.7-98.3) %, specificity 49.5 (45.5-53.6) %, positive likelihood ratio 1.8 (1.6-2.0) and negative likelihood ratio 0.17 (0.04-0.37). CONCLUSION: We describe a readily available score with simple criteria and good diagnostic performance that could be used to screen patients for ferroportin disease in routine clinical practice. LAY SUMMARY: Increased iron burden associated with metabolic syndrome is a very common condition. Ferroportin disease is a dominant genetic iron overload disorder whose prevalence is higher than initially thought. They can be difficult to distinguish from each other, but the limited availability of genetic testing and the lack of definitive guidelines prevent adequate screening. We herein describe a simple and definitive clinical score to help clinicians decide whether to perform genetic testing.


Asunto(s)
Proteínas de Transporte de Catión/análisis , Hemocromatosis/diagnóstico , Proyectos de Investigación/normas , Anciano , Proteínas de Transporte de Catión/sangre , Estudios de Cohortes , Femenino , Hemocromatosis/sangre , Humanos , Hierro/metabolismo , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/complicaciones , Modelos Logísticos , Masculino , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Persona de Mediana Edad , Curva ROC , Proyectos de Investigación/estadística & datos numéricos
6.
Haematologica ; 106(12): 3056-3066, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33054115

RESUMEN

Neoplasms involving plasmacytoid Dendritic Cells (pDCs) include Blastic pDC Neoplasms (BPDCN) and other pDC proliferations, where pDCs are associated with myeloid malignancies: most frequently Chronic MyeloMonocytic Leukemia (CMML) but also Acute Myeloid Leukemia (AML), hereafter named pDC-AML. We aimed to determine the reactive or neoplastic origin of pDCs in pDC-AML, and their link with the CD34+ blasts, monocytes or conventional DCs (cDCs) associated in the same sample, by phenotypic and molecular analyses (targeted NGS, 70 genes). We compared 15 pDC-AML at diagnosis with 21 BPDCN and 11 normal pDCs from healthy donors. CD45low CD34+ blasts were found in all cases (10-80% of medullar cells), associated with pDCs (4-36%), monocytes in 14 cases (1-10%) and cDCs (2 cases, 4.8-19%). pDCs in pDC-AML harbor a clearly different phenotype from BPDCN: CD4+ CD56- in 100% of cases, most frequently CD303+, CD304+ and CD34+; lower expression of cTCL1 and CD123 with isolated lymphoid markers (CD22/CD7/CD5) in some cases, suggesting a pre-pDC stage. In all cases, pDCs, monocytes and cDC are neoplastic since they harbor the same mutations as CD34+ blasts. RUNX1 is the most commonly mutated gene: detected in all AML with minimal differentiation (M0-AML) but not in the other cases. Despite low number of cases, the systematic association between M0-AML, RUNX1 mutations and an excess of pDC is puzzling. Further evaluation in a larger cohort is required to confirm RUNX1 mutations in pDC-AML with minimal differentiation and to investigate whether it represents a proliferation of blasts with macrophage and DC progenitor potential.


Asunto(s)
Células Dendríticas , Leucemia Mieloide Aguda , Proliferación Celular , Humanos , Leucemia Mieloide Aguda/genética , Mutación , Fenotipo
7.
Am J Hematol ; 96(8): 934-944, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-33909916

RESUMEN

Prolonged Covid-19 is an emerging issue for patients with lymphoma or immune deficiency. We aimed to examine prolonged length of in-hospital stay (LOS) due to Covid-19 among patients with lymphoma and assess its determinants and outcomes. Adult patients with lymphoma admitted for Covid-19 to 16 French hospitals in March and April, 2020 were included. Length of in-hospital stay was analyzed as a competitor vs death. The study included 111 patients. The median age was 65 years (range, 19-92). Ninety-four patients (85%) had B-cell non-Hodgkin lymphoma. Within the 12 months prior to hospitalization for Covid-19, 79 patients (71%) were treated for their lymphoma. Among them, 63 (57%) received an anti-CD20 therapy. Fourteen patients (12%) had relapsed/refractory disease. The median LOS was 14 days (range, 1-235). After a median follow-up of 191 days (3-260), the 6-month overall survival was 69%. In multivariable analyses, recent administration of anti-CD20 therapy was associated with prolonged LOS (subdistribution hazard ratio 2.26, 95% confidence interval 1.42-3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04-4.52, p = 0.039). An age ≥ 70 years and relapsed/refractory lymphoma were also associated with prolonged LOS and decreased overall survival. In conclusion, an age ≥ 70 years, a relapsed/refractory lymphoma and recent administration of anti-CD20 therapy are risk factors for prolonged LOS and death for lymphoma patients hospitalized for Covid-19. These findings may contribute to guide the management of lymphoma during the pandemic, support evaluating specific therapeutic approaches, and raise questions on the efficacy and timing of vaccination of this particular population.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfocitos B/efectos de los fármacos , COVID-19/complicaciones , Inmunoterapia/efectos adversos , Tiempo de Internación/estadística & datos numéricos , Linfoma no Hodgkin/complicaciones , SARS-CoV-2 , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antígenos CD20/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , COVID-19/mortalidad , Terapia Combinada , Comorbilidad , Resistencia a Antineoplásicos , Femenino , Humanos , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Rituximab/administración & dosificación , Rituximab/efectos adversos , Análisis de Supervivencia , Adulto Joven
8.
Cytokine ; 117: 50-58, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30825834

RESUMEN

BACKGROUND & AIMS: We have reported a significant association between HLA-G expression or the number of hepatic mast cells and liver fibrosis. Here, we investigated the role of HLA-G and mast cells in liver fibrosis, focusing, in particular, on interactions between human mast and stellate cells. METHODS: Human mast cells (HMC cell line, CD34-derived mast cells, or tissue-derived mast cells) were co-cultured with purified human hepatic stellate cells (HSCs), and collagen I production by HSCs was evaluated. Mast cells and HSCs were characterized by immunocytochemistry. Various conditions were tested: different times in direct or indirect contact, presence or absence of cytokines, addition or not of HLA-G, and presence or absence of specific protease inhibitors. RESULTS: The reciprocal interaction between HSCs and mast cells led to the attraction of mast cells to HSCs in vivo and in vitro, and to a significant decrease in collagen production, at all times of co-culture, following the direct or indirect contact of mast cells with HSCs alone or in the presence of TGF-ß, IFN-α or IL-10. We identified the diffusible factors involved in collagen I degradation as mast cell proteases. Moreover, HLA-G expression increased during the co-culture of HSCs and mast cells, with HLA-G acting on both mast cells and HSCs, to enhance collagen I degradation. CONCLUSIONS: Mast cells play a beneficial, anti-fibrotic role in liver fibrosis, via the HLA-G-mediated decrease of collagen I. These findings are consistent with high levels of cross-communication between mast cells and hepatic stellate cells and the role of HLA-G.


Asunto(s)
Antígenos HLA-G/metabolismo , Células Estrelladas Hepáticas/patología , Cirrosis Hepática/patología , Hígado/patología , Mastocitos/patología , Antígenos CD34/metabolismo , Biopsia , Línea Celular , Colágeno Tipo I/metabolismo , Células Estrelladas Hepáticas/metabolismo , Humanos , Inflamación/patología , Mastocitos/metabolismo , Proteolisis , Serina Endopeptidasas/metabolismo
9.
Haematologica ; 104(3): 497-504, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30287621

RESUMEN

Erythropoiesis-stimulating agents are generally the first line of treatment of anemia in patients with lower-risk myelodysplastic syndrome. We prospectively investigated the predictive value of somatic mutations, and biomarkers of ineffective erythropoiesis including the flow cytometry RED score, serum growth-differentiation factor-15, and hepcidin levels. Inclusion criteria were no prior treatment with erythropoiesis-stimulating agents, low- or intermediate-1-risk myelodysplastic syndrome according to the International Prognostic Scoring System, and a hemoglobin level <10 g/dL. Patients could be red blood cell transfusion-dependent or not and were given epoetin zeta 40 000 IU/week. Serum erythropoietin level, iron parameters, hepcidin, flow cytometry Ogata and RED scores, and growth-differentiation factor-15 levels were determined at baseline, and molecular analysis by next-generation sequencing was also conducted. Erythroid response (defined according to the International Working Group 2006 criteria) was assessed at week 12. Seventy patients, with a median age of 78 years, were included in the study. There were 22 patients with refractory cytopenia with multilineage dysplasia, 19 with refractory cytopenia with unilineage dysplasia, 14 with refractory anemia with ring sideroblasts, four with refractory anemia with excess blasts-1, six with chronic myelomonocytic leukemia, two with del5q-and three with unclassifiable myelodysplastic syndrome. According to the revised International Prognostic Scoring System, 13 had very low risk, 47 had low risk, nine intermediate risk and one had high-risk disease. Twenty patients were transfusion dependent. Forty-eight percent had an erythroid response and the median duration of the response was 26 months. At baseline, non-responders had significantly higher RED scores and lower hepcidin:ferritin ratios. In multivariate analysis, only a RED score >4 (P=0.05) and a hepcidin:ferritin ratio <9 (P=0.02) were statistically significantly associated with worse erythroid response. The median response duration was shorter in patients with growth-differentiation factor-15 >2000 pg/mL and a hepcidin:ferritin ratio <9 (P=0.0008 and P=0.01, respectively). In multivariate analysis, both variables were associated with shorter response duration. Erythroid response to epoetin zeta was similar to that obtained with other erythropoiesis-stimulating agents and was correlated with higher baseline hepcidin:ferritin ratio and lower RED score. ClinicalTrials.gov registration: NCT 03598582.


Asunto(s)
Eritropoyesis/efectos de los fármacos , Eritropoyetina/uso terapéutico , Ferritinas/sangre , Hepcidinas/sangre , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Biomarcadores , Eritropoyetina/administración & dosificación , Eritropoyetina/efectos adversos , Femenino , Citometría de Flujo , Humanos , Hierro/metabolismo , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Pronóstico , Curva ROC , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento
10.
Ann Hematol ; 98(6): 1341-1350, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30915499

RESUMEN

Eltrombopag (ELT), an oral thrombopoietin receptor agonist, has recently emerged as a promising new drug for the treatment of aplastic anemia (AA). How ELT is used outside of clinical trials in the real-world setting and results of this treatment are not known. We conducted therefore a retrospective survey on the use of ELT in AA among EBMT member centers. We analyzed the 134 patients reported in our survey together with 46 patients recently published by Lengline et al. The median follow-up from start of ELT treatment was 15.3 months, with 85.6% patients alive at last follow-up. Importantly, only 28.9% of our patients received ELT according to the FDA/EMA label as monotherapy in the relapsed/refractory setting, whereas 16.7% received ELT upfront. The overall response rate in our cohort was 62%, very similar to the results of the pivotal ELT trial. In multivariate analysis, combination therapy with ELT/cyclosporine/ATG and response to previous therapy were associated with response. Overall survival was favorable with a 1-year survival from ELT start of 87.4%. We identified age, AA severity before ELT start and response to ELT as variables significantly associated with OS. Two patients transformed to MDS; other adverse events were mostly benign. In sum, ELT is used widely in Europe to treat AA patients, mostly in the relapsed/refractory setting. Response to ELT is similar to the clinical trial data across different age groups, treatment lines, and treatment combinations and results in favorable survival.


Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Benzoatos/uso terapéutico , Hidrazinas/uso terapéutico , Pirazoles/uso terapéutico , Adulto , Anciano , Anemia Aplásica/mortalidad , Evaluación de Medicamentos , Utilización de Medicamentos , Europa (Continente) , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/etiología , Modelos de Riesgos Proporcionales , Receptores de Trombopoyetina/agonistas , Estudios Retrospectivos , Adulto Joven
11.
Haematologica ; 103(2): 212-220, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29170252

RESUMEN

Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012-2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8-50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4-4.5) and 42×109/L (interquartile range, 11-100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag.


Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Benzoatos/uso terapéutico , Hidrazinas/uso terapéutico , Pirazoles/uso terapéutico , Anciano , Suero Antilinfocítico/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Terapia Recuperativa/métodos , Encuestas y Cuestionarios , Resultado del Tratamiento
14.
Eur J Cancer ; 208: 114210, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39002346

RESUMEN

INTRODUCTION: Considering the notable advances made in the treatment of lymphoma, assessment of health-related quality of life (HRQoL) of lymphoma patients has become a critical aspect to consider both in clinical research and routine practice. However, there is paucity of information about lymphoma specific HRQoL profile at diagnosis. PATIENTS AND METHODS: HRQoL at diagnosis was assessed for 3922 adult patients with newly diagnosed high-grade (HG) (n = 1994), low-grade (LG) (n = 1053) non-Hodgkin (NHL) and Hodgkin (HL) (n = 875) lymphomas included in REal world dAta in LYmphoma and Survival in Adults (REALYSA, NCT03869619), a prospective non-interventional multicentric cohort in France. Disease-specific HRQoL aspects were assessed with three validated EORTC questionnaires, namely, the QLQ-NHL-HG29, the QLQ-NHL-LG20 and the QLQ-HL27, for patients with NHL-HG, NHL-LG and HL, respectively. RESULTS: We confirmed the high-level of completion of these questionnaires in REALYSA cohort, ranging from 84 % for QLQ-HG29 to 88 % for QLQ-HL27. The proportion of patients with impaired global health status was as follows: T-cell NHL, 67 %; diffuse large B-cell (DLBCL), 62 %; Burkitt, 61 %; HL, 53 %; marginal zone, 49 %; mantle cell, 48 %; follicular, 47 %. Multivariable regression analyses for DLBCL, follicular and HL showed that gender, performance status and B symptoms were independently associated with all HRQoL dimensions. However, a variable effect of age and stage were observed among these three subtypes. CONCLUSIONS: A comprehensive analysis was made describing the HRQoL profile of newly diagnosed patients with different types of lymphomas. Our data may help to enhance the interpretation of HRQoL results in future studies using the recently validated EORTC lymphoma specific questionnaires.


Asunto(s)
Enfermedad de Hodgkin , Linfoma no Hodgkin , Calidad de Vida , Humanos , Enfermedad de Hodgkin/psicología , Masculino , Femenino , Persona de Mediana Edad , Linfoma no Hodgkin/psicología , Francia/epidemiología , Adulto , Anciano , Estudios Prospectivos , Encuestas y Cuestionarios , Adulto Joven , Adolescente , Estado de Salud , Anciano de 80 o más Años
15.
Nat Commun ; 15(1): 6822, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39122717

RESUMEN

Richter transformation (RT) is an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia. Here we investigated the anti-CD3/anti-CD19 T-cell-engager blinatumomab after R-CHOP (i.e. rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with untreated RT of diffuse large B-cell lymphoma histology (NCT03931642). In this multicentre phase 2 study, patients without complete response (CR) after two cycles of R-CHOP were eligible to receive an 8-week blinatumomab induction via continuous vein infusion with stepwise dosing until 112 µg/day. The primary endpoint was the CR rate after blinatumomab induction and secondary endpoint included safety, response duration, progression-free and overall survival. Thirty-nine patients started the first cycle of R-CHOP, 25 of whom received blinatumomab. After blinatumomab induction, five (20%) patients achieved CR, four (16%) achieved partial response, and six (24%) were stable. Considering the entire strategy, the overall response rate in the full-analysis-set was 46% (n = 18), with CR in 14 (36%) patients. The most common treatment-emergent adverse events of all grades in the blinatumomab-safety-set included fever (36%), anaemia (24%), and lymphopaenia (24%). Cytokine release syndrome (grade 1/2) was observed in 16% and neurotoxicity in 20% of patients. Blinatumomab demonstrated encouraging anti-tumour activity (the trial met its primary endpoint) and acceptable toxicity in patients with RT.


Asunto(s)
Anticuerpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Linfoma de Células B Grandes Difuso , Prednisona , Rituximab , Vincristina , Humanos , Masculino , Femenino , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Persona de Mediana Edad , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Rituximab/efectos adversos , Doxorrubicina/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Anciano , Prednisona/uso terapéutico , Prednisona/administración & dosificación , Prednisona/efectos adversos , Vincristina/uso terapéutico , Vincristina/efectos adversos , Vincristina/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adulto , Anciano de 80 o más Años , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Resultado del Tratamiento
16.
Blood Adv ; 8(2): 296-308, 2024 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-37874913

RESUMEN

ABSTRACT: Real-world data (RWD) are essential to complement clinical trial (CT) data, but major challenges remain, such as data quality. REal world dAta in LYmphoma and Survival in Adults (REALYSA) is a prospective noninterventional multicentric cohort started in 2018 that included patients newly diagnosed with lymphoma in France. Herein is a proof-of-concept analysis on patients with first-line diffuse large B-cell lymphoma (DLBCL) to (1) evaluate the capacity of the cohort to provide robust data through a multistep validation process; (2) assess the consistency of the results; and (3) conduct an exploratory transportability assessment of 2 recent phase 3 CTs (POLARIX and SENIOR). The analysis population comprised 645 patients with DLBCL included before 31 March 2021 who received immunochemotherapy and for whom 3589 queries were generated, resulting in high data completeness (<4% missing data). Median age was 66 years, with mostly advanced-stage disease and high international prognostic index (IPI) score. Treatments were mostly rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP 75%) and reduced dose R-CHOP (13%). Estimated 1-year event-free survival (EFS) and overall survival rates were 77.9% and 90.0%, respectively (median follow-up, 9.9 months). Regarding transportability, when applying the CT's main inclusion criteria (age, performance status, and IPI), outcomes seemed comparable between patients in REALYSA and standard arms of POLARIX (1-year progression-free survival 79.8% vs 79.8%) and SENIOR (1-year EFS, 64.5% vs 60.0%). With its rigorous data validation process, REALYSA provides high-quality RWD, thus constituting a platform for numerous scientific purposes. The REALYSA study was registered at www.clinicaltrials.gov as #NCT03869619.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B Grandes Difuso , Adulto , Humanos , Anciano , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Rituximab/uso terapéutico , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Prednisona/uso terapéutico , Vincristina/uso terapéutico , Doxorrubicina/uso terapéutico
17.
Cytometry A ; 83(12): 1066-72, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24151234

RESUMEN

Flow cytometry (FC) instruments settings classically rely on local establishment of photomultipliers (PMT) voltages adapted to the measurements expected to be performed. In the era of multiparameter FC (MFC), it appears more and more desirable that comparable patterns of fluorescence are obtained in different settings. This relies on a harmonization of settings between instruments. Although this has been shown to be feasible within a given brand of flow cytometers, little information is available about broader comparisons in a given center or in a multicenter fashion. Here, we report a two-phase series of experiments first performed between a Canto II (BD Biosciences) and a Navios (Beckman Coulter) instruments in the same center. PMT values adjusted on the reference instrument (RI) Canto II were used to establish target values for PMT settings on the paired Navios practice instrument (PI). This allowed to show the good correlation of all but peaks 1 and 2 of Rainbow(®) beads between RI and PI. Using 4- or 8-color stained leukocytes, the similitude of the settings was further confirmed. A complex set of matrices was then established between five centers all equipped with both instruments. Using Bland & Altman difference comparisons for median fluorescence values, it was shown that using either Rainbow beads or CD16 stained polymorphonuclears to set-up target values on the RI CantoII, highly superimposable results could be obtained on all 9 PI. The latter were obtained using Rainbow beads or Compbeads(®) for comparisons. In summary, this two-phase study demonstrates the feasibility of different methods allowing for a robust harmonization of settings for MFC.


Asunto(s)
Citometría de Flujo/métodos , Calibración , Citometría de Flujo/normas , Colorantes Fluorescentes/química , Proteínas Ligadas a GPI/metabolismo , Humanos , Neutrófilos/metabolismo , Receptores de IgG/metabolismo , Estándares de Referencia , Coloración y Etiquetado
18.
Lab Med ; 53(6): e145-e148, 2022 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-35482291

RESUMEN

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy that is deadly if not treated promptly. The treatment of choice in patients presenting with TTP is plasma exchanges. However, immunosuppressive therapy and caplacizumab have significantly improved outcomes in TTP. This microangiopathy is classically divided into 2 entities: hereditary and acquired TTP (aTTP), caused by an autoantibody against ADAMTS 13. We present a case study of a patient wth TTP occurring after a second dose of the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine along with a review of the literature. A 55-year-old patient presented with gastrointestinal symptoms, anemia, and severe thrombocytopenia. The blood film revealed the presence of schistocytes. A diagnosis of aTTP was established because the patient had severe ADAMTS 13 deficiency and autoantibodies against ADAMTS 13 were positive. This episode occurred 10 days after the patient received the COVID-19 vaccine. The patient received plasma exchanges, prednisone, rituximab, and caplacizumab and achieved complete remission. Ten patients with aTTP induced by the COVID-19 vaccine have been reported in the literature. Most of these situations occurred after the second dose of COVID-19 vaccine, and 7 patients were noted to have received the BNT162b2 vaccine. Caplacizumab was used in 6 patients, and complete remission was achieved in 8 patients.


Asunto(s)
COVID-19 , Púrpura Trombocitopénica Trombótica , Humanos , Persona de Mediana Edad , Proteína ADAMTS13 , Vacunas contra la COVID-19/efectos adversos , Vacuna BNT162 , Autoanticuerpos
19.
J Cancer Res Clin Oncol ; 148(8): 2013-2022, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35476232

RESUMEN

BACKGROUND: Hairy cell leukemia (HCL) is a rare chronic B cell malignancy, characterized by infiltration of bone marrow, blood and spleen by typical "hairy cells" that bear the BRAFV600E mutation. However, in addition to the intrinsic activation of the MAP kinase pathway as a consequence of the BRAFV600E mutation, the potential participation of other signaling pathways to the pathophysiology of the disease remains unclear as the precise origin of the malignant hairy B cells. MATERIALS AND METHODS: Using mRNA gene expression profiling based on the Nanostring technology and the analysis of 290 genes with crucial roles in B cell lymphomas, we defined a 17 gene expression signature specific for HCL. RESULTS: Separate analysis of samples from classical and variant forms of hairy cell leukemia showed almost similar mRNA expression profiles apart from overexpression in vHCL of the immune checkpoints CD274 and PDCD1LG2 and underexpression of FAS. Our results point to a post-germinal memory B cell origin and in some samples to the activation of the non-canonical NF-κB pathway. CONCLUSIONS: This study provides a better understanding of the pathogenesis of HCL and describes new and potential targets for treatment approaches and guidance for studies in the molecular mechanisms of HCL.


Asunto(s)
Leucemia de Células Pilosas , Linfocitos B/patología , Humanos , Leucemia de Células Pilosas/tratamiento farmacológico , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , ARN Mensajero , Transcriptoma
20.
Blood Adv ; 6(1): 207-211, 2022 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-34844264

RESUMEN

Immunocompromised individuals such as patients with chronic lymphocytic leukemia (CLL) are at risk of impaired immune responses to vaccination. The objective of our study was to evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses in patients with CLL after the first, second, and third doses of the BNT162b2 or mRNA-1273 vaccines and after a single dose for patients with confirmed previous COVID-19. In all, 530 patients were included in the study. Patients received 2 doses at a 4-week interval and a third dose if they were seronegative after the second dose. Response rate was 27% after dose 1 and 52% after dose 2. Post-dose 2 treatment-naïve patients had the highest response rate (72%) followed by patients previously treated by chemoimmunotherapy (60%). Among patients receiving therapy, those receiving Bruton tyrosine kinase inhibitor alone (22%) or in combination with anti-CD20 monoclonal antibodies or venetoclax (0%) had the poorer response rate whereas patients who received venetoclax monotherapy achieved a significantly higher response rate (52%). A multivariable analysis identified age older than 65 years, ongoing CLL treatment, and gamma globulin ≤6 g/L as independent predictors of the absence of seroconversion. Post-dose 2 seronegative patients had a global response rate of 35% after dose 3. This study provides an argument for the use of a third dose and for prophylactic SARS-CoV-2 neutralizing monoclonal antibodies.


Asunto(s)
COVID-19 , Leucemia Linfocítica Crónica de Células B , Vacuna nCoV-2019 mRNA-1273 , Anciano , Anticuerpos Antivirales , Vacuna BNT162 , Vacunas contra la COVID-19 , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , ARN Mensajero/genética , SARS-CoV-2
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