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ABSTRACT: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.
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Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica , Transtornos Linfoproliferativos , Recém-Nascido , Humanos , Etoposídeo/uso terapêutico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Resultado do Tratamento , Transplante de Células-Tronco Hematopoéticas/métodos , Transtornos Linfoproliferativos/etiologiaRESUMO
ABSTRACT: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK)-cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Assessment of Fc receptor-triggered NK-cell and T-cell receptor (TCR)-triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH than routine K562 cell-based assays, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis after K562 target cell stimulation displayed a higher interindividual variability, in part explained by differences in NK-cell differentiation or large functional reductions after shipment. We thus recommend combined analysis of TCR-triggered CTL and Fc receptor-triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis.
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Exocitose , Células Matadoras Naturais , Linfo-Histiocitose Hemofagocítica , Linfócitos T Citotóxicos , Humanos , Linfócitos T Citotóxicos/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Adolescente , Criança , Adulto , Feminino , Células K562 , Masculino , Pré-Escolar , Pessoa de Meia-Idade , Lactente , Adulto Jovem , Idoso , Sensibilidade e Especificidade , Estudos Prospectivos , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Flow cytometry (FCM) is a precise and well-established tool to assess the minimal residual disease (MRD) level in childhood acute lymphoblastic leukemia (ALL). It is crucial to distinguish leukemic cells from their normal counterparts; thus new markers should be evaluated, to increase the accuracy of the analysis. The expression of CD73 on blast cells was measured and compared at the day of diagnosis and at days 15 and 33 of treatment. To determine antigen expression levels, a normalized scale based on median fluorescence intensity (nMFI) was used. The study group consisted of 188 patients from the Polish Pediatric Leukemia and Lymphoma Study Group. From 177 patients with positive MRD at day 15 of treatment, in 147 (83.1%) cases an increase of CD73 expression was observed (mean increase of +17 nMFI units). In addition, an increase of CD73 expression was noted in 26 of 31 (83.9%) patients at day 33 of treatment. In turn, a decrease of CD73 expression was observed only in 13/177 (7.3%) and 1/31 (3.2%) cases at days 15 and 33 of treatment, respectively. In 17 (9.6%) patients no change in expression of CD73 between diagnosis and day 15 of treatment was observed. In the great majority of cases the expression of CD73 is not only stable but increases during the early stages of treatment, which makes it a very useful marker to be used for MRD monitoring in childhood B-cell precursor (BCP)-ALL patients.
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Failure of autologous peripheral blood CD34+ stem cells collection can adversely affect the treatment modality for patients with hematological and nonhematological malignant diseases where high dose chemotherapy followed by hematopoietic stem cell transplantation has become part of their treatment. Plerixafor in conjunction with G-CSF is approved for clinical use as a mobilization agent. The clinical efficacy of Plerixafor in CD34+ cells collection was analyzed in our institution. A total of 13 patients aged 1-15,5 years received Plerixafor in combination with G-CSF: 7 with neuroblastoma, 2 with Ewing's sarcoma and single patients with Hodgkin's lymphoma, germ cell tumor, retinoblastoma and Wilms tumor. Twelve patients (923%) achieved CD34+ cell counts of ≥ 20 × 106/L after 1-7 doses of Plerixafor. The average 9,9 - fold increase in number of CD34+ cells were achieved following the first dose and 429 - fold after second dose of plerixafor. Among the 13 patients, 12 yielded the minimum required cell collection of 2 × 106/kg within an average of 2 doses of Plerixafor. The mean number of apheresis days was 1.75. The median total number of collected CD34+ cells was 982 × 106/kg. Plerixafor enables rapid and effective mobilization, and collection of sufficient number of CD34+ cells.
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Benzilaminas/uso terapêutico , Ciclamos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante Autólogo/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzilaminas/farmacologia , Criança , Pré-Escolar , Ciclamos/farmacologia , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The aim of this study was to assess the incidence of DNA aneuploidy in Polish children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and the relationship between aneuploidy and immunological phenotype, age, leukocyte count, S-phase fraction (SPF) and early response to induction chemotherapy assessed by the percentage of residual blast cells in bone marrow aspirates. The study group consisted of 267 patients. DNA content and immunophenotype were assessed in the bone marrow before treatment using multicolor flow cytometry (FC). DNA aneuploidy was detected in 50/267 (19%) patients. High hyperdiploidy was found to be associated with lower leukocyte count (p = 0.006) and common ALL immunophenotype. Flow cytometry analysis revealed that high hyperdiploid BCP-ALL patients showed significantly higher expression of CD9, CD20, CD22, CD58, CD66c, CD86 and CD123 antigens as compared to other groups of ploidy. In contrast, CD45 showed decreased expression. The percentage of leukemic blasts at diagnosis was lower in high hyperdiploid BCP-ALL cases than in diploid (79% vs. 85.7%, p = 0.001). The difference in minimal residual disease (MRD) levels on day 15 and 33 of induction therapy between analyzed groups was not significant. This study showed that high hyperdiploidy is associated with lower WBC count and specific immunological phenotype. Flow cytometric evaluation of expression of selected antigens can be used for fast identification of markers of aneuploidy in pediatric BCP-ALL, before genetic tests results are available. Understanding the biological significance of aneuploidy in leukemia can potentially be exploited therapeutically using targeted therapies against specific blast cell subclones.
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Anti-cancer treatment in children can deteriorate gonadal function and affect future fertility. We analyzed the hormonal markers of gonadal function in adolescent leukemia survivors, treated in childhood with different levels of aggressiveness. We analyzed hormone levels in 69 adolescents and young adults, leukemia survivors stratified into standard (SR), intermediate (IR), and high (HR) risk groups, and in 80 healthy controls (38 men) at a similar age. We assessed follicular stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B in the whole group, testosterone in males, and E2 and anti-Müllerian hormone (AMH) in females. Males classified into HR group presented, in comparison to control, higher levels of FSH, LH, lower inhibin B, and normal testosterone, whereas in SR and IR group, the hormonal values were comparable to the control. In females, in all risk groups, the levels of FSH, LH, E2, and inhibin B were comparable with the control, but the mean AMH levels were slightly lowered. We did not observe the effect of prophylactic cranial irradiation (12 or 18 Gy) or the time of treatment (before vs. during puberty) on hormone levels. In females, a positive correlation was found between the time interval after the end of treatment and AMH levels. Male leukemia survivors having undergone more intensive chemotherapy show the symptoms of disturbed spermatogenesis and need to be followed-up in the future. Women, irrespective of the risk group, can develop the signs of preterm ovarian insufficiency. They should be informed about the impact of the treatment on gonadal function.
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Biomarcadores , Sobreviventes de Câncer , Hormônios Esteroides Gonadais/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Adolescente , Criança , Pré-Escolar , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Feminino , Fertilidade , Seguimentos , Gônadas/metabolismo , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease associated with immune system hyperactivation and the appearance of serious systemic disturbances. The purpose of this study was an assessment of natural killer (NK) cell disturbances in a group of children with clinical signs of HLH. A total of 43 children with HLH and 17 healthy children were enrolled in the study. NK phenotyping, intracellular perforin staining, and cytotoxicity tests were performed by using the flow cytometry method. HLH patients were divided into 6 HLH types: 9% infection-related HLH; 7% malignancy-related HLH; 21% macrophage activating syndrome; 12% familial hemophagocytic lymphohistiocytosis; 2% X-linked lymphoproliferative syndrome; and 49% as HLH of unknown background. A positive correlation was observed between cytotoxicity and NK cells in children with HLH (P=0.01). In all HLH groups, the percentage of NK cells was significantly lower than in the control population. The spontaneous cytotoxicity was significantly lower in HLH patients. The results presented in this study indicate the importance of impaired function and the number of NK cells in the pathogenesis of HLH. Nonetheless, the background of disturbances seems to be different in various cases.
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Células Matadoras Naturais/patologia , Linfo-Histiocitose Hemofagocítica/imunologia , Estudos de Casos e Controles , Criança , Testes Imunológicos de Citotoxicidade , Citotoxicidade Imunológica , Feminino , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem , Contagem de Linfócitos , Linfo-Histiocitose Hemofagocítica/epidemiologia , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Perforina/metabolismo , PolôniaRESUMO
In this study, we compare two commercial automated immunoassays used to evaluate serum anti-Müllerian hormone (AMH) levels as a prognostic value for ovarian response and pregnancy outcome in assisted reproductive technology cycles. Serum AMH was measured for 193 women. We performed a simultaneous measurement in serum AMH with the two alternative kits VIDAS® and Elecsys® AMH assay. For all women undergoing in vitro fertilization cycle, we collected data on their antral follicle count (AFC) and numbers of retrieved cumulus oocyte complexes (OC) and metaphase II oocytes and pregnancy outcome. The AMH values provided by VIDAS® were correlated with the values obtained with Elecsys® (0.977 for fresh and 0.971 for the frozen samples). For both assays AMH exhibited a moderate positive correlation with AFC, OC and MII oocytes (0.612, 0.674, 0.605 for VIDAS® and 0.570, 0.617, 0.530 for Elecsys®, respectively). AMH prediction of biochemical and clinical pregnancy was similar. The present results suggest that the VIDAS® AMH assay is broadly comparable to the Elecsys-AMH assay in terms of technical performance for clinical or epidemiological use. Both automated assays performed in a similar way and the choice of assay can be made depending on the technical configuration of each laboratory.
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Hormônio Antimülleriano/sangue , Reserva Ovariana , Testes Imediatos , Adulto , Automação Laboratorial , Biomarcadores/sangue , Feminino , Fertilização in vitro , Humanos , Técnicas Imunoenzimáticas , Infertilidade Feminina/sangue , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/terapia , Limite de Detecção , Polônia/epidemiologia , Valor Preditivo dos Testes , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Kit de Reagentes para Diagnóstico , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and mixed-lineage leukemia gene-partial tandem duplication (MLL-PTD) are aberrations associated with leukemia which indicate unsatisfactory prognosis. Downstream regulatory targets of FLT3-ITD and MLL-PTD are not well defined. We have analyzed the expression of MDR-1, multidrug resistant protein-1 (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) messenger RNA (mRNA) in relation to the mutational status of FLT3-ITD and MLL-PTD in 185 acute myeloid leukemia (AML) adult patients. The real-time quantitative polymerase chain reaction method was performed to assess the expression of the MDR-1, MRP-1, BCRP, and LRP mRNA, and the results were presented as coefficients calculated using an intermediate method according to Pfaffl's rule. Significantly higher expressions of MDR-1 mRNA were found in patients who did not harbor FLT3-ITD (0.20 vs. 0.05; p = 0.0001) and MRP-1 mRNA in patients with this mutation (0.96 vs. 0.70; p = 0.002) and of BCRP mRNA in patients with MLL-PTD (0.61 vs. 0.38; p = 0.03). In univariate analysis, the high expression of MDR-1 mRNA (≥0.1317) negatively influenced the outcome of induction therapy (p = 0.05), whereas the high expression of BCRP mRNA (≥1.1487) was associated with a high relapse rate (RR) (p = 0.013). We found that the high expression of MDR-1 (≥0.1317), MRP-1 (≥0.8409), and BCRP mRNA (≥1.1487) significantly influenced disease-free survival (DFS; p = 0.059, 0.032, and 0.009, respectively) and overall survival (0.048, 0.014, and 0.059, respectively). Moreover, a high expression of BCRP mRNA (≥1.1487) proved to be an independent prognostic factor for RR (p = 0.01) and DFS (p = 0.002) in multivariate analysis. The significant correlation between the expression of MDR-1, MRP-1, and BCRP mRNA and FLT3-ITD or MLL-PTD in AML patients requires further investigation.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Partículas de Ribonucleoproteínas em Forma de Abóbada/genética , Tirosina Quinase 3 Semelhante a fms/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Duplicação Gênica/genética , Histona-Lisina N-Metiltransferase , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Proteína de Leucina Linfoide-Mieloide/biossíntese , Proteínas de Neoplasias/biossíntese , Prognóstico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Partículas de Ribonucleoproteínas em Forma de Abóbada/biossíntese , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/biossínteseRESUMO
OBJECTIVES: Ovarian reserve is the main factor influencing the efficacy of infertility treatment. Currently the anti- Müllerian hormone is the main indicator of the ovarian reserve and has a wide spectrum of clinical importance. It achieved a high clinical value right after the introduction of the first commercial AMH assays in 2005. Lack further research and development of the tests and monopoly on their production have led to a significant reduction of their quality resulting in lowered veracity and usefulness. Therefore, we searched for an alternative to the Beckman Coulter assay. The objective of the study was to draw a comparison between the commonly used second-generation assay by Beckman Coulter and the ultra-sensitive first-generation assay by AnshLabs. MATERIALS AND METHODS: Serum samples (n=520) were collected from female patients undergoing routine AMH evaluation before entering an IVF program. We chose samples of patients with the lowest correlation between the AMH serum level and response to stimulation. The AMH serum levels of the patients were examined using two AMH tests, the second-generation assay by Beckman Coulter and the first-generation assay by AnshLabs. Precision and accuracy of both methods were determined and the results of AMH serum levels of 130 patients were correlated with the number of: antral follicles (AFC), follicles after stimulation, and the obtained cumulus cells. RESULTS: Both precision and accuracy of the compared methods were highly satisfactory. The coefficients of variation obtained in the study conducted on two different levels of control material were lower than 12% and the load did not exceed 9%. The study proved that both of the methods yielded comparable results. The coefficient of variation between the first-generation and the second-generation AMH assays was 0.871. CONCLUSION: Both methods might be applied in the evaluation of the ovarian reserve. The first- and second-generation assays show comparable correlation with the clinical effects of stimulation, however it seems that first-generation assays are a better alternative to the unstable second-generation kits. The results from the first-generation assays are distributed on a wider range, which facilitates clinical interpretation.
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Hormônio Antimülleriano/análise , Ensaio de Imunoadsorção Enzimática/métodos , Fertilização in vitro , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Manejo de Espécimes/métodosRESUMO
Venetoclax, the best established BH3-mimetic, is a practice-changing proapoptotic drug in blood cancers in adults. In paediatrics the data are fewer but exciting results were recently presented in relapsed or refractory leukaemias demonstrating significant clinical activity. Importantly, the in-terventions could be potentially molecularly guided as vulnerabilities to BH3-mimetics were re-ported. Currently venetoclax is not incorporated into paediatric treatment schedules in Poland but it has been already used in patients that failed conventional therapy in Polish paediatric haemato-oncology departments. The aim of the study was to gather clinical data and correlates of all paediatric patients treated so far with venetoclax in Poland. We set out to gather this experience to help choose the right clinical context for the drug and stimulate further research. The questionnaire regarding the use of venetoclax was sent to all 18 Polish paediatric haemato-oncology centres. The data as available in November 2022 were gathered and analysed for the diagnoses, triggers for the intervention, treatment schedules, outcomes and molecular associations. We received response from 11 centres, 5 of which administered venetoclax to their patients. Clinical benefit, in most cases consistent with hematologic complete remission (CR), was reported in 5 patients out of ten, whereas 5 patient did not show clinical benefit from the intervention. Importantly, patients with CR included subtypes expected to show venetoclax vulnerability, such as poor-prognosis ALL with TCF::HLF fusion. We believe BH3-mimetics have clinical activity in children and should be available to pae-diatric haemato-oncology practitioners in well-selected applications.
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BACKGROUND: The proteasome chymotrypsin-like (Cht-L) activity was determined in plasma of children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in correlation to baseline leukocytosis, immunophenotype, LDH at the time of diagnosis and after remission induction. PROCEDURE: The activity was assayed using the fluorogenic peptide substrate in the presence of an artificial activator sodium dodecyl sulfate (SDS) in the plasma of healthy donors (n=25), acute lymphoblastic leukemia, ALL (n=95) and AML (n=17) patients. RESULTS: As compared to healthy subjects, the plasma proteasome ChT-L activity was significantly increased (p=0.001) in ALL patients prior to treatment, especially in those with T-ALL immunophenotype and with high LDH activity. Similarly, in AML patients the plasma proteasome ChT-L activity was elevated (p=0.001). Following remission-inducing chemotherapy, the activity of the ChT-L proteasome was significantly reduced both in ALL and AML patients. CONCLUSION: Plasma proteasome ChT-L activity may serve as an additional marker in monitoring anticancer therapy.
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Biomarcadores Tumorais/sangue , Quimases/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Complexo de Endopeptidases do Proteassoma/sangue , Adolescente , Antineoplásicos Hormonais/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , L-Lactato Desidrogenase/sangue , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Contagem de Leucócitos , Leucocitose , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Prednisolona/uso terapêuticoRESUMO
Introduction: Myeloid sarcoma (MS) is an extramedullary malignant tumor composed of immature myeloid cells. It occurs in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myeloid leukemia (CML). MS may coincide with disease diagnosis or precede bone marrow involvement by months or even years; it can also represent the extramedullary manifestation of a relapse (1, 2). Aim: The aim of this study is to describe clinical characteristics of children diagnosed with MS in Poland as well as to analyze diagnostic methods, treatment, and outcomes including overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS). The study also attempted to identify factors determining treatment outcomes. Patients: The study group comprised 43 patients (F=18, M=25) aged 0-18 years (median age, 10.0 years; mean age, 8.8 years) diagnosed with MS based on tumor biopsy and immunohistochemistry or identification of underlying bone marrow disease and extramedullary tumor according to imaging findings. Methods: The clinical data and diagnostic and therapeutic methods used in the study group were analyzed. A statistical analysis of the treatment outcomes was conducted with STATISTICA v. 13 (StatSoft, Inc., Tulsa, OK, USA) and analysis of survival curves was conducted with MedCalc 11.5.1 (MedCalc Software, Ostend, Belgium). Statistical significance was considered at p<0.05. Results: In the study group, MS was most frequently accompanied by AML. The most common site of involvement was skin, followed by orbital region. Skin manifestation of MS was more common in the age group <10 years. The most frequent genetic abnormality was the t(8;21)(q22;q22) translocation. The 5-year OS probability (pOS), 5-year RFS probability (pRFS), and 5-year EFS probability (pEFS) were 0.67 ± 0.08, 0.79 ± 0.07, and 0.65 ± 0.08, respectively. In patients with isolated MS and those with concurrent bone marrow involvement by AML/MDS, pOS values were 0.56 ± 0.12 and 0.84 ± 0.09 (p=0.0251), respectively, and pEFS values were 0.56 ± 0.12 and 0.82 ± 0.08 (p=0.0247), respectively. In patients with and without the t(8;21)(q22;q22) translocation, pEFS values were 0.90 ± 0.09 and 0.51 ± 0.14 (p=0.0490), respectively. Conclusions: MS is a disease with a highly variable clinical course. Worse treatment outcomes were observed in patients with isolated MS compared to those with concurrent bone marrow involvement by AML/MDS. Patients with the t(8;21)(q22;q22) translocation were found to have significantly higher pEFS. MS location, age group, chemotherapy regimen, surgery, and/or radiotherapy did not have a significant influence on treatment outcomes. Further exploration of prognostic factors in children with MS is indicated.
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Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta superfamily, resulting in erythroid maturation and differentiation. On June 25, 2020, a marketing authorization valid through the European Union (EU) was issued for luspatercept for the treatment of adult patients with transfusion-dependent anemia caused by very low-, low-, and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, or those with transfusion-dependent beta thalassemia (BT). Luspatercept was evaluated in 2 separate phase 3, double-blind, placebo-controlled multicentre trials. The primary endpoints of these trials were the percentage of patients achieving transfusion independence over ≥8 weeks or longer for patients with MDS, and the percentage of patients achieving a ≥33% reduction in transfusion burden from baseline to week 13-24 for patients with BT. In the MDS trial, the percentage of responders was 37.91% versus 13.16%, P < 0.0001, for patients receiving luspatercept versus placebo, respectively. In the BT trial, the percentage of responders was 21.4% versus 4.5% (P < 0.0001) for luspatercept versus placebo, respectively. Treatment with luspatercept led to similar incidences of adverse events (AEs), but higher incidences of grade ≥3 AEs and serious AEs compared to placebo. The most frequently reported treatment-emergent AEs (≥15%) in the pooled luspatercept group were headache; back pain, bone pain, and arthralgia; diarrhea; fatigue; pyrexia; and cough. The aim of this article is to summarize the scientific review of the application, which led to the regulatory approval in the EU.
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Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of life-threatening inflammation caused by an excessive, prolonged and ineffective immune response. An increasing number of HLH cases is recognized in Poland, but the genetic causes of familial HLH (FHL) have not been reported. We investigated the molecular genetics and associated outcomes of pediatric patients who met HLH criteria. We studied 54 patients with HLH, 36 of whom received genetic studies. Twenty-five patients were subjected to direct sequencing of the PRF1, UNC13D, STX11, XIAP and SH2D1A genes. Additionally, 11 patients were subjected to targeted next-generation sequencing. In our study group, 17 patients (31%) were diagnosed with primary HLH, with bi-allelic FHL variants identified in 13 (36%) patients whereas hemizygous changes were identified in 4 patients with X-linked lymphoproliferative diseases. In addition, one patient was diagnosed with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia due to a hemizygous MAGT1 variant; another newborn was diagnosed with auto-inflammatory syndrome caused by MVK variants. The majority (65%) of FHL patients carried UNC13D pathogenic variants, whereas PRF1 variants occurred in two patients. Novel variants in UNC13D, PRF1 and XIAP were detected. Epstein-Barr virus was the most common trigger noted in 23 (65%) of the patients with secondary HLH. In three patients with secondary HLH, heterozygous variants of FHL genes were found. Overall survival for the entire study group was 74% with a median of 3.6 years of follow-up. Our results highlight the diversity of molecular causes of primary HLH in Poland.
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Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Criança , Herpesvirus Humano 4 , Humanos , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/genética , Proteínas de Membrana , Biologia Molecular , Perforina/genética , PolôniaRESUMO
Hemophagocytic syndrome (HS) is a life-threatening condition of hyperinflammation. Main symptoms are: prolonged fever, cytopenia, hepatosplenomegaly, hemophagocytosis, hyperferritinemia, hypertriglyceridemia and hypofibrinogenemia. Primary genetic form and secondary HS associated with infections, malignancies or autoimmune disorders can be distinguished. Untreated HS in most cases leads to death. We analyzed retrospectively 7 cases of HS in children (3 girls, 4 boys; aged 10 days -14 years) treated in 3 different pediatric centers from 2004 to 2009. In 3 cases HS was associated with infections (EBV, CMV, Bacillus Calmette Guerin - BCG), in 1 child with non-Hodgkin anaplastic large cell lymphoma (ALCL), in 1 patients probably with side effect of antiepileptic drug. In 2 cases cause of HS remained unknown. Fever, hepatomegaly, pan- or bicytopenia and hyperferritinemia were present in all children. In addition, splenomegaly was noted in 6 cases, hemophagocytosis in 6 children, impaired function or decreased number of NK cells in 4 cases, hypofibrino-genemia in 5 and hypotriglyceridemia in 4 patients. Among other symptoms and signs we observed: lymphadenopathy, hepatic failure, oedema, rash, neurological symptoms, increased level of LDH and inflammatory markers. In one child acute pancreatitis occurred. Among others, antibiotics, antiviral and immunosuppressive drugs were used in therapy. HLH-2004 protocol was applied in 4 cases. Patient with ALCL was treated with chemotherapy and allogeneic stem cell transplantation. Four patients are alive, 2 died because of HS, child with ALCL died because of generalized infection in peritrans-plantation period. In case of prolonged fever, splenomegaly and cytopenia diagnosis of HS should be considered. Following tests are recommended: complete blood count, ferritin, triglycerides, fibrinogen, bone marrow aspiration and NK cell assessment. Patients should be also screened for infections and malignancies. Early diagnosis of HS and underlying condition is crucial to start lifesaving therapy.
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Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Adolescente , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Viroses/complicações , Viroses/diagnósticoRESUMO
The aim of the paper is to present the initial results of molecular examination which was started in 2006 for children with acute myeloid leukemia. Better knowledge of biology of this disease, can result in establishing of new risk factors what allows more precise patient stratification to different therapeutic groups. Study was obtained patients until to 18 years of age treated according to AML-BFM 2004 INTERIM protocol in 14 centers of the Polish Pediatric Leukemia/Lymphoma Study Group. Mononuclear cells were collected from bone marrow on time points established according to the AML-BFM 2004 INTERIM protocol. Collected cells were isolated on Ficoll gradient, and RNA and DNA were isolated using TRIZOL reagent. To synthesize cDNA an amount of 1 mg of total RNA was used. To perform quantitative RT-PCR and RQ-PCR reactions 4 fusion gene transcripts (AML1-ETO, CBFb-MYH11, PML-RARA /subtype bcrl and bcr3/) were used according to the protocol established by Europe Against Cancer Program. An expression of WT1 gene was tested additionally. An analysis of ABL control gene was used to normalize of achieved results. Determination of duplication of FLT3 gene in DNA sample was performed with starters complementary to JM region. Genotyping was performed in 75 patients with acute myeloid leukemia so far. AML1-ETO fusion gene transcript was found in 14 patients (19%). PML-RARA (subtype bcr3) and CBFB-MYH11 gene transcripts were detected in 3 (4%) and 3 (4%) patients, respectively. Duplication of FLT3 gene was found in 4 (5.3%) cases. Between 67 tested children over expression of WT1 was present in 51 patients (76%). Analysis of MRD level in subsequent time points showed systematic decrease of number of fusion gene transcript copies and gene WT1 expression. To establish the rate of molecular marker presence in AML in children and the influence of the presence of MRD on the treatment results as well, the study has to be conducted on a larger group of patients with longer follow-up.
Assuntos
Genes do Tumor de Wilms , Marcadores Genéticos/genética , Genótipo , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
Four consecutive intensive unified regimens (BFM-AML-83, PGP-AML 94, PGP-AML 98 AML-BFM 2004 Interim) for acute myelocytic leukemia (AML) have been conducted by the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) since 1983. The last one, introduced four years ago is still active, and only preliminary result may be presented. There were 726 children with AML diagnosed (226, 102, 247 and 151 in the I, II , III and IV periods, respectively), and 603 of them were eligible for evaluation (208, 83, 195 and 117, respectively). Complete remission rates were: 71.4%, 67.5%, 81.4% and 87% in consecutive periods, respectively. Five-year overall survival (OS) and event-free survival (EFS) rates were: 33% and 32% for PGP-AML 83 regimen, 38% and 36% for PGP-AML 94 regimen, and 53% and 46% for PGP-AML 98 regimen, respectively. For AML-BFM Interim 2004 the 3-year OS and EFS were 57% and 57%, respectively. Despite continuous improvement of the treatment results, the number of failures have remained too high, but the pattern have changed in the following way: Early deaths (from diagnosis to 15 day of treatment) decreased only in the fourth period to 3%. "Aplasia deaths" (between day 15 and 42) decreased gradually from 16% in the first period to 1.5% and 2.2% in the third and in the fourth period, respectively. Deaths in remission decreased from 10% in first and second period to 3.5% at present. Number of non responders increased between first and second period from 6% to 18%, later decreased to 8.2% at present. These trends e.g. decrease of early death and treatment related mortality reflect both the better efficacy of antileukemic treatment and the improvement of supportive care.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Polônia/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Indução de Remissão , Taxa de Sobrevida , Falha de TratamentoRESUMO
BACKGROUND: The role of cellular drug resistance in childhood acute myeloid leukemia (AML) has not yet been established. The aim of the study was the analysis of the clinical value of ex vivo drug resistance in pediatric AML. PATIENTS AND METHODS: A cohort of 90 children with de novo AML were assayed for drug resistance profile by the 3-4,5-dimethylthiazol-2-yl-2,5-difenyl tetrazolium bromide (MTT) assay and prognostic model of in vitro drug sensitivity was analyzed. RESULTS: Children who relapsed during follow-up showed higher in vitro resistance of leukemic blasts to most of the drugs tested, except for cytarabine, cladribine, vincristine, mercaptopurine and thioguanine. A combined in vitro drug resistance profile to fludarabine, treosulfan and mitoxantrone (FTM score) was defined and it had an independent prognostic significance for disease free survival in pediatric AML. CONCLUSION: The combined fludarabine, treosulfan and mitoxantrone resistance profile to possibly may be used for better stratification of children with AML or indicate the necessity for additional therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Bussulfano/administração & dosagem , Bussulfano/análogos & derivados , Criança , Pré-Escolar , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/patologia , Masculino , Mitoxantrona/administração & dosagem , Prognóstico , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
PURPOSE: Cellular resistance in childhood acute leukemias might be related to profile and function of multidrug resistance proteins and apoptosis regulating proteins. The aims of the study were: (1) analysis of expression of MRP1, PGP1, LRP, BCL-2 and p53 proteins; (2) correlation with ex vivo drug resistance, and (3) analysis of their prognostic impact on clinical outcome in childhood acute lymphoblastic (ALL) and acute myeloid (AML) leukemia. METHODS: Total number of 787 children diagnosed for initial ALL (n = 527), relapsed ALL (n = 104), initial AML (n = 133) and relapsed AML (n = 23) were included into the study. Mean follow-up period was 3.5 years. Drug resistance for up to 30 anticancer agents was performed by the MTT assay. Expression of all proteins was tested by flow cytometry. RESULTS: Both initial AML and relapsed ALL samples showed higher drug resistance than initial ALL samples. No significant differences were found in drug resistance between initial and relapsed AML samples. The presence of multidrug resistance and apoptosis proteins had no impact on pDFS in iALL and iAML, however strong trend towards adverse prognostic impact of MRP1, PGP and LRP on pDFS in rALL was observed. The same trend was observed for each of analyzed co-expressions of tested multidrug resistance proteins. CONCLUSIONS: The phenomenon of cellular drug resistance in childhood acute leukemias is multifactorial and plays an important role in response to therapy. Expression of MRP1, PGP and LRP proteins, as well as their co-expression play possible role in childhood relapsed ALL.