RESUMO
BACKGROUND: Mercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6-thioguanine nucleosides (6-TGN) are believed to be the primary contributor to myelosuppression and immunosuppressive effects, while 6-methylmercaptopurine (6-MMPN) is believed to be responsible for several toxicities including hepatotoxicity, pancreatitis, and hypoglycemia. Previous reports suggest the addition of allopurinol may reduce these toxicities. AIMS: To assess the use of allopurinol to improve both safety and efficacy of mercaptopurine in pediatric patients with ALL and LLy during maintenance therapy. Secondary objectives included evaluating patient tolerability and skewed metabolism. In addition, we also analyzed mercaptopurine daily dose reduction upon allopurinol initiation. METHODS AND RESULTS: The primary endpoint was time within goal ANC prior to and after initiation of allopurinol. Secondary endpoints included; improvement in selective toxicities (hepatotoxicity, pancreatitis, and hypoglycemia) and 6-MMPN to 6-TGN ratio prior to and after allopurinol initiation. In addition, an exploratory endpoint assessing mercaptopurine daily dose reduction prior to and after allopurinol initiation was included. Sixteen patients met inclusion criteria and 15 (94%) of which were included in this study. Median percent of maintenance days within goal ANC prior to and after initiation of allopurinol was 27.8 (IQR 22.6-44.9) and 41.6 (IQR 20.2-58.2) respectively. All patients experienced selective toxicities; 15 (100%) hepatotoxicity, 1 (7%) pancreatitis, and 3 (20%) hypoglycemia. Improvement of toxicities was seen in 13/15 (87%), 1/1 (100%), and 2/3 (67%) respectively. Average 6-MMPN:6-TGN ratio prior to allopurinol initiation was 304:1 and after, allopurinol initiation improved to 15:1, resulting in a 95% reduction. Average mercaptopurine dose prior to and after allopurinol initiation decreased by about 56% (63 to 28 mg/m2 /day). CONCLUSION: Results suggest that the use of allopurinol in pediatric patients with ALL and LLy receiving mercaptopurine during maintenance therapy is both safe and effective.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hipoglicemia , Linfoma , Pancreatite , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Mercaptopurina/efeitos adversos , Alopurinol/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Linfoma/diagnóstico , Linfoma/tratamento farmacológico , Pancreatite/induzido quimicamente , Pancreatite/diagnósticoRESUMO
ABSTRACT: Working groups of the European LeukemiaNet have published several important consensus guidelines. Acute lymphoblastic leukemia (ALL) has many different clinical and biological subgroups and the knowledge on disease biology and therapeutic options is increasing exponentially. The European Working Group for Adult ALL has therefore summarized the current state of the art and provided comprehensive consensus recommendations for diagnostic approaches, biologic and clinical characterization, prognostic factors, and risk stratification as well as definitions of endpoints and outcomes. Aspects of treatment, management of subgroups and specific situations, aftercare, and supportive care are covered in a separate publication. The present recommendation intends to provide guidance for the initial management of adult patients with ALL and to define principles as a basis for future collaborative research.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Prognóstico , Adulto , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Europa (Continente)RESUMO
OBJECTIVES: Measurable residual disease (MRD) is the most relevant predictor of disease-free survival in B-cell acute lymphoblastic leukemia (B-ALL). We aimed to establish a highly sensitive flow cytometry (MFC)-based B-ALL-MRD (BMRD) assay for patients receiving anti-CD19 immunotherapy with an alternate gating approach and to document the prevalence and immunophenotype of recurrently occurring low-level mimics and confounding populations. METHODS: We standardized a 15-color highly-sensitive BMRD assay with an alternate CD19-free gating approach. The study included 137 MRD samples from 43 relapsed/refractory B-ALL patients considered for anti-CD19 immunotherapy. RESULTS: The 15-color BMRD assay with CD22/CD24/CD81/CD33-based gating approach was routinely applicable in 137 BM samples and could achieve a sensitivity of 0.0005%. MRD was detected in 29.9% (41/137) samples with 31.7% (13/41) of them showing <.01% MRD. Recurrently occurring low-level cells that showed immunophenotypic overlap with leukemic B-blasts included: (a) CD19+CD10+CD34+CD22+CD24+CD81+CD123+CD304+ plasmacytoid dendritic cells, (b) CD73bright/CD304bright/CD81bright mesenchymal stromal/stem cells (CD10+) and endothelial cells (CD34+CD24+), (c) CD22dim/CD34+/CD38dim/CD81dim/CD19-/CD10-/CD24- early lymphoid progenitor/precursor type-1 cells (ELP-1) and (d) CD22+/CD34+/CD10heterogeneous/CD38moderate/CD81moderate/CD19-/CD24- stage-0 B-cell precursors or ELP-2 cells. CONCLUSIONS: We standardized a highly sensitive 15-color BMRD assay with a non-CD19-based gating strategy for patients receiving anti-CD19 immunotherapy. We also described the immunophenotypes of recurrently occurring low-level populations that can be misinterpreted as MRD in real-world practice.
Assuntos
Anticorpos Biespecíficos , Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Humanos , Citometria de Fluxo , Células Endoteliais , Antígenos CD19 , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Neoplasia Residual/diagnósticoRESUMO
T-lineage acute lymphoblastic leukemia (T-ALL) accounts for about 15% of pediatric and about 25% of adult ALL cases. Minimal/measurable residual disease (MRD) assessed by flow cytometry (FCM) is an important prognostic indicator for risk stratification. In order to assess the MRD a limited number of antibodies directed against the most discriminative antigens must be selected. We propose a pipeline for evaluating the influence of different markers for cell population classification in FCM data. We use linear support vector machine, fitted to each sample individually to avoid issues with patient and laboratory variations. The best separating hyperplane direction as well as the influence of omitting specific markers is considered. Ninety-one bone marrow samples of 43 pediatric T-ALL patients from five reference laboratories were analyzed by FCM regarding marker importance for blast cell identification using combinations of eight different markers. For all laboratories, CD48 and CD99 were among the top three markers with strongest contribution to the optimal hyperplane, measured by median separating hyperplane coefficient size for all samples per center and time point (diagnosis, Day 15, Day 33). Based on the available limited set tested (CD3, CD4, CD5, CD7, CD8, CD45, CD48, CD99), our findings prove that CD48 and CD99 are useful markers for MRD monitoring in T-ALL. The proposed pipeline can be applied for evaluation of other marker combinations in the future.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Citometria de Fluxo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Neoplasia Residual/diagnóstico , Linfócitos TRESUMO
The translocation t(1;19)(q23;p13) with the resulting chimeric TCF3::PBX1 gene is the third most prevalent recurrent chromosomal translocation in acute lymphoblastic leukemia and accounts for 3-5% of cases. The molecular background of this translocation has been incompletely studied, especially in adult cases. We characterized the chromosomal breakpoints of 49 patients with TCF3::PBX1 and the corresponding reciprocal PBX1::TCF3 breakpoints in 15 cases at the molecular level, thus providing an extensive molecular overview of this translocation in a well-defined study patient population. Breakpoints were found to be remarkably clustered not only in TCF3 but also in PBX1. No association with DNA repeats or putative cryptic recombination signal sequence sites was observed. A simplified detection method for breakpoint identification was developed and the feasibility of patient-specific chromosomal break sites as molecular markers for detecting measurable residual disease (MRD) was explored. A highly sensitive generic real-time PCR for MRD assessment using these breakpoint sequences was established that could serve as a useful alternative to the classical method utilizing rearranged immune gene loci. This study provides the first extensive molecular data set on the chromosomal breakpoints of the t(1;19)/TCF3::PBX1 aberration in adult ALL. Based on the obtained data a generic MRD method was developed that has several theoretical advantages, including an on average higher sensitivity and a greater stability of the molecular marker in the course of disease.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Pontos de Quebra do Cromossomo , Medicamentos Genéricos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reação em Cadeia da Polimerase em Tempo Real , Translocação GenéticaRESUMO
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with diagnosis preceded by symptoms that may include fever, weight loss, fatigue, bleeding, and bruising. Timely diagnosis and treatment of ALL may lead to improved outcomes and reduced morbidity from associated complications, including tumor lysis syndrome, hyperviscosity, and stroke. We performed a retrospective cohort analysis of 274 pediatric pre-B cell ALL and acute lymphoblastic lymphoma patients within Montefiore Health System to determine whether there were factors associated with time from symptom onset to diagnosis. The median time to diagnosis for all patients was 11.5 days (interquartile range: 7.8, 14.3). Those with Medicaid insurance (n=189) were diagnosed sooner than those with private/self-pay insurance (n=85) (median of 10 vs. 16 days; P =0.05). English and other language speakers experienced fewer median days from symptom onset to diagnosis date compared with Spanish speakers (11 vs. 7 vs. 14; P =0.05). Insurance status may impact the time to diagnosis to a greater degree in non-Hispanic patients, while the English language and female sex may represent a greater advantage to Hispanic patients. Insurance status and language preference may impact the time to diagnosis of pediatric ALL. There is a further need to confirm our findings and to study possible causes driving these disparities.
Assuntos
Etnicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras , Estados Unidos , Criança , Humanos , Feminino , Estudos Retrospectivos , Medicaid , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Cobertura do SeguroAssuntos
Proteínas de Fusão bcr-abl , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Mutação , Proteínas de Fusão bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reação em Cadeia da Polimerase , Inibidores de Proteínas QuinasesRESUMO
Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, RT-PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay (sensitivity of 10-6 ) and its correlation with RT-PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT-PCR and NGS, and 31% of patients who achieved NGS MRD negativity were PCR+ at the same timepoint. Among eight patients with long-term detectable BCR::ABL1 by PCR, six were PCR+/NGS-. These patients generally had stable PCR levels that persisted despite therapeutic interventions, and none subsequently relapsed; in contrast, patients who were PCR+/NGS+ had more variable PCR values that responded to therapeutic intervention. In a separate cohort of prospectively collected clinical samples, 11 of 65 patients (17%) with Ph+ ALL who achieved NGS MRD negativity had detectable BCR::ABL1 by PCR, and none of these patients relapsed. Relapse-free survival and overall survival were similar in patients who were PCR+/NGS- and PCR-/NGS-, suggesting that PCR for BCR::ABL1 did not provide additional prognostic information in patients who achieved NGS MRD negativity. NGS-based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low-level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.
Assuntos
Proteínas de Fusão bcr-abl , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Proteínas de Fusão bcr-abl/genética , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Sequenciamento de Nucleotídeos em Larga Escala , RecidivaRESUMO
BACKGROUND: Acute Leukaemia is a malignant disorder characterized by an abnormal proliferation of immature cells, called blasts. Classically, acute leukaemia is classified into acute myeloid leukaemia and acute lymphoblastic leukaemia depending on the lineage of the immature cells. Objective of the study was to evaluate the clinical presentations, analyze the haematologic parameters at time of diagnosis and assess the post-induction status in newly diagnosed ALL patients. This cross-sectional study was conducted in the Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi from June to November 2019. METHODS: A total of 55 newly diagnosed ALL patients were recruited including children, adults and elderly. Detailed medical history and physical findings were noted. Haematologic parameters were documented. Each patient was treated as per standard protocol and remission induction status was determined on day 29 of treatment. RESULTS: The median age of the study cohort of 55 newly diagnosed ALL patients was 8.5 years. Males were 37 (67.3%) and females were 18 (32.7%) with a male to female ratio of 2:1. Paediatric group included 31 (56.4%) patients. Nine (16.4%) patients were in the adult group and 15 (27.3%) in the elderly age group. The time from onset of symptoms to diagnosis of acute lymphoblastic leukaemia was 98.87±79.21 days. Fever was the most common symptom but body aches were common among paediatric group while pallor was the most common sign. Mean WBC was 29.1±27.9 x109/l, Hb was 8.1±2.9 g/dl and platelet count was 60±41.8 x109/l B-acute lymphoblastic leukaemia was more common than T-acute lymphoblastic leukaemia. A total of 52 patients were assessed on day 29 to evaluate for post-induction remission status. The remission rate of our cohort of patients was 82.7%. CONCLUSIONS: Most of the patients were in paediatric age group and remission rate was better in this age group compared to elderly population. B-ALL was associated with good response to induction chemotherapy while patients with BCR-ABL1 gene rearrangement did not respond well to treatment. Identification of prognostic features at diagnosis will further help our clinicians to predict outcomes of the disease.
Assuntos
Hematologia , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Idoso , Criança , Adulto , Masculino , Feminino , Estudos Transversais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Indução de RemissãoRESUMO
Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent "MRD negativity" by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD+ by the NGS assay. After 1 cycle of induction chemotherapy, MRD negativity by MFC at a sensitivity of 1 × 10-4 and NGS at a sensitivity of 1 × 10-6 was achieved in 66% and 23% of patients, respectively. The 5-year cumulative incidence of relapse (CIR) among patients who achieved MRD negativity by MFC at complete remission (CR) was 29%; in contrast, no patients who achieved early MRD negativity by NGS relapsed, and their 5-year OS was 90%. NGS MRD negativity at CR was associated with significantly decreased risk of relapse compared with MRD positivity (5-year CIR, 0% vs 45%, respectively; P = .04). Among patients who were MRD negative by MFC, detection of low levels of MRD by NGS identified patients who still had a significant risk of relapse (5-year CIR, 39%). Early assessment of MRD using a highly sensitive NGS assay adds clinically relevant prognostic information to standard MFC-based approaches and can identify patients with ALL undergoing frontline therapy who have a very low risk of relapse and excellent long-term survival.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Adulto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RecidivaRESUMO
PURPOSE: Most cases of pediatric acute leukemia occur in low- and middle-income countries, where health centers lack the tools required for accurate diagnosis and disease classification. Recent research shows the robustness of using unbiased short-read RNA sequencing to classify genomic subtypes of acute leukemia. Compared with short-read sequencing, nanopore sequencing has low capital and consumable costs, making it suitable for use in locations with limited health infrastructure. MATERIALS AND METHODS: We show the feasibility of nanopore mRNA sequencing on 134 cryopreserved acute leukemia specimens (26 acute myeloid leukemia [AML], 73 B-lineage acute lymphoblastic leukemia [B-ALL], 34 T-lineage acute lymphoblastic leukemia, and one acute undifferentiated leukemia). Using multiple library preparation approaches, we generated long-read transcripts for each sample. We developed a novel composite classification approach to predict acute leukemia lineage and major B-ALL and AML molecular subtypes directly from gene expression profiles. RESULTS: We demonstrate accurate classification of acute leukemia samples into AML, B-ALL, or T-lineage acute lymphoblastic leukemia (96.2% of cases are classifiable with a probability of > 0.8, with 100% accuracy) and further classification into clinically actionable genomic subtypes using shallow RNA nanopore sequencing, with 96.2% accuracy for major AML subtypes and 94.1% accuracy for major B-lineage acute lymphoblastic leukemia subtypes. CONCLUSION: Transcriptional profiling of acute leukemia samples using nanopore technology for diagnostic classification is feasible and accurate, which has the potential to improve the accuracy of cancer diagnosis in low-resource settings.
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Leucemia Mieloide Aguda , Sequenciamento por Nanoporos , Nanoporos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Doença Aguda , Criança , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , RNA Mensageiro/genéticaRESUMO
Assestment of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) is of utmost importance both for risk classification and tailoring of the therapy. The data of pediatric ALL patients that received treatment with Berlin-Frankfurt-Münster (BFM) protocols were retrospectively collected from 5 university hospitals in Turkey. Of the 1388 patients enrolled in the study 390 were treated according to MRD-based protocols. MRD assestment was with real time quantitative polymerase chain reaction (qPCR) in 283 patients and with multiparametric flow cytometry (MFC)-MRD in 107 patients. MRD monitoring had upstaged a total of 8 patients (2%) from intermediate risk group to high-risk group. Univariate analysis revealed age 10 years or above, prednisone poor response, PCR-MRD ≥10-3 on day 33 and on day 78 as poor prognostic factors affecting event-free survival (EFS). Detection of >10% blasts on day 15 with MFC (MFC-high-risk group) was not shown to affect EFS and/or overall survival (log-rank P=0.339). Multiple logistic regression analysis revealed PCR-MRD ≥10-3 on day 78 as the only poor prognostic factor affecting EFS (odds ratio: 8.03; 95% confidence interval: 2.5-25; P=0.000). It is very important to establish the infrastructure and ensure necessary standardization for both MRD methods for optimal management of children with ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Intervalo Livre de Doença , Humanos , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Estudos Retrospectivos , Turquia/epidemiologiaAssuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Adulto , Antígenos CD19 , Análise Custo-Benefício , Humanos , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos TRESUMO
For the detection of BCR-ABL1-like ALL cases, two methodologies, specifically Gene expression profiling (GEP) or Next-generation targeted sequencing (NGS) and TaqMan based low-density (TLDA) card, are being used. NGS is very costly and TLDA is not widely commercially available. In this study, we quantified the expression of 8 selected overexpressed genes in 536 B-ALL cases. We identified 26.67% (143/536) BCR-ABL1-like ALLs using hierarchical clustering and principal component analysis. BCR-ABL1-like ALL cases were significantly older at presentation (p = 0.036) and had male preponderance (p = 0.047) compared to BCR-ABL1-negative ALL cases. MRD-positivity and induction failure were more commonest in BCR-ABL1-like ALL cases (30.55 vs.19.35% in BCR-ABL1-negative ALL cases). Lastly, we built a PHi-RACE classifier (sensitivity = 95.2%, specificity= 83.7%, AUC= 0.927) using logistic regression to detect BCR-ABL1-like ALL cases promptly at diagnosis. This classifier is beneficial for hematologists in quick decision making at baseline to start tailored treatment regimes.
Assuntos
Proteínas de Fusão bcr-abl , Leucemia-Linfoma Linfoblástico de Células Precursoras , Análise por Conglomerados , Análise Custo-Benefício , Proteínas de Fusão bcr-abl/genética , Perfilação da Expressão Gênica , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMO
OBJECTIVES: To study the value of serum miR-922 and miR-506 expression levels in the diagnosis and prognostic assessment of childhood acute lymphoblastic leukemia (ALL). METHODS: A total of 132 children with ALL (ALL group) and 80 healthy children (healthy control group) were prospectively selected in this study. Quantitative real-time polymerase chain reaction was used to measure the expression levels of serum miR-922 and miR-506 in both groups. Receiver operating characteristic (ROC) curves were plotted to analyze the diagnostic value of miR-922 and miR-506 for childhood ALL. The Kaplan-Meier method was used to plot survival curves, and multivariate COX regression models were used to analyze the risk factors for poor prognosis in children with ALL. RESULTS: The ALL group had significantly higher expression levels of serum miR-922 and miR-506 than the control group (P<0.001). The ROC curve analysis showed that the optimal cut-off values of miR-922 and miR-506 for the diagnosis of childhood ALL were 1.46 and 2.17, respectively. The high miR-922 expression (≥1.46) group and high miR-506 expression (≥2.17) group had significantly higher incidence rates of lymph node enlargement, leukocyte count ≥50×109/L, medium-high risk stratification, mixed-lineage leukemia (MLL) gene rearrangement, and karyotype abnormality than the low miR-922 expression group and low miR-506 expression group (P<0.05). The Kaplan-Meier analysis showed that high expression of miR-922 and miR-506 was associated with short survival time in children with ALL (P<0.05). The multivariate COX regression analysis showed that leukocyte count ≥50×109/L, medium-high risk stratification, MLL gene rearrangement, miR-922≥1.46, and miR-506≥2.17 could indicate poor prognosis in children with ALL (P<0.05). CONCLUSIONS: The expression levels of miR-922 and miR-506 are of good value in the diagnosis and prognostic assessment of childhood ALL.
Assuntos
MicroRNAs , Leucemia-Linfoma Linfoblástico de Células Precursoras , Biomarcadores Tumorais , Criança , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/sangue , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Curva ROCRESUMO
Ph-like acute lymphocytic leukemia (ALL) is a subtype of Ph-negative B precursor ALL, and its gene expression profile is similar to that of Ph+ALL. In recent decades, comprehensive genomic analyses have revealed that Ph-like ALL has two types. The first type is associated with the ABL-class tyrosine kinase fusion gene, and the second type with fusion genes involving cytokine receptors or molecules, including CRLF2, which are correlated with the activation of the JAK/STAT pathway. Based on these findings, tyrosine kinase or JAK inhibitors were found to be effective for Ph-like ALL. Genetic abnormalities identified in Ph-like ALL, except for CRLF2 rearrangement, are quite rare. Thus, functional studies regarding each genomic abnormality are relevant for establishing targeted therapies for Ph-like ALL. To develop a targeted molecular therapy, a functional study of NCOR1-LYN, which is a novel ABL-class fusion gene, was conducted on pediatric patients with Ph-like ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Genômica , Humanos , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Tirosina Quinases , TranscriptomaRESUMO
White blood cell count (WBC) at diagnosis is the conventional prognostic factor in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Nevertheless, little is known about the impact of WBC at diagnosis considering the minimal residual disease (MRD) status at allogeneic hematopoietic cell transplantation (HCT). We evaluated adult patients with Ph+ ALL who achieved negative-MRD and received HCT in first complete remission between 2006 and 2018. The entire cohort was temporally divided into derivation (n = 258) and validation cohorts (n = 366). Using a threshold of 15,000/µL, which was determined by a receiver operating characteristic curve analysis in the derivation cohort, high WBC was associated with an increased risk of hematological relapse in both the derivation cohort (25.3% vs. 11.6% at 7 years, P = 0.004) and the validation cohort (16.2% vs. 8.5% at 3 years, P = 0.025). In multivariate analyses, high WBC was a strong predictor of hematological relapse in the derivation cohort (HR, 2.52, 95%CI 1.32-4.80, P = 0.005) and in the validation cohort (HR, 2.32, 95%CI, 1.18-4.55; P = 0.015). In conclusion, WBC at diagnosis with a new threshold of 15,000/µL should contribute to better risk stratification in patients with negative-MRD at HCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Contagem de Leucócitos , Neoplasia Residual/diagnóstico , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Recidiva , Medição de RiscoRESUMO
BACKGROUND: Although different treatment protocols for childhood acute lymphoblastic leukaemia (ALL) all achieve high cure rates, their health care utilisation and costs have not been rigorously compared. METHODS: Disease, treatment, and outcome data were chart abstracted for all children with ALL in Ontario, Canada, diagnosed 2002-2012. Linkage to population-based databases identified health care utilisation. Utilisation-associated costs were determined through validated algorithms. Chemotherapy-associated costs were calculated separately. Health care utilisation and costs were compared between patients receiving Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI)-based treatment. FINDINGS: Of 802 patients, 146 (18.2%) were treated on DFCI-based protocols. COG patients experienced significantly higher rates of emergency department (ED) visits (adjusted rate ratio [aRR]: 1.3, 95% confidence interval [CI]: 1.1-1.5; p = 0·01), whereas outpatient visit rates were 60% higher among DFCI patients (aRR: 1.6, 95% CI: 1.5-1.7, p < 0.0001). In adjusted analyses, DFCI-associated cost intensity was 70% higher (aRR: 1.7, 95% CI: 1.5-1.9; p < 0.0001), mainly attributable to outpatient visit costs. Total chemotherapy costs were higher among COG-treated patients ($39,400 ± $1100 versus $33,400 ± $2800; p = 0.02). Among PEG-ASNase-treated patients, total chemotherapy costs were highest among DFCI patients (median $54,200 ± $7400; p = 0.003 versus COG patients). INTERPRETATION: COG and DFCI treatments were associated with higher ED visit rates and higher outpatient visit rates, respectively. Overall utilisation-associated costs were increased in DFCI-treated patients. Administration of some intravenous chemotherapy at home and decreases in PEG-ASNase cost would decrease health care utilisation and costs for all patients and mitigate differences between COG and DFCI protocols. FUNDING: C17 Research Network.