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PURPOSE: AML is a genetically heterogeneous disease, particularly in older patients. In patients older than 60 years, survival rates are variable after the most important curative approach, intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HCT). Thus, there is an urgent need in clinical practice for a prognostic model to identify older patients with AML who benefit from curative treatment. METHODS: We studied 1,910 intensively treated patients older than 60 years with AML and high-risk myelodysplastic syndrome (HR-MDS) from two cohorts (NCRI-AML18 and HOVON-SAKK). The median patient age was 67 years. Using a random survival forest, clinical, molecular, and cytogenetic variables were evaluated in an AML development cohort (n = 1,204) for association with overall survival (OS). Relative weights of selected variables determined the prognostic model, which was validated in AML (n = 491) and HR-MDS cohorts (n = 215). RESULTS: The complete cohort had a high frequency of poor-risk features, including 2022 European LeukemiaNet adverse-risk (57.3%), mutated TP53 (14.4%), and myelodysplasia-related genetic features (65.1%). Nine variables were used to construct four groups with highly distinct 4-year OS in the (1) AML development, (2) AML validation, and (3) HR-MDS test cohorts ([1] favorable: 54% ± 4%, intermediate: 38% ± 2%, poor: 21% ± 2%, very poor: 4% ± 1%; [2] 54% ± 9%, 43% ± 4%, 27% ± 4%, 4% ± 3%; and [3] 54% ± 10%, 33% ± 6%, 14% ± 5%, 0% ± 3%, respectively). This new AML60+ classification improves current prognostic classifications. Importantly, patients within the AML60+ intermediate- and very poor-risk group significantly benefited from allo-HCT, whereas the poor-risk patients showed an indication, albeit nonsignificant, for improved outcome after allo-HCT. CONCLUSION: The new AML60+ classification provides prognostic information for intensively treated patients 60 years and older with AML and HR-MDS and identifies patients who benefit from intensive chemotherapy and allo-HCT.
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We present a practical guide for analyzing the genetic aspects of lymphoblastic leukaemia/lymphoma according to the 5th edition of the World Health Organization (WHO) classification of haematolymphoid neoplasms (WHO-HAEM5) issued in 2024. The WHO-HAEM5 acknowledges the increasing importance of genetics in the diagnosis of lymphoid neoplasia. Classification is based on the established genetic subtypes according to cell lineage, with precursor cell neoplasms followed by mature malignancies. This guide describes those genetic abnormalities in acute precursor B- and T-cell neoplasms required for risk stratification, and for treatment, providing diagnostic algorithms under the headings of 'essential' and 'desirable' diagnostic criteria.
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Acute lymphoblastic leukaemia (ALL) is a haematological malignancy characterized by the uncontrolled proliferation of immature lymphoid cells. Over past decades, significant progress has been made in understanding the biology of ALL, resulting in remarkable improvements in its diagnosis, treatment and monitoring. Since the advent of chemotherapy, ALL has been the platform to test for innovative approaches applicable to cancer in general. For example, the advent of omics medicine has led to a deeper understanding of the molecular and genetic features that underpin ALL. Innovations in genomic profiling techniques have identified specific genetic alterations and mutations that drive ALL, inspiring new therapies. Targeted agents, such as tyrosine kinase inhibitors and immunotherapies, have shown promising results in subgroups of patients while minimizing adverse effects. Furthermore, the development of chimeric antigen receptor T cell therapy represents a breakthrough in ALL treatment, resulting in remarkable responses and potential long-term remissions. Advances are not limited to treatment modalities alone. Measurable residual disease monitoring and ex vivo drug response profiling screening have provided earlier detection of disease relapse and identification of exceptional responders, enabling clinicians to adjust treatment strategies for individual patients. Decades of supportive and prophylactic care have improved the management of treatment-related complications, enhancing the quality of life for patients with ALL.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Genômica , Terapia de Alvo Molecular , Qualidade de Vida , Imunoterapia AdotivaRESUMO
ABSTRACT: A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.
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Histona-Lisina N-Metiltransferase , Leucemia Mieloide Aguda , Proteína de Leucina Linfoide-Mieloide , Humanos , Proteína de Leucina Linfoide-Mieloide/genética , Criança , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Feminino , Pré-Escolar , Adolescente , Lactente , Prognóstico , Aberrações Cromossômicas , Rearranjo Gênico , Estudos RetrospectivosRESUMO
ABSTRACT: Risk stratification is crucial to the successful treatment of acute lymphoblastic leukemia (ALL). Although numerous risk factors have been identified, an optimal prognostic model for integrating variables has not been developed. We used individual patient data from 4 contemporary academic national clinical trials, UKALL14, NILG-ALL10/07, GIMEMA-LAL1913, and PETHEMA-ALL-HR2011, to generate and validate the European Working Group for Adult ALL prognostic index (EWALL-PI), which is based on white blood cell count, genetics, and end of induction minimal residual disease (MRD). Individual patient risk scores were calculated for 778 patients aged 15 to 67 years in complete remission using the validated UKALL-PI formula, applying minor modifications to reflect differences between pediatric and adult ALL. Per-trial analysis revealed that EWALL-PI correlated with relapse and death. Regression analysis revealed that each unit increase in EWALL-PI increased the risk of relapse or death by â¼30% with no evidence of heterogeneity across trials or patient subgroups. EWALL-PI-defined risk models outperformed the stratification algorithms used by each trial. Threshold analysis revealed an EWALL-PI threshold that divided patients with B cell and T cell into standard (EWALL-PI <2.50) and high (EWALL-PI ≥2.50) risk groups, respectively. Per-trial analysis showed that patients at high risk had a significantly increased relapse rate and inferior survival compared with patients with standard risk (subdistribution hazard ratio for relapse, ranged from 1.85 to 3.28; hazard ratio for death, 1.73 to 3.03). Subgroup analysis confirmed the robustness of these risk groups by sex, age, white blood cell count, and lineage. In conclusion, we validated an integrated risk model across 4 independent adult ALL clinical trials, demonstrating its utility defining clinically relevant risk groups.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Criança , Prognóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Algoritmos , Fatores de Risco , RecidivaRESUMO
Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.
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Cromossomos Humanos Par 21 , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Cromossomos Humanos Par 21/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Aberrações Cromossômicas , Citogenética , Genômica , Fator 1 de Modelagem da Cromatina/genéticaRESUMO
PURPOSE: A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS: A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS). RESULTS: The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION: EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Criança , Humanos , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas/métodos , Prognóstico , Recidiva , Neoplasia Residual/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapiaRESUMO
Genomic profiling during the diagnosis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification, and treatment decisions. Patients for whom diagnostic screening fails to identify disease-defining or risk-stratifying lesions are classified as having B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) of paired tumor-normal samples. For 52 patients with B-other, we compared the WGS findings with data from clinical and research cytogenetics. WGS identified a cancer-associated event in 51 of 52 patients, including an established subtype defining genetic alterations that were previously missed with standard-of-care (SoC) genetics in 5 of them. Of the 47 true B-other ALL, we identified a recurrent driver in 87% (41). A complex karyotype via cytogenetics emerges as a heterogeneous group, including distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r and IGK::BCL2). For a subset of 31 cases, we integrated the findings from RNA sequencing (RNA-seq) analysis to include fusion gene detection and classification based on gene expression. Compared with RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes; however, RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrated that WGS can identify clinically relevant genetic abnormalities missed with SoC testing as well as identify leukemia driver events in virtually all cases of B-other ALL.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Mutação , Sequenciamento Completo do Genoma , Cariótipo AnormalRESUMO
Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by recurrent genetic abnormalities that drive risk-directed treatment strategies. Using current techniques, accurate detection of such aberrations can be challenging, due to the rapidly expanding list of key genetic abnormalities. Whole genome sequencing (WGS) has the potential to improve genetic testing, but requires comprehensive validation. We performed WGS on 210 childhood B-ALL samples annotated with clinical and genetic data. We devised a molecular classification system to subtype these patients based on identification of key genetic changes in tumour-normal and tumour-only analyses. This approach detected 294 subtype-defining genetic abnormalities in 96% (202/210) patients. Novel genetic variants, including fusions involving genes in the MAP kinase pathway, were identified. WGS results were concordant with standard-of-care methods and whole transcriptome sequencing (WTS). We expanded the catalogue of genetic profiles that reliably classify PAX5alt and ETV6::RUNX1-like subtypes. Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r): a good-risk B-ALL subtype with high survival rates. Overall, we have validated that WGS provides a standalone, reliable genetic test to detect all subtype-defining genetic abnormalities in B-ALL, accurately classifying patients for the risk-directed treatment stratification, while simultaneously performing as a research tool to identify novel disease biomarkers.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Biologia Computacional , Testes Genéticos , Sequenciamento Completo do GenomaRESUMO
A common problem in the study of human malignancy is the elucidation of cancer driver mechanisms associated with recurrent deletion of regions containing multiple genes. Taking B-cell acute lymphoblastic leukaemia (B-ALL) and large deletions of 6q [del(6q)] as a model, we integrated analysis of functional cDNA clone tracking assays with patient genomic and transcriptomic data, to identify the transcription factors FOXO3 and PRDM1 as candidate tumour suppressor genes (TSG). Analysis of cell cycle and transcriptomic changes following overexpression of FOXO3 or PRDM1 indicated that they co-operate to promote cell cycle exit at the pre-B cell stage. FOXO1 abnormalities are absent in B-ALL, but like FOXO3, FOXO1 expression suppressed growth of TCF3::PBX1 and ETV6::RUNX1 B-ALL in-vitro. While both FOXOs induced PRDM1 and other genes contributing to late pre-B cell development, FOXO1 alone induced the key transcription factor, IRF4, and chemokine, CXCR4. CRISPR-Cas9 screening identified FOXO3 as a TSG, while FOXO1 emerged as essential for B-ALL growth. We relate this FOXO3-specific leukaemia-protective role to suppression of glycolysis based on integrated analysis of CRISPR-data and gene sets induced or suppressed by FOXO1 and FOXO3. Pan-FOXO agonist Selinexor induced the glycolysis inhibitor TXNIP and suppressed B-ALL growth at low dose (ID50 < 50 nM).
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Fatores de Transcrição Forkhead , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Fatores de Transcrição Forkhead/metabolismo , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Cromossomos Humanos Par 6/metabolismo , Regulação da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genéticaAssuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Estudos Retrospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Rearranjo Gênico , Fatores de Transcrição MEF2 , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genéticaRESUMO
Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin- MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.
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Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Criança , Humanos , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/genética , Linfoma de Burkitt/terapia , Estudos Prospectivos , Imunoglobulinas/genética , Rearranjo Gênico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapiaRESUMO
PURPOSE: We aimed to study prognostic factors and efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first remission of patients with noninfant childhood acute lymphoblastic leukemia (ALL) with 11q23/KMT2A rearrangements treated with chemotherapy regimens between 1995 and 2010. PATIENTS AND METHODS: Data were retrospectively retrieved from 629 patients with 11q23/KMT2A-rearranged ALL from 17 members of the Ponte-di-Legno Childhood ALL Working Group. Clinical and biologic characteristics, early response assessed by minimal residual disease at the end of induction (EOI) therapy, and allo-HSCT were analyzed for their impact on outcomes. RESULTS: A specific 11q23/KMT2A translocation partner gene was identified in 84.3% of patients, with the most frequent translocations being t(4;11)(q21;q23) (n = 273; 51.5%), t(11;19)(q23;p13.3) (n = 106; 20.0%), t(9;11)(p21_22;q23) (n = 76; 14.3%), t(6;11)(q27;q23) (n = 20; 3.8%), and t(10;11)(p12;q23) (n = 14; 2.6%); 41 patients (7.7%) had less frequently identified translocation partner genes. Patient characteristics and early response varied among subgroups, indicating large biologic heterogeneity and diversity in therapy sensitivity among 11q23/KMT2A-rearranged ALL. The EOI remission rate was 93.2%, and the 5-year event-free survival (EFS) for the entire cohort was 69.1% ± 1.9%, with a range from 41.7% ± 17.3% for patients with t(9;11)-positive T-ALL (n = 9) and 64.8% ± 3.0% for patients with t(4;11)-positive B-ALL (n = 266) to 91.2% ± 4.9% for patients with t(11;19)-positive T-ALL (n = 34). Low EOI minimal residual disease was associated with favorable EFS, and induction failure was particularly predictive of nonresponse to further therapy and relapse and poor EFS. In addition, EFS was not improved by allo-HSCT compared with chemotherapy only in patients with both t(4;11)-positive B-ALL (n = 64 v 51; P = .10) and 11q23/KMT2A-rearranged T-ALL (n = 16 v 10; P = .69). CONCLUSION: Compared with historical data, prognosis of patients with noninfant 11q23/KMT2A-rearranged ALL has improved, but allo-HSCT failed to affect outcome. Targeted therapies are needed to reduce relapse and treatment-related mortality rates.
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Produtos Biológicos , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Recidiva , Estudos Retrospectivos , Translocação Genética , Cromossomos Humanos Par 11RESUMO
Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n = 91), whereas PAX5 P80R mutations (n = 11) defined a distinct PAX5 subtype. DUX4-r subtype (n = 80) was defined by DUX4 rearrangements and/or ERG deletions. These patients had a low relapse rate and excellent survival. ETV6::RUNX1-like subtype (n = 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n = 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Ensaios Clínicos como Assunto , Marcadores Genéticos , Genômica , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , CriançaRESUMO
Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.
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Células-Tronco Pluripotentes Induzidas , Leucemia , Neoplasias , Animais , Medula Óssea/patologia , Dexametasona/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia/patologia , Camundongos , Neoplasias/patologia , Microambiente TumoralRESUMO
The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.
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Proteína de Leucina Linfoide-Mieloide , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Epigênese Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Genes Reguladores , CromatinaRESUMO
We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.
Assuntos
Neoplasias Hematológicas , Linfoma , Humanos , Linfoma/patologia , Organização Mundial da SaúdeRESUMO
PURPOSE: The aim of the randomized trial, UKALL2003, was to adjust treatment intensity on the basis of minimal residual disease (MRD) stratification for children and young adults with acute lymphoblastic leukemia. We analyzed the 10-year randomized outcomes and the time for patients to be considered cured (ClinicalTrials.gov identifier: NCT00222612). METHODS: A total of 3,113 patients were analyzed including 1,054 patients who underwent random assignment (521 MRD low-risk and 533 MRD high-risk patients). Time to cure was defined as the point at which the chance of relapse was < 1%. The median follow-up time was 10.98 (interquartile range, 9.19-13.02) years, and survival rates are quoted at 10 years. RESULTS: In the low-risk group, the event-free survival was 91.7% (95% CI, 87.4 to 94.6) with one course of delayed intensification versus 93.7% (95% CI, 89.9 to 96.1) with two delayed intensifications (adjusted hazard ratio, 0.73; 95% CI, 0.38 to 1.40; P = .3). In the high-risk group, the event-free survival was 82.1% (95% CI, 76.9 to 86.2) with standard therapy versus 87.1% (95% CI, 82.4 to 90.6) with augmented therapy (adjusted hazard ratio, 0.68; 95% CI, 0.44 to 1.06; P = .09). Cytogenetic high-risk patients treated on augmented therapy had a lower relapse risk (22.1%; 95% CI, 15.1 to 31.6) versus standard therapy (52.4%; 95% CI, 28.9 to 80.1; P = .016). The initial risk of relapse differed significantly by sex, age, MRD, and genetics, but the risk of relapse for all subgroups quickly coalesced at around 6 years after diagnosis. CONCLUSION: Long-term outcomes of the UKALL2003 trial confirm that low-risk patients can safely de-escalate therapy, while intensified therapy benefits patients with high-risk cytogenetics. Regardless of prognosis, the time to cure is similar across risk groups. This will facilitate communication to patients and families who pose the question "When am I/is my child cured?"