Relapsed acute lymphoblastic leukemia (ALL) has remained challenging to treat in children, with survival rates lagging well behind those observed at initial diagnosis. Although there have been some ...improvements in outcomes over the past few decades, only ∼50% of children with first relapse of ALL survive long term, and outcomes are much worse with second or later relapses. Recurrences that occur within 3 years of diagnosis and any T-ALL relapses are particularly difficult to salvage. Until recently, treatment options were limited to intensive cytotoxic chemotherapy with or without site-directed radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). In the past decade, several promising immunotherapeutics have been developed, changing the treatment landscape for children with relapsed ALL. Current research in this field is focusing on how to best incorporate immunotherapeutics into salvage regimens and investigate long-term survival and side effects, and when these might replace HSCT. As more knowledge is gained about the biology of relapse through comprehensive genomic profiling, incorporation of molecularly targeted therapies is another area of active investigation. These advances in treatment offer real promise for less toxic and more effective therapy for children with relapsed ALL, and we present several cases highlighting contemporary treatment decision-making.
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Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and remains a leading cause of cancer death in the young. In the last decade, microarray and sequencing analysis of large ALL ...cohorts has revolutionized our understanding of the genetic basis of this disease. These studies have identified new ALL subtypes, each characterized by constellations of structural and sequence alterations that perturb key cellular pathways, including lymphoid development, cell-cycle regulation, and tumor suppression; cytokine receptor, kinase, and Ras signaling; and chromatin modifications. Several of these pathways, particularly kinase-activating lesions and epigenetic alterations, are logical targets for new precision medicine therapies. Genomic profiling has also identified important interactions between inherited genetic variants that influence the risk of leukemia development and the somatic genetic alterations that are required to establish the leukemic clone. Moreover, sequential sequencing studies at diagnosis, remission, and relapse have provided important insights into the relationship among genetic variants, clonal heterogeneity, and the risk of relapse. Ongoing studies are extending our understanding of coding and noncoding genetic alterations in B-progenitor and T-lineage ALL and using these insights to inform the development of faithful experimental models to test the efficacy of new treatment approaches.
Acute Lymphoblastic Leukemia in Children Hunger, Stephen P; Mullighan, Charles G
The New England journal of medicine,
10/2015, Letnik:
373, Številka:
16
Journal Article
Recenzirano
Odprti dostop
The most common cancer in childhood is now curable in 90% of patients. Current efforts are focused on devising molecular-based therapy for the subsets of acute lymphoblastic leukemia that are most ...resistant to current therapy.
Approximately 6000 cases of acute lymphoblastic leukemia (ALL) are diagnosed in the United States annually; half the cases occur in children and teenagers. In the United States, ALL is the most common cancer among children and the most frequent cause of death from cancer before 20 years of age.
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Presenting symptoms of ALL include bruising or bleeding due to thrombocytopenia, pallor and fatigue from anemia, and infection caused by neutropenia. Leukemic infiltration of the liver, spleen, lymph nodes, and mediastinum is common at diagnosis. Extramedullary leukemia in the central nervous system (CNS) or testicles may require specific modifications in . . .
Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), also referred to as BCR-ABL1–like ALL, is a high-risk subset with a gene expression profile that shares significant overlap with ...that of Ph-positive (Ph+) ALL and is suggestive of activated kinase signaling. Although Ph+ ALL is defined by BCR-ABL1 fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1 and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling. Additional genomic alterations in Ph-like ALL activate other kinases, including BLNK, DGKH, FGFR1, IL2RB, LYN, NTRK3, PDGFRA, PTK2B, TYK2, and the RAS signaling pathway. Recent studies have helped to define the genomic landscape of Ph-like ALL and how it varies across the age spectrum, associated clinical features and outcomes, and genetic risk factors. Preclinical studies and anecdotal reports show that targeted inhibitors of relevant signaling pathways are active in specific Ph-like ALL subsets, and precision medicine trials have been initiated for this high-risk ALL subset.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and constitutes approximately 25 % of cancer diagnoses among children under the age of 15 (Howlader et al., 2013) 1. Overall, ...about half of ALL cases occur in children and adolescents and it is the most common acute leukemia until the early 20s, after which acute myeloid leukemia predominates. ALL is the most successful treatment paradigm in pediatric cancer medicine as illustrated by the significant survival rate improvement from ∼10 % in the 1960s to >90 % today (Hunger et al., 2015) 2. This remarkable success stems from the progressive improvement in the efficacy of risk-adapted multiagent chemotherapy regimens with effective central nervous system (CNS) prophylaxis via well-designed randomized clinical trials conducted by international collaborative consortia, enhanced supportive care measures to decrease treatment-related mortality, in-depth understanding of the genetic basis of ALL, and refinement in treatment response assessment through serial minimal residual disease (MRD) monitoring (Pui et al., 2015) 3. These advances collectively contribute to a decline in mortality rate of 23.5% for children diagnosed with ALL in the US from 2000 to 2010 (Smith et al., 2014) 4. Nevertheless, outcomes of older adolescents and young adults with ALL still lag behind those of their younger counterparts despite pediatric-inspired chemotherapy regimens (Stock et al., 2019) 5, relapsed/refractory childhood ALL is associated with poor outcomes (Rheingold et al., 2019) 6, and ALL still represents the leading causes of cancer-related deaths (Smith et al., 2010) 7. The last two decades have witnessed important genomic discoveries in ALL, enabled by advances in next-generation sequencing (NGS) technologies to characterize the landscape of germline and somatic alterations in ALL, some of which have important diagnostic, prognostic and therapeutic implications. Comprehensive genomic analysis of large cohorts of children and adults with ALL has revised the taxonomy of ALL in the molecular era by identifying novel clonal, subtype-defined chromosomal alterations associated with distinct gene expression signatures, thus reducing the proportion of patients previously labelled as “Others” from 25 % to approximately 5 % (Mullighan et al., 2019) 8. Insights into the genomics of ALL further provide compelling biologic rationale to expand the scope of precision medicine therapies for childhood ALL. Herein, we summarize a decade of genomic discoveries to highlight three different facets of precision medicine in pediatric ALL: 1) inherited predispositions of ALL; 2) relevant molecularly targeted therapies in genomically-defined ALL subtypes; and 3) treatment response monitoring via pharmacogenomics and novel MRD biomarkers.
In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell's transcriptional apparatus and are ...defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase–binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells.
Over the past several decades, survival of children with ALL has improved dramatically with treatment regimens refined through cooperative group trials. Despite aggressive treatment and iterative ...therapy changes for adolescents and young adults (AYAs), improvement has not been as promising. Comparisons between pediatric and adult clinical trials have consistently demonstrated superior outcomes for AYAs treated on pediatric ALL protocols, leading to the implementation of pediatric-inspired ALL protocols by several groups worldwide and/or expansion of the age limit of pediatric trials to include the full spectrum of the AYA population. Despite these efforts, AYAs in both pediatric and adult settings continue to have inferior survival compared with younger children with ALL. Real-world data suggest that uptake of pediatric-style treatment is variable, and even with identical pediatric-style treatment, AYAs still fare worse than younger children. As we enter an era of immunotherapy and precision medicine for newly diagnosed ALL, now is an opportune time to consider how best to approach future therapy for AYA patients. Comparisons of pediatric and adult treatment approaches and subanalyses of AYA patients will help guide harmonization of treatment. The focus of the next stage of ALL therapy for AYA should not only involve novel treatment approaches but also standardization and optimization of supportive care measures, psychosocial support, adherence interventions, oncofertility treatment, and survivorship care. All these efforts should simultaneously work to address health disparities to ensure that a future of improved outcomes is experienced equitably for all AYA patients.
A majority of children and young adults with acute lymphoblastic leukemia (ALL) are cured with contemporary multiagent chemotherapy regimens. The high rate of survival is largely the result of 70 ...years of randomized clinical trials performed by international cooperative groups. Contemporary ALL therapy usually consists of cycles of multiagent chemotherapy administered over 2 to 3 years that includes central nervous system (CNS) prophylaxis, primarily consisting of CNS-penetrating systemic agents and intrathecal therapy. Although the treatment backbones vary among cooperative groups, the same agents are used, and the outcomes are comparable. ALL therapy typically begins with 5 to 9 months of more-intensive chemotherapy followed by a prolonged low-intensity maintenance phase. Historically, a few cooperative groups treated boys with 1 more year of maintenance therapy than girls; however, most groups treated boys and girls with equal therapy lengths. This practice arose because of inferior survival in boys with older less-intensive regimens. The extra year of therapy added significant burden to patients and families and involved short- and long-term risks that were potentially life threatening and debilitating. The Children's Oncology Group recently changed its approach as part of its current generation of trials in B-cell ALL and now treats boys and girls with the same duration of therapy. We discuss the rationale behind this change, review the data and differences in practice across cooperative groups, and provide our perspective regarding the length of maintenance therapy.
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To examine population-based improvements in survival and the impact of clinical covariates on outcome among children and adolescents with acute lymphoblastic leukemia (ALL) enrolled onto Children's ...Oncology Group (COG) clinical trials between 1990 and 2005.
In total, 21,626 persons age 0 to 22 years were enrolled onto COG ALL clinical trials from 1990 to 2005, representing 55.8% of ALL cases estimated to occur among US persons younger than age 20 years during this period. This period was divided into three eras (1990-1994, 1995-1999, and 2000-2005) that included similar patient numbers to examine changes in 5- and 10-year survival over time and the relationship of those changes in survival to clinical covariates, with additional analyses of cause of death.
Five-year survival rates increased from 83.7% in 1990-1994 to 90.4% in 2000-2005 (P < .001). Survival improved significantly in all subgroups (except for infants age ≤ 1 year), including males and females; those age 1 to 9 years, 10+ years, or 15+ years; in whites, blacks, and other races; in Hispanics, non-Hispanics, and patients of unknown ethnicity; in those with B-cell or T-cell immunophenotype; and in those with National Cancer Institute (NCI) standard- or high-risk clinical features. Survival rates for infants changed little, but death following relapse/disease progression decreased and death related to toxicity increased.
This study documents ongoing survival improvements for children and adolescents with ALL. Thirty-six percent of deaths occurred among children with NCI standard-risk features emphasizing that efforts to further improve survival must be directed at both high-risk subsets and at those children predicted to have an excellent chance for cure.
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