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Summary Acute lymphoblastic leukaemia (ALL) remains a leading cause of non‐traumatic death in children, and the majority of adults diagnosed will succumb to the disease. Recent advances in molecular biology and bioinformatics hav...
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Summary Acute lymphoblastic leukaemia (ALL) remains a leading cause of non‐traumatic death in children, and the majority of adults diagnosed will succumb to the disease. Recent advances in molecular biology and bioinformatics have enabled more detailed genomic analysis and a better understanding of the molecular biology of ALL. A number of recurrent genomic drivers have recently been described, which not only aid in diagnosis and prognostication, but also may offer opportunities for specific therapeutic targeting. The present review summarises B‐ALL genomic pathology at diagnosis, including lesions detectable using traditional cytogenetic methods as well as those detected only through advanced molecular techniques.
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SummaryTreatment of acute lymphoblastic leukaemia (ALL) in adults presents a formidable challenge. While overall results have improved over the past 3 decades, the long-term survival for patients aged less than 60 years is only in...
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SummaryTreatment of acute lymphoblastic leukaemia (ALL) in adults presents a formidable challenge. While overall results have improved over the past 3 decades, the long-term survival for patients aged less than 60 years is only in the range of 30–40% and is 10–15% if between 60 and 70 years and <5% for those over 70 years. The historic lack of clear-cut biological prognostic factors has led to over- or under-treatment of some patients. Response to initial therapy is an important prognosticator of outcome based on disease biology, as well as pharmacogenetics, which include the patient’s response to drugs given. The more widespread availability of allogeneic transplantation and reduced-intensity regimens for older patients have opened up this curative modality to a greater number of patients. Hopefully, those options, as well as novel cytogenetic and molecular markers, will enable a better selection of patients who undergo intensive therapies and finally break the 30–40% cure barrier for adults with ALL.
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Since July 2008, children and adults 1-45years, diagnosed with acute lymphoblastic leukaemia (ALL) in Denmark have been treated according to the common Nordic Society for Paediatric Haematology and Oncology ALL2008 protocol. To ex...
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Since July 2008, children and adults 1-45years, diagnosed with acute lymphoblastic leukaemia (ALL) in Denmark have been treated according to the common Nordic Society for Paediatric Haematology and Oncology ALL2008 protocol. To explore whether this strategy will improve survival compared with historical controls, we performed a retrospective national population-based study of adult ALL between 1998 and 2008. Patients were identified through the Danish Patobank and the Danish Cancer Registry; data was collected from patient files, and included 277 patients (median age, 47years, range 15-91years). The 5-year projected event-free survival (pEFS 5y) and overall survival (pOS 5y) for the whole cohort was 27·5% [95% confidence interval (CI) 22·4-33·6] and 34·1% (95% CI 28·7-40·4), respectively. No patient above 65years survived beyond 5years from diagnosis. For patients receiving curatively intended treatment, the pEFS 5y and pOS 5y were 36·6% and 44·1%, respectively, with a significantly higher pOS 5y for patients 15-35years compared with patients 36-65years (50·7% vs. 38·9%, P=0·006). Cox multiple regression analysis identified age (Hazard Ratio=1·7, P<0·006) as a statistically significant predictor of EFS. The cure rates, not least for the elderly, are unacceptably low, and call for new strategies in the treatment of adult ALL in all age groups.
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Background: Adopting paediatric-based protocol for adolescent acute lymphoblastic leukaemia (ALL) patients has been reported leading to superior prognosis, however, large group of study in Chinese population has not been documente...
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Background: Adopting paediatric-based protocol for adolescent acute lymphoblastic leukaemia (ALL) patients has been reported leading to superior prognosis, however, large group of study in Chinese population has not been documented. Purpose: To analyse the clinical characteristics, prognostic factors and outcome of adolescent patients with newly diagnosed ALL treated with paediatric-based protocol in a tertiary centre in China. Methods: We summarised our data of 121 adolescent ALL (aged 10-16 years) treated with Chinese Children's Leukemia Group (CCLG-ALL 2008) protocol from 2008 to 2013. Results: During 2008-2012, a total of 121 adolescent patients with ALL were enrolled in our study. The 5-year overall survival rate (OS) and event-free survival rate (EFS) was 82.64% and 80.78%, respectively. The 5-year EFS rate was 89.05% in intermediate risk patients, whereas, it was significantly lower for the high risk group (59.54%). High initial leukocyte count (WBC >50 x 109 /L), T-immunophenotype, BCR/ BAL and poor response to prednisone at Day 8 were associated with inferior prognosis. Conclusions: Adolescent ALL patients achieved satisfactory outcome using paediatric-based protocol of CCLG-ALL 2008.
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Very little is known about secondary acute lymphoblastic leukaemia (s-ALL). This retrospective analysis studied a cohort of s-ALL patients treated at a single centre between 1994 and 2013, while comparing therapy-associated ALL (t...
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Very little is known about secondary acute lymphoblastic leukaemia (s-ALL). This retrospective analysis studied a cohort of s-ALL patients treated at a single centre between 1994 and 2013, while comparing therapy-associated ALL (t-ALL) and antecedent malignancy ALL (am-ALL) patients. Thirty-two patients with s-ALL were identified. The overall incidence was 94% among ALL adults while T-cell s-ALL was rare (12% of s-ALLs). The median time interval between two malignant diagnoses was 53years (range: 01-28). In contrast to previous reports, most of the s-ALLs were CD10+ and without KMT2A (MLL) abnormalities. The overall survival (OS) rates of the entire cohort at 12 and 24months from ALL diagnosis was 49% and 25%, respectively. Most patients (n=23, 72%) received prior chemo-/radio-therapy for their first malignancy (t-ALL) and only 9 (28%) did not (am-ALL). No significant difference was found in the incidence of B-/T- lineage ALL, extramedullary disease, blood count, and the rate of Philadelphia-positive ALL, nor in the rates of complete remission (P=055) and OS (P=097). This similarity, together with high incidence of family malignancy in both groups, raise the possibility that s-ALL patients may have an inherent predisposition to malignancies and a history of previous therapy may be of lesser importance in the pathogenesis of s-ALL.
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Acute lymphoblastic leukaemia (ALL) occurs at all ages but is the most common cancer of childhood. The current treatment of paediatric ALL is highly successful with up to 90% children being cured. In contrast, survival rates for a...
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Acute lymphoblastic leukaemia (ALL) occurs at all ages but is the most common cancer of childhood. The current treatment of paediatric ALL is highly successful with up to 90% children being cured. In contrast, survival rates for adult ALL are significantly lower at around 40%. The discovery and characterisation of genetic abnormalities have increased our understanding of the biology of the disease and provided important prognostic and predictive markers which have improved patient outcome. Not only is the spectrum of these aberrations vast but, due to advances in technology, continually expanding. A wide range of chromosomal and genomic abnormalities have been reported as being associated with patient outcome but only a subset are currently used to risk stratify patients. This review highlights the main genetic abnormalities which are used to manage patients with B-cell precursor ALL and discusses the evidence which has been accumulated on several newly described genomic abnormalities.
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Minimal residual disease (MRD) has acquired a prominent role in the management of childhood and adult Acute Lymphoblastic Leukaemia (ALL) for its high prognostic value. Several studies have demonstrated the strong association betw...
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Minimal residual disease (MRD) has acquired a prominent role in the management of childhood and adult Acute Lymphoblastic Leukaemia (ALL) for its high prognostic value. Several studies have demonstrated the strong association between MRD and risk of relapse in childhood and adult ALL, irrespective of the methodology used. MRD is now used in clinical trials for risk assignment and to guide clinical management. Negativity at early time points may be considered to decrease treatment burden in patients who are likely to be cured with reduced intensity regimens. On the other hand, high MRD levels at late time points (end of consolidation) define ALL subgroups which deserve investigation of more effective treatments. The predictivity of MRD as a measurement of drug response in vivo opened new perspectives for its use in clinical decision, to deliver risk-based treatments, and possibly as a surrogate for efficacy in the evaluation of novel therapeutic approaches.
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Summary Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. He...
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Summary Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T‐lymphoblastic leukaemia ( AMTL ), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T‐lymphoid lineages, such as myeloperoxidase and CD 3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia ( AML ) harbour hallmarks of T cell development, such as T‐cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T‐ ALL ), including WT 1, PHF 6, RUNX 1 and BCL 11B . This proposed diagnostic entity overlaps with early T cell precursor ( ETP ) T‐ ALL and T cell/myeloid mixed phenotype acute leukaemias ( MPAL s), and also includes a subset of leukaemias currently classified as AML with features of T‐lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches.
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Summary We investigated 390 paediatric B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL) patients treated according to NOPHO ALL 2008, regarding copy number alterations (CNA) of eight loci associated with adverse prognosi...
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Summary We investigated 390 paediatric B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL) patients treated according to NOPHO ALL 2008, regarding copy number alterations (CNA) of eight loci associated with adverse prognosis, including IKZF1. The impact on outcome was investigated for each locus individually, combined as CNA profiles and together with cytogenetic information. The presence of IKZF1 deletion or a poor‐risk CNA profile was associated with poor outcome in the whole cohort. In the standard‐risk group, IKZF1‐deleted cases had an inferior probability of relapse‐free survival (pRFS) (p?≤?0.001) and overall survival (pOS) (p?≤?0.001). Additionally, among B‐other patients, IKZF1 deletion correlated with poor pRFS (60% vs. 90%) and pOS (65% vs. 89%). Both IKZF1 deletion and a poor‐risk CNA profile were independent factors for relapse and death in multivariable analyses adjusting for known risk factors including measurable residual disease. Our data indicate that BCP‐ALL patients with high‐risk CNA or IKZF1 deletion have worse prognosis despite otherwise low‐risk features. Conversely, patients with both a good CNA and cytogenetic profile had a superior relapse‐free (p?≤?0.001) and overall survival (p?≤?0.001) in the cohort, across all risk groups. Taken together, our findings highlight the potential of CNA assessment to refine stratification in ALL.
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Summary: Activating mutations of NOTCH1 are a common occurrence in T-cell acute lymphoblastic leukaemia (T-ALL), but its impact on T-ALL treatment is still controversial. In this study, the incidence, clinical features, and progno...
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Summary: Activating mutations of NOTCH1 are a common occurrence in T-cell acute lymphoblastic leukaemia (T-ALL), but its impact on T-ALL treatment is still controversial. In this study, the incidence, clinical features, and prognosis of 92 Chinese children with T-ALL treated using the Beijing Children's Hospital-2003 and Chinese Childhood Leukaemia Group-2008 protocols were analysed. NOTCH1 mutations were found in 42% of T-ALL patients and were not associated with clinical features, prednisone response, and minimal residual disease (MRD) at day 33 and 78. However, proline, glutamate, serine, threonine (PEST)/transactivation domain (TAD) mutations were associated with younger age (15/16 mutant vs. 48/76 wild-type, P = 0·018) and more central nervous system involvement (4/16 mutant vs. 3/76 wild-type, P = 0·016); while heterodimerization domain (HD) mutations were associated with KMT2A-MLLT1 (MLL-ENL; 4/30 mutant vs. 1/62 wild-type, P = 0·037). Furthermore, prognosis was better in patients with NOTCH1 mutations than in those with wild-type NOTCH1 (5-year event-free survival [EFS] 92·0 ± 4·5% vs. 64·0 ± 7·1%; P = 0·003). Long-term outcome was better in patients carrying HD mutations than in patients with wild-type HD (5-year EFS 89·7 ± 5·6% vs. 69·3 ± 6·2%; P = 0·034). NOTCH1 mutations and MRD at day 78 were independent prognostic factors. These findings indicate that NOTCH1 mutation predicts a favourable outcome in Chinese paediatric patients with T-ALL on the BCH-2003 and CCLG-2008 protocols, and may be considered a prognostic stratification factor.
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