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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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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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As a group, acute leukaemias are the most common childhood malignancies, and continue to be an important cause of non-accident related childhood mortality. Fortunately, with modern chemotherapy the majority of children and young p...
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As a group, acute leukaemias are the most common childhood malignancies, and continue to be an important cause of non-accident related childhood mortality. Fortunately, with modern chemotherapy the majority of children and young people with leukaemia can be cured. However, this treatment comes with a significant burden for our young patients and their families. Here, we review the essential and differential diagnostics and the initial management of children with suspected leukaemia, as relevant for secondary paediatric care. We will give a short overview of current treatment protocols for childhood acute lymphoblastic and acute myeloid leukaemia. We will explain how stratification according to certain prognostic factors - most importantly response to therapy - guides treatment intensity. Using modern molecular techniques for minimal residual disease monitoring and molecular disease classification, it is increasingly possible to identify patients with a cure rate well above 90% in whom a reduction in treatment intensity may seem feasible. In addition, these techniques also allow the definition of poor-risk patients who may benefit from more intensive chemotherapy and bone-marrow transplantation. Finally, we discuss long-term follow-up of survivors of childhood leukaemia as a multidisciplinary paediatric team approach, as well as the challenges of transition into adult care.
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摘要 :
As a group, acute leukaemias are the most common childhood malignancies, and continue to be an important cause of non-accident related childhood mortality. Fortunately, with modern chemotherapy the majority of children and young p...
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As a group, acute leukaemias are the most common childhood malignancies, and continue to be an important cause of non-accident related childhood mortality. Fortunately, with modern chemotherapy the majority of children and young people with leukaemia can be cured. However, this treatment comes with a significant burden for our young patients and their families. Here, we review the essential and differential diagnostics and the initial management of children with suspected leukaemia, as relevant for secondary paediatric care. We will give a short overview of current treatment protocols for childhood acute lymphoblastic and acute myeloid leukaemia. We will explain how stratification according to certain prognostic factors - most importantly response to therapy - guides treatment intensity. Using modern molecular techniques for minimal residual disease monitoring and molecular disease classification, it is increasingly possible to identify patients with a cure rate well above 90% in whom a reduction in treatment intensity may seem feasible. In addition, these techniques also allow the definition of poor-risk patients who may benefit from more intensive chemotherapy and bone-marrow transplantation. Finally, we discuss long-term follow-up of survivors of childhood leukaemia as a multidisciplinary paediatric team approach, as well as the challenges of transition into adult care.
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Acute myeloid leukaemia (AML) is the most frequent acute leukaemia of adults. Mutations in the FMS-like tyrosine kinase-3 (FLT3) occur in 25-30% of AML patients, leading to internal tandem duplications in the juxtamembrane domain ...
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Acute myeloid leukaemia (AML) is the most frequent acute leukaemia of adults. Mutations in the FMS-like tyrosine kinase-3 (FLT3) occur in 25-30% of AML patients, leading to internal tandem duplications in the juxtamembrane domain of the receptor (FLT3-ITD) (Stirewalt & Radich, 2003). Since the FLT3-ITD mutation dictates a particularly poor clinical outcome (Stirewalt & Radich, 2003), several specific FLT3 inhibitors have been developed and evaluated in clinical trials, but their overall clinical efficacy in AML to date must be considered as minor. A new class of pharmacological compounds with the potential to target FLT3-ITD is represented by the second generation of protein kinase inhibitors. Therefore, we have compared the anti-leukaemic activity of the multi-kinase inhibitors Dasatinib and Sorafenib in a panel of myeloid leukaemic cells and primary AML blasts with different FLT3 (FLT3~(wild-type) and FLT3~(mutated)) status. Dasatinib (BMS-354825), which is currently used in clinical trials for the treatment of chronic myeloid leukaemia, was chosen based on recent data suggesting that it might also display potential cytotoxic activity in AML (Guerrouahen et al, 2010), while Sorafenib (Nexavar) was chosen based on preliminary clinical studies in which it was found particularly active in FLT3-ITD positive patients (Metzelder et al, 2009).
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In the 1980s and 1990s, successive large, national leukaemia trials helped to determine basic treatment strategies that are effective in most children with leukaemia. In acute lymphoblastic leukaemia, the UKALL studies addressed C...
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In the 1980s and 1990s, successive large, national leukaemia trials helped to determine basic treatment strategies that are effective in most children with leukaemia. In acute lymphoblastic leukaemia, the UKALL studies addressed CNS prophylaxis, duration of therapy, and intensive treatment blocks in improving event-free survival. Sufficient patients were recruited to permit direct comparison of individual drugs and deliver the answers within a timescale relevant to clinical practice. In acute myeloid leukaemia, collaboration with UK adult trials led to results in children that were not bettered anywhere in the world. The results of these trials were improved by advances in supportive care that were highly effective in reducing treatment-related mortality. The emphasis for paediatric leukaemia studies has changed over the last decade; more attention is being paid to patient subgroups that are performing badly, such as infants, Philadelphia chromosome-positive leukaemias, and relapsed and refractory acute myeloid leukaemia. Studies of these rare patients have been made possible by increased international collaboration that has allowed patients from many different countries to enter the same clinical trials. Interest in these difficult therapeutic areas has also been stimulated by the development of new agents and treatment strategies that have come directly from improved understanding of leukaemia biology.
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The prognosis of patients with relapsed and refractory acute leukaemia (RRAL) is very poor. Forty patients with RRAL were enroled [28 acute myeloid leukaemia (AML), 12 acute lymphoblastic leukaemia (ALL)] in this Phase 1 dose-esca...
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The prognosis of patients with relapsed and refractory acute leukaemia (RRAL) is very poor. Forty patients with RRAL were enroled [28 acute myeloid leukaemia (AML), 12 acute lymphoblastic leukaemia (ALL)] in this Phase 1 dose-escalation trial of daily-infused clofarabine (CLO) followed by cyclophosphamide (CY) for four consecutive days (CLO-CYx4). The median age was 48·5 years. The median number of prior regimens was 2 (range 1-5), and 6/40 patients (15%) had prior allogeneic haematopoietic stem cell transplant. 28/40 patients (70%) had adverse genetic features. 6/40 patients (15%) died within 60 d of induction (two infections, four progressive disease). The average time to neutrophil recovery (absolute neutrophil count ≥0·5 × 10 9/l was 34 d, (range, 17-78). The overall response rate (ORR) was 33% (13/40), with seven complete remissions (18%), four complete remissions with incomplete recovery of blood counts (10%), and two partial remissions (5%). ORR was 25% (7/28), and 50% (6/12), for AML and ALL respectively. Notably, the clinical responses were independent of dose level. 7/17 patients (41%) exhibited CLO-mediated enhancement of CY-induced DNA, which was associated with, but not necessary for, improved clinical outcomes. In summary, the CLO-CYx4 regimen was well tolerated and had activity in patients with RRAL, especially relapsed ALL. Therefore, CLO-CYx4 can be considered a salvage therapy for adults with RRALs, and warrants further investigations.
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As a group, the leukaemias represent the most common malignant conditions of childhood. The treatment of childhood leukaemia, and in particular the treatment of acute lymphoblastic leukaemia (ALL), has shown tremendous improvement...
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As a group, the leukaemias represent the most common malignant conditions of childhood. The treatment of childhood leukaemia, and in particular the treatment of acute lymphoblastic leukaemia (ALL), has shown tremendous improvement in outcome in the last 40 years. Much of the success is due to the improvements in leukaemia therapy demonstrated in improved disease-free survival and reduced relapse rates in clinical trials but improvements in supportive care over the years have also had a very significant contribution. Over the last 30 years we have also seen reduced treatment related mortality due to better management of complications and better detection and treatment of infections. The emphasis of treatment as well as being cure is now focussing on targeting therapy to reduce the treatment burden in good risk disease and identify and intensify treatment for those with poor risk disease. The development of molecularly targeted therapies has changed the therapeutic landscape and this last decade has seen many improvements in outcome associated with these new agents. This review will give a brief overview of current treatment protocols used in childhood leukaemia, focussing specifically on the latest improvements and strategies in treating these conditions.
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