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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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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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MicroRNAs (miRNAs) are key to the pathogenesis of human malignancies and increasingly recognized as potential biomarkers and therapeutic targets. Haematological malignancies, being the earliest human malignancies linked to aberran...
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MicroRNAs (miRNAs) are key to the pathogenesis of human malignancies and increasingly recognized as potential biomarkers and therapeutic targets. Haematological malignancies, being the earliest human malignancies linked to aberrant miRNA expression, have consistently underpinned our understanding of the role that miRNAs play in cancer development. Here, we review the expanding roles attributed to miRNAs in the pathogenesis of different types of myeloid malignancies and highlight key findings.
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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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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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Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young a...
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Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2·5 cycles (range 1-4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long-term CR.
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There are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender ...
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There are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi-institutional treatment studies from March 1984 to November 2008. Kaplan-Meier estimates were used to estimate event-time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two-sided tests. Non-APL female patients had a significantly better overall (OS) but not disease-free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.
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