Age-related differences in leukemia biology and prognosis: the paradigm of MLL-AF4-positive acute lymphoblastic leukemia

Ch, Pui; Campana, Dario

doi:10.1038/sj.leu.2404598

Cited by 27 publications

(19 citation statements)

References 19 publications

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“…In addition, the type of patients treated in the ALL-4 trial differed greatly from that in the pediatric trials with respect to age and to the percentage of high-risk patients. The difference in efficacy of dexamethasone in children and adult ALL could also be related to a different biology of the disease in children and adults, 21 and the different intensity of treatment protocols used. 22 More aggressive chemotherapy, together with a better prognosis of ALL in children, 23,24 could be of importance in predicting better response to steroids.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group

Labar

Suciu²,

Willemze³

et al. 2010

Haematologica

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BackgroundCorticosteroids are a standard component of the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Our aim was to determine whether dexamethasone results in a better outcome than prednisolone. Design and MethodsAdult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma were randomized to receive, as part of their induction therapy on days 1-8 and 15-22, either dexamethasone 8 mg/m 2 or prednisolone 60 mg/m 2 . Those who reached complete remission were given two courses of consolidation therapy with high-dose cytarabine and mitoxantrone and methotrexate and asparaginase. Subsequently patients younger than 50 years, with a suitable donor, were to undergo allogeneic stem cell transplantation, whereas the others were planned to receive either an autologous stem cell transplant or high-dose maintenance chemotherapy with prophylactic central nervous system irradiation. Randomization was done with a minimization technique. The primary endpoint was event-free survival and the analyses was conducted on an intention-to-treat basis. ResultsBetween August 1995 and October 2003, 325 patients between 15 to 72 years of age were randomized to receive either dexamethasone (163 patients) or prednisolone (162 patients). After induction and the course of first consolidation therapy, 131 (80.4%) patients in the dexamethasone group and 124 (76.5%) in the prednisolone group achieved complete remission. No significant difference was observed between the two treatment groups with regards to 6-year event-free survival rates (±SE) which were 25.9% (3.6%) and 28.7% (3.5%) in the dexamethasone and prednisolone groups, respectively (P=0.82, hazard ratio 0.97; 95% confidence interval, 0.75-1.25). Disease-free survival after complete remission was also similar in the dexamethasone and prednisolone groups, the 6-year rates being 32.3% and 37.5%, respectively (hazard ratio 1.03; 95% confidence interval 0.76-1.40). The 6-year cumulative incidences of relapse were 49.8% and 53.5% (Gray's test: P=0.30) while the 6-year cumulative incidences of death were 18% and 9% (Gray's test: P=0.07). ConclusionsIn the ALL-4 trial in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma, treatment with dexamethasone did not show any advantage over treatment with prednisolone. (ClinicalTrials.gov Identifier: NCT00002700)

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Section: Discussionmentioning

confidence: 99%

Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group

Labar

Suciu²,

Willemze³

et al. 2010

Haematologica

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“…9,10 In ALL, t(4;11) is the most frequent translocation, whereas t(9;11)(p21;q23) is most commonly associated with AML and myelodysplastic syndrome (MDS)/secondary leukemia, respectively. In MLL-rearranged leukemia, translocation of MLL with a variety of translocation partner genes, such as AF4, AF9, and ENL, results in the loss of the catalytic SET domain.…”

Section: Introductionmentioning

confidence: 99%

Identification of CD34+ and CD34− leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia

Aoki

Watanabe

Saito

et al. 2015

Blood

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“…There are multifarious translocations found in leukaemias/lymphomas, typically transcription regulators (Rabbitts, 1991), but among the most frequent targets of translocations in human leukaemias is the mixed-lineage leukaemia (MLL) gene, located on chromosome 11, band q23 Daser and Rabbitts, 2004). MLL gene abnormalities are found in both childhood (B10% of all paediatric leukaemias) and adult leukaemias (B5% of acute leukaemias; Pui et al, 2002b;Pui and Campana, 2007). Around 5-10% of all MLL-associated leukaemias are cancer therapy related, arising, regardless of the primary cancer type, as a side effect of treatment with topoisomerase II targeting drugs or of other treatments including radiotherapy (Felix, 2001;Huret et al, 2001;Bloomfield et al, 2002;Pui et al, 2002a).…”

Section: Introductionmentioning

confidence: 99%

Leukaemia lineage specification caused by cell-specific Mll-Enl translocations

et al. 2007

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Chromosomal translocations involving the Mixed-Lineage Leukaemia (MLL) gene underlie many human leukaemias and MLL rearrangements are found in both acute myelogenous and acute lymphoblastic leukaemias. To assess the functionally relevant haematopoietic cell contexts for MLL fusions to be tumorigenic, we have generated different lines of mice in which de novo Mll-associated translocations occur. In these models, reciprocal chromosomal translocations occur by means of Cre-loxPmediated recombination (translocator mice) in different cells of the haematopoietic system (namely haematopoietic stem cells, semi-committed progenitors or committed T or B cells). Translocations between Mll and Enl cause myeloid neoplasias, initiating in stem cells or progenitors while no tumours arose when the translocation was restricted to the B-cell compartment. Despite the absence of tumorigenesis, Mll-Enl translocations did occur and Mll-Enl fusion mRNA was expressed in B-cell-restricted translocators. A permissive cellular environment is therefore required for oncogenicity of Mll-associated translocations since the occurrence of Mll-Enl does not promote unrestricted proliferation in all haematopoietic cellular contexts, consistent with a specific instructive role of the MLL-fusion proteins in leukaemogenesis.

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Age-related differences in leukemia biology and prognosis: the paradigm of MLL-AF4-positive acute lymphoblastic leukemia

Cited by 27 publications

References 19 publications

Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group

Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group

Identification of CD34+ and CD34− leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia

Leukaemia lineage specification caused by cell-specific Mll-Enl translocations

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