Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X

Chessells, J M; Harrison, Gill; Lilleyman, J S; Bailey, Chris; Richards, Sue

doi:10.1046/j.1365-2141.1997.3113127.x

Cited by 49 publications

(32 citation statements)

References 17 publications

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“…A number of basic aspects has been considered including the use during induction of 40 mg/m 2 /day of prednisolone rather than 60 mg/m 2 ; the lack of use of dexamethasone; the dropping of daunorubicin from induction, the potentially sub-optimal route of administration (s.c.), dosage, and scheduling of asparaginase, the presence of a gap to allow recovery of normal marrow following early intensification between weeks 5 and 8 (and again between weeks 20 and 23), as a result of the form of intensification used in UKALLX and XI, and a possible lack of intensive and strict compliance with delivery of continuation therapy to the patient. Chessells et al 23 demonstrated that children in UKALLX with one or more episodes of neutropenia with a count of Ͻ0.5 × 10 9 /l had an improved prognosis compared with those who never became neutropenic. Whether neutropenia or lymphopenia induced by continuation therapy is the best guide of efficacy remains unclear, but it is certain that to be successful certainly for most childhood ALL, therapy must be of 2-3 years duration and induce significant immunosuppression.…”

Section: Figurementioning

confidence: 99%

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980–1997

Eden

Harrison²,

Richards³

et al. 2000

Leukemia

115

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Results of three consecutive completed UK trials (1980)(1981)(1982)(1983)(1984)(1985)(1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (Ͻ1 year Ͼ10 years) sex (male) and white count Ͼ50 × 10 9 /l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and highrisk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics. Leukemia (2000) 14, 2307-2320.

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Section: Figurementioning

confidence: 99%

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980–1997

Eden

Harrison²,

Richards³

et al. 2000

Leukemia

115

View full text Add to dashboard Cite

show abstract

“…[4][5][6][7] This variance is only partially explained by patient factors including comorbidity, age and individual chemotherapeutical pharmacokinetics and pharmacodynamics. 8 Genetic variance may also contribute to the risk of developing neutropenia during chemotherapy, but to date this possibility has not been investigated. A candidate gene that might be associated with the risk of developing chemotherapy-induced neutropenia is Toll-like receptor 4 (TLR4), as TLR4 has been shown to have a role in inhibition of neutrophil apoptosis, and extension of the functional lifespan of neutrophils during stimulation with lipopolysaccharide.…”

Section: Introductionmentioning

confidence: 99%

Association of polymorphisms in the TLR4 gene with the risk of developing neutropenia in children with leukemia

et al. 2011

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Infections are a major cause of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). Susceptibility to infections increases as the neutrophil count decreases. Despite identical treatment patients vary considerably in the number of neutropenic episodes. Toll-like receptor 4 (TLR4) has been shown to have a role in inhibiting apoptosis of neutrophils. Therefore, we hypothesized that polymorphisms in the TLR4 gene may influence the number of chemotherapyinduced neutropenic episodes. Eight single-nucleotide polymorphisms (SNPs) of the TLR4 gene were determined in 194 children aged 0-17 years, who were diagnosed with ALL. We compared the genotype distributions of the SNPs with the frequency of neutropenic episodes during treatment with chemotherapeutic regimens. The number of neutropenic episodes varied from 0 to 17, with a median of four neutropenic episodes. Four SNPs in the TLR4 gene (rs10759931, rs11536889, rs1927911 and rs6478317) were associated with an increased risk of developing chemotherapy-induced neutropenia, each sustaining correction for multiple testing. Further studies are required to elucidate whether pediatric patients with ALL with the particular SNPs in the TLR4 gene also experience more infections and would benefit from prophylactic antibiotic treatment, by a reduction of morbidity and mortality due to infections.

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“…In the past 2 decades, the cure rate for ALL has dramatically increased, 1 and much of this success can be attributed to improved stratification of tumors paired with finely tuned treatment protocols. [1][2][3] Further improvements in the cure of this disease, however, are hampered by a lack of understanding of molecular variability among tumors and targets for the further individualization of treatment. Treatments directed toward specific biologic pathways involved in leukemia pathology not only may improve outcome for some patients but may also reduce the toxicity and nonspecificity associated with conventional chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-κB survival pathway signaling

Weston

Austen

Wei

et al. 2004

Blood

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To investigate possible causes of the variable response to treatment in pediatric B-precursor acute lymphoblastic leukemia (ALL) and to establish potential novel therapeutic targets, we used ionizing radiation (IR) exposure as a model of DNA damage formation to identify tumors with resistance to p53-dependent apoptosis. Twenty-one of 40 ALL tumors responded normally to IR, exhibiting accumulation of p53 and p21 proteins and cleavage of caspases 3, 7, and 9 and of PARP1. Nineteen tumors exhibited apoptotic resistance and lacked PARP1 and caspase cleavage; although 15 of these tumors had normal accumulation of p53 and p21 proteins, examples exhibited abnormal expression of TRAF5, TRAF6, and cIAP1 after IR, suggesting increased NF-B prosurvival signaling as the mechanism of apoptotic resistance. The presence of a hyperactive PARP1 mutation in one tumor was consistent with such increased NF-B activity. PARP1 inhibition restored p53-dependent apoptosis after IR in these leukemias by reducing NF-B DNA binding and transcriptional activity. In the remaining 4 ALL tumors, apoptotic resistance was associated with a TP53 mutation or with defective activation of p53. We conclude that increased NF-B prosurvival signaling is a frequent mechanism by which B-precursor ALL tumors develop apoptotic resistance to IR and that PARP1 inhibition may improve the DNA damage response of these leuke-

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Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X

Cited by 49 publications

References 17 publications

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980–1997

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980–1997

Association of polymorphisms in the TLR4 gene with the risk of developing neutropenia in children with leukemia

Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-κB survival pathway signaling

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