Sensitivity to L-asparaginase is not associated with expression levels of asparagine synthetase in t(12;21)+ pediatric ALL

Stams, W A G; Boer, Monique L. den; Beverloo, H. Berna; Meijerink, Jules P.P.; Stigter, R. H.; Wering, E. R. Van; Janka‐Schaub, Gritta; Slater, Rosalyn; Pieters, Rob

doi:10.1182/blood-2002-08-2446

Cited by 136 publications

(111 citation statements)

References 32 publications

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“…We found significantly higher AsnS N level in the presentation samples of TEL/AML1[ þ ] ALL patients compared to TEL/AML1 [À] patients. This observation is in a perfect confluence with the data presented by Stams et al, 24 although it contradicts what always has been thought, namely that a high level of AsnS expression is related to L-asparaginase resistance and not sensitivity. Conversely, both studies indicate an existing relationship between sensitivity to L-asparaginase and AsnS expression in untreated cells.…”

Section: Discussioncontrasting

confidence: 53%

Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells

et al. 2004

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Section: Discussioncontrasting

confidence: 53%

Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells

et al. 2004

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“…19,20 The mechanism for the increased sensitivity to asparaginase among TEL/AML1-positive lymphoblasts is unclear and does not appear to be related to the levels of asparagine synthetase, either at baseline or after exposure to the drug. 21 The favorable outcome of TEL/AML1-positive patients on DFCI ALL Consortium protocols may be the result of protracted use of asparaginase during intensification and frequent pulses of vincristine and steroids during the 2 years of treatment. The exposure to weekly L-asparaginase during the intensification phase in DFCI clinical trials has been closely linked with EFS.…”

Section: Analysis Of Tel/aml1-positive Patients On Dfci 95-01 4511mentioning

confidence: 99%

Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01

Loh

Goldwasser

Silverman

et al. 2006

Blood

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In a retrospective analysis, we previously reported that children whose leukemia cells harbored the TEL/AML1 gene rearrangement have excellent outcomes. From 1996 to 2000, we conducted a prospective study to determine the incidence and outcomes of children with TEL/AML1-positive acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were treated on DFCI ALL Consortium Protocol 95-01. Patients were risk stratified primarily by current National Cancer Institute (NCI)-Rome risk criteria. With a median follow-up of 5.2 years, the 5-year event-free survival for TEL/AML1-positive patients was 89% compared with 80% for TEL/AML1-negative B-precursor patients (P ‫؍‬ .05). The 5-year overall survival rate was 97% among TEL/AML-positive patients compared with 89% among TEL/ AML1-negative patients (P ‫؍‬ .03). However, in a multivariable analysis, risk group (age and leukocyte count at diagnosis) and asparaginase treatment group, but not TEL/AML1 status, were found to be independent predictors of outcome. We conclude that TEL/AML1-positive patients have excellent outcomes, confirming our previous findings. However, factors such as age at diagnosis and presenting leukocyte count should be taken into consideration when treating this group of patients. (Blood. 2006;107:4508-4513)

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“…A possible explanation for this finding can be ascribed to the fact that t(12;21)-positive ALL cells are in vitro more sensitive to L-Asparaginase (L-Asp) than t(12;21) negative ALL cells. 9,10 However, within the t(12;21)-positive ALL group, large interindividual differences in cellular in vitro sensitivity to L-Asp were found. The clinical heterogeneity in response to therapy as well as the large heterogeneity in in vitro sensitivity to L-Asp suggests that additional genetic changes might be important for the differences in drug sensitivity and clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome

et al. 2006

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Clinical heterogeneity within t(12;21) or TEL/AML1-positive ALL (25% of childhood common/preB ALL) indicates that additional genetic changes might contribute to outcome. We studied the relation between additional genetic changes in TEL(ETV6) and AML1(RUNX1) (FISH), drug sensitivity (MTT assay) and clinical outcome in 143 DCOG and COALL-treated t(12;21)-positive ALL patients. Additional genetic changes in TEL and AML1 were present in 83% of the patients, and consisted of (partial) deletion of the second TEL gene (70%), an extra AML1 gene (23%) or an extra der(21)t(12;21) (10%). More than one additional change was observed in 20%. Disease-free survival (pDFS) of DCOG patients without additional genetic changes (4 years pDFS7s.e. 53717%) and of those with an extra der(21)t(12;21) (60722%) is poorer than that of compared to patients with other additional genetic changes in TEL or AML1 (7976%; P-trend ¼ 0.02). This was mainly due to the occurrence of early relapses within 2.5 years after the first diagnosis. Similar observations were found in the COALL cohort, albeit not significant owing to limited follow-up. Multivariate analysis including age, WBC and genetic abnormalities in TEL and/or AML1 showed that especially, in vitro resistance to prednisolone (hazard ratio 5.78, 95% CI 1.45-23.0; P ¼ 0.01) is an independent prognostic factor in DCOG-and COALL-treated t(12;21)-positive ALL.

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Sensitivity to L-asparaginase is not associated with expression levels of asparagine synthetase in t(12;21)+ pediatric ALL

Cited by 136 publications

References 32 publications

Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells

Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells

Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01

Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome

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