Clinical relevance of in vitro drug resistance testing in childhood acute lymphoblastic leukemia: The state of the art

Pieters, Rob; Kaspers, Gertjan J. L.; Klumper, E.; Veerman, A. J. P.

doi:10.1002/mpo.2950220502

Cited by 33 publications

(14 citation statements)

References 33 publications

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“…This breakthrough idea made subsequent gains possible. Clinical and laboratory observations linking treatment outcome to glucocorticoid steroid sensitivity 75,76 and our demonstration of the superiority of dexamethasone over prednisone 26 may provide additional opportunities. Further opportunities may derive from our observation that patients with a suboptimal response may be rescued with changes in therapy 6 weeks later.…”

Section: Discussionmentioning

confidence: 99%

Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983–1995

et al. 2000

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Since 1968, the Children's Cancer Group (CCG) has treated more than 16 000 children with acute lymphoblastic leukemia (ALL). Herein, we report improvements obtained in CCG trials during two successive series of studies (1983-1988 and 1989-1995). Overall, 10-year EFS was 62% ± 10% for the 1983-1988 series and 72% ± 1% for the 1988-1995 series (P Ͻ 0.0001). Five-year cumulative rates of isolated CNS relapses were 5.9% and 4.4%. Therapy based on the Berlin-Frankfurt-Mü nster 76/79 study improved outcomes for intermediate and higher risk patients in the first series. For intermediate risk patients, delayed intensification (DI) was most crucial for improved outcome and cranial irradiation was safely replaced with maintenance intrathecal methotrexate, providing patients received intensified systemic therapy. In the second series, randomized trials showed better outcome with one vs no DI phase for lower risk patients, with two vs one DI phase for intermediate risk patients, and with the CCG 'augmented regimen' for higher risk patients with a slow day 7 marrow response. Cranial irradiation was safely replaced with additional intrathecal methotrexate for higher risk patients with a rapid day 7 marrow response. In a subsequent study, substitution of dexamethasone in place of prednisone in induction and maintenance improved outcome for standard risk patients. All patients received dexamethasone in DI. These successful treatment strategies form the basis for our current ALL trials. Leukemia (2000) 14, 2223-2233.

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Section: Discussionmentioning

confidence: 99%

Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983–1995

et al. 2000

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“…These conclusions fully warrant investigations of new biological prognostic markers ( Campana & Pui, 1995; Hecker et al , 1994 ; Kaspers et al , 1995 ; Pieters et al , 1994 ; Privitera et al , 1992 ; Steinherz et al , 1996 ; Uckun et al , 1995 ; McLean et al , 1996 ), whose value should be assessed not only by univariate analysis, but also taking into account the four main prognostic variables (WBC, age, sex and cytogenetics).…”

Section: Discussionmentioning

confidence: 94%

Critical study of prognostic factors in childhood acute lymphoblastic leukaemia: differences in outcome are poorly explained by the most significant prognostic variables

et al. 1998

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Summary.We determined the proportion of survival variability explained by the usual prognostic factors in childhood acute lymphoblastic leukaemia (ALL) during a prognostic study of 1552 patients enrolled in three consecutive Fralle group protocols (Fralle 83, Fralle 87 and Fralle 89). The event-free survival rates at 5 years were 54·8% (SD 1·9), 43·1% (SD 2·7) and 55·6% (SD 2·2), respectively. In the univariate analysis the following variables were predictive of poor outcome: male gender, elevated leucocytosis (> 50 × 10 9 /l), circulating blastosis, haemoglobin >12 g/dl, platelet count <100 × 10 9 /l, age under 1 year or over 9 years, enlarged mediastinum, nodes, spleen and liver, T phenotype, absence of CD10 þ cells; testicular and meningeal involvement, poor response to induction therapy (CCSG M3), and LDH >400 U/l. Among the cytogenetic features, hyperdiploidy had a protective effect, whereas hypodiploidy, translocation and other structural abnormalities had a negative influence, particularly in cases of t(9;22) or t(4;11). Multivariate analysis summarized the prognostic information in terms of four variables: age, gender, leucocytosis and cytogenetic features. Missing data had little influence on the results. However, despite their significance in the multivariate analysis, these four variables each had very low predictive power (1·1% for gender, 2·0% for age, 3·5% for leucocytosis, and 1·6% for cytogenetic features). Thus, the most significant prognostic factors in childhood ALL each explain no more than 4% of the variability in prognosis. This may explain the disappointing practical value of these factors and underlines the need for prognostic tools in childhood ALL.

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“…Although the leukaemic cell sample that was most resistant to 2‐CdA and araC was from a patient with T‐cell ALL, an immunophenotype often associated with an unfavourable outcome (Mahony, 1994), two T‐cell ALL samples in this study were also among those that were most sensitive to the nucleosides. Pieters et al (1994) have shown a wide variation in sensitivity to a number of antitumour agents in leukaemic blasts from patients with ALL. Campana et al (1993) also observed considerable interpatient variation in lymphoblast sensitivity to vincristine, 6‐thioguanine, araC and teniposide, using a novel stroma‐supported immunocytometric assay (SIA) to evaluate blasts from patients with ALL.…”

Section: Discussionmentioning

confidence: 99%

“…AraC was chosen for this comparison because of its current use in remission induction and consolidation protocols in ALL therapy; araC has also been used in combinations prophylactically, to reduce the possibility of central nervous system (CNS) involvement in childhood ALL (Morra et al , 1993). Pieters and colleagues (Pieters et al , 1994; Klumper et al , 1995) showed that the MTT chemosensitivity assay may be a good predictor of clinical outcome in acute leukaemia of childhood, and a retrospective study in adult AML also demonstrated the prognostic value of the MTT assay (Sargent & Taylor, 1989).…”

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confidence: 99%

Cytotoxicity of 2‐chlorodeoxyadenosine and arabinosylcytosine in leukaemic lymphoblasts from paediatric patients: significance of cellular nucleoside transporter content

Wright¹,

Paterson²,

Sowa³

et al. 2002

Br J Haematol

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Summary. 2‐chlorodeoxyadenosine (2‐CdA) and arabinosylcytosine (araC) are nucleoside drugs that are used to treat various leukaemias, although 2‐CdA has not been tested extensively in children with acute lymphoblastic leukaemia (ALL). Nucleoside cytotoxicity depends on the conversion of these agents to 5′‐phosphate derivatives, following drug entry into cells via nucleoside transport (NT) processes. This study compared es nucleoside transporter content, determined using a flow cytometric assay with SAENTA [5′‐S‐(2‐aminoethyl)‐N6‐(4‐nitrobenzyl)‐5′‐thioadenosine] fluorescein, and cytotoxicities of 2‐CdA and araC in fresh lymphoblasts from previously untreated paediatric ALL patients and the human T‐lymphoblast cell line, CCRF‐CEM. Lymphoblast samples from individual patients ranged widely in sensitivity to both 2‐CdA (IC50, 6 nmol/l to > 5 μmol/l; mean = 418 nmol/l; n = 8) and araC (IC50, 59 nmol/l to > 5 μmol/l; mean = 1050 nmol/l; n = 7), although IC50 values for the two drugs were correlated (r = 0·78, P = 0·032, n = 7). Cellular es nucleoside transporter content varied more than 35‐fold among samples from 10 patients. The correlation between es nucleoside transporter content and drug sensitivity was statistically significant for araC (r = −0·93, P = 0·023, n = 5), but not for 2‐CdA (r = −0·57, P = 0·23, n = 6). Exposure of CCRF‐CEM cells to araC resulted in a substantial araC concentration‐dependent increase in the relative survival of es transporter‐deficient cells, whereas the increase was slight following exposure to 2‐CdA. We conclude that, in ALL lymphoblasts, es nucleoside transporter content is a determinant of araC sensitivity and that a deficiency in NT may impart resistance to araC.

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Clinical relevance of in vitro drug resistance testing in childhood acute lymphoblastic leukemia: The state of the art

Cited by 33 publications

References 33 publications

Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983–1995

Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983–1995

Critical study of prognostic factors in childhood acute lymphoblastic leukaemia: differences in outcome are poorly explained by the most significant prognostic variables

Cytotoxicity of 2‐chlorodeoxyadenosine and arabinosylcytosine in leukaemic lymphoblasts from paediatric patients: significance of cellular nucleoside transporter content

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