The Seventh International Childhood Acute Lymphoblastic Leukemia Workshop Report: Palermo, Italy, January 29–30, 2005

Aricò, Maurizio; Baruchel, André; Bertrand, Yves; Biondi, Andrea; Conter,; Eden, Tim; Gadner, Helmut; Gaynon, Paul S.; Horibe, Keizo; Sp, Hunger; Janka-Schaub, G. E.; Masera, Giuseppe; Nachman, James B.; Pieters, Rob; Schrappe, Martin; Schmiegelow, Kjeld; Valsecchi, M. G.; Ch, Pui

doi:10.1038/sj.leu.2403783

Cited by 56 publications

(46 citation statements)

References 39 publications

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“…Maintenance therapy of childhood ALL and NHL is traditionally monitored and adjusted by the degree of myelosuppression [3] which reXects the assumption that eYcacy and toxicity are interrelated, and that myelosuppression is required for a successful anticancer eVect [2]. The treatment intensity obtained during maintenance therapy reXects the dose adjustment guidelines of the relevant protocol, individual drug disposition, and the compliance to the protocol by both the physician and the patient [20,21].…”

Section: Discussionmentioning

confidence: 99%

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DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

Hedeland

Hvidt

Nersting

et al. 2009

Cancer Chemother Pharmacol

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Purpose To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT). Methods We studied these metabolites in 229 blood samples from 18 children with ALL (N = 16) or NHL (N = 2) on 6MP/Methotrexate maintenance therapy. Results DNA-6TGN levels were signiWcantly correlated to E-6TGN (r p = 0.66, p = 0.003) with a trend to reach a plateau at high E-6TGN levels. To explore the relative DNA incorporation of 6TGN in relation to cytosol 6TGN levels, a DNA-6TGN index was calculated as DNA-6TGN/ E-6TGN. The DNA-6TGN index was inversely correlated to E-6TGN (r p = ¡0.58, p = 0.012), which implies that with increasing levels of E-6TGN relatively less 6TGN are incorporated into DNA. E-MeMP levels were correlated to the DNA-TGN index (r p = 0.60, p = 0.008), indicating that high levels of MeMP result in enhanced DNA-6TGN incorporation, possibly due to inhibition of purine de novo synthesis, mediated by some of the methylated 6MP metabolites. Conclusions DNA-6TGN may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than the previously used erythrocyte 6MP metabolites levels. Prospective clinical trials are needed to evaluate the usefulness of DNA-6TGN for individual dose adjustments.

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Section: Discussionmentioning

confidence: 99%

“…Due to large interindividual variations in the metabolism of these antimetabolites, the response to standard 6MP/ MTX doses varies signiWcantly, and 6MP/MTX maintenance therapy of childhood ALL and NHL is usually adjusted and targeted to speciWed degrees of bone marrow suppression [2,3]. 6MP is a pro-drug with no intrinsic anticancer activity.…”

mentioning

confidence: 99%

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

Hedeland

Hvidt

Nersting

et al. 2009

Cancer Chemother Pharmacol

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“…[1][2][3] Based on these results, MRD testing has become a part of the risk-group stratification procedure in several of the most progressive ALL treatment protocols. [4][5][6][7] In 2000, the International BerlinFrankfurt-Mü nster Study Group (I-BFM-SG) incorporated MRD testing into risk-group stratification in the AIEOP-BFM ALL 2000 trial. Almost all 'classical' risk features (except prednisone response, t(4;11), t(9;22) and induction failure) were omitted in this risk-group stratification.…”

Section: Introductionmentioning

confidence: 99%

Minimal residual disease (MRD) analysis in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: is it possible to avoid MRD testing?

et al. 2008

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The ALL IC-BFM 2002 protocol was created as an alternative to the MRD-based AIEOP-BFM ALL 2000 study, to integrate early response criteria into risk-group stratification in countries not performing routine PCR-based MRD testing. ALL IC stratification comprises the response to prednisone, bone marrow (BM) morphology at days 15 and 33, age, WBC and BCR/ABL or MLL/ AF4 presence. Here, we compared this stratification to the MRDbased criteria using MRD evaluation in 163 patients from four ALL IC member countries at days 8, 15 and 33 and week 12. MRD negativity at day 33 was associated with an age of 1-5 years, WBCo20 000 ll À1 , non-T immunophenotype, good prednisone response and non-M3 morphology at day 15. There were no significant associations with gender or hyperdiploidy in the study group, or with TEL/AML1 fusion within BCP-ALL. Patients with M1/2 BM at day 8 tended to be MRD negative at week 12. Patients stratified into the standard-risk group had a better response than intermediate-risk group patients. However, 34% of them were MRD positive at day 33 and/or week 12. Our findings revealed that morphology-based ALL IC risk-group stratification allows the identification of most MRD high-risk patients, but fails to discriminate the MRD low-risk group assigned to therapy reduction.

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“…Thus, although we have now learned that up to twothirds of patients may be cured with only 12 months of treatment, 39 since we are not yet able to recognize them upfront, the duration of treatment in most current trials is still at least 24 months. 40,41 The most popular combination is daily mercaptopurine and weekly methotrexate, orally. It is common experience that moderate cytopenia and rises in the concentrations of liver enzymes are promptly reversible, herald intracellular accumulation of active metabolites, and are associated with a lower risk of relapse.…”

Section: Continuation Therapymentioning

confidence: 99%

Treatment of pediatric acute lymphoblastic leukemia

Tucci¹

2008

Haematologica

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F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o nEditorialsthe cases, had an excellent outcome with over 90% surviving at 4 years.14 One main next step for evaluation is the achievement of morphological remission by the end of induction therapy, usually between day 28 and 42. It is well known that patients failing to have <5% blasts in the bone marrow, as assessed by morphology, have a dismal prognosis, although many of them may have a chance to achieve morphological remission by subsequent chemotherapy, thus opening the way to alternative modalities of consolidation.During the last decade, measurement of blast reduction during the first weeks became a relevant issue. Morphological evaluation is not sufficiently accurate for this purpose and methods aimed at detecting of limited numbers of blast cells (minimal residual disease) in the bone marrow, or even in the peripheral blood, have been explored. Such methods may provide the advantage of an early information allowing significant modifications of the treatment schedule according to the prognostic indications. Both flow cytometry and polymerase chain reaction (PCR) analysis have been used for the detection of minimal residual disease. Patients with leukemic blast concentrations below 0.01% by the end of induction therapy have a good prognosis because of their low risk of relapse. Contrariwise, when the concentration of leukemic blasts is 10% on day 15, or 1% by the end of induction therapy or later on, the risk of leukemia relapse is very high. [15][16] PCR analysis is a very sensitive method for identifying very low risk patients, although it is very expensive and time-consuming, and up to 20% of patients may be ineligible for technical reasons by the more stringent protocols of analysis. Its extensive use in the AIEOP-BFM-ALL 2000 stydy recently provided evidence that PCR analysis can discriminate patients with different prognoses even within groups defined as non-high risk by traditional criteria.17 Flow cytometry appears a very promising technique for the detection of minimal residual disease, is relatively cheap and almost all patients can be studied within hours. Its extensive clinical use by the St. Jude Children's Research Hospital in Memphis demonstrated its feasibility in a single, large institution. More recently, two large co-operative studies have confirmed the feasibility of this method in children with ALL. 18-20 Front-line treatment of childhood acute lymphoblastic leukemiaWith the only exception of patients with mature Bcell ALL, for whom a specific short and very intense chemotherapy program has been developed by most groups, all patients with childhood ALL are treated according to a similar strategy. Front-line therapy consists of several phases, with different aims; initial induction (of the first remission) therapy is delivered over 4-5 weeks; central nervous system (CNS)-directed therapy is administered to prevent meningeal progression or relapse; intensive post-remission chemotherapy is aimed at...

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The Seventh International Childhood Acute Lymphoblastic Leukemia Workshop Report: Palermo, Italy, January 29–30, 2005

Cited by 56 publications

References 39 publications

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

Minimal residual disease (MRD) analysis in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: is it possible to avoid MRD testing?

Treatment of pediatric acute lymphoblastic leukemia

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