The Clinical Relevance of Cellular Drug Resistance Testing in Childhood Acute Myeloid Leukemia (AML)

Abstract • 182

Childhood acute lymphoblastic leukemia (ALL) is known to have a better clinical outcome (±75% survival) compared with childhood AML (±50% survival). Cellular drug resistance may explain this difference and can be measured with the MTT-assay. We showed AML cells (n=28) to be < 75 fold more resistant to glucocorticoids and 2-fold more resistant to vincristine than ALL cells (n=128), all untreated. This is in concordance with clinical experience. Differences for other drugs (Ara-C, anthracyclines, thiopurines, etoposide, asparaginase) were not significant. In childhood AML, there is, with the exception of cytogenetics, a lack of prognostic factors at initial diagnosis. In-vitro drug resistance testing may provide new prognostic factors. We found clinically good responders (defined as achieving CR after 1 course of chemotherapy) to be significantly (p=0.05) more sensitive to Ara-C in-vitro (2.9 fold) than poor-responders (defined as achieving CR after 2 or more courses). This was not the case for the other drugs tested like daunorubicin, 6-thioguanine, VP16, mitoxantrone and, doxorubicin. Also, relapsed childhood AML was in-vitro 3.2 fold more resistant to Ara-C than untreated AML (p=0.05), but again not to the other drugs. We have studied cross-resistance between Ara-C and 2-CDA in childhood AML. Although in general cross-resistance is present (rho 0.6, p=<0.001), this is not the case for relapsed childhood AML samples: they are as sensitive (p=0.44) to 2-CDA in-vitro as untreated samples, and therefore 2-CDA may circumvent Ara-C resistance in relapsed childhood AML. Another application of in-vitro drug resistance testing may be to explain why certain subgroups of childhood AML patients do well and others do not considering outcome. Children with Down syndrome (DS) and AML are known to have a better prognosis than children with AML without DS. We found untreated AML cells from children with DS to be median 1.4 to 33.3 more sensitive in comparison with AML cells from non-DS patients, for all drugs used in treatment (p<0.05). In conclusion: cellular drug resistance testing provides clinically relevant information in pediatric AML.

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Zwaan, C., Kaspers, G., Creutzig, U. et al. The Clinical Relevance of Cellular Drug Resistance Testing in Childhood Acute Myeloid Leukemia (AML). Pediatr Res 45, 773 (1999).

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