In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups

Dutch and German Leukemia Study Groups, N L Ramakers-van Woerden, R Pieters, D Hoelzer, R M Slater, M L den Boer, A H Loonen, J Harbott, G E Janka-Schaub, W-D Ludwig, G J Ossenkoppele, E R van Wering, A J P Veerman

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Samenvatting

BACKGROUND: The t(9;22)(q34;q11) translocation leading to the Philadelphia (Ph) chromosome resulting in BCR-ABL gene fusion is associated with a poor prognosis in acute lymphoblastic leukemia (ALL).

PROCEDURE: We studied the relation between t(9;22), determined by karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), and in vitro drug resistance, measured by the MTT assay, in precursor B-cell ALL at diagnosis. The findings in twenty-one Ph-positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph-negative (Ph-) ALL cases.

RESULTS: A large range of LC(50) values was found within the Ph+ patients. Moreover, LC(50) values did not differ significantly between Ph+ and Ph- samples for prednisolone, dexamethasone, L-asparaginase, vincristine, anthracyclines, thiopurines, epipodophyllotoxins, and 4H00-ifosfamide, even after matching for important prognostic features (age, white blood cell count (WBC), and immunophenotype). Adult Ph+ (n = 12) ALL was more resistant to prednisolone (> 270-fold, P = 0.030), and displayed an overall tendency to resistance when compared to matched cases of Ph- (n = 15) adult precursor B-cell ALL. Within Ph+ ALL, in vitro prednisolone resistance increased significantly with age (P = 0.006). The expression of lung resistance protein (LRP), but not P-glycoprotein (P-gp) or multidrug resistance protein (MRP), was significantly higher in all Ph+ patients.

CONCLUSIONS: Both childhood and adult Ph+ precursor B-cell ALL samples display a heterogeneous in vitro resistance profile, with relatively sensitive and resistant cases. The adult Ph+ samples, however, are generally more resistant compared to matched Ph- controls, reaching significance for prednisolone. The correlation of prednisolone resistance with age within the Ph+ cases might help explain the poorer prognosis of adult Ph+ ALL.

Originele taal-2Engels
Pagina's (van-tot)379-86
Aantal pagina's8
TijdschriftMedical and pediatric oncology
Volume38
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - jun. 2002
Extern gepubliceerdJa

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