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

• Published in: Medical and pediatric oncology 2002-06, Vol.38 (6), p.379-386
• Main Authors: Woerden, N.L. Ramakers-van, Pieters, R., Hoelzer, D., Slater, R.M., den Boer, M.L., Loonen, A.H., Harbott, J., Janka-Schaub, G.E., Ludwig, W-D, Ossenkoppele, G.J., van Wering, E.R., Veerman, A.J.P.
• Format: Article
• Language: English
• Subjects: 22)(q34; acute lymphoblastic leukemia; Adult; Antineoplastic agents; Antineoplastic Agents - therapeutic use; ATP-Binding Cassette, Sub-Family B, Member 1 - analysis; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; BCR-ABL fusion; Biological and medical sciences; Child; drug resistance; drug resistance proteins; Drug Resistance, Neoplasm - genetics; Drug Screening Assays, Antitumor; General aspects; Humans; Immunophenotyping; In Vitro Techniques; Leukocyte Count; Medical sciences; Multidrug Resistance-Associated Proteins - analysis; Multidrug Resistance-Associated Proteins - genetics; Neoplasm Proteins - analysis; Neoplasm Proteins - genetics; Pharmacology. Drug treatments; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; prednisolone; Prednisolone - therapeutic use; Prognosis; q11; t(9; 22)(q34; q11); Vault Ribonucleoprotein Particles - genetics
• ISSN: 0098-1532; 1096-911X
• DOI: 10.1002/mpo.10087

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‐0positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph‐negative (Ph−) ALL cases. Results A large range of LC50 values was found within the Ph+ patients. Moreover, LC50 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. Med Pediatr Oncol 2002;38:379–386. © 2002 Wiley‐Liss, Inc.