Two Groups of Philadelphia Chromosome—Positive Childhood Acute Lymphoblastic Leukemia Classified by Pretreatment Multidrug Sensitivity or Resistance in In Vitro Testing

  • Teruaki Hongo
  • Shuichi Okada
  • Noriko Inoue
  • Sayuri Yamada
  • Shuhei Yajima
  • Chieko Watanabe
  • Yuji Fujii
  • Yasuo Horikoshi
Case Report


The development of effective chemotherapy is imperative for children with Philadelphia chromosome—positive (Ph) acute lymphoblastic leukemia (ALL) because of the poor prognosis of this condition. Initial cellular drug resistance is thought to be an important cause of induction failure and early relapse.We carried out in vitro tests using a methyl-thiazol-tetrazolium assay on bone marrow samples from 274 children with newly diagnosed ALL. Sixteen children (5.8%) had Ph-positive results of cytogenetic analysis. We examined in vitro drug resistance to 14 agents and found that leukemic cells in Ph ALL were significantly more resistant than were cells in non-Ph ALL to melphalan, bleomycin, etoposide, mitoxantrone, L-asparaginase, and vinblastine. With the prednisolone, L-asparaginase, and vincristine (PAV) combination of drugs, 10 of the 16 Ph patients with ALL (62.5%) showed relative resistance (RR) (sensitivity to only 1 or to none of the 3 drugs) at initiation of treatment.These 10 patients experienced significantly poorer event-free survival (EFS) than did the 6 patients with supersensitivity (SS) (defined as sensitivity to all 3 or to 2 of the 3 drugs,P = .019). Leukemic cells from RR patients were found to be multiresistant to 12 drugs with 2.0- to 58.4-fold RR compared with cells from SS patients. This PAV sensitivity delineates initially sensitive and resistant groups. Of these, the SS subgroup of Ph ALL patients may be curable with chemotherapy and stem cell transplantation. For EFS improvement in the RR group, it may be necessary to use a new chemotherapy approach from initiation.

Key words

Philadelphia chromosome positive Acute lymphoblastic leukemia Childhood Methyl-thiazol-tetrazolium (MTT) assay Drug resistance Drug sensitivity 


  1. 1.
    Bloomfield CD, Goldman AI, Alimena G, et al. Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia.Blood. 1986;67:415–420.PubMedGoogle Scholar
  2. 2.
    The Groupe Français de Cytogénétique Hématologique. Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings and outcome. A collaborative study of the Français de Cytogénétique Hématologique.Blood. 1996;87:3135–3142.Google Scholar
  3. 3.
    Fletcher JA, Lynch EA, Kimball VM, Donnelly M, Tantravahi R, Sallan SE. Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia.Blood. 1991;77:435–439.PubMedGoogle Scholar
  4. 4.
    Crist W, Carroll A, Shuster J, et al. Philadelphia chromosome positive childhood acute lymphoblastic leukemia: clinical and cytogenetic characteristics and treatment outcome.A Pediatric Oncology Group Study.Blood. 1990;76:489–494.PubMedGoogle Scholar
  5. 5.
    Uckun FM, Nachman JB, Sather HN, et al. Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies.Cancer. 1998;83:2030–2039.PubMedCrossRefGoogle Scholar
  6. 6.
    Hongo T, Yajima S, Sakurai M, Horikoshi Y, Hanada R. In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia.Blood. 1997; 89:2959–2965.PubMedGoogle Scholar
  7. 7.
    Hongo T, Yamada S, Yajima S, et al. Biological characteristics and prognostic value of in vitro three-drug resistance to prednisolone, L-asparaginase, and vincristine in childhood acute lymphoblastic leukemia.Int J Hematol. 1999;70:268–277.PubMedGoogle Scholar
  8. 8.
    Pieters R, den Boer ML, Durian M, et al. Relation between age, immunophenotype andin vitro drug resistance in 395 children with acute lymphoblastic leukemia: implications for treatment of infants.Leukemia. 1998;12:1344–1348.PubMedCrossRefGoogle Scholar
  9. 9.
    Pieters R, Loonen AH, Huismans DR, et al. In vitro drug sensitivity of cells from children with leukemia using the MTT assay with improved culture conditions.Blood. 1990;76:2327–2336.PubMedGoogle Scholar
  10. 10.
    Pui CH. Childhood leukemias.N Engl J Med. 1995;332:1618–1630.PubMedCrossRefGoogle Scholar
  11. 11.
    Roberts WM, Rivera GK, Raimondi SC, et al. Intensive chemotherapy for Philadelphia-chromosome-positive acute lymphoblastic leukemia.Lancet. 1994;343:331–332.PubMedCrossRefGoogle Scholar
  12. 12.
    Arico M, Valsecchi MG, Camitta B, et al. Outcome of treatment in children with Philadelphia chromosome—positive acute lymphoblastic leukemia.N Engl J Med. 2000;342:998–1006.PubMedCrossRefGoogle Scholar
  13. 13.
    Schrappe M, Arico M, Harbott J, et al. Philadelphia chromosome- positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome.Blood. 1998;92:2730–2741.PubMedGoogle Scholar
  14. 14.
    Radich JP, Kopecky KJ, Boldt DH, et al. Detection of BCR-ABL fusion genes in adult acute lymphoblastic leukemia by the polymerase chain reaction.Leukemia. 1994;8:1688–1695.PubMedGoogle Scholar
  15. 15.
    Voncken JW, Kaartinen V, Pattengale PK, Germeraad WTV, Groffen J, Heisterkamp N.BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice.Blood. 1995;86:4603–4611.PubMedGoogle Scholar
  16. 16.
    Preudhomme C, Henic N, Cazin B, et al. Good correlation between RT-PCR analysis and relapse in Philadelphia (Ph1)-positive acute lymphoblastic leukemia (ALL).Leukemia. 1997;11:294–298.PubMedCrossRefGoogle Scholar
  17. 17.
    Kaspers GJL, Kardos G, Pieters R, et al. Different cellular drug resistance profiles in childhood lymphoblastic and non-lymphoblastic leukemia: a preliminary report.Leukemia. 1994;8:1224–1229.PubMedGoogle Scholar
  18. 18.
    Kasprzyk A, Harrison CJ, Secker-Walker LM. Investigation of clonal involvement of myeloid cells in Philadelphia chromosome— positive and high hyperdiploid acute lymphoblastic leukemia.Leukemia. 1999;13:2000–2006.PubMedCrossRefGoogle Scholar
  19. 19.
    Hongo T, Fujii Y, Igarashi Y. Anin vitro chemosensitivity test for the screening of anti-cancer drugs in childhood leukemia.Cancer. 1990;65:1263–1272.PubMedCrossRefGoogle Scholar
  20. 20.
    Pieters R, Huismans DR, Loonen AH, et al. Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia.Lancet. 1991;338:399–403.PubMedCrossRefGoogle Scholar
  21. 21.
    Klumper E, Pieters R, Veerman AJP, et al. In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia.Blood. 1995;86:3861–3868.PubMedGoogle Scholar
  22. 22.
    Kaspers GJL, Smets LA, Pieters R, van Zantwijk CH, van Wering ER, Veerman ALP. Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: results of anin vitro study.Blood. 1995;85:751–756.PubMedGoogle Scholar
  23. 23.
    Ramakers—van Woerden NL, Pierters R, Hoelzer D, et al. 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.Med Pediatr Oncol. 2002;38:379–386.PubMedCrossRefGoogle Scholar
  24. 24.
    Scherf U, Ross DT, Waltham M, et al. A gene expression database for the molecular pharmacology of cancer.Nat Genet. 2000;24: 236–244.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2002

Authors and Affiliations

  • Teruaki Hongo
    • 1
  • Shuichi Okada
    • 1
  • Noriko Inoue
    • 1
  • Sayuri Yamada
    • 1
  • Shuhei Yajima
    • 1
  • Chieko Watanabe
    • 1
  • Yuji Fujii
    • 1
  • Yasuo Horikoshi
    • 2
  1. 1.Department of PediatricsHamamatsu University School of MedicineHamamatsu CityJapan
  2. 2.Division of Hematology/OncologyShizuoka Prefectural Children’s HospitalShizuokaJapan

Personalised recommendations