Abstract
To determine the clinical relevance of in vitro drug chemoresistance in childhood acute myeloid leukemia, we used an MTT assay to test leukemic cells from 132 newly diagnosed children. Patients were diagnosed according to the French–American–British (FAB) classification as follows: M0 (n = 12), M1 (n = 16), M2 (n = 53), M4 (n = 17), M5 (n = 19) and M7 (n = 15). The results revealed that, compared to leukemic cells from complete-responders (n = 107), those from non-responders who failed induction therapy (n = 17) were 1.4 to 5.0 times more resistant in vitro to cytarabine (P = 0.005), melphalan (P = 0.003), etoposide (P = 0.011), L-asparaginase (P = 0.017), aclarubicin (P = 0.026) and dexamethasone (P = 0.039). For seven other drugs tested, the median lethal dose of 70% and leukemic cell survival of non-responders were higher than those of complete-responders, but the difference was not statistically significant. We sought correlations between FAB subtypes and in vitro drug resistance. Leukemias of the FAB M4 and M5 subtype were more sensitive to L-asparaginase (P = 0.01, P = 0.0036) than those of the FAB M2 subtype. FAB M5 leukemia was more sensitive to etoposide than were the FAB M2, M4 and M7 subtypes (P = 0.001, P = 0.034, P = 0.023, respectively). By contrast, FAB M5 leukemia was significantly more resistant to prednisolone and dexamethasone than were the FAB M0, M1, M2, M4 and M7 subtypes. We sought correlations between in vitro drug resistance and long-term clinical outcome, but found no associations in this case. These results suggest that in vitro resistance to cytarabine, melphalan, etoposide, L-asparaginase, aclarubicin and dexamethasone might represent factors that can predict response to the early course of therapy. Selecting an appropriate anti-cancer drug according to the FAB classification together with drug sensitivity testing may contribute to improved prognoses in childhood acute myeloid leukemia.
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References
Creutzig U, Ritter J, Schellerg G for the AML-BFM Study Group . Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78 Blood 1990 75: 1932–1940
Kersey JH . Fifty years of studies of the biology and therapy of childhood leukemia Blood 1997 90: 4243–4251
Pui CH . Childhood leukemias N Engl J Med 1997 332: 1618–1630
Stevens RF, Hann IM, Wheatley K, Gray RG on behalf of the MRC Childhood Leukemia Working Party . Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial Br J Haematol 1998 101: 130–140
Kigasawa H . Progress of treatment of acute myeloid leukemia in children Jpn J Ped Hematol 2000 14: 288–297
Hongo T, Fujii Y, Igarashi Y . An in vitro chemosensitivity test for the screening of anti-cancer drugs in childhood leukemia Cancer 1990 65: 1263–1272
Pieters R, Huismans DR, Loonen AH, Hählen K, Van der Dose-van den Berg A, Wering ER, Veerman AJP . Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukemia Lancet 1991 338: 399–403
Hongo T, Fujii Y . In vitro chemosensitivity of lymphoblasts at relapse in childhood leukemia using the MTT assay Int J Hematol 1991 54: 219–230
Hongo T, Yajima S, Sakurai M, Horikoshi Y, Hanada R . In vitro drug sensitivity can predict induction failure and early relapse of childhood acute lymphoblastic leukemia Blood 1997 89: 2959–2965
Kaspers GJL, Veerman AJP, Pieters R, Van Zantwijk CH, Van Wering ER, Van Der Does-Van Den Berg A . In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia Blood 1997 90: 2723–2729
Hongo T, Yamada S, Yajima S, Watanabe C, Fujii Y, Kawasaki H, Yazaki M, Hanada R, Horikoshi Y . 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
Sargent JM, Taylor CG . Appraisal of the MTT assay as a rapid test of chemosensitivity in acute myeloid leukemia Br J Cancer 1989 60: 206–210
Twentyman PR, Fox NE, Rees JKH . Chemosensitivity testing of fresh leukaemia cells using MTT colorimetric assay Br J Haematol 1989 71: 19–24
Klumper E, Pieters R, Kaspers GJL, Huismans DR, Loonen AH, Rottier MMA, Van Wering ER, Van der Does-van den Berg A, Hählen K, Creutzig U, Veerman AJP . In vitro chemosensitivity assessed with the MTT assay in childhood acute non-lymphoblastic leukemia Leukemia 1995 9: 1864–1869
Klumper E, Ossenkoppele GJ, Pieters R, Huismans DR, Loonen AH, Rottier A, Westra G, Veerman AJP . In vitro resistance to cytosine arabinoside, not to daunorubicin, is associated with the risk of relapse in de novo acute myeloid leukaemia Br J Haematol 1996 93: 903–910
Kaspers GJL, Zwaan ChM, Veerman AJP, Rots MG, Pieters R, Bucsky P, Domula M, Göbel U, Graf N . Havers W, Jorch N, Kabisch K, Spaar H-J, Ritter J, Creutzig U. Cellular drug resitance in acute myeloid leukemia: literature review and preliminary analysis of an ongoing collaborative study Klin Pädiatr 1999 211: 239–244
Zwaan CM, Kaspers GJL, Pieters R, Ramakers-Van Woerden NL, Den Boer ML, Wünsche R, Rottier MMA, Hählen K, Van Wering ER, Janka-Schaub GE, Creutzig U, Veerman AJP . Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia Blood 2000 96: 2879–2886
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C . Proposals for the classification of the acute leukaemias Br J Haematol 1976 33: 451–458
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C . Proposals revised criteria for the classification of acute myeloid leukemia. A report of the French–American–British Cooperative Group Ann Int Med 1985 103: 620–625
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C . Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7) Ann Int Med 1985 103: 460–462
Pui CH, WE Evans . Acute lymphoblastic leukemia N Engl J Med 1998 339: 605–615
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A . The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial Blood 1999 92: 2322–2333
Lie SO, Jonmundsson G, Mellander L, Siimes M, Yssing M, Gustafsson G . A population-based study of 272 children with acute myeloid leukemia treated on two consecutive protocols with different intensity: best outcome in girls, infants, and children with Down's syndrome Br J Haematol 1996 94: 82–88
Pui CH, Raimondi SC, Srivastava DK, Tong X, Behm FG, Razzouk B, Rubnitz JE, Sandlund JT, Evans WE, Ribeiro R . Prognostic factors in infants with acute myeloid leukemia Leukemia 2000 14: 684–687
Chang M, Raimondi SC, Ravindranath Y, Carroll AJ, Camitta B, Gresik MV, Steuber CP, Weinstein H . Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POG) Study 8821 Leukemia 2000 14: 1201–1207
Hann IM, Stevens RF, Goldstone AH, Ress JKH, Wheatley K, Gray RG, Burnett AK . Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the medical research council's 10th AML trial (MRC AML10) Blood 1997 89: 2311–2318
Woods WG, Kobrinsky N, Buckley JD, Lee JW, Sanders J, Neudorf S, Gold S, Barnard DR, DeSwarte J, Dusenbery K, Kalousek D, Arther DC, Lange BJ . Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia Blood 1996 87: 4979–4989
Dübbers A, Würthwein G, Müller HJ, Schulze-Westhoff P, Winkelhorst M, Kurzknabe E, Lanvers C, Pieters R, Kaspers GJL, Creutzig U, Ritter J, Boos J . Asparagine synthetase activity in paediatric acute leukaemias: AML-M5 subtype shows lowest activity Br J Haematol 2000 109: 427–429
Odom LF, Gordon EM . Acute monoblastic leukemia in infancy and early childhood: successful treatment with an epipodophyllotoxin Blood 1984 64: 875–882
Nishikawa A, Nakamura Y, Nobori U, Aoki T, Higashino H, Matsui T, Kobayashi Y, Yamashita M, Unishi G . Acute monocytic leukemia in children: response to VP-16–213 as a single agent Cancer 1987 60: 2146–2149
Acknowledgements
The authors would like to thank Dr Hiroki Hori (Mie University, Mie), Dr Makoto Yazaki (Nagoya City University, Nagoya), Dr Ryoji Hanada (Saitama Children's Medical Center, Iwatsuki), Dr Yasuo Horikoshi (Shizuoka Prefectural Children's Hospital, Shizuoka) and Dr Shuhei Yajima (Hamamatsu Medical Center, Hamamatsu) for providing the leukemia samples and for data collection.
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Yamada, S., Hongo, T., Okada, S. et al. Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia. Leukemia 15, 1892–1897 (2001). https://doi.org/10.1038/sj.leu.2402305
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DOI: https://doi.org/10.1038/sj.leu.2402305
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