Abstract
Imatinib mesylate, an Abl-specific kinase inhibitor, produces sustained complete hematologic responses (CHR) and major cytogenetic responses (MCR) in chronic myeloid leukemia (CML) patients, but long-term outcomes in these patients are not yet known. This article reports the identification of clonal abnormalities in cells lacking detectable Philadelphia (Ph) chromosome/BCR–ABL rearrangements from seven patients with chronic- or accelerated-phase CML, who were treated with imatinib. All seven patients were refractory or intolerant to interferon therapy. Six of seven patients demonstrated MCR and one patient, who had a cryptic translocation, achieved low-level positivity (2.5%) for BCR–ABL by fluorescence in situ hybridization. The median duration of imatinib treatment before the identification of cytogenetic abnormalities in BCR–ABL-negative cells was 13 months. The most common cytogenetic abnormality was trisomy 8, documented in three patients. All patients had varying degrees of dysplastic morphologic abnormalities. One patient exhibited increased numbers of marrow blasts, yet consistently demonstrated no Ph-positive metaphases and the absence of morphologic features of CML. The presence of clonal abnormalities in Ph-negative cells of imatinib-treated CML patients with MCR and CHR highlights the importance of routine metaphase cytogenetic testing and long-term follow-up of all imatinib-treated patients.
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References
Nowell PC, Hungerford DA . A minute chromosome in human chronic granulocytic leukemia. Science 1960; 132: 1497–1501.
Rowley JD . Letter: a new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243: 290–293.
Shtivelman E, Lifshitz B, Gale RP, Canaani E . Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 1985; 315: 550–554.
Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824–830.
Lugo TG, Pendergast AM, Muller AJ, Witte ON . Tyrosine kinase activity and transformation potency of BCR–ABL oncogene products. Science 1990; 247: 1079–1082.
Druker BJ, Talpaz M, Resta DJ, Phen B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BDR–ABL tyrosine kinase in chronic myelogenous leukemia. N Engl J Med 2001; 344: 1031–1037.
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–652.
Druker BJ . STI571 (Gleevec/Glivec, imatinib) versus interferon (IFN)+cytarabine as initial therapy for patients with CML: results of a randomized study. Proc. ASCO 2002; 21: 1a (Abstract).
Marktel S, Bua M, Marin D, Chase A, Udom C, Armstrong L et al. Emergence of additional chromosomal abnormalities following treatment with STI571 (imatinib mesylate) for Philadelphia positive chronic myelogenous leukemia in chronic phase. Proc Am Soc Hematol 2001 (Abstract 2584).
Mohamed AN, Pemberton P, Zonder JA, Homisha S, Ford J, Schiffer CA . The effect of Gleevec (STI571;imatinib mesylate) in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) with secondary chromosomal aberrations. Proc Am Soc Hematol 2001 (Abstract 2343).
Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99: 1928–1937.
Heaney ML, Golde DW . Myelodysplasia. N Engl J Med 1999; 340: 1649–1660.
Fayad L, Kantarjian H, O'Brien S, Seong D, Albitar M, Keating M, et al. Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. Leukemia 1997; 11: 767–771.
Bilhou-Nabera C, Marit G, Devianne I, Viard F, Salzes S, Montastruc M, et al. A second case of trisomy 8 in Philadelphia chromosome (Ph)-negative cells during the course of Ph-positive chronic myelocytic leukemia. Genes Chromosomes Cancer 1993; 6: 255–256.
Ariyama T, Inazawa J, Uemura Y, Kakazu N, Maekawa T, Urase F et al. Clonal origin of Philadelphia chromosome negative cells with trisomy 8 appearing during the course of alpha-interferon therapy for Ph positive chronic myelocytic leukemia. Cancer Genet Cytogenet 1995; 81: 20–23.
Maserati E, Aprili F, Vinante F, Locatelli F, Amendola G, Zatterale A et al. Trisomy 8 in myelodysplasia and acute leukemia is constitutional in 15–20% of cases. Genes Chromosomes Cancer 2002; 33: 93–97.
Granada I, Luno E, Ribera JM, Sanzo C, Muniz SG, Milla F . Translocation (3;10)(q26;q22): a new nonrandom abnormality in three patients with 3q26 involvement. Cancer Genet Cytogenet 2000; 121: 99–100.
Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ . Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000; 96: 925–932.
Lyman SD, Jacobsen SE . c-Kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 1998; 91: 1101–1134.
Anderson MK, Pdersen-Bjergaard, Kjeldsen L, Dufva IH, Brondum-Nielsen K . Clonal Ph-negative hematopoiesis in CML after therapy. Leukemia 2002; 16: 1390–1393.
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We thank Susan Oliver for administrative assistance.
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O'Dwyer, M., Gatter, K., Loriaux, M. et al. Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate. Leukemia 17, 481–487 (2003). https://doi.org/10.1038/sj.leu.2402848
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DOI: https://doi.org/10.1038/sj.leu.2402848
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