Several different cytogenetic clones arising during treatment of Philadelphia positive chronic myeloid leukemia with tyrosine kinase inhibitors lead to the progression into Philadelphia negative acute myeloid leukemia

Marija Denčić-Fekete; Danijela  Leković; Vesna  Djordjević; Jelica  Jovanović; Biljana Todorić-Živanović; Ljubomir  Jaković; Andrija  Bogdanović

doi:10.2298/VSP180723010D

Marija Denčić-Fekete Clinical Center of Serbia, Clinic for Hematology, Belgrade, Serbia
Danijela Leković Clinical Center of Serbia, Clinic for Hematology, Belgrade, Serbia
Vesna Djordjević Clinical Center of Serbia, Clinic for Hematology, Belgrade, Serbia
Jelica Jovanović Clinical Center of Serbia, Clinic for Hematology, Belgrade, Serbia
Biljana Todorić-Živanović Military Medical Academy, Belgrade, Serbia
Ljubomir Jaković Clinical Center of Serbia, Clinic for Hematology, Belgrade, Serbia
Andrija Bogdanović Clinical Center of Serbia, Clinic for Hematology, Belgrade, Serbia

DOI: https://doi.org/10.2298/VSP180723010D

Keywords: leukemia, myelogenous, chronic, bcr-abl positive;, leukemia, myeloid, acute;, karyotyping;, enzyme inhibitors;, cytogenetics

Abstract

Introduction. Additional karyotype abnormalities in the Philadelphia-positive (Ph+) clone can emerge during the progression of chronic myeloid leukemia (CML) and are often associated with the resistance to treatment with tyrosine kinase inhibitors (TKI). Sometimes, during the TKI treatment, karyotype abnormalities can appear in the Philadelphia-negative (Ph-) cells as well but do not seem to adversely affect the outcome except for chromosome 7 abnormalities. Case report. The patient presented was in the chronic phase of Ph+ CML with highly diverse karyotype abnormalities. The abnormalities appeared in three unrelated clones during the TKIs treatment, followed by the evolution of the disease into acute myeloid leukemia (AML). The primary Ph+ clone was revealed during the chronic phase of CML, and therapy with imatinib mesylate was commenced. After a three-year hematologic and cytogenetic remission period, the evolution of the primary clone was noticed. Nilotinib was introduced, leading to a good molecular response and the disappearance/loss of the Ph+ clone with additional abnormalities but with the appearance of the Ph- clone with trisomy 8. Finally, after 5.5 years of nilotinib therapy, the Ph- clone with monosomy 7 occurred during the deep molecular response for BCR-ABL. At that time, the FISH analysis for trisomy 8 was negative, but the rise in blast count was noticed in the bone marrow, and the diagnosis of the secondary AML was established soon after. Conclusion. The achievement of the deep molecular response in CML patients does not rule out regular cytogenetic testing of their bone marrow. This is of crucial importance for detecting adverse karyotype abnormalities leading to the development of the myelodysplastic syndrome and AML.

References

Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122(6): 872‒84.

Deininger MW, Cortes J, Paquette R, Park B, Hochhaus A, Bacca-rani M, et al. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Phila-delphia chromosome-negative cells. Cancer 2007; 110(7): 1509-19.

Perel JM, McCarthy C, Walker O, Irving I, Williams B, Kennedy GA. Clinical significance of development of Philadelphia chromosome negative clones in patients with chronic myeloid leukemia treated with imatinib mesylate. Haematologica 2005; 90 (Suppl): ECR25.

Bacher U, Hochhaus A, Berger U, Hiddemann W, Hehlmann R, Haferlach T, et al. Clonal aberrations in Philadelphia chromo-some negative hematopoiesis in patients with chronic myeloid leukemia treated with imatinib or interferon alpha. Leukemia 2005; 19(3): 460‒3.

Kovitz C, Kantarjian H, Garcia-Manero G, Abruzzo LV, Cortes J. Myelodysplastic syndromes and acute leukemia developing af-ter imatinib mesylate therapy for chronic myeloid leukemia. Blood 2006; 108(8): 2811‒3.

Terre C, Eclache V, Rousselot P, Imbert M, Charrin C, Gervais C, et al. Report of 34 patients with clonal chromosomal abnor-malities in Philadelphia negative cells during imatinib treat-ment of Philadelphia-positive chronic myeloid leukemia. Leu-kemia 2004; 18(8): 1340-6.

Andersen MK, Pedersen-Bjergaard J, Kjeldsen L, Dufva IH, Brøn-dum-Nielsen K. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia 2002; 16(8): 1390–1393.

Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extrac-tion. Anal Biochem 1987; 162(1): 156‒9.

Moravcová J, Lukásová M, Starý J, Haskovec C. Simple competi-tive two-step RT-PCR assay to monitor minimal residual dis-ease in CML patients after bone marrow transplantation. Leu-kemia 1998; 12(8): 1303‒12.

Denčić-Fekete M, Đorđević V, Storlazzi C. T, Janković G, Bogdanov-ić A, Jovanović J, et al. t(5;6;12) associated with resistance with imatinib mesylate in chronic myeloid leukemia. Int J Hematol 2009; 89(4): 508‒12.

Storlazzi CT, Albano F, Dencić-Fekete M, Djordjević V, Rocchi M. Late-appearing pseudocentric fission event during chronic my-eloid leukemia progression. Cancer Genet Cytogenet 2007; 174(1): 61‒7.

Baldazzi C, Luatti S, Marzocchi G, Stacchini M, Gamberini C, Castagnetti F, et al. Emergence of clonal chromosomal abnor-malities in Philadelphia negative hematopoiesis in chronic my-eloid leukemia patients treated with nilotinib after failure of imatinib therapy. Leukemia Res 2009; 33(12): e218‒20.

Ribeiro de Mello Conchon M, Bendit I, Ferreira P, Lima W, Kumeda C, Dias L, et al. Emergence of abnormal clone with monosomy 7 in Philadelphia negative cells of CML patients treated with tyrosine kinase inhibitors. Int J Hematol 2009; 89(1): 123‒5.

McMullin MF, Humphreys M, Byrne J, Russell NH, Cuthbert RJ, O’Dwyer ME. Chromosomal abnormalities in Ph- cells of pa-tients on imatinib. Blood 2003; 102(7): 2700‒1; author reply 2701.

Bumm T, Müller C, Al-Ali HK, Krohn K, Shepherd P, Schmidt E, et al. Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003; 101(5): 1941‒9.

Kharbanda S, Pandey P, Jin S, Inoue S, Bharti A, Yuan ZM, et al. Functional interaction between DNA-PK and c-Abl in re-sponse to DNA damage. Nature 1997; 386(6626): 732‒5.

Fabarius A, Haferlach C, Müller M, Erben P, Lahaye T, Giehl M, et al. Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during da-satinib therapy of chronic myeloid leukemia patients after imatinib failure. Haematologica 2007; 92(6): 834‒7.

Tanaka H, Tanaka K, Oguma N, Ito K, Ito T, Kyo T, et al. Effect of interferon-α on chromosome abnormalities in treated chronic myelogenous leukemia patients. Cancer Genet Cyto-genet 2004; 153(2): 133‒43.

Groves MJ, Sales M, Baker L, Griffiths M, Pratt N, Tauro S. Fac-tors influencing a second myeloid malignancy in patients with Philadelphia-negative -7 or del(7q) clones during tyrosine ki-nase inhibitor therapy for chronic myeloid leukemia. Cancer Genet 2011; 204(1): 39‒44.