Emergence of abnormal clone with monsomy 7 in Philadelphia negative cells of CML patients treated with tyrosine kinase inhibitors

Abstract

We report the occurrence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with monosomy 7 transformation in two patients with chronic myeloid leukemia (CML) after imatinib and dasatinib treatment without previous exposure to chemotherapeutic agents. Case 1In May 2004, a 50-year-old man was diagnosed with CML accelerated phase. This was supported by blood basophils [20% and cytogenetic evidence of Philadelphia chromosome (Ph), t(9;22)(q34;q11) observed in 100% of metaphases analyzed. He was subsequently treated with imatinib (600 mg/day) and was followed. Four weeks later, the patient achieved complete hematological remission but had grade 2-skin toxicity. In December 2004, the patient developed grade 4 neutropenia and presented blastic crisis based on the presence of 20% of blast cells in his bone marrow. Inconclusive results was obtained with flow cytometric analysis for cell surface markers (immunophenotyping). Consequently, therapeutic regimen with Ara-C (40 mg/m 2 /day) was given together with imatinib (600 mg/day). Four months later, he developed a severe thrombocytopenia (grade 4) and treatments were discontinued. In June 2005, a new cytological investigation disclosed a picture of blastic crisis (100% of Ph?) and the patient considered resistant to imatinib. Despite the presence of thrombocytopenia, the patient was placed on dasatinib at an initial dose of 70 mg/BID. Because he did not achieve any cytogenetic response, dasatinib was progressively increased to 100 mg/BID. Complete cytogenetic response (CCR) was reached at 11 months (0% Ph? marrow metaphases) but the patient showed monosomy 7 in all Phmarrow metaphases cells and this was confirmed by the fluorescence in situ hybridization (FISH) technique. At this point, the complete blood cell count disclosed cytopenia and the myelogram did not show sign for dysplastic maturation in any cell lineages. Retrospective analysis of the sample collected prior to treatment with dasatinib did not show evidence of monosomy 7. In October 2006, the patient had lost the CCR and showed the presence of 25% of ph? and monosomy 7 in Ph-clone. In April 2007, blast cells were positive for CD34, CD13, CD33 and CD 64. G-banding karyotype showed 46,XY,t(9;22)(q34.1;q11.2)[5]/45,XY,-7[12]/46, XY[3] in 20 metaphases tested. The origin of blasts was not clear only by the karyotype. Accordingly, a diagnosis of AML was made and the patient received induction chemotherapy with Ara-C and daunorubicin. Despite treatment, the patient died 3 months later of refractory disease. Case 2A 22 year-old man was diagnosed with CML in 1997. The patient started treatment with µ interferon, but had failed to M. R. de Mello Conchon Á I. Bendit Á W.

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

“…Despite introducing a high-dose therapy for AML, she died 6 months after the diagnosis of the secondary AML had been established. Ph-negative clones with -7 were described in the CML cases with high propensity to evolve into MDS/AML [13]. However, there have been rare cases with -7 without disease evolution [4,5,14].…”

“…In several studies, factors contributing to the appearance of chromosomal aberrations in the Ph-negative clone have been discussed. The previous cytotoxic treatment [13], the negative effect of TKIs on DNA repair mechanisms [15][16][17] or the innate genetic instability in the CML marrow [18] are described as potential causes of the Ph-negative clone appearance. However, among all the abnormalities, only those involving chromosome 7 (del(7q) and/or -7) bear a higher risk of secondary malignancies [5,19].…”