A Cell Line SYRMO Derived From AML with EVI 1 Rearrangements Following Imatinib Mesylate Therapy for Chronic Myeloid Leukaemia

Abstract 4470

Chronic Myeloid Leukaemia (CML) is a malignant disorder of the haematopoeitic stem cell, usually characterised by the t(9;22) giving rise to the Philadelphia chromosome (Ph), and by the BCR-ABL gene rearrangement at the molecular level. Imatinib mesylate (IM), which targets the tyrosine kinase (TK) activity of BCR-ABL, has become the first line therapy for CML patients. Dasatinib or Nilotinib is now indicated as a second line therapy for patients who develop resistance or intolerance to IM.

Here we report the case of a 51 year old woman who was diagnosed in Cyprus (2007) with BCR/ABL1 positive CML. After failing to respond to IM therapy, she was treated with Dasatinib achieving complete cytogenetic remission (CCR), and subsequent complete molecular remission. In July 2009 the patient presented with 88% blasts in the bone marrow. Immunophenotyping showed the presence of CD34+, CD117+ myeloblasts, and a diagnosis of AML was confirmed. Analysis of G banded metaphases from cultured peripheral blood revealed a complex karyotype: 46,XX, t(2;3)(p21;q26),t(4;8)(q12;q22), del(6)(q13;q23)[1]/45,idem,der(6)ins(6;6)(q23;),-7[9]. FISH revealed EVI 1 rearrangement resulting from the t(2;3) in the absence of BCR/ABL1 fusion and confirmed the secondary monosomy 7. The patients failed to respond to treatment and passed away shortly afterwards. Whole genome screening by aCGH using a 244K platform (Agilent) confirmed the loss of chromosome 7 and the 6q22/23 region.

Clonal cytogenetic abnormalities (CCA) in Ph-negative metaphases are known to develop in some patients during IM therapy. The most frequent of these abnormalities are trisomy 8, -7, del(7q), and del(20q), which are also associated with MDS and AML. These abnormalities are usually transient and disappear after a short time, or have no clinical consequence (Deininger et al., Cancer 2007). However, reports of development of high risk MDS or AML in association with CCA in Ph-negative cells are rare, but patients with chromosome 7 abnormalities appear to be at greater risk. The t(2;3) is a non random abnormality in MDS and AML, including therapy-related leukaemias, frequently associated with -7 and a complex karyotype with a poor prognosis (Stevens-Kroef et al Leukemia 2004).

This is the first report of a CML patient on TKI treatment with t(2;3) and EVI1 gene rearrangements in Ph(-) cells. This cryptic translocation could easily be overlooked in the presence of a monosomy 7 with a dramatic effect on patient management.