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  • The ETV ABL fusion has been reported as a

    2019-06-26

    The ETV6-ABL1 fusion has been reported as a poor prognostic factor when found in acute leukemia (AML and ALL) and MDS. The prognostic significance of an ETV6/ABL1 chronic myeloproliferative neoplasm is less clear due to the paucity of cases and the lack of controlled clinical trials [5]. There is a significant overlap of molecular targets of ETV6-ABL1 with those of BCR-ABL1, and the ETV6-ABL1 fusion protein triggers similar oncogenic cascades like the BCR-ABL1 fusion protein [3,10]. Similar to BCR-ABL1 positive cells, ETV6-ABL1 positive Lonafarnib show in-vitro sensitivity to the tyrosine kinase inhibitor Imatinib [7,8]. Several authors have also reported a transient [5,14–16] or prolonged [3,17–19] response to Imatinib or second generation tyrosine kinase inhibitor treatment in ETV6-ABL1-positive neoplasms, with the response to TKI being better and longer in ETV6-ABL1-positive myeloproliferative neoplasms. Thus, the detection of a cryptic ETV6-ABL1 rearrangement has a significant impact on patient care, especially in the case of chronic myeloproliferative neoplasms or chronic myeloid leukemia like phenotypes. However, there are only reports of 8 ETV6-ABL1 positive patients having been treated with Imatinib for various diseases (CML, AML, MPN, ALL) according to different therapy protocols [3,5,14–21]. Of the 7 patients with ETV6-ABL1-positive CML or MPN, who received TKI treatment, 5 responded, 4 with a prolonged remission. In contrast, of the 2 patients with an ETV6/ABL1 positive AML or ALL, who received TKI treatment, none responded with a longer remission duration (Table 1). However, the efficacy of Imatinib and second generation TKIs as well as the optimal treatment schedule for ETV6-ABL1 positive hematological malignancies still needs to be determined. This case illustrates the importance of a careful cytogenetic work-up for patients with a myeloproliferative neoplasm. If a patient can be treated with a tyrosine kinase inhibitor instead of chemotherapy, a significant improvement in his/her quality of life and survival can be achieved. The benefits of long term TKI treatment in young patients compared to a potentially curative bone marrow transplant need to be carefully assessed. In this situation, careful MRD monitoring is warranted. However despite good response to TKI, even tight MRD monitoring was not able to predict the rapid transformation from a myeloproliferative neoplasm into an acute lymphoblastic leukemia in our patient. Additionally, the clinical presentation of the secondary ETV6/ABL-positive ALL in our case was associated with a fatal paraneoplastic thrombophilic syndrome. We can only speculate as to what caused this rapid transformation from a relatively benign myeloproliferative neoplasm to an aggressive ALL. It is known from cytogenetic studies of CML in blast crisis that additional chromosomal abnormalities arise at blast crisis (e.g. an additional copies of the Philadelphia chromosome). This indicates that additional genetic changes, either additional chromosomal abnormalities or point mutations, are most likely responsible for disease transformation. Also in our patient, chromosomal analysis showed that, in addition to the rearrangements affecting chromosomes 9, 10, and 12 found at presentation, there were additional changes on chromosome 11 in the ALL clone. It is also highly likely that more detailed genomic analyses like exome sequencing, SNP array CGH etc., would detect additional driver mutations or deletion in genes previously shown to be affected in ETV6-ABL1-positive ALL like CDKN2A/B and IKZF1[31] as well as cryptic chromothripsis events [32]. To the best of our knowledge, this is the first description of an ETV6-ABL1-positive myeloid neoplasm that transformed into an ALL. Therefore, ETV6-ABL1 positive patients, even with a myeloid phenotype and CML-like clinical course, should be viewed as high risk patients.
    Acknowledgement