A genomic analysis of Philadelphia chromosome-negative AML arising in patients with CML
Authors: K Krysiak, M J Christopher, Z L Skidmore, R T Demeter, V Magrini, J Kunisaki, M O'Laughlin, E J Duncavage, C A Miller, B A Ozenberger, M Griffith, L D Wartman, O L Griffith
Journal: Blood Cancer Journal (2016)

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia chromosome, an acquired clonal abnormality resulting from translocation of chromosomes 9 and 22, and the generation of the BCR-ABL fusion oncogene.The development of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of CML, as TKI therapy leads to inhibition of BCR-ABL activity, suppression of the BCR-ABL-containing clone and restoration of normal hematopoiesis in the vast majority of cases.Although TKI therapy is remarkably effective in clearing the BCR-ABL-containing clone in CML, it has been associated with the development of non-BCR-ABL rearranged (Ph -) clonal cytogenetic abnormalities (CCA). 1-4CCA have been observed in 3-10% of cases after complete cytogenetic resolution of the BCR-ABL fusion oncogene, occurring 6-18 months after initiation of TKI therapy. 2,3hese abnormalities-suggestive of clonal hematopoiesis-are often transient and not associated with CML progression.However, as routine cytogenetic monitoring during TKI therapy is rarely performed, the occurrence of CCA may be underestimated. 2,4evelopment of Ph -MDS/AML (myelodysplastic syndrome/ acute myeloid leukemia) following TKI therapy has been reported to occur infrequently and, in contrast to Ph -CCA, is associated with poor outcomes. 1,2,5,6Analysis of two CML patient cohorts treated with TKI therapy reported 2/985 and 3/1701 patients subsequently developed MDS/AML. 1,5Both studies were published with relatively short follow-up, raising the possibility that they may also underestimate the prevalence of Ph -AML.The relationship between CML and other clonal abnormalities that arise after TKI therapy is unclear, but they have been theorized to result from the unmasking of a premalignant clone that existed before acquisition of BCR-ABL. 2,3,5,7This scenario raises the possibility of a 'multi-hit' mechanism of CML development in which an early mutation(s) occurs and predisposes the premalignant clone to acquisition (or tolerance) of BCR-ABL.A high frequency of somatic mutations was reported in genes associated with myeloid malignancies in Ph -cells of CML patients treated with TKI. 7 Reports published prior to the TKI era suggested that multiple events are required for CML pathogenesis (postulated by Phil Fialkow and as reviewed by Deininger et al.). 4 In this scenario, one could hypothesize that the early mutation(s) that cooperates with BCR-ABL could also cooperate with mutations that lead to AML.Thus, a premalignant clone could increase susceptibility to both leukemias.Alternatively, it is possible that some CML patients harbor an abnormal bone marrow stroma that predisposes them to both the acquisition of BCR-ABL and other genetic aberrations (that could lead to MDS or AML), which could arise in distinct founding clones.Here we report two patients with CML treated with TKIs who achieved complete molecular remission but subsequently developed Ph -AML (Case Synopses).Both patients achieved durable complete molecular remissions before being referred to our center with AML.Consistent with the multi-hit model of leukemogenesis, we hypothesized that both malignancies were