Chronic myeloid leukemia (CML) is characterised by the presence of the Philadelphia chromosome (Ph), which results in the production of the constitutively active tyrosine kinase BCR-ABL1, with tyrosine kinase inhibitors (TKI) targeted against this protein now being the mainstay of therapy. Clonal evolution in Ph-positive cells is rather uncommon in the chronic phase of CML (CP-CML) but is associated with disease progression, and although chromosomal abnormalities in Ph-negative cells have been described during imatinib therapy and more recently with newer TKIs, albeit rarely, clinical consequences remain unclear. Some of these patients do however evolve to a myelodysplastic syndrome (MDS) or an acute myeloid leukemia (AML), with loss of chromosome 7 seeming to confer the highest risk.
The case is that of a patient with CP-CML diagnosed in 2008 who initially experienced secondary resistance to imatinib, with the G250E and E459K point mutations in the BCR-ABL1 kinase domain (KD) being detected. Secondary resistance to dasatinib later developed, and this time the F317L BCRABL1 KD mutation was detected. Furthermore, a MDS with features of poor prognosis including loss of chromosome 7 in Ph-negative cells was diagnosed in 2012 while she was demonstrating a deep molecular response of her CML on nilotinib therapy. Azacitidine was added and resulted in a response of the MDS with a transfusion independency. The -7 clone was never again detected, but a gain of chromosome 8 (+8) was found on subsequent cytogenetic studies, as well as a sub-clone of Ph-positive cells harboring a t(5;20) (q32;q13) translocation. Due to loss of molecular and cytogenetic responses of her CML on nilotinib, the patient was switched to ponatinib and azacitidine was stopped. This resulted in a sustained major molecular response of her CML at 24 months, with no signs of recurrence of the MDS. Interestingly, the +8 clone has persisted on two cytogenetic studies performed after initiating ponatinib.
This report raises important issues regarding the natural history of CML and to the significance of seemingly independent Ph-negative clones identified during TKI therapy, as well as suggesting the efficacy of ponatinib in the presence of complicated clonal and mutational evolution of the Ph-positive cells as well as a MDS.
Keywords: Chronic myeloid leukemia, ponatinib, loss of chromosome 7, gain of chromosome 8, secondary myelodysplastic syndrome, clonal evolution, CML, chromosomal cytogenetic abnormalities, monosomy 7, trisomy 8