Hematology and Leukemia

Hematology and Leukemia

ISSN 2052-434X
Case report

Case report: Efficacy of ponatinib in a case of chronic myeloid leukemia with a complicated clonal evolution including a myelodysplastic syndrome

William McCarvill, Harold J Olney, Xiaoduan Weng, Boli Fan and Denis Soulières*

*Correspondence: Denis Soulières denis.soulieres@umontreal.ca

Department of Medicine, Service of Hemato-Oncology, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada.

Abstract

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

ISSN 2052-434X
Volume 6
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