Abstract B38: F317i mutation-associated nilotinib resistance in a child with CML: A first report.

Background: Philadelphia chromosome, t(9;22), positive (Ph+) chronic myelogenous leukemia (CML) accounts for only 2-2.5% of childhood leukemia cases or about 60 cases per year in the US. Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis and treatment of CML in adults and children. Failure of TKIs is often due to mutations. In adult CML, the F317i mutation has been implicated in resistance to first and second line TKIs (imatinib/dasatinib) without affecting sensitivity to the third line TKI, nilotinib. The F317i mutation has been documented a handful of times in adult CML and in childhood Ph+ALL cases. We describe what we believe to be a first report of F317i mutation in a child with Ph+ CML who, after initial major molecular responses, rapidly developed resistance to first, second and third line TKIs.

The current Childrens Oncology Group trial of oral nilotinib (COG AAML1321) does not recognize F317i as a mutation associated with nilotinib resistance.

Case: An 11-year old female with classic chronic phase (CP) CML was found to have the F317i mutation after initially achieving an MMR during the first 3 months of treatment while on dasatinib. After results of the F317i mutation were received, the patient was switched to nilotinib and again achieved an MMR in the first 2 months before rapidly decompensating with a pre B cell ALL blast crisis. The child was then treated with ALL induction and consolidation and allogeneic stem cell transplant and again achieved an MMR which has been sustained for 5 months.

Methods: Cases of the F317i mutation have been documented in adults, however, we did an extensive literature search of PubMed, Ovid, and Google Scholar using keywords “F317” as well as F317i, ” and we were unable to find another report of this mutation in a child.

Discussion: CML in children is rare and to our knowledge the F317i mutation in children has not been previously reported. In contrast to how the F317i mutation is expected to behave in adult Ph+ CML, our patient developed resistance to nilotinib.

Conclusion: Our CML patient failed nilotinib. The F317i mutation in a child may warrant closer molecular monitoring and the consideration of early stem cell transplantation.

Citation Format: Heidi Tucker, Paul Kent. F317i mutation-associated nilotinib resistance in a child with CML: A first report. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B38.