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Fisch Highlights Patient Case of Relapse Following Gilteritinib Treatment in FLT3-TKD+ AML

Danielle Ternyila
Published Online: Nov 29,2019
Adam Fisch, MD, PhD
Adam Fisch, MD, PhD
Following the FDA’S approval of gilteritinib (Xospata) in November 2018, adult patients with FLT3-mutant acute myeloid leukemia (AML) were able to receive the FLT3 tyrosine kinase inhibitor (TKI) when they relapsed or became refractory to a prior therapy. The agent has demonstrated promising efficacy in the population of patients with AML harboring FLT3 mutations.

However, at the Association for Molecular Pathology 2019 Annual Meeting and Expo (AMP 2019), Adam Fisch, MD, PhD, presented a unique case: A patient with AML harboring a FLT3–tyrosine kinase domain (TKD) mutation lost the mutation following relapse on gilteritinib.1

More than a dozen small molecule FLT3 TKIs have been investigated in early-phase trials,2-9 and midostaurin (Rydapt), sorafenib (Nexavar), quizartinib, gilteritinib (Xospata), and crenolanib are either being investigated or were recently studied in randomized phase III studies.

The National Comprehensive Cancer Network stratifies patients into 3 risk groups: favorable, intermediate, and poor/adverse (TABLE).10 Patients with AML with normal cytogenetics harboring the FLT3-internal tandem duplication (ITD) or TP53 mutations are classified as poor risk. Because FLT3-ITD mutations are considered to confer a significantly poor outcome, these guidelines suggest that patients with these mutations be considered for clinical trials.

The patient received a diagnosis of NPM1-mutated AML, based on World Health Organization diagnostic criteria. Other mutations were also presented at diagnosis. The patient received chemotherapy and achieved remission, followed by a matched unrelated stem cell donor transplant. Pathologists noted that, upon relapse, her mutational signature was still the same, and she was put on a different treatment under a clinical trial.

At the patient’s second relapse, pathologists found the appearance of a FLT3-TKD mutation, which made her a candidate to receive gilteritinib. She received chemotherapy and the FLT3 inhibitor and remained in remission for about 1 year. However, following this relapse, the patient no longer had the FLT3-TKD mutation. All other mutations and her diagnosis of NPM1-mutated AML remained the same.

Investigators hypothesized that the FLT3-TKD mutation appeared under 1 clonal expansion, then went away while a FLT3 wild-type appeared under another clonal expansion. This case appears to be unique because, although FLT3-TKD is typically discussed in the context of initial diagnosis or resistance following TKI treatment for FLT3-ITD, it is not often described as a dynamic process appearing in one relapse and absent in a subsequent one, particularly in the setting of gilteritinib therapy.



This patient’s case was presented at AMP 2019 to demonstrate that clinicians should be aware of this possible occurrence when treating patients with gilteritinib. This may be an area of interest to researchers in the field, Fisch added.

“I think what is unique about this case is that we have data from before the TKD mutation happening in FLT3,” said Fisch, a clinical fellow in molecular genetic pathology at Brigham and Women’s Hospital in Boston, Massachusetts. “We can compare what was in the backdrop as far as prior mutations and how this clonal evolution occurred over time.” Fisch spoke with Targeted Therapies in Oncology to highlight the uniqueness of this patient case and how clinicians should be aware of this possibility when treating patients with an FLT3 TKI.

Fisch hypothesized that gilteritinib may have created a selective pressure that knocked out all the FLT3-TKD–positive cells but allowed clonal expansion of FLT3 wild-type cells. “Gilteritinib [is] efficacious in many different patients with FLT3-positive AML, [but] this is just an unexpected thing that has not been reported much in the literature,” Fisch said. “We do not see a lot of discussion about FLT3-TKDs first appearing in relapse of AML and then absent in a subsequent relapse following TKI treatment.”

The patient received an experimental therapy that is undergoing investigation. She went into remission and is now being monitored. “Her story is still definitely ongoing and seems to be going well, but beyond that, we can’t really say,” Fisch said.
 
 
References:
  1. Fisch A. Clonal selection following FLT3 tyrosine kinase inhibitor treatment for acute myeloid leukemia. Presented at: Association for Molecular Pathology 2019 Annual Meeting and Expo; November 7-9, 2019; Baltimore, MD.
  2. O’Farrell AM, Foran JM, Fiedler W, et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res. 2003;9(15):5465-5476.
  3. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103(10):3669-3676. doi: 10.1182/blood-2003-11-3775.
  4. Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105(1):54-60. doi: 10.1182/ blood-2004-03-0891.
  5. Pratz KW, Cortes J, Roboz GJ, et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood. 2009;113(17):3938-3946. doi: 10.1182/blood-2008-09-177030.
  6. Pratz KW, Cho E, Levis MJ, et al. A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias. Leukemia. 2010;24(8):1437-1444. doi: 10.1038/leu.2010.132.
  7. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681-3687. doi: 10.1200/JCO.2013.48.8783.
  8. Galanis A, Ma H, Rajkhowa T, et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood. 2014;123(1):94-100. doi: 10.1182/blood-2013-10-529313.
  9. Borthakur G, Kantarjian H, Ravandi F, et al. Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica. 2011;96(1):62-68. doi: 10.3324/haematol.2010.030452.
  10. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia, version 2.2020- National Comprehensive Cancer Center website. https://bit. ly/37bmk1y. Published September 3, 2019. Accessed November 15, 2019.



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Fisch Highlights Patient Case of Relapse Following Gilteritinib Treatment in FLT3-TKD+ AML
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