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

Adam Fisch, MD, PhD

Following approval from the FDA in November 2018, adult patients withFLT3-mutant acute myeloid leukemia (AML) were able to receive gilteritinib (Xospata), a 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 harboringFLT3mutations. However, at the 2019 Association for Molecular Pathology (AMP) Annual Meeting and Expo (AMP 2019), Adam Fisch, MD, PhD, presented a unique patient case where a patient with AML harboring aFLT3-TKD mutation lost the mutation following relapse on gilteritinib.

The patient was diagnosed withNPM1-mutated AML, based on World Health Organization (WHO) 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. Upon relapse, pathologists noted that her mutational signature was still the same, and the patient was put on a different treatment under a clinical trial.

At the patient’s second relapse, pathologists found the appearance of aFLT3-tyrosine kinase domain (TKD) mutation, which made her a candidate to receive gilteritinib. She received chemotherapy and the FLT3 inhibitor, and she remained in remission for about 1 year. However, following this relapse, the patient no longer had theFLT3-TKD mutation. All other mutations and her diagnosis ofNPM1-mutated AML remained the same.

Investigators hypothesized that theFLT3-TKD mutation appeared under 1 clonal expansion, then went away while aFLT3wildtype appeared under another clonal expansion. This case appears to be unique because while FLT3-TKD is typically discussed in the context of initial diagnosis or resistance following TKI treatment for FLT3-internal tandem duplication (ITD), it is not often described as a dynamic process appearing in one relapse and absent in a subsequent relapse, particularly in the setting of gilteritinib therapy.

This patient case was presented at AMP 2019 to demonstrate to clinicians that this can occur in patients and is something they should be aware of when treating patients with gilteritinib. Fisch also noted that this may be an area of interest to researchers in the field moving forward.

In an interview withTargeted Oncology, Fisch, a clinical fellow in molecular genetic pathology at the Brigham’s Women’s Hospital, discussed this case of a patient with AML that was treated with gilteritinib and lost theFLT3-TKD mutation upon relapse. He highlighted the uniqueness of this patient case and how clinicians should be aware of this possibility when treating patients with a FLT3 TKI.

TARGETED ONCOLOGY:Can you provide an overview of this case scenario?

Fisch:This is an interesting case where a patient with known AML who had prior diagnosis and multiple relapses had a relapse with aFLT3-TKD mutation. This was treated with a FLT3 inhibitor, gilteritinib. Following the treatment, we saw a reduction of her leukemic cells, so we saw a remission again, but when she relapsed following that, she actually did not have theFLT3-TKD anymore. It looked like what might have happened is that gilteritinib may have created a selective pressure such that it knocked out all theFLT3-TKD—positive cells but allowed clonal expansion ofFLT3wild-type cells.

TARGETED ONCOLOGY:What are the key points you are highlighting with this case?

Fisch:Ultimately, the key points are that gilteritinib [is] efficacious in many different patients withFLT3-positive AML, [but] this is just an unexpected thing that has not been reported much in the literature. 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 all in the context of a consistent genetic profile throughout the patient’s disease course. This provides insight into the possible subclonal dynamics of the patient’s disease. This presentation is [important] to highlight for other researchers [to know] that this happened and that maybe this is something worth looking into. [We would] also like to relay to clinicians if they see this sort of pattern in patients that are receiving gilteritinib, this exists and is something that has occurred, and it may be something they’ll see more down the road.

TARGETED ONCOLOGY:Could you elaborate on this patient case?

Fisch:The patient was initially diagnosed with AML and wasNPM1-mutated, which is a specific subtype by WHO criteria. She had multiple other mutations that were also present in her leukemia, and after chemotherapy she achieved remission and received a matched unrelated stem cell donor transplant. She relapsed about a year later and achieved remission again.

It was on the second relapse that we saw this appearance on molecular testing of aFLT3-TKD mutation. That is when she was a candidate for gilteritinib. She received chemotherapy as well as gilteritinib therapy, and in that time, we saw a reduction of her leukemia. She went back into remission again and seemed very successful. About 1 year after that, she relapsed again, and that is when she hadFLT3wild-type. It was stillNPM1-mutated AML. All the same mutations from before were still there, so we are confident it was still the same leukemia. It’s not some sort of new diagnosis, but theFLT3just came with 1 clonal expansion and went away in another clonal expansion in the next relapse.

TARGETED ONCOLOGY:What happened with this case moving forward?

Fisch:She received another therapy that is on trial following this relapse, but we cannot go into the mechanism of [this drug]. However, she did go 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.

TARGETED ONCOLOGY:What do you hope the audience was able to take away from this case?

Fisch:I think the main thing is that with disease presentation, you’re providing an anecdotal case of interest. I think what is unique about this case is that we have data from before the TKD mutation happening inFLT3, so we can compare what was in the backdrop as far as prior mutations and how this clonal evolution occurred overtime. When we see that theFLT3-TKD had occurred and she received treatment, [we saw] things got better and she relapsed, then theFLT3-TKD mutation was gone. We have some idea of maybe a subclonal change that is occurring, but this is a hint to researchers that maybe this is an area of interest that is worth looking into, as well as to clinicians that if they see this pattern occurring, this might be the path it is going down. Clinicians should maybe prepare by adjusting accordingly if they feel that is appropriate for the patient.

Reference:

Fisch A. Clonal Selection Following FLT3 Tyrosine Kinase Inhibitor Treatment for Acute Myeloid Leukemia. Presented at: 2019 Association for Molecular Pathology Annual Meeting and Expo; November 7-9, 2019; Baltimore, MD.