EHA 2019 round up – FLT3 mutations in AML

Last year, at the European Hematology Association (EHA) meeting, a lot of attention was focused on the FMS-like tyrosine kinase-3 (FLT3) mutations in acute myeloid leukemia (AML). With the next annual EHA meeting fast approaching, we are going to see more reports on this topic, including the ADMIRAL trial update on the emerging mutations after treatment with a FLT3 inhibitor, results from the RATIFY study on the molecular landscape and prognostic impact of the FLT3 internal tandem duplication (ITD) insertion site, and a retrospective study of posttransplant maintenance therapy in patients with FLT3 mutations. 

In this article we created a summary of the highlights on this topic with expert interviews and articles we have covered since the last EHA meeting.

FLT3 mutations

FLT3 mutations are one of the most common molecular abnormalities in AML. ITD of the juxtamembrane domain of the FLT3 gene (FLT3-ITD) is detected in 25–30% of all newly diagnosed patients with AML, and is associated with poor prognosis due to the aggressive course of the disease and the risk of early relapse.¹ 

The reasons why FLT3 testing of patients with AML should become incorporated into clinical practice were discussed by Jorge Sierra, from the Hospital de la Santa Creu i Sant Pau, ES, during the last EHA meeting. He stressed the importance of testing patients for FLT3 mutations from the prognostic point of view. But he also highlighted the fact that tumors with FLT3 mutations can be specifically targeted with selective FLT3 inhibitors such as gilteritinib and midostaurin.

Gilteritinib

Gilteritinib is a second generation selective dual FLT3/AXL inhibitor which was investigated in the ADMIRAL (NCT02421939) phase III trial for relapsed or refractory (R/R) AML. Last year, during the EHA meeting, we interviewed Alexander Perl from the University of Pennsylvania, US, who presented the data from the trial.

He described the study design and results of the study. The favorable outcomes of gilteritinib observed in this trial (increased complete response rate and overall survival) led to its FDA approval for R/R AML.

The results of the ADMIRAL study were later published and summarized in the article available here. In summary, a total of 371 patients with R/R AML were included in the study, all of whom had either the FLT3-ITD or tyrosine kinase domain (D835 or I836) mutations. Patients were randomly allocated in a 2:1 ratio to either gilteritinib or one of the following four chemotherapy regimens, based on their response to previous treatment: mitoxantrone, etoposide, and cytarabine; fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin; low-dose cytarabine; or azacitidine. The study demonstrated improved overall survival (9.3 vs 5.6 months) and remission rates with gilteritinib vs chemotherapy in patients with R/R FLT3 mutated AML.

Based on the results of the study, the European Commission approved gilteritinib for the treatment of FLT3-mutated R/R AML in October 2019.

During the European School of Haematology (ESH) Translational Research Conference, we asked Catherine Smith, from the Department of Medicine, University of California San Francisco, US, how will the use of FLT3 inhibitors evolve in the future.

She provided her expert opinion outlining the challenge of resistance development, both on-target and off-target, and how the field is currently trying to overcome them with drug combination regimens. She provided arguments for a sequential use of different treatment modalities to better address the heterogeneity of AML at diagnosis and relapse.

During the 61st American Society of Hematology (ASH) annual meeting & exposition, we spoke to Siddhartha Ganguly, University of Kansas, US, and asked whether quizartinib maintenance should become standard of care after stem cell transplantation for patients with FLT3 mutated AML.

In the video, Siddhartha Ganguly talked about the role of quizartinib in the posttransplant and pretransplant setting. He discussed the results of the QuANTUM-R study that compared quizartinib with salvage chemotherapy in patients with R/R FLT3-ITD AML. He also described the post hoc analysis of that study, in which he examined the clinical characteristics and the outcome of patients that underwent subsequent allogeneic HSCT (allo-HSCT).

Acute Leukaemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) guidelines

While there is general agreement on the incorporation of FLT3 inhibitors in the frontline treatment and the use of measurable residual disease (MRD) assays, the strategy for allo-HSCT differs between centers.

Globally, hematologists agree on quick treatment initiation followed by allo-HSCT once patients have achieved their first complete remission. However, clinical protocols vary regarding indication for allo-HSCT according to risk profiles, modalities of allo-HSCT, and post-transplant maintenance. Therefore, in May 2020 the ALWP of the EBMT published their position statement on allo-HSCT for patients with FLT3-ITD AML.

A panel of 32 members, mostly from the EBMT, was selected by the chairs, Professor Ali Bazarbachi and Professor Mohamad Mohty, based on their expertise in research and clinical practice in AML and allo-HSCT. Using the Delphi technique, three panelists provided statements addressing key questions to the remaining panel members who scored their agreement with those statements and suggested rephrasing where necessary. Available evidence from public databases was used to rate the strength of recommendations and evidence level. A summary of the article is available here.

Pre-transplant FLT3-ITD status as a prognostic marker for outcome in FLT3-mutated AML

It has been shown that negative effects of FLT3-ITD are only seen if the ratio of mutated to normal alleles is > 0.5, which adds to the controversy of the role of allo-HSCT in FLT3-mutated patients in their first complete remission. In a retrospective study, Grzegorz Helbig and colleagues, from the Medical University of Silesia, PL, aimed to evaluate the potential factors that may have an impact on the outcome of FLT3-mutated patients after allo-HSCT. They found that the strong positive correlation between FLT3 MRD positivity and flow-cytometric MRD positivity suggests that pretransplant detection of the FLT3-ITD mutation by PCR may serve as a reliable MRD marker, and predict posttransplant outcome better than the hematological disease status. The article is available here.

Conclusion

Since the last EHA meeting, we developed a deeper understanding of the prognostic value of testing patients with AML for FLT3 mutations. FLT3 inhibitors have been demonstrated to be safe and active in these settings. Additionally, we now have the recommendations on how to manage patients with FLT3-ITD. We are looking forward to the updates from the ADMIRAL and RATIFY clinical trials, among others, that will provide further insights, including the molecular landscape after the FLT3 inhibitors relapse.