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IKZF1 Alterations an Independent Marker of AML Risk

February 2, 2024

February 2024

Leah Lawrence

Leah Lawrence is a freelance health writer and editor based in Delaware.

Mutated IKZF1 was an independent marker of adverse risk in patients with acute myeloid leukemia (AML), and patients whose AML had these alterations were at higher risk for unfavorable outcomes, according to the results of a retrospective study published in Leukemia.1

Jan-Niklas Eckardt, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany, and lead author of the paper, said that based on these results, these patients have to be identified and monitored accordingly and that “incorporation of IKZF1 mutation screening into clinical risk assessment can provide a more nuanced guidance of therapeutic decision-making for this subset of patients, in addition to existing risk assessment tools such as the European Leukemia Net 2022.”

Dr. Eckardt and colleagues conducted this retrospective, observational study looking at 1,606 adults with newly diagnosed and intensively treated AML who participated in previously reported trials. They performed screening for genetic alterations using pretreatment peripheral blood or bone marrow aspirates covering 54 genes known to be associated with myeloid neoplasms.

In a separate paper published in Haematologica, Dr. Eckardt explained that an artificial intelligence (AI) model was used to predict treatment response and overall survival in patients with intensively treated AML.2 They used next-generation sequencing (NGS) in conjunction with clinical information to train the AI classifier.

“The model picked up on several risk markers in AML and quantified their predictive power. It provided a high predictive accuracy in identifying patients who will (or will not) achieve complete remission with upfront intensive therapy and will (or will not) survive the first two years after diagnosis,” Dr. Eckardt said. “Regarding specific variables that the AI model selected, one that stood out to us was IKZF1. It was included in the NGS panel that we used to screen our patients and was given high attention by our AI model.”

After seeing the effect sizes for IKZF1, Dr. Eckardt and colleagues were intrigued, and that prompted the current retrospective study of IKZF1 in AML.

Of the 1,606 patients, IKZF1 alterations were found in 45 cases (2.8%) with a mutational hotspot at N159S. AML with IKZF1 had a median of four co-mutations.

Patients with IKZF1-mutated AML had increased rates of alterations in RUNX1 (26.6% vs. 8.7%, p<0.001), GATA2 (15.6% vs. 5.8%, p=0.016), KRAS (15.6% vs. 5.0%, p=0.008), KIT (15.6% vs. 4.6%, p=0.005), SF3B1 (15.6% vs. 2.5%, p<0.001), and ETV6 (8.9% vs. 0.7%, p=0.001). Less prevalent were co-occurring mutations of NPM1 (4.4% vs. 32.0%, p<0.001), FLT3-ITD (6.6% vs. 22.2%, p=0.010), and TET2 (4.4% vs. 19.8%, p=0.007).

“We demonstrated that mutations of IKZF1 are independent risk factors in AML even after adjusting for the current risk assessment standards in clinical routine such as the European Leukemia Net 2022 risk categories, de novo or secondary disease status, and age,” Dr. Eckardt said.

Indeed, multivariable analysis showed that IKZF1 alterations were independent markers for adverse risk related to complete remission rate (odds ratio = 0.45; 95% CI 0.22–0.91; p=0.026), event-free survival (hazard ratio [HR] = 1.59; 95% CI 1.15-2.18; p=0.004), relapse-free survival (HR=1.87; 95% CI 1.17-3.00; p=0.009), and overall survival (HR=1.68; 95% CI 1.22-2.32; p=0.002).

This study was limited by its patient sample of Caucasian adults; therefore, the findings may not be generalizable to other patient populations.

Dr. Eckardt said it is also important to bear in mind that the study was a retrospective multicenter observational study instead of a prospective randomized controlled trial. Therefore, treatment recommendations cannot confidently be inferred from its findings.

“In our cohort, we have seen patients with [IKZF1-mutated AML] bear high-risk disease, which was not mitigated by allogeneic hematopoietic cell transplantation,” Dr. Eckardt said. “The optimal treatment algorithm for this subset of patients remains yet to be determined.”

Additionally, several preclinical studies with menin inhibitors or specific degraders of IKZF proteins have demonstrated effectiveness in killing leukemic cells, and some early clinical trials are under way.

Any conflicts of interest declared by the authors can be found in the original article.

References

  1. Eckardt JN, Stasik S, Röllig C, et al. Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia [published online ahead of print, 2023 Oct 13]. doi: 10.1038/s41375-023-02061-1.
  2. Eckardt JN, Röllig C, Metzeler K, et al. Prediction of complete remission and survival in acute myeloid leukemia using supervised machine learning. Haematologica. 2023;108(3):690-704.

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