Risk Classification, Mutational Analysis Are Key in Informing AML Management

Naval Daver, MD

During an OncLive® workshop titled Key Updates in the Management of Acute Myeloid Leukemia (AML) and Their Application in Clinical Practice,¹ moderated by Naval Daver, MD, faculty reviewed updates to the classification of AML and its effects on the treatment paradigm and provided insight on the management of adverse-risk and secondary AML.

Daver, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, was joined by fellow colleagues:

1. Hetty Carraway, MD, MBA, FACP, director, Leukemia Program, vice chair, Strategy and Enterprise Development, Taussig Cancer Institute, progressor of medicine, Cleveland Clinic Lerner College of Medicine in Ohio;
2. Ann-Kathrin Eisfeld, MD, assistant professor, director, Clara D. Bloomfield Center for Leukemia Outcomes Research, Division of Hematology, The Ohio State University Comprehensive Cancer Center–James in Columbus;
3. Hagop Kantarjian, MD, professor and chairman, Department of Leukemia, Samsung Distinguished University Chair in Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston;
4. Rami Komrokji, MD, senior member and professor of oncologic sciences, vice chair, Malignant Hematology Department, Moffitt Cancer Center in Tampa, Florida;
5. Farhad Ravandi-Kashani, MD, professor of medicine, The University of Texas MD Anderson Cancer Center in Houston;
6. Gustavo Rivero, MD, associate professor, Lombardi Cancer Center, Georgetown University in Washington, DC;
7. Jonathan Webster, MD, assistant professor, hematologic malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins in Baltimore, Maryland; and
8. Nidia Zapata, MD, associate professor, Instituto Nacional de Cancerologia in Mexico City, Mexico.

Changes to the International Consensus Classification/European LeukemiaNet Guidelines

In 2022, the European LeukemiaNet (ELN) updated its risk classification guidelines to include bZIP in-frame CEBPA mutations in the favorable-risk category, FLT3 ITD mutations with mutant or wild-type NPM1 for intermediate-risk, and mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2into the adverse-risk category.

“CEBPA, which historically used to be considered favorable if you had a biallelic CEBPA, now, it’s really based on the mutational isoform, so the presence of the CEBPA bZIP is considered to be favorable, whether it’s single or multi-allelic,” Daver said.

“Similarly, FLT3, based on the results from RATIFY as well as from other studies, was shown to be prominently intermediate risk, whether it was with an NPM1 [mutation] or without, so this was all collapsed into one group [as] intermediate if you have a FLT3 mutation, regardless of the allelic ratio or the NPM1 [status], which also helps to simplify the prognostic impact of a FLT3 mutation,” Daver added. “Then importantly, this group of what was called secondary-like mutations was identified, and this was based on a paper showing that patients who had these mutations behave like secondary AML and had a poor outcome.”

Patients with adverse risk represent most patients with AML, according to both the 2017 and 2022 ELN recommendations. Favored treatment for this population includes CPX-351 (liposomal daunorubicin plus cytarabine), which showed improved survival compared with 7+3 chemotherapy (HR, 0.65; 95% CI, 0.48-0.87) and an estimated 5-year survival rate of 15% vs 5% with 7+3 alone.

Moreover, the new International Consensus Classification suggests screening for gene mutations including FLT3, IDH1, IDH2, NPM1, CEBPA, DDX41, TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2; and gene rearrangements including PML::RARA, CBFB::MYH11, RUNX1:RUNX1T1, KMT2A::R, BCR::ABL1, and other fusion genes if available.

As part of the diagnostic workup, the guidelines also recommend gene testing for ANKRD26, BCORL1, BRAF, CBL, CSF3R, DNMT3A, ETV6, GATA2, JAK2, KIT, KRAS, NRAS, NF1, PHF6, PPM1D, PTPN11, RAD21, SETBP1, TET2, and WT1, which can be used to monitor the disease through next-generation sequencing (NGS)-based minimal residual disease analyses.

Following the presentation of the latest risk classification guidelines, the faculty discussed whether molecular testing is necessary in all patients up front and whether to hold or delay treatment until results are returned. 

Komrokji stated that cytogenetic analysis, fluorescence in situ hybridization, and NGS is routine at Moffitt Cancer Center. Although NGS results generally take around 2 weeks to be returned, Komrokji stated that he generally will wait for results to be returned unless a patient has highly proliferative disease requiring immediate therapy. Komrokji added that he’ll send for polymerase chain reaction testing for FLT3, in addition to NGS, because the results can be turned around within approximately 48 hours and has greater bearing on frontline treatment.

Kantarjian added that at MD Anderson they’ll wait for an elderly patient’s FLT3 and IDH status, which if mutated would sway treatment toward a hypomethylating agent (HMA), venetoclax (Venclexta), and the appropriate targeted therapy. Kantarjian added that TP53 evaluation, which can be turned around in less 24 hours with immunohistochemistry, can be tricky to interpret without an expert eye. “It’s just not something that everybody will be able to do,” he said.

The faculty also acknowledged the challenges of waiting 2 weeks for complete results to be returned. “I think there’s a lot of opportunity for us to advocate and have results sooner than we do,” Carraway stated.

“I feel it’s also overcoming the need of the individual institutions to develop the panels. I think moving forward, especially with these multiple therapies, having the same panels and increasing comparability in-between centers would be something that I would find desirable,” Eisfeld said.

Following diagnostic workup, the first decision tree in AML is whether a patient is eligible for intensive induction therapy. “For patients who are not suitable for intensive induction chemotherapy, the backbone is an HMA and venetoclax, whether it’s azacitidine or decitabine,” Daver said.

Kantarjian added that the “ocular metric approach” or “eyeball approach,” although subjective and dependent on expertise, should take precedence over any existing scoring system.

However, Carraway stated, “I think so many of us are really wanting to put patients on a study and so that’s really the go-to. When you look at the National Comprehensive Cancer Network [guidelines], they even have clinical trial as the first thing.”

Outside of the score of a clinical trial and in the context of a patient with TP53-mutant disease, Webster stated that data support the consideration of azacitidine alone, which showed comparable survival to azacitidine and venetoclax. “We’re seeing a lot more cytopenias and a lot more toxicity with adding venetoclax, so if you can’t put somebody on a trial, then we do think about sparing them that toxicity.”

The question of transplant is less of a debate, Daver explained, stating, “Other than [those with] core-binding factor and isolated NPM1, [for] everybody else we are moving towards transplant now.”

Reference

Key updates in the management of acute myeloid leukemia and their application in clinical practice. OncLive® Scientific Interchange & Workshop. March 24, 2023. Accessed April 5, 2023.