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Experts Answer Questions on Optimizing Therapeutic Approaches in AML

Naval G. Daver, MD

Director
Leukemia Research Alliance Program
Associate Professor
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, Texas


Naval G. Daver, MD: consultant/advisor/speaker: AbbVie, Agios, Amgen, Arog, Astellas, Bristol-Myers Squibb, Celgene, Daiichi-Sankyo, Genentech, Gilead Sciences, Jazz, Novartis, Pfizer, Servier, Shattuck Labs, Syndax, Trillium; researcher: AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Daiichi-Sankyo, FATE Therapeutics, Genentech, Gilead Sciences, Glycomimetics, Hanmi, ImmunoGen, Novimmune, Pfizer, Trilium, Torvagene; independent contractor: ImmunoGen.


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Amir T. Fathi, MD

Director, Leukemia Program
Massachusetts General Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts


Amir T. Fathi, MD: consultant/advisor/speaker: AbbVie, Agios, Amgen, Astellas, Bristol-Myers Squibb, Celgene, EnClear, Foghorn, Forma, Genentech, Immunogen, Ipsen, Kite, Mablytics, MorphoSys, Novartis, Orum, PureTech, Servier, Takeda.


View ClinicalThoughts from this Author

Released: September 7, 2022

Key Takeaways

  • Having adequate support for patients undergoing intensive induction chemotherapy is crucial to prevent complications
  • Targeted therapies for actionable molecular alterations are increasingly available for the treatment of acute myeloid leukemia and will likely transform the management of this disease state

In this commentary adapted from a discussion between Naval G. Daver, MD, and Amir T. Fathi, MD, the experts address important clinical questions regarding the treatment of patients with acute myeloid leukemia (AML).

Is there still a place for fludarabine, cytarabine, granulocyte colony stimulating factor with idarubicin (FLAG-Ida) as induction chemotherapy, or is “7+3” the preferred induction therapy?

Naval G. Daver, MD:
This is more institutional preference and comfort; I do not know if this debate will ever be resolved. FLAG-Ida is a very effective regimen in both the salvage and frontline settings. At MD Anderson, we do use FLAG‑Ida. If you have a fit, young patient and practice at a large medical center with strong ICU support and infectious diseases colleagues, I think FLAG‑Ida is a reasonable option. A healthcare professional must know what they are comfortable with and what their support system can handle, but other than that I do not think it really matters which induction therapy you use—FLAG-Ida or 7+3.

How would you approach a 40-year-old patient with newly diagnosed AML that is FLT3-negative and has IDH2, EZH2, and BCOR mutations?

Amir T. Fathi, MD:
This is a young patient who is intermediate risk. Historically, you could make the argument that this patient would receive induction followed by either consolidative transplant or chemotherapy. When mutations are present, we become concerned that there might be some suggestion of preceding disease and that this patient may not do well with just consolidation and should instead go to transplant. There may be some benefit to looking at maintenance therapy with IDH inhibitors following transplant for these patients who have an IDH mutation; an ongoing study is examining this. Time will tell with larger studies whether maintenance therapy might benefit them following transplant, but I would recommend transplant.

Are there any genetic mutations or genetic features more related to secondary AML than primary AML?

Amir T. Fathi, MD:
Yes, there are. Splicing alterations in a patient who has AML typically indicates the patient previously had myelodysplastic syndrome (MDS). BCOR mutations have been associated with prior MDS. ASXL1 mutations also could be related to prior MDS. TP53‑mutated AML is associated with the presence of a complex karyotype, previous exposure to chemotherapy, or previous radiation therapy. There are also fusions (eg, MLL fusions) that might be related to prior therapy. These signatures indicate preceding disease in patients and may sway you one way or another in terms of treatment choice.

Naval G. Daver, MD:
European LeukemiaNet 2022 recommendations include these mutations very clearly now. Splicing alterations, EZH and RUNX1, are strongly associated with AML following prior MDS.

What dose of gilteritinib do you recommend in combination with venetoclax 120 mg or 80 mg?

Naval G. Daver, MD:
Gilteritinib 80 mg with venetoclax is very effective with less myelosuppression than 120 mg of gilteritinib. Another thing to note is the reduction of the venetoclax duration to manage myelosuppression. We start with 21 days, but we are quickly coming down to 14 days. An update on this study is expected at American Society of Hematology 2022.

Are there any agents specifically being developed for TP53-mutated AML?

Naval G. Daver, MD:
Beyond the CD47 agents such as magrolimab, not really. Eprenetapopt was being developed, but unfortunately, the phase III trial of frontline eprenetapopt plus azacitidine vs azacitidine alone in TP53-mutant MDS was negative. It is not clear whether this will be further developed. Immunotherapies such as natural killer (NK) cell and CAR T-cell therapies are being investigated. These therapies should work in TP53-mutant AML, but there is nothing specifically in development for TP53-mutant AML that I am aware.

If venetoclax is interrupted with a drug-free interval of 3 months, should there be a dose ramp-up upon resumption?

Naval G. Daver, MD:
I would, but I do not think there are any hard data. If the patient has active disease and a high white count, I would be cautious and do a 3‑day ramp-up.

Is targeted therapy the future for AML? Will there be an “all-for-one” treatment?

Amir T. Fathi, MD:
I do not think there will be a one-for-all treatment; rather I think it will be the opposite. AML is a highly heterogeneous disease. I truly feel that we are treating 20 or 25 different types of disease that may look similar underneath the microscope but are very different from each other. Finding tailored therapy that is more effective for the individual patient will be more beneficial. I hope that is the future.

Naval G. Daver, MD:
I think this question may be angling toward using CAR T-cell therapy and what has happened in lymphoma and in acute lymphoblastic leukemia. I hope the future is going to be a combination of targeted therapies with lower intensity upfront. Then, for patients with minimal residual disease, we will bring in immunotherapies, which might be CAR T-cells, NKs, or bispecific antibodies. It is going to take 5-10 years, but I do think that is where the field will go, just like in lymphoma and myeloma.

Your Thoughts?
What challenges have you encountered in treating patients with AML? Share your experiences in the comment box below.

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