clinical topic updates

Approach to Patients With MDS/AML Who Are Ineligible for Intensive Chemotherapy

by Courtney D. DiNardo, MD, MSCE

Overview

Patients who are ineligible for intensive chemotherapy are in need of effective and well-tolerated alternatives. Our featured expert describes the recent progress that has been made with lower-intensity combination therapies in myelodysplastic syndrome and acute myeloid leukemia (AML).

Expert Commentary

Courtney D. DiNardo, MD, MSCE

Associate Professor
Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

“Increasingly, patients who are not eligible for intensive chemotherapy can receive and benefit from lower-intensity combination therapy. In the past, the approach would have been more palliative. . . .”

Courtney D. DiNardo, MD, MSCE

The majority of patients with myelodysplastic syndrome and AML are in their late 60s and early 70s, so the question of whether they are eligible for a standard intensive chemotherapy approach is among the most important questions that we, as clinicians, must try to answer in the treatment of leukemia.

For patients who are ineligible for intensive chemotherapy, there have been tremendous advances in the field recently. Just approximately 10 years ago, we had mainly palliative approaches. We would use azacitidine alone, decitabine alone, or low-dose cytarabine. Approximately 40% of patients would experience an improvement in their counts or a true remission with this approach. The challenge with these therapies is that none of them are particularly durable.

What has changed so significantly is that we are making progress with the recent US Food and Drug Administration approval of several different combinations and, in particular, venetoclax with a hypomethylating agent in patients with AML. The outlook used to be anchored in a median survival of less than 1 year, whereas now that median survival extends beyond 1 year. And there are some particularly outstanding responders who initiated venetoclax with hypomethylating agent therapy in 2015 and are still in my clinic today. This has really dramatically changed the outlook for many of our patients. We currently have more effective combination therapies that are also well tolerated. Increasingly, patients who are not eligible for intensive chemotherapy can receive and benefit from lower-intensity combination therapy. In the past, the approach would have been more palliative, as previously noted.

Of course, there are nuances between each new therapy, as every treatment has side effects. For example, with venetoclax use, you do see more cytopenias at the beginning, and it is very rare that I have a patient on continuous ongoing venetoclax. Most of my patients in remission end up on venetoclax for 21 days—sometimes 14 days—per cycle to allow the patient's counts to recover and normalize before I start the next cycle.

Although the durability of response to venetoclax may vary depending on the underlying molecular and genomic features of the disease, venetoclax tends to be overall agnostic to a single specific mutation or genomic subtype. Unfortunately, however, we are not seeing an improvement in the survival of TP53-mutated AML, and this continues to represent one of the greatest unmet needs in the field.

Nonetheless, we now also have targeted therapies that include IDH1, IDH2, and FLT3 inhibitor therapy, as well as the small-molecule inhibitor glasdegib. Additionally, we are poised to study new ways to optimize combination therapy for our patients. For example, a randomized trial of azacitidine with the IDH1 inhibitor ivosidenib has shown impressive remission rates and improved overall survival among intensive chemotherapy–ineligible patients with newly diagnosed AML with an IDH1 mutation.

References

Almeida AM, Ramos F. Acute myeloid leukemia in the older adults. Leuk Res Rep. 2016;6:1-7. doi:10.1016/j.lrr.2016.06.001

Juárez-Salcedo LM, Desai V, Dalia S. Venetoclax: evidence to date and clinical potential. Drugs Context. 2019;8:212574. doi:10.7573/dic.212574

Lachowiez C, DiNardo CD, Konopleva M. Venetoclax in acute myeloid leukemia - current and future directions. Leuk Lymphoma. 2020;61(6):1313-1322. doi:10.1080/10428194.2020.1719098

Montesinos P, Recher C, Vives S, et al. AGILE: a global, randomized, double-blind, phase 3 study of ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation [abstract 697]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Norsworthy KJ, By K, Subramaniam S, et al. FDA approval summary: glasdegib for newly diagnosed acute myeloid leukemia. Clin Cancer Res. 2019;25(20):6021-6025. doi:10.1158/1078-0432.CCR-19-0365

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