Challenging Cases: The Evolving Treatment Landscape for Therapy-Related and De Novo AML
Key Points
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CPX-351 is the preferred induction therapy for fit patients with therapy-related acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS)-associated AML compared with standard 7+3.
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For older or unfit patients with newly diagnosed AML, as well as those with NPM1-mutated, FLT3–wild-type disease, azacitidine plus venetoclax is a favored treatment option.
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Allowing adequate time for remission assessment and hematologic recovery is critical in the management of AML.
AML is a heterogeneous disease with complex cytogenetics that requires treatment decisions that balance disease risk, patient fitness, and long-term goals.
Naval Daver, MD, of MD Anderson Cancer Center, joined co-hosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss how to treat both therapy-related AML and de novo AML based on evolving data and guidelines.
Managing Therapy-Related AML: CPX-531 vs 7+3
The first case presented involved a 63-year-old woman with a history of breast cancer who was treated with neoadjuvant anthracycline-based chemotherapy, surgery, and radiation. She subsequently developed AML.
Therapy-related AML and MDS are increasingly common, now accounting for about 30% to 35% of AML cases, Dr. Daver said. Although outcomes have improved compared with several decades ago, these diseases remain high-risk.
Two biologically distinct patterns are usually observed, he explained. One occurs 5 to 7 years after exposure to alkylating agents, anthracyclines, or radiation and is often associated with abnormalities of chromosomes 5, 7, or 17 and TP53 mutations. These cases have a poor prognosis, and allogeneic stem cell transplant (allo-SCT) remains the only potentially curative option. The second pattern follows topoisomerase II inhibitor exposure and presents earlier, within 1 to 3 years, often with KMT2A (11q23) rearrangements.
For fit patients in their early 60s, the treatment goal is disease control followed by allo-SCT. Induction-based therapy remains appropriate in this setting, with the standard being 7+3, Dr. Daver said. However, the phase 3 CLTR0310-301 trial comparing CPX-351 (liposomal daunorubicin and cytarabine) with 7+3 in therapy-related AML and AML with myelodysplasia-related changes demonstrated a clear benefit with CPX-351. Overall survival (OS, median 9.6 months vs 5.9 months), complete remission rates, and induction mortality all improved with CPX-351, leading to its approval by the Food and Drug Administration (FDA).
Long-term follow-up further strengthened its role, Dr. Daver said. Five-year OS was approximately 22% with CPX-351, compared with 9%-10% with 7+3. Among patients who went on to transplant after CPX-351, 5-year survival approached 50%.
Furthermore, CPX-351 is associated with fewer side effects, including mucositis, enterocolitis, Gram-negative infections, gastrointestinal toxicity, and alopecia, compared with 7+3. Although hematologic recovery is delayed by approximately 5-6 days, this has not resulted in increased infection-related mortality, Dr. Daver said.
Induction can be administered inpatient or in closely monitored outpatient settings, with patient age, frailty, distance from the treatment center, and caregiver support guiding the clinician’s decision.
While CPX-351 is not appropriate for all AML subtypes, it remains the preferred induction option for therapy-related and MDS-associated AML, consistent with National Comprehensive Cancer Network (NCCN) recommendations, Dr. Daver said.
De Novo AML Treatment
The discussion turned to de novo AML, with a second case of a 76-year-old man with progressive fatigue, bruising, and cytopenias. He received a new AML diagnosis with an NPM1 mutation and FLT3–wild-type disease. Comorbidities included heart failure, chronic kidney disease, and a reduced ECOG performance status of 1.5, which did not make him a candidate for intensive induction therapy.
For patients aged 75 years or older, or those with significant comorbidities, Dr. Daver said that low-intensity regimens are preferred. Current NCCN- and FDA-supported options include azacitidine plus venetoclax, decitabine plus venetoclax, or low-dose cytarabine plus venetoclax. Among these, Dr. Daver doesn’t favor low-dose cytarabine/venetoclax.
He most commonly uses the azacitidine/venetoclax regimen based on the VIALE-A trial and his real-world experience. Patients with NPM1-mutated, FLT3–wild-type AML, have a high response rate with this combination, Dr. Daver said.
At the 2025 American Society of Hematology Annual Meeting, data from the phase 2 PARADIGM study showed that hypomethylating agents (azacitidine/decitabine) plus venetoclax had superior efficacy compared with intensive chemotherapy in fit patients with AML. Moreover, Dr. Daver reported durable responses in patients with specific mutations, such as NPM1.
Best practices include early bone marrow assessment around day 21, stopping venetoclax once remission or marrow ablation is achieved, and allowing adequate time for count recovery, Dr. Daver explained. He also advised clinicians not to rush treatment since cycles can often extend to 5-6 weeks.
He also emphasized two key points: antifungal prophylaxis is necessary, typically with second-generation azoles; and although tumor lysis syndrome incidence remains low, it requires monitoring, especially in venetoclax-sensitive disease.
Although early data on novel combinations such as revumenib or ziftomenib are emerging, these approaches remain investigational, and more data is needed, Dr. Daver said.