Azacitidine and venetoclax (AZA/VEN) for older adults with AML ineligible for intensive chemotherapy
Hematologist-oncologists at the Abramson Cancer Center and Penn Hematology Oncology are using innovative approaches for older adults who are ineligible for high-intensity first-line therapy for acute myeloid leukemia (AML).
AML: Historical treatments
The most common form of acute leukemia, AML is a disease of older adults, with a median age at diagnosis of 68 years in the United States. The goal of first-line treatment for all patients, including older adults, is complete remission, defined as bone marrow blasts <5% with blood count recovery (ANC >1000, platelets >100,000). First-line induction therapy in fit patients, whatever their age, typically involves standard 7+3 (continuous cytarabine for 7 days combined with an anthracycline for the first 3 days). Following remission, these patients are candidates for consolidation therapy, including allogeneic stem cell transplant, depending on their risk of relapse.
However, because standard cytotoxic induction chemotherapy for AML causes severe myelosuppression, among other toxicities, only about half of older patients with AML are considered eligible for induction therapy. Prior to the development of newer lower-intensity therapies, older patients unfit to tolerate this first-line therapy received treatment with a hypomethylating agent (azacitidine or decitabine) alone or only supportive care.
Changing the landscape of treatment in AML: Treating older, unfit adult patients
At the Abramson Cancer Center (ACC), the combination of molecular abnormalities, age, and physical function are considerations for a patient’s ability to tolerate intensive versus non-intensive therapy. For older patients diagnosed with AML, the Abramson Cancer Center offers advanced and novel treatment options.
This effort is founded in a nuanced knowledge of the disease, and a comprehensive understanding of the many FDA-approved treatments for AML introduced in the last decade. From a practical perspective, this means knowing when and how to modify doses of drugs and duration of treatment based on response to therapy toxicities, functional capacity, and drug-drug interactions. An individual’s genetic profile is also important for both diagnosis and treatment strategy.
Biomarker-guided therapy for AML at the ACC
At the Abramson Cancer Center, patients with AML are categorized based upon molecular findings to aid in prognosis and to guide treatment decisions, including specific gene mutations and chromosomal changes, including IDH1/2 and FLT3, among others. Testing for prognostic mutations guides therapeutic decision-making.
For example, both ivosidenib (IDH1 inhibitor) combined with azacitidine and azacitidine combined with the BCL-2 inhibitor venetoclax (AZA/VEN), have been found to be equally efficacious in IDH1-mutant AML. [1,2] Agents for patients with relapsed or refractory FLT-3 mutant AML include gilteritinib, which was approved on the basis of the international, multicenter, Phase 3 ADMIRAL study, led by Alexander Perl, MD, MS, at the Perelman School of Medicine and the Abramson Cancer Center. [3]
The role of azacitidine plus venetoclax in AML therapy
While the Abramson Cancer Center offers a variety of options for all patients with AML, AZA/VEN is considered the new standard of care for older adults not eligible for intensive first-line therapy.
What is AZA/VEN?
Azacitidine is a chemotherapy drug that alters a cancer cell's genetic epigenetics by inhibiting DNA methyltransferase. This reduces the production of leukemia cells and permits bone marrow to produce more healthy functioning cells.
Venetoclax is a targeted cancer drug that binds to and inhibits BCL-2, a protein overexpressed in AML, preventing apoptosis in leukemia cells.
Goals of therapy: AZA/VEN is administered with the goal of complete remission, increased blood cell counts, and transfusion independence which leads to an improved quality of life and overall survival. Treatment is often continued after remission to keep patients in remission long term or as a bridge to bone marrow transplant in younger patients.
Safety: AZA/VEN is generally safe; however, certain facets of therapy must be closely monitored to prevent tumor lysis syndrome, minimize infectious complications during treatment, and to limit cumulative marrow suppression during ongoing treatment.
AZA/VEN Outcomes
In VIALE-A, the randomized phase III study that led to the FDA approval of AZA/VEN in AML, CRc rates (a composite of complete remission (CR) + CR with incomplete hematological recovery) was higher and median duration of response longer in the AZA/VEN arm vs AZA alone at all age groups, including patients >85 years of age. [4]
Case Report
Mr. S, an 89-year-old farmer, was referred to the Abramson Cancer Center in December 2024 after receiving a diagnosis of AML. He originally presented with pancytopenia (absolute neutrophil count 0.24, hemoglobin 7.8, platelets 129) during a hospitalization for a GI bleed. A bone marrow biopsy found 50% blasts. His course was complicated by neutropenic fever secondary to influenza.
Although Mr. S had a good performance status, his age and past medical history, which included left circumflex artery stenosis and abdominal aortic aneurysm, precluded him from induction therapy for AML. He then began supportive blood transfusions as needed as an outpatient.
Subsequently, Mr. S was referred to Catherine Lai, MD, MPH, at the Abramson Cancer Center, where in January 2025, a mutational analysis revealed an IDH2 mutation. IDH2 mutations drive AML by promoting the cellular accumulation of 2-hydroxyglutarate (2HG), a metabolite that disrupts normal cell function and promotes tumor growth. IDH-2 and its homolog IDH1 are found in approximately 10-15% of patients with AML. Because mutations in IDH1/2 are uniquely sensitive to treatment with azacitidine and venetoclax, Dr. Lai recommended that Mr. S start treatment with AZA/VEN.
Mr. S tolerated AZA/VEN well, and after one cycle, he went into complete remission and became transfusion independent with normalization of blood counts. Last seen in February 2026, he reports that he continues to tolerate treatment well. He was back to his usual daily activities including being active around the farm and riding his tractor.
Because he lives quite a distance from the Abramson Cancer Center, Mr. S has a local oncologist that Dr. Lai partners with so that he can continue to receive care closer to home. He sees Dr. Lai monthly for regular check-ins, lab review, and adjustment of chemotherapy doses, as needed, to keep his blood counts stable.
About Hematology Oncology at the Abramson Cancer Center
Penn Hematology Oncology and the specialists at the Abramson Cancer Center offer advanced AML treatments, including chemotherapy, stem cell transplants, targeted therapies, such as FLT3 inhibitors and venetoclax, as well as CAR T-cell therapy and other immunotherapies. Personalized approaches to therapy are a specialty, particularly for complex cases, as is the leveraging of combination therapies and clinical trials to enhance survival outcomes.
Referrals to Penn Hematology Oncology
Primary care providers and community oncologists are encouraged to develop a relationship with an academic partner to co-manage patients with AML, with the understanding that the preferred option for patients is to be treated in the community, allowing them to be closer to home.
To refer a patient to Dr Lai or her partners at Penn Hematology Oncology, please call 215-615-5858, or submit a referral through our secure on Refer patient line referral form.
References
[1] Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–731.
[2] Montesinos P, Recher C, Vives S, et al. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med 2022;386:1519-1531.
[3] Perl AE, Altman JK, Cortes JE, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncology 2017;18:1061-1075.
[4] DiNardo, CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 2020;383:617-629.