“Knowledge is like a lion; it cannot be gently embraced.” –South African Proverb

Long-term efficacy and safety confirm that a hypomethylating agent and venetoclax is an improvement in the standard of care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities. Ensuring proper patient selection, dosing and frequency adjustments, and close monitoring for potential drug interactions when using venetoclax-based therapy for patients newly diagnosed with acute myeloid leukemia (AML) is crucial in optimizing outcomes. Given the complexity of managing AML, especially with the evolving role of venetoclax, it is highly beneficial to stay up to date with the latest trial data and therapeutic consensus guidelines. Here, we discuss strategies and clinical considerations when treating patients with AML who are ineligible for intensive chemotherapy as well as those who are eligible for intensive chemotherapy.

Syed Ali Abutalib, MD

Courtney DiNardo, MD, MSCE

For Patients Who Are Ineligible for Intensive Chemotherapy

Dr. Abutalib: In your experience, is a hypomethylating agent or low-dose cytarabine a “better partner” for venetoclax when treating patients with non-APL?

Dr. DiNardo: The VIALE-A trial confirmed that the combination of a hypomethylating agent and venetoclax led to a significant improvement in both composite complete remission rates and median overall survival (azacitidine plus venetoclax was associated with a composite complete remission rate of 66% and a median overall survival of 15 months). So, generally, I would view a hypomethylating agent as a “better partner” for treating AML.

Dr. Abutalib: In your experience, what is the reasonable starting dose and frequency for venetoclax (14 vs 21 vs 28 days)?

Dr. DiNardo: I typically start with venetoclax × 21 days with the first cycle. In patients who recover quickly, I might keep it to 21 days (often over a 5–6-week cycle), but in most patients, I will decrease it over time to 14 days per cycle.

Dr. Abutalib: How should venetoclax dosing be adjusted if the patient is on antifungal prophylaxis? And do all patients require posaconazole during induction?

Dr. DiNardo: It is important to pay attention to the occurrence of CYP3A4 interaction. In the setting of a moderate CYP3A4 inhibitor (ie, ciprofloxacin, fluconazole, isavuconazole), venetoclax should be reduced by 50% to 200 mg daily. With a strong CYP3A4 inhibitor such as voriconazole, venetoclax should be reduced to 100 mg daily. Since posaconazole is a particularly strong CYP3A4 inhibitor, the dose of venetoclax should be reduced further to 50 to 70 mg daily as a starting dose.

Dr. Abutalib: Do you maintain the same venetoclax dose even if antifungal therapy is intermittently introduced? How do you navigate potential drug interactions with dosing recommendations?

Dr. DiNardo: I typically stop the azole once the patient is in a remission, so there are no long-term interactions; interactions primarily occur just in the first cycle or two. But yes, drug-drug interactions are very important, and patients should know to inform their care team (especially pharmacy colleagues) of any new drugs started by other treating physicians, since these interactions can be significant.

Dr. Abutalib: If venetoclax is initiated and a targetable or actionable mutation (eg, FLT3-ITD, IDH1/2) is later discovered, would you discontinue venetoclax in favor of targeted therapy (eg, gilteritinib), or would you consider using a triplet regimen in combination with the targeted agent?

Dr. DiNardo: My recommendation would be to wait for genomic information prior to starting a treatment regimen whenever possible. AML is not usually proliferative in most older patients, so you can wait 1 to 2 weeks to start treatment with careful follow-up for genetic results. But if no genetic testing is done, I would keep the azacitidine plus venetoclax going if a patient was responding well to it. I may add the targeted therapy if there was evidence of ongoing disease (ie, measurable residual disease–positive disease), in an attempt to prevent relapse, which makes sense. However, there are limited data currently available to support such an approach.

Dr. Abutalib: Is there a biologic subtype of AML in which a venetoclax combination therapy may not provide additional benefit?

Dr. DiNardo: Patients with TP53-mutated disease have an improved initial response rate, but it does not translate into improved overall survival.

Dr. Abutalib: If a patient presents with a white blood cell (WBC) count > 25,000/mL, do you hold venetoclax until counts drop below 25,000/mL, as per the package insert, or would you initiate venetoclax with more caution in this scenario?

Dr. DiNardo: I would give hydroxyurea (or a one-time dose of cytarabine, perhaps 500–1,000 mg × 1) for cytoreduction and then start the azacitidine plus venetoclax. I do not like starting venetoclax until the WBC is closer to 10,000/mL to 15,000/mL to prevent the risk of tumor-lysis syndrome.

Dr. Abutalib: For a patient with favorable-risk AML, a potentially curative disease in a patient eligible for intensive chemotherapy induction and consolidations, is venetoclax-based therapy part of your treatment approach, or would you avoid it in favor of another less-intensive chemotherapy-based regimen?

Dr. DiNardo: I prioritize intensive chemotherapy plus gemtuzumab ozogamicin in patients with core-binding factor (CBF) leukemias whenever possible. Favorable-risk patients with nucleophosmin 1 (NPM1) mutations do quite well with a hypomethylating agent plus venetoclax, but if patients are fit for intensive chemotherapy, I would still opt for intensive chemotherapy to improve the chance of a long-term remission and cure. And remember, patients with favorable-risk disease by European LeukemiaNet (ELN) 2022 who receive lower-intensity venetoclax-based strategies (eg, those with CBF leukemias, mutations in CEBPA within the bZIP (basic leucine zipper) domain, NPM1) will require long-term ongoing hypomethylating agent plus venetoclax therapy, as this is not currently considered a time-limited curative approach. 

Dr. Abutalib: When is the optimal time to perform a bone marrow biopsy after induction chemotherapy, and how should you interpret and manage the results? Hypocellular marrow with no detectable blasts? Residual disease with a reduction in blast count?

Dr. DiNardo: My feelings on this have changed over time. Since I now give only 21 days of venetoclax during the first cycle, I do not run to do a day-21 marrow to “stop” the venetoclax. I have returned to a day ~28 marrow, which informs the timing of cycle 2. If there is residual disease with a reduction in blast count, I would proceed directly to cycle 2. If there is hypocellular marrow without blast count recovery, I would wait 1 to 2 weeks for blast count recovery; and if there is no blast recovery, I would perform another marrow 2 weeks later.

Dr. Abutalib: How do you define treatment failure with a hypomethylating agent plus venetoclax?

Dr. DiNardo: If a patient has blast reduction and is tolerating therapy well, I will continue for up to six cycles. However, most patients will respond within the first two cycles.

Dr. Abutalib: If a patient in morphologic complete remission is tolerating venetoclax without issues, would you ever stop or reduce the dose of venetoclax as maintenance?

Dr. DiNardo: If the patient is tolerating venetoclax well, I don’t stop or modify the dosing. However, most patients have persistent neutropenia with ongoing venetoclax, so treatment for most of my patients is reduced to 14-day cycles with time.

For Patients Who Are Eligible for Intensive Chemotherapy

Dr. Abutalib: Do you combine venetoclax with intensive chemotherapy during induction for patients with newly diagnosed AML in this group of patients?

Dr. DiNardo: Yes, our institution has front-line clinical trials of intensive chemotherapy plus venetoclax, with more than 90% composite complete remission rates and more than 85% MRD-negative rates. The patients who benefit most from the addition of venetoclax to intensive chemotherapy are the patients with ELN 2022 adverse risk (except patients with TP53-mutated disease; these patients do not appear to benefit from the addition of venetoclax with either intensive chemotherapy or a hypomethylating agent).

Closing Remarks

“As we continue to refine and expand our approaches to AML treatment, it is essential to adhere to best practices, particularly when integrating venetoclax-based regimens,” stated Dr. Abutalib. “For community oncologists, collaboration with leukemia physicians can provide invaluable support. By following evidence-based guidelines and recognizing when referral to a tertiary center is necessary, community oncologists can play a pivotal role in the successful management of AML.” 

Dr. DiNardo is Professor of Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

DISCLOSURE: Dr. Abutalib reported a financial relationship with AstraZeneca. Dr. DiNardo serves as a consultant for AbbVie, Astellas Pharma, AstraZeneca, BMS, Daiichi Sankyo, GenMab, Rigel Pharmaceuticals, Ryvu Therapeutics, Servier, and Schrödinger.

SUGGESTED READINGS

1. Döhner H, Wei AH, Appelbaum FR, et al: Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140:1345-1377, 2022.

2. Pratz KW, Jonas BA, Pullarkat V, et al: Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol 99:615-624, 2024.