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BCL-2i AE Management

CE / CME

Expert Management of Treatment-Related Adverse Events From BCL-2 Inhibitors

Nurses: 1.00 Nursing contact hour

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Released: October 01, 2024

Expiration: March 31, 2025

Courtney DiNardo
Courtney DiNardo, MD, MSCE
Caitlin R. Rausch
Caitlin R. Rausch, PharmD, BCOP
CME/CE Information

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Evolving Diagnostic and Treatment Paradigm for Newly Diagnosed AML

Courtney DiNardo, MD, MSCE:
Now we will switch our discussion to the care of patients with AML. For AML, we still think in terms of whether our patient is fit or not fit for standard intensive chemotherapy, but we do not have only the same 2 options anymore. When considering intensive chemotherapy, the knowledge of whether there are core binding factor fusions, a FLT3 mutation, or therapy‑related AML or AML with myelodysplastic syndromes (MDS)–related changes can impact the treatment decision for a patient. 

For patients who are ineligible for intensive chemotherapy, venetoclax in combination with either azacitidine or decitabine (HMA therapy) is now approved as the standard of care for older (>75 years) or unfit patients with newly diagnosed AML. In addition, combinations with glasdegib plus low-dose cytarabine or, for IDH1‑mutated patients, azacytidine with ivosidenib are approved for our patients with newly diagnosed AML.15 

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Patient Case: Treatment Considerations for Newly Diagnosed AML

Courtney DiNardo, MD, MSCE:
Let’s consider a patient case: A 77-year-old female presents with fatigue and dyspnea on exertion. Her past medical history is significant for breast cancer status post radiotherapy, ischemic cardiomyopathy with atrial fibrillation, and type 2 diabetes. Her current ECOG PS is 2. 

Her diagnosis confirms AML with del(20q) and ASXL1, RUNX1 and TET2 mutations. She has a supportive family and is interested in a leukemia-directed therapy.

Based on the current treatment paradigm for patients with newly diagnosed AML, what would be the recommended approach for this patient?

Although CPX-351 is approved for therapy-related AML, anthracycline-based intensive chemotherapy is not recommended for patients older than age 75, especially in the setting of cardiomyopathy. However, this patient desires leukemia-directed treatment, so hospice/supportive care alone is not in line with this patient’s wishes.

Venetoclax in combination with either azacitidine or decitabine (HMA therapy) is now approved as the standard of care for older (>75 years) or unfit patients with newly diagnosed AML, improving remission rates and overall survival (OS) compared with azacitidine alone in the VIALE-A trial.

VIALE-A: Azacitidine ± Venetoclax in Treatment-Naive AML Ineligible for Standard Induction Therapy

Courtney DiNardo, MD, MSCE:
In AML, venetoclax was approved based on the phase III VIALE-A trial. This was a randomized study that assessed the role of venetoclax in addition to azacitidine compared with placebo and azacitidine for patients who were older or unfit for intensive chemotherapy with a new diagnosis of AML. The primary endpoint was OS.16-18

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Results of VIALE-A: Azacitidine ± Venetoclax

Courtney DiNardo, MD, MSCE:
In this trial, the complete remission (CR) rate in patients receiving azacitidine and venetoclax was 36.7% vs 17.9% with azacitidine and placebo. The composite remission rate (CR and CR with incomplete hematologic recovery) was 66.4% with azacitidine and venetoclax vs 28.3% with azacitidine and placebo.  Of importance, there was a response regardless of the genomics profile of patients with AML, with a benefit with the addition of venetoclax to azacitidine in all the various high‑risk genomic subgroups.

In addition, an analysis of OS showed an improvement in patients receiving azacitidine plus venetoclax vs those who received azacitidine plus placebo (HR: 0.58; 95% CI: 0.47-0.72; P <.001).16-18

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VIALE-A: Overall Survival by MRD Status

Courtney DiNardo, MD, MSCE:
There are 2 main factors that help identify who is most likely to benefit and benefit the longest from the combination of azacitidine and venetoclax. One factor is whether your patient attains measurable residual disease (MRD)‑negative status.

MRD negativity was assessed by flow cytometry in the VIALE‑A study at the end of cycle 1 and then after every 3 cycles. MRD negativity was defined as any patient who became MRD negative at any point on study. Patients who were MRD negative and receiving venetoclax plus azacitidine had a substantially improved OS (median: 34.2 months) compared with patients who were MRD positive receiving venetoclax plus azacitidine (median: 18.7 months), patients who were MRD negative receiving placebo plus azacitidine (median: 25.0 months), and patients who were MRD positive receiving placebo plus azacitidine (median: 15.1 months).18

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Patients Receiving VEN + AZA Are Distinguishable Into 3 Efficacy Subgroups by OS Benefit

Courtney DiNardo, MD, MSCE:
When determining how likely it is that your patient will have a durable response with azacitidine and venetoclax, the second important factor to consider is the underlying genomics. Of interest, the standard European LeukemiaNet (ELN) 2022 criteria that is associated with a response or lack of response to intensive chemotherapy is not the same for venetoclax plus azacitidine. Because venetoclax plus azacitidine is a different therapy, different mutations and genetics are important for determining response. There is a 4‑gene classifier that has been identified as the most useful in classifying risk of progression for this regimen.19  This has now been incorporated into the ELN 2024 criteria for lower intensity therapy.20

In this 4-gene panel, patients with TP53 mutations do quite poorly overall. Even though approximately half of these patients respond to treatment, this response does not correlate with improved survival, with a median OS of 5.5 months. Patients who do not have a TP53 mutation but do have receptor tyrosine kinase mutations in FLT3-ITD, KRAS, or NRAS are considered to have intermediate benefit with venetoclax plus azacitidine, with a median OS of approximately 1 year. Finally, patients who do not have any of those mutations are considered to have higher benefit with venetoclax plus azacitidine, with an anticipated median survival of more than 2 years.19 

Next, let’s consider management of AEs associated with venetoclax in AML.

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