Courtney D. DiNardo, MD, MSCE

The combination of azacytidine and venetoclax has been paradigm shifting in our older intensive-chemotherapy-ineligible patients because it’s the first time in decades that we’ve improved our standard of care. This has become our de facto standard of care throughout the world for our newly diagnosed patients with AML [acute myeloid leukemia], but not everyone is going to be cured with this therapy. Unfortunately, a minority of patients will be cured with this therapy. There are definitely ongoing unmet needs. Even though this is a great step ahead, we’re not done. We still need to improve these.

One thing I’m interested in, and that are in ongoing trials, is figuring out which patients have 

 mutations and other things that we can potentially target. Can we add that to the azacytidine-venetoclax regimen to make it even more effective? How do we improve upon the outcomes in some of these higher-risk sufferers? The other question you asked me is if there are other therapies that I’d consider.

I want to highlight the fact that there’s a new FDA approval for the combination of azacytidine and ivosidenib, which is an IDH1 inhibitor for the 8% or so of patients who are 

 mutated. That’s a very compelling, well-tolerated combination. At [The University of Texas] MD Anderson [Cancer Center], which is where I practice, we’re fortunate in that we have targeted panels returning in 3 to 5 days. We can use that information to identify the best treatment option for our patients and incorporate targeted therapies if appropriate and available. That’s another great option.

In the first month is when you’re going to get a sense of how your patient is going to respond to azacytidine and venetoclax. Monitor them with blood counts twice a week during their second, third, and fourth week of [INAUDIBLE]. Get a sense of how many transfusions they need. Make sure you’re doing the end of cycle 1 bone marrow because that’s going to help you determine how to go about continuing therapy in a well-tolerated way for your patients. I have all my patients on a fluoroquinolone prophylaxis, levofloxacin in particular, because there are no CYP interactions.

That leads me to the last comment, which is to make sure you’re aware of drug-drug interactions. Because of that CYP interaction, you really need to know if your patient is on an azole or even a ciprofloxacin, which is a moderate CYP inhibitor. There are adjustments. If your patient is on a moderate CYP inhibitor, then you have to drop the venetoclax dose by 50%. It’s important that you’re not compounding myelosuppression and cytopenias in patients to make sure this therapy is well tolerated. It’s very effective, and patients are definitely benefiting from this therapy, but you want to make sure you’re using it in an optimized way.

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Courtney DiNardo, MD, concludes with discussing some challenges faced when treating patients with AML and shares some advice for community oncologists treating acute myeloid leukemia.

Unmet Needs of AML and Advice for Community Oncologists

There are 3 main toxicities to think about when you’re using azacytidine and venetoclax. The first is tumor lysis syndrome, which is rare in patients with AML [acute myeloid leukemia]. You very rarely see tumor lysis. In the Viale-a study, there were 3 patients out of hundreds. If you’re going to see tumor lysis, it’s going to happen at the beginning, during the first 2 or 3 days of dosing. That’s why it’s important to do those labs during those first 3 days, to make sure your patient doesn’t have electrolyte derangements or isn’t developing renal insufficiency. That way, you can hold therapy and manage it. Tumor lysis is very manageable if you catch it before it becomes an issue.

The 2 main concerns in terms of safety are cytopenias and cytopenia-related infections. We talked a little about cytopenia management. For the inpatients who are in a remission with or without count recovery, you’ve cleared their leukemia. Oftentimes, with subsequent cycles, you’ve shortened the venetoclax duration. I frequently have patients on 21 days of venetoclax, and one-third or so end up needing 14 days of venetoclax for them not to become profoundly neutropenic and transfusion dependent, with subsequent ongoing cycles of patients in remission. Oftentimes, instead of 4-week cycles, I’m doing 5-week cycles to allow that full-count recovery to happen before I start the next cycle. That’s important, the somewhat-nuanced management guidelines, because each patient is a little different. I have a couple of patients on continuous venetoclax. They’re doing great. Their counts never budge in a remission. But that’s not [the case for] many patients. Most patients end up needing 14 or 21 days of venetoclax for 4-, 5-, or 6-week cycles. You end up getting a rhythm, but it can take a month or 2 to figure out exactly how much venetoclax your patient [needs]—what their happy place is in terms of maintaining that remission but keeping counts recovering without needing transfusions in cycles where they’re in a remission.

Then there are neutropenic-related infections. In patients who are on therapies that cause mild suppression and neutropenia—and leukemia itself causes immunosuppression—you can see neutropenic-related infections that are life-threatening. When individuals have fevers, when their ANC [absolute neutrophil count] is below 1000 per mm3, you need to have them on broad-spectrum antibiotics and make sure there’s no life-threatening infection. We typically give patients prophylaxis with fluoroquinolone if they don’t have an allergy. So they’re on levofloxacin and prophylaxis throughout the periods of neutropenia. It’s very institution and investigator dependent in terms of whether they’re also getting antifungal prophylaxis. During the first month or so when my patients have active leukemia and are immunosuppressed, I’ll have them on an antifungal and an antiviral for prevention as well.

A review of the safety outcome data of venetoclax plus azacitidine from the VIALE-A trial.

Safety Outcomes from the VIALE-A Trial

The recommendation and the approved dosing of the combination is standard azacytidine or standard decitabine. Azacytidine is 7 days, 75 mg/m2 days 1 to 7 either IV [intravenously] or subcutaneously with venetoclax, with a goal dose of venetoclax 400 mg. There’s a daily dose ramp up. You go from 100 to 200 to 400 mg of venetoclax for the first 3 days, and you make sure during those first 3 days that your patient hasn’t had any evidence of tumor lysis. You’re checking labs daily. The venetoclax is, in theory, continuous for 28 days. Many patients have cytopenias and therapy-related myelosuppression from this combination. Very few patients in my clinic get continuous 28-day venetoclax cycles. That’s the recommendation, and we’ll talk about how I dose adjust and attenuate the venetoclax in the next few segments.

I said the dose was 400 mg of venetoclax. That’s true, but there are a lot of drug-drug interactions with venetoclax because it’s a CYP3A inhibitor. If you’re using another CYP3A inhibitor, like voriconazole or posaconazole—1 of the azoles—you absolutely need to modify the venetoclax dose. There are recommended guidelines so that you end up getting an equivalent venetoclax concentration. If you’re using venetoclax 400 mg with an azole, the venetoclax concentration is going to be much too high because of those CYP interactions.

When you’re using a venetoclax-azacytidine regimen, the most important thing is to do a bone marrow [evaluation] at the end of the first cycle. It doesn’t have to be exactly on day 28. It can be day 21, 24, 28—sometime during that last week—because the majority of patients are going to respond, and they’re going to respond within the first cycle. It’s really important to know if patients’ counts are low. If it’s because they’re in a remission, they’ve already cleared their leukemia out of their bone marrow. If they still have persistent leukemia, then you can go straight into the second cycle. You can continue the venetoclax, and you can start the second cycle on day 29 of that patient’s treatment plan. But most of the time, that end-of-cycle bone marrow is going to be clear. There are not going to be blasts there, and the counts are still going to be low. In that case, you hold therapy for a week or 2, for a full-count recovery to happen. That patient is in a remission, so their counts are low not because of leukemia but because of the combination therapy you’ve given them. So you hold therapy, you wait a week or 2, the counts recover, and then you start the next cycle. When you start the next cycle, if you have to hold therapy for a week or 2—which the majority of the time you’re doing—I’ll typically transition them to 21 days of venetoclax per cycle, so they get that break at the end of the cycle to allow those counts to recover and stay on schedule.

The reason the bone marrow assessment at the end of cycle 1 is so important is because almost all the patients that you’ll see at the end of the first cycle on azacytidine and venetoclax will still be cytopenic. Their white blood cell count is still going to be neutropenic. They’re still going to be anemic. They may still be requiring blood and platelet transfusions. If that’s because of leukemia, that’s fine. We know how to give ongoing hypomethylating agent cycles. We’ve done that for decades in patients with MDS [myelodysplastic syndrome] and AML [acute myeloid leukemia], and it typically takes 4 to 6 cycles to respond. We keep the treatment going on a 4-week cycle because it can take that long for responses to happen.

But in the majority of patients getting these venetoclax combinations, you see very early responses. The average response time is 1 cycle. If those counts are still low, if they’re still neutropenic and requiring transfusions not because of the leukemia but because their bone marrow is still ablated from the venetoclax combination, then you don’t want to start another cycle. You don’t want to compound toxicity that they haven’t recovered from, so you need to do that bone marrow to figure out why your patients’ counts are still low. If they’re still low because the leukemia is clear, then this therapy has worked well. You need to wait a week or 2 for counts to recover before you start the next cycle to improve the tolerability of this therapy for your patient.

Dr Courtney DiNardo details the dosing recommendations for venetoclax plus azacitidine and the importance of bone marrow assessments.

Dose Management for Venetoclax plus Azacitidine

The rationale to look at venetoclax in combination with the hypomethylating agents azacytidine or decitabine came from those who worked in the lab studying AML [acute myeloid leukemia]. Marina Konopleva at [The University of Texas] MD Anderson [Cancer Center], Tony Letai, Dan Pollyea. They saw this dramatic synergy in patients with leukemia who were getting venetoclax in combination with hypomethylating agents. Venetoclax was evaluated first as a single agent in the relapsed setting, and…we saw very modest responses of less than 20%. It’s a testament to some of these great translational researchers that we moved it to a frontline combination. There was such strong preclinical data that this was going to be a benefit, and it was.

The initial phase 1 study showed dramatic responses. Within a cycle, the majority of patients were going into a remission. That moved into the phase 3 Viale-a study to confirm this benefit, and that was a randomized placebo-controlled study conducted globally. Hundreds of patients were enrolled, and two-thirds of patients responded to the combination of azacytidine and venetoclax with a complete remission or a complete remission with incomplete count recovery. A composite remission is what we call it, and that correlated with an improved overall survival. An improvement in overall survival and median survival was 15 months, compared with about 10 months. In my opinion, we’re still not done. The story doesn’t end here. But it’s the first randomized phase 3 study of older, intensive-chemotherapy-ineligible patients with AML to show a survival benefit of anything compared with a hypomethylating agent alone. This is a huge advance in our field. We’ve seen many patients respond and do quite well with this regimen.

What’s great about the combination of azacytidine and venetoclax is that it’s genomically agnostic, meaning that you don’t have to have a specific genomic subtype to respond to this therapy. In the original studies, we looked at patients with high-risk, poor-risk, and intermediate-risk cytogenetics, therapy-related disease, various mutational patterns. All these patients do better with the combination than with azacytidine alone as was proven in the Viale-a study. It’s appropriate for any newly diagnosed patient AML who’s not a good candidate for standard intensive chemotherapy.

To go a little more into the weeds, we’ve realized that certain mutations predict a more durable remission. Individuals with 

 mutations do particularly well. These patients had deep remissions that may even turn into cures. However, patients with 

 mutations, for instance, respond, but they unfortunately have relatively short responses and a shorter overall survival, so we still need to improve the outcomes of patients with 

Dr Courtney DiNardo reviews the efficacy data from the VIALE-A trial and explains the rationale for combining venetoclax with azacitidine as a treatment option for patients with AML.

The VIALE-A Trial: Venetoclax plus Azacitidine in AML Treatment

Hi, everyone. I’m Courtney DiNardo at [The University of Texas] MD Anderson [Cancer Center] in Houston, Texas. Today I’ll be talking about the use of venetoclax in newly diagnosed acute myeloid leukemia [AML].

Treatment has changed so much in terms of opportunities and treatments available for our patients. There’s an age cutoff of 60 years old, which is very arbitrary, so I encourage you not to think about it as a discrimination point but to evaluate the fitness of your patient and the appropriateness of an intensive chemotherapy regimen or a non-intensive chemotherapy regimen. Patients who are appropriate for an intensive chemotherapy regimen are typically younger patients who don’t have underlying comorbidities.

There’s what we call the standard 7+3 therapy, which is 7 days of cytarabine and 3 days of anthracycline. We also have the approval of CPX-351, called Vyxeos. That’s for patients who have therapy-related AML, or AML from an underlying secondary malignancy, whether it’s a solid or different hematologic malignancy. They go on to develop AML or AML with MDS [myelodysplastic syndrome]–related changes. For our intensive chemotherapy–eligible patients who are 

 mutated, the standard is intensive chemotherapy with a FLT3 inhibitor. Midostaurin is the recommendation for those patients.

For patients who are older or unfit for intensive chemotherapy because of underlying comorbidities or things of that sort, the standard used to be a hypomethylating agent alone: azacytidine or decitabine primarily in the United States, or a low-dose cytarabine, which is 1 of the old standards and used globally but not often in the United States. Over the past few years, we’ve had approvals of several combinations that have improved the outcome of older individuals. They’re getting low-intensity combinations: azacytidine with venetoclax, decitabine, a hypomethylating agent with venetoclax, and a low-dose cytarabine with glastegib or venetoclax. We don’t use a lot of low-dose cytarabine-based regimens in the United States, but these are approved and available. A recent approval just came through in May: azacytidine with ivosidenib, the IDH1 inhibitor, for patients with newly diagnosed 

Fitness is a challenging thing to discuss in 1 sentence because we still don’t have a great 1-size-fits-all approach to say who’s fit for intensive chemotherapy. We look at patient age because age is associated with frailty and other comorbidities. In general, individuals over age 70 or 75 are not appropriate for a standard intensive chemotherapy regimen. For patients in their 70s and above, the risk of toxicity from intensive chemotherapy is a challenge; the risks outweigh the benefits. But for younger patients who have underlying comorbidities, especially cardiac or pulmonary comorbidities, or who have a poor performance status—meaning they’re not out of bed more than half of their day—these things are associated with a higher risk of toxicity, morbidity, and mortality to standard intensive chemotherapy. The FDA uses the Ferrara criteria to determine fitness. They include things I’ve talked about: age over 75, underlying cardiac dysfunction, underlying pulmonary dysfunction, poor performance status, or something else that makes the patient a risk for a standard intensive chemotherapy, like an inflammatory bowel disease.

Courtney DiNardo, MD, describes how the treatment options for patients with newly diagnosed acute myeloid leukemia differs for patients under and over 60 years of age.

Treatment Options for Newly-Diagnosed AML

Courtney D. DiNardo, MD, clinical researcher in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the current treatment landscape for patients with 

-mutated acute myeloid leukemia (AML) and how potential doublet and triplet combinations may play a role in this setting.

 mutations occur in about 6% to 15% of all patients with AML, says DiNardo, which makes this subgroup a sizable minority in AML. These patients tend to be older and are usually either not appopriate for or are not benefiting from standard intensive chemotherapy, so there is a lot of interest in finding more tolerable and efficacious regimens for 

The FDA approved an IDH inhibitor, ivosidenib (Tibsovo), as well as the combination of venetoclax (Venclexta) plus azacitidine (CC-486), which is a separate, more broad treatment option for patients with AML but has shown responses in 

The question now is when you have these different treatment options, how should these agents be used? DiNardo questions whether ivosidenib could be given with venetoclax, which could be a well-tolerated oral regimen given in the outpatient setting, or should all 3 agents, including ivosidenib, venetoclax, and azacitidine, be given together to improve the outcomes that have been observed with each of these therapies.

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Courtney D. DiNardo, MD, discusses the current treatment landscape for patients with IDH1-mutated acute myeloid leukemia and how potential doublet and triplet combinations may play a role in this setting.

Courtney D. DiNardo, MD, MSCE | Authors

Articles

Unmet Needs of AML and Advice for Community Oncologists

Safety Outcomes from the VIALE-A Trial

Dose Management for Venetoclax plus Azacitidine

The VIALE-A Trial: Venetoclax plus Azacitidine in AML Treatment

Treatment Options for Newly-Diagnosed AML

Expert Explores Potential Role of Doublets and Triplets in IDH1-Mutant Acute Myeloid Leukemia