Treating Elderly Patients With AML: The AP's Role in Managing Toxicities

Miki Haraguni

Let’s talk about a particular patient, an 80-year-old female with AML and a TP53 mutation. She presented with an ECOG performance status of 2 to 3, and she has baseline dementia. She begins oral therapy at home with venetoclax and azacitidine. She lives near the clinic in a retirement home with a 24/7 caregiver, so medication management is fairly easy for her, but it’s difficult to get clear answers from her about whether she’s experiencing pain or other side effects. At her recent follow-up visit, her labs reveal pancytopenia. How do you manage patients like this, Karolina?

Karolina Faysman

When your patient is starting to get pancytopenia on oral oncolytics, you need to determine whether they need a drug hold or a dose adjustment. This patient is receiving venetoclax and azacitidine. Venetoclax is a steady dose and azacitidine is dosed every two weeks. So is this patient ready for the next dose of azacitidine? Does her next dose have to be postponed? Does the dose have to be delineated?

You also need to take into consideration the patient’s baseline neutrophil and platelet counts. If pancytopenia was not an issue at the beginning of the treatment, then obviously we want to make sure that it is controlled for each cycle. However, if this is a patient who is baseline pancytopenic, we don't expect the cells to recover. So our decision on whether to hold the drugs or adjust the dose would be based on each individual patient.

Miki Haraguni

I agree. For example, if a patient experiences a grade 4 neutropenia (with or without fever or infection) or thrombocytopenia, our course of action depends on several factors, such as whether the patient has achieved remission yet, if it’s the first or a subsequent occurrence, or how long the adverse effect has lasted. If it occurs prior to achieving remission, we consider supportive measures, such as anti-infectives, and in most instances, do not interrupt therapy.¹ But if it’s after achieving remission, we typically hold therapy until neutropenia has resolved to ≤ grade 2, potentially changing the cadence of therapy moving forward.¹

And patient involvement is very important in these decisions too. They need to be aware of the risks and the potential benefits. In clinical trials, 95% to 100% of patients with AML treated with venetoclax plus azacitidine (or decitabine or low-dose cytarabine) experienced worsening baseline neutrophil counts.¹ However, with a patient like this, with dementia, that conversation is not always possible. So we also consider the goals of care.

For this patient, the focus of therapy is palliative. In her case it might be more beneficial to hold the therapy until she recovers from any treatment-related AEs, whether it's hematologic toxicity or non-hematologic toxicity. But overall, it's important for us as APPs to monitor and manage these patients so they can continue their therapy and maintain the best quality of life as possible, especially when transplant isn’t an option, like with this patient.

Karolina Faysman

Right. And thankfully, for most of the regimens we have, the non-hematologic toxicities are really minimal. For some of the oral oncolytics, such as azacitidine, we know that in clinical trials and in clinical practice, we see some GI side effects, mainly nausea.² And we’re able to help patients control that fairly well. The patients who do experience GI toxicity typically have grade 2 or grade 3 toxicity, and for them, a dose adjustment or a dose holiday would be more beneficial.

But we also need to choose the right anti-emetic for each patient. Working in hem/onc, we’re definitely not as accustomed to highly emetic treatment regimens as our colleagues who treat solid tumors. So we can learn from them about how to manage a patient with GI side effects. We should also look at each patient individually and ask questions like, is this a patient who is prone to constipation and has a QTc interval increase? If so, they may not be a good candidate for ondansetron, but we have a lot of other oral and intravenous options for them nowadays. There are patches, there are 7-day drug regimens, there are all kinds of different anti-emetic regimens available. There are even some psychiatric drugs, like olanzapine that are very useful in highly or moderately emetogenic treatments.

Miki Haraguni

You're correct. Olanzapine can be very effective, but caution is advised among elderly patients, like the one we’re discussing here. We could also use olanzapine and kill several birds with one stone because it has been shown to help control anxiety, improve sleep, and increase appetite.³ There are also non-medical approaches, like acupuncture, hypnosis, and ginger, that we can suggest to patients to help them control their GI toxicities.

Karolina Faysman

Yes, alternative approaches can be important. Something important to remember when treating adverse effects is decreasing the multi-pharmacy aspect. The more drugs you take, the more risk there is for additional side effects or drug-drug interactions, so we need to be monitoring for those.

Something else to consider is that we’re also prescribing different antimicrobial regimens for these AML patients, specifically antibiotics. The rate of developing infectious colitis is really high in this patient population, so when they develop diarrhea, we shouldn’t immediately assume that it's being caused by the drugs. We know that most of the oral oncolytics, azacitidine specifically, can cause diarrhea; however, we can't automatically assume that's what it is. We need to evaluate the patient, remembering that they have been on oral antimicrobial regimens, so their risk of C. diff is really high.

And this is really important because I’ve seen AML patients who are put on anti-motility drugs for treatment-related diarrhea without consideration of their infectious profile, and then they develop megacolon. And the risk of gram-negative sepsis for those patients is really high, so we've seen patients growing E. coli bacteria in their PICC line.

Miki Haraguni

Yes, and sometimes, due to neutropenia, they may not even present with fever. So when patients do develop sepsis, particularly in our patient setting, they need to be hit hard with the double antibiotic coverage initially to control it until you know what the patient is growing, because the risk of gram-positive sepsis is always there with the PICC lines—gram-negative sepsis particularly if they have GI symptoms or if they have mucositis. And mucositis is something that we also have be aware of with these patients.

Karolina Faysman

Right, thankfully we don't see as much mucositis with today's regimens. But we need to evaluate a patient who develops mucositis for potential HSV and bacteria. And the patient who does have frequent herpetic infections may benefit from suppressive therapy.

Sometimes it scares patients when we come right out and ask, “Do you have herpes?” because it's associated with a sexually transmitted disease. So frequently we'll instead ask, “Do you get fever blisters?” or something like that because we shouldn’t underestimate the power of HSV. When it disseminates and/or turns into severe mucositis, it will affect the entire treatment regimen.

Miki Haraguni

It will also affect their quality of life. They could eventually need IV treatment, which is more difficult to manage in the outpatient setting, so they’ll have to come back into the clinic too. And for non-hematologic toxicities like this, if supportive measures don’t work, we would want to hold the venetoclax and only start it back up again once the AE is gone or down to a grade 1.¹

Karolina Faysman

There are definitely a lot of factors to consider when treating elderly patients with AML. As we’ve said before, it all comes back to taking an individual approach for each patient, factoring in their comorbidities, their medical and treatment history, what potential AEs could occur, and which AEs or their management would be potentially more detrimental to this patient than the disease itself. And importantly, we need to consider the goals of care, which has to start at the beginning.

Miki Haraguni

Yes, and goals of care need to be continually revisited too. I had one patient, a 70-year-old female who was wheelchair bound, and we decided initially to focus on palliative care. Then after a couple of cycles of treatment, her disease burden decreased and she started doing better. So we modified her goals of care at that point. It’s important to have that discussion again based on how the patient responds to treatment.

Karolina Faysman

Absolutely. And frequently your goal of care, as the APP, may be completely different than the patient's goal of care. I had an elderly patient just recently whose goal was to continue therapy, but we all understood that this patient was not going to be able to make it through treatment. And in the elderly AML population, the 5-year survival is under 5%,⁴ so the discussion of goals of care, symptom management, and the potential to switch to comfort care is particularly important for these patients.