Treating Elderly Patients With AML: Focus on the Newly Diagnosed Patient

Karolina Faysman

Let’s say we have 76-year-old patient newly diagnosed with acute myeloid leukemia (AML). The patient is presenting with myelodysplastic syndrome (MDS)-related disease, as well as a white cell count of 85,000 with 100 circulating blasts, requiring combination of oral oncolytic with parenteral therapy. You talk with the patient about adjustment to their newly diagnosed disease, the need for further therapy, the change in lifestyle regarding activities, and potential complications from the disease and the new therapy.

What are your initial thoughts about this patient, Miki?

Miki Haraguni

So this is often challenging, especially with an elderly patient with newly diagnosed or refractory AML. They rarely start with really good physical performance; usually their ECOG will be 1 to 2, sometimes they’re wheelchair bound, so they have limited treatment options. Besides that, elderly patients with AML tend to have high-risk disease, which is very refractory to the traditional chemotherapy-related treatments, and their body also may not tolerate certain chemotherapy agents, so that may narrow down the treatment options.

When possible, more-intensive therapy is recommended over less-intensive therapy.¹ However, for an elderly patient like this who is not a candidate for intensive antileukemic therapy, American Society of Hematology guidelines recommend offering therapy over best supportive care.² Hypomethylating agents (such as azacitidine or decitabine) or low-dose cytarabine in combination with venetoclax may be considered.¹ This treatment regimen tends to be well tolerated compared with traditional intensive chemotherapy.³ And some literature suggests that venetoclax plus decitabine (or azacitidine) showed a tolerable safety profile and favorable overall survival rate.⁴

This HMA plus venetoclax regimen is an oral oncolytic therapy, which is also good for patients like this who are not good candidates for prolonged hospitalization. However, we really need to monitor these patients closely once we initiate treatment so they don’t end up needing to be hospitalized later.

Karolina Faysman

Yes, when treating patients like this, individualization of therapy is important. We need to take into consideration the patient’s disease, what the malignancy panel looks like, if actionable mutations are present, what kind of disease it is—secondary or primary AML. In elderly patients, a majority are diagnosed with secondary disease, whether therapy related or previous hematologic malignancy related, or MDS transforming into AML. Also, this individual approach takes into consideration patients' comorbidities, performance status, and other medications the patient may be on. And in this specific patient population, the choice of oral oncolytic therapy creates an additional important part of assessment: Is this patient a good candidate for oral oncolytics? Is this a patient who would be compliant? Is this a patient who has good social support and is able to tolerate oral medications? How do we help the patient remember to take their medications? What is the patient's memory profile? Heath system factors are also considered¹: are either the patient or physician reluctant to initiate therapy? Is there access to allogeneic transplant for those who achieve remission?

It’s exciting to be able to offer patients oral oncolytics. It enables them to have much better quality of life and not have to come to the clinic all the time. But it's also very nerve-racking for me as a nurse practitioner with over 20 years of experience, because we're not the ones who are administering the therapy. There's no direct supervision, so the patients are on their own, treating themselves, and that's where the education, the support, and very close follow-up become even more essential for successful treatment.

Miki Haraguni

We also need to discuss what other over-the-counter (OTC) medications and supplements the patient is taking, including teas and other natural therapies, to avoid a potential conflict or other issue. For example, with venetoclax, we have to monitor for strong to moderate CYP3A inhibitors or P-gp inhibitor as these drugs may increase the toxicity of venetoclax.⁵ Strong CYP3A inhibitors may include some antivirals, antibiotics, antifungals, and antidepressants. Some OTC medications are moderate CYP3A inhibitors, such as cimetidine. We want to examine the diet intake too; grapefruit is a notorious CYP3A inhibitor. If the patient must take one of these inhibitors while on these medications, the venetoclax dose may need reduction as noted in the prescribing information.⁵

Also we need to review the medication schedule with the patient to make sure they know when and how to dose. Some of the medications are okay to take with food, some of them you cannot take with food, some of them cause GI upset, some of them may not.

And in addition to the medications for the treatment of AML, patients may be using supportive therapy for nausea control, they may also be taking antimicrobial therapy that may be, to some degree, contraindicated. So you have to evaluate which other comorbid conditions the patients have in regard to oral intake of the other medications and ensure that their medication schedule and administration is appropriate.

Karolina Faysman

So after you choose an appropriate therapy, and counsel the patient on dosing themselves and any potential interactions, how do we now manage the potential complications? One of them is tumor lysis syndrome (TLS). The risk of TLS can be evaluated based on patient disease burden and pretreatment white blood cell count (WBC), serum lactate dehydrogenase, creatinine, and uric acid.⁵ Venetoclax can cause such a rapid tumor response that the risk of TLS is further increased. All patients treated with venetoclax should have a WBC of less than 25 x 10⁹/L; therefore, cytoreduction prior to treatment may be required. Patients should be prehydrated and kept well hydrated throughout treatment. Anti-hyperuricemic agents will be required. Because of the TLS risk, the dose of venetoclax will be increased over the 3 or 4 day ramp-up phase. Dosage adjustments may be required based on the patient’s status. 

This patient has a white count of 85,000 with 100 circulating blasts, which is an extremely high disease burden. We should also look at the patient’s baseline counts as we just noted to determine their risk of TLS and other complications. If possible, pre-existing abnormalities should be corrected. If this patient has renal insufficiency already at baseline, he is at higher risk of developing TLS-related complications such as renal failure. We would closely monitor these counts throughout therapy. 

If this patient is already neutropenic, they would be at high risk of developing neutropenic complications while taking venetoclax and a hypomethylating agent. Ideally, we would treat any infection prior to treatment and might even consider prophylactic treatment throughout therapy, for example, if the patient had a history of fungal infection or if they live in an area with a high risk of fungal infections. In California, the high Santa Ana winds bring a heat wave as well as a bunch of fungi spores in the air, which becomes quite dangerous for this patient population. Whenever prescribing other supportive therapies, we must consider the possibility of drug-drug interactions as we noted earlier.

Miki Haraguni

We should also evaluate the patient’s risk of developing GI symptoms of nausea and vomiting. It's absolutely essential for them to remain well during their treatment, and their nutrition has to be well controlled and balanced. And if this patient develops nausea, anorexia, or perhaps diarrhea, we definitely will run into more problems and complications. Thankfully we have multiple different anti-emetic therapies to choose from for each patient. For example, if this patient is prone to constipation, one regimen may not work for him, but something else may work differently. Again, we have to be careful with drug-drug interactions. For example cannabinoids, cimetidine, dexamethasone, omeprazole, and ranitidine are a few antiemetics that are CYP3A inhibitors.

Karolina Faysman

And as this is an elderly patient, even if they don't have a history of cardiovascular disease, if you are starting them on a regimen that is cardiotoxic, such as cytarabine/daunorubicin for example, you must consider a cardiology evaluation. In our practice, when starting them on oral oncolytics, we always do at least an EKG in the clinic just to have that baseline. And in doing this, we've diagnosed lots of asymptomatic atrial fibrillation that we didn't know about, which is important to know up front. Does the patient have QTc prolongation at baseline? You need to know this so you can avoid certain medications to avoid further prolongations and the potential risk of a deadly arrhythmia.

Whether the patient would benefit from additional cardiac or renal evaluation all depends on the patient baseline and history, but we do at least all the basic tests for all elderly patients like this.

In terms of other potential complications, if your patient is a candidate for intensive remission induction therapy and they are receiving cytarabine with daunorubicin, some of those patients will have a longer hospitalization based on their pancytopenia. The administration of cytarabine/daunorubicin in the outpatient setting had been shown to be as effective as in inpatient,⁴ but eventually most of these patients get admitted during the pancytopenic period. In clinical trials, we know that the use of the liposomal formulation of cytarabine/daunorubicin (CPX-351) did extend pancytopenia for about a week or so, compared with the conventional 7+3.⁶ So we need to educate these patients about the potential for extensive pancytopenia and the high risk of hemorrhage and infection.

Also patients who have actionable mutations and receive a combination of cytotoxic and targeted therapy may have increased toxicity because of the combination’s synergism. Those two drugs, whatever the regimen is, for example, if it's a combination of current cytotoxic therapy with one of the IDH inhibitors or with FLT3 inhibitor, would definitely increase synergism and effectiveness, but it also increases the synergism of potential toxicities. For example, if it's Hif-α or IDH mutation drugs, they're known to cause more hepatic abnormalities, and FLT3-mutated drugs may cause more pancytopenia or GI disturbance, while midostaurin will cause more skin disturbances. So again, it’s important to look at each individual patient before starting a therapy regimen and make sure they understand the potential complications.

Miki Haraguni

Preparing patients for potential complications was especially important during the COVID-19 pandemic when we had to move to using telemedicine for some of our patients. Having thorough baseline data on our patients was also helpful, as it enabled us to use telemedicine even more. We were able to have patients utilize their local laboratory and then hold telemedicine follow-up appointments where we would assess their tolerance to the treatment and assess their compliance without the need for them to come all the way to us.

Karolina Faysman

Yes, during the COVID-19 pandemic, we had to get a little creative with ensuring our patients with AML received the care they needed. This patient population is at an increased risk of experiencing complications from SARS-CoV-2 not only because they are immunocompromised but also because of the acute nature of the disease and its intense treatment.⁷  And telemedicine is a great tool to minimize clinic visits and therefore decrease patients’ risk of exposure to the virus. But we should never use it as a total replacement for traditional in-clinic care. In-person care is a critical aspect of AML patient care.