A diagnosis of acute myeloid leukemia (AML) is particularly challenging in older adults, whose age makes them highly susceptible to the disease and treatment-related toxicity. To help patients and practitioners navigate the clinical decision-making process, the American Society of Hematology (ASH) convened an panel of experts who conducted a thorough review of the literature. The result of their work can be found in a new set of guidelines for the treatment of newly diagnosed AML in older adults.
Medscape spoke with Mikkael Sekeres, MD, chair of the ASH AML guideline panel and director of the Leukemia Program at Cleveland Clinic Taussig Cancer Institute. Sekeres shared the rationale behind the panel’s key recommendations and the importance of keeping the patient’s goals in mind.
Medscape: What is the average life expectancy of a 75-year-old developing AML compared with someone of the same age without AML?
Dr Sekeres: A 75-year-old developing AML has an average life expectancy measured in fewer than 6 months. Somebody who is 75 without leukemia in the United States has a life expectancy that can be measured in a decade or more. AML is a really serious diagnosis when someone is older and significantly truncates expected survival.
What is the median age at AML diagnosis in the United States?
About 67 years.
What are the biological underpinnings for poor outcomes in older AML patients?
There are a few of them. Older adults with AML tend to have a leukemia that has evolved from a known or unknown previous bone marrow condition such as myelodysplastic syndrome. Older adults also have worse genetics driving their leukemia, which makes the leukemia cells more resistant to chemotherapy. And the leukemia cells may even have drug efflux pumps that extrude chemotherapy that tries to enter the cell. Finally, older adults are more likely to have comorbidities that make their ability to tolerate chemotherapy much lower than for younger adults.
In someone who is newly diagnosed with AML, what initial options are they routinely given?
For someone who is older, we divide those options into three main categories.
The first is to take intensive chemotherapy, which requires a 4-6 week hospitalization and has a chance of getting somebody who is older into a remission of approximately 50% to 60%. But this also carries with it significant treatment-related mortality that may be as high as 10% to 20%. So, I have to look my older patients in the eyes when I talk about intensive chemotherapy and say, “There is a 1 in 10 or 1 in 5 chance that you might not make it out of the hospital alive.”
The second prong is lower-dose therapy. While the more-intensive therapy requiring hospitalization does have a low, but real, chance of curing that person, less-intensive therapy is not curative. Our best hope with less-intensive therapy is that our patients enter a remission and live longer. With less-intensive therapy, the chance that someone will go into remission is probably around 20%, but again it is not curative. The flip side to that is that it improves a person’s immediate quality of life, because they’re not in the hospital for 4 to 6 weeks.
The final prong is to discuss palliative care or hospice upfront. We designed these guidelines to be focused on a patient’s goals of therapy and to constantly revisit those goals to make sure that the treatment options we are offering are aligning with them.
The panel’s first recommendation is to offer antileukemic therapy over best supportive care in patients who are appropriate candidates. Can you provide some context for this recommendation?
Doesn’t that strike you as funny that we even have to make a recommendation about getting chemotherapy? Some database studies conducted over the past two decades show that, as recently as 15 years ago, only one third of patients who were over the age of 65 received any type of chemotherapy for AML. More recently, as we have had a few more drugs available that allow us to use lower-dose approaches, that number has crept up to probably about 50%. We still have half the patients offered no therapy at all. So, we felt that we had to deliberately make a recommendation saying that, if it aligns with a patient’s goals, he or she should be offered chemotherapy.
The second recommendation is that patients considered candidates for intensive antileukemic therapy should receive it over less-intensive antileukemic therapy. How did you get to that recommendation?
There is a debate in our field about whether older adults should be offered intensive inpatient chemotherapy at all or whether we should be treating all of them with less-intensive therapy. There are not a huge amount of high-quality studies out there to answer some of these questions, in particular whether intensive chemotherapy should be recommended over less-intensive therapy. But with the available evidence, what we believe is that patients live longer if they are offered intensive antileukemic chemotherapy. So, again, if it aligns with a patient’s goals, we support that patient receiving more-intensive therapy in the hospital.
What does the panel recommend for patients who achieve remission after at least a single cycle of intensive antileukemic therapy and who are not candidates for allogeneic hematopoietic stem cell transplantation?
Once again, this may seem at first blush to be an obvious recommendation. The standard treatment of someone who is younger with AML is to offer intensive inpatient chemotherapy to induce remission. This is followed by a few cycles of chemotherapy, mostly in an outpatient setting, to consolidate that remission.
What is the underlying philosophy for this approach?
Every time we give chemotherapy, we probably get about a 3 to 4 log kill of leukemia cells. Imagine when a person first presents with AML, they may have 10 billion leukemia cells in his or her body. We are reducing that 3 to 4 log with the first course of chemotherapy.
When we then look at a bone marrow biopsy, it may appear to be normal. When leukemia is at a lower level in the body, we simply can’t see it using standard techniques. But that doesn’t mean the leukemia is gone. For younger patients, we give another cycle of chemotherapy, then another, then another, and then even another to reduce the number of leukemia cells left over in the body until that person has a durable remission and hopefully cure.
For someone who is older, the data are less clear. While some studies have shown that if you give too much chemotherapy after the initial course, it doesn’t help that much, there is a paucity of studies that show that any chemotherapy at all after the first induction course is helpful. Consequently, we have to use indirect data. Older people who are long-term survivors from their acute leukemia always seem to have gotten more than one course of chemotherapy. In other words, the initial course of chemotherapy that a patient receives in the hospital isn’t enough. They should receive more than that.
What about older adults with AML considered appropriate for antileukemic therapy but not for intensive antileukemic therapy?
This again gets to the question of what are a patient’s goals. It takes a very involved conversation with a person at the time of their AML diagnosis to determine whether he or she would want to pursue an aggressive approach or a less-aggressive approach. If a person wants a less-aggressive approach, and wants nothing to do with a hospital stay, then he or she is also prioritizing initial quality of life. In this recommendation, based on existing studies, we didn’t have a preference for which of the available less-aggressive chemotherapies a person selects.
There’s also debate about what to do in those considered appropriate for antileukemic therapy, such as hypomethylating agents (azacitidine and decitabine) or low-dose cytarabine, but not for intensive antileukemic therapy. What did the available evidence seem to indicate about this issue?
There have been a lot of studies trying to add two drugs together to see if those do better than one drug alone in patients who are older and who choose less-intensive therapy. The majority of those studies have shown no advantage to getting two drugs over one drug.
Our recommendation is that in these situations a patient gets one drug, not two, but there are a couple of caveats. One caveat is that there has been a small study showing the effectiveness of one of those low-dose chemotherapies combined with the drug glasdegib. The second caveat is that there have been results presented combining one of these low-dose chemotherapies with the drug venetoclax. One of those was a negative study, and another was a positive study showing a survival advantage to the combination vs the low-dose therapy alone. We had to couch our recommendation a little bit because we knew this other study had been presented at a conference, but it hadn’t come out in final form yet. It did recently, however, and we will now revisit this recommendation.
The other complicated aspect to this is that we weren’t 100% convinced that the combination of venetoclax with one of these lower-dose therapies is truly less-intensive therapy. We think it is starting to creep up toward more-intensive chemotherapy, even though it is commonly given to patients in the outpatient setting. It gets into the very complicated area of what are we defining as more-intensive therapy and less-intensive therapy.
Is there a recommended strategy for older adults with AML who achieve a response after receiving less-intensive therapy?
This is also challenging because there are no randomized studies in which patients received less-intensive therapy for a finite period of time vs receiving those therapies ad infinitum. Given the lack of data and also given a lot of anecdotal data out there about patients who stopped a certain therapy and relapsed thereafter, we recommended that patients continue the less-intensive therapy ad infinitum. So as long as they are receiving a response to that therapy, they continue on the drug.
Of course, there are also unique considerations faced by older patients who are no longer receiving antileukemic therapy, and have moved on to receiving end-of-life care or hospice care. What advice do the guidelines offer in this situation?
There are a lot of aspects of these recommendations that I think are special. The first is the focus on patient goals of care at every point in these guidelines. The second is that the guidelines follow the real disease course and a real conversation that doctors and patients have at every step of the way to help guide the decisions that have to be made in real time.
A problem we have in the United States is that once patients enter a hospice, most will not allow blood transfusions. One reason is that some say it is antithetical to their philosophy and consider it aggressive care. The second reason is that, to be completely blunt, economically it doesn’t make sense for hospices to allow blood transfusions. The amount that they are reimbursed by Medicare is much lower than the cost of receiving blood in an infusion center.
We wanted to make a clear recommendation that we consider transfusions in a patient who is in a palliative care or hospice mode to be supportive and necessary, and that these should be provided to patients even if they are in hospice, and as always if consistent with a patient’s goals of care.
How does a patient’s age inform the discussion surrounding what intensity treatment to offer?
With younger adults, this is not as complicated a conversation. A younger person has a better chance of being cured with intensive chemotherapy and is much more likely to tolerate that intensive chemotherapy. For someone who is younger, we offer intensive chemotherapy and the chance of going into remission is higher, at 70% to 80%. The chance of dying is lower, usually less than 5%. It is an easy decision to make.
For an older adult, the risk–benefit ratio shifts and it becomes a more complicated option. Less-intensive therapy or best supportive care or hospice become viable.
Are there other factors confounding the treatment decision-making process in older adults with AML that practitioners should consider?
Someone who is older is making a different decision than I would. I have school-aged children and believe that my job as a parent is to successfully get them to adulthood, so I would take any treatment under the sun to make sure that happens. People who have lived a longer life than I have may have children and even grandchildren who are adults, and they might have different goals of care. My goals are not going to be the same as my patient’s goals.
It is also harder because someone who is older may feel that he or she has lived a good life and doesn’t need to go through heroic measures to try to be around as long as possible, and those goals may not align with the goals of that person’s children who want their parent to be around as long as possible. One of the confounding factors in this is navigating the different goals of the different family members.
Dr Sekeres has disclosed no relevant financial relationships.
Kate O’Rourke is a freelance writer in Portland, Maine. She has covered the field of oncology for over 10 years.