Current Era Means More AML Treatment Options for Elderly

Eunice S. Wang, MD

As part of our coverage of the American Society of Hematology (ASH) 2014 Annual Meeting, Cancer Network is speaking today with Eunice S. Wang, MD, associate professor and staff physician at Roswell Park Cancer Institute. Dr. Wang is participating in an education session at this year’s meeting discussing acute myeloid leukemia in the elderly patient.

-Interviewed by Leah Lawrence 

Cancer Network: Dr. Wang, can you tell us first, how common is acute myeloid leukemia in the elderly, and how do you define this population?

Dr. Wang: Acute myeloid leukemia, or AML, is a disease of older adults. The median age of presentation of patients with AML is 69 to 70 years old. In 2014, an estimated 18,860 new cases of AML are expected to be diagnosed in the United States. We also expect there to be a significant mortality associated with this disease and statistics show that about 11,000 patients of these 18,000 will eventually die from this diagnosis.

We define elderly in this patient population as those patients above the age of 60 years old. Given the fact that the median age is 69 to 70, this allows us to place half of patients with this diagnosis above the age of 60 to be considered elderly and anyone under the age of 60 to be considered younger patients.  

Cancer Network: What makes the elderly population a challenging population to treat?

Dr. Wang: Adults greater than or equal to the age of 60 years old obviously have significant comorbidities or medical problems that younger individuals don’t have. They may have underlying diabetes, high blood pressure, high cholesterol, history of stroke, etc., and they may be on multiple medications to control their medical comorbidities, which may interact or confound the treatment of AML.

In addition, patients in the elderly category have a different type of tumor biology than younger patients. AML in the elderly population tends to have a lot of biological features, which are associated with therapy resistance. For example, elderly patients have increased numbers of leukemia cells, which have unfavorable cytogenetics or molecular characteristics, which make it more difficult for them to be cured with standard chemotherapy. Sometimes the leukemia cells in older patients express drug resistant proteins, which also mediate therapy resistance. As well, many older patients have had a pre-existing hematologic disorder, such as MDS, or myeloproliferative disorders, which then make subsequent AML disease much harder to treat.

For all of these reasons, the treatment of elderly patients with AML is very complex and challenging. We have reported in the past that cure rates or remission rates can be as low as 5% to 10%.

Cancer Network: What sort of factors must be considered when evaluating elderly patients for treatment?

Dr. Wang: We need to consider the fact that many of these patients may not be cured of their disease. Let’s also keep in mind, what are the goals of these older individuals with treatment. One of the things that I like to discuss at the beginning of treatment is to talk to them about what is truly important to them given that they have life-threatening cancer. What type of treatment would they like? Would they want more quality or quantity of life? Would they like treatment as an inpatient or an outpatient? Would they want truly lifesaving therapies such as stem cell transplant or intensive care, or were they looking for prolongation of life but not necessarily aggressive resuscitation at the end?

Obviously, one of the things I would recommend for all older patients undergoing that discussion is for their underlying leukemia to be characterized biologically. To look for features of that leukemia that predict for therapy resistance or might lead us to discussions of which type of therapy might be best for the type of cancer those individuals have.

Cancer Network: Can you walk us through some of the strategies that currently exist for this patient population?

Dr. Wang: There currently are a number of very exciting therapeutic options that have arisen in the past several years for the treatment of this patient population.

In the past, patients with AML were only offered intensive induction chemotherapy using a cytarabine and anthracycline based backbone, so called the 7+3 regimen. This regimen is associated with the highest remission rates in AML patients, but is also associated with significant mortality and morbidity of up to 20% to 45%, particularly in the elderly population. Administration of intensive induction chemotherapy requires patients to be in-patient in the hospital for 4 to 5 weeks and has significant risk, particularly of infectious complications due to prolonged neutropenia. In the past, there have been a lot of prognostic models to predict which patients with AML most benefited from this intensive approach. Data generated at many centers have suggested that patients who are older in age (ie, 70 and above), who have low performance status, poor cytogenetic features, poor molecular features, and have significant comorbidities as demonstrated by organ dysfunction are particularly not suitable for this type of therapy because of the high risk of complications and the low chance of clinical benefit. On the other hand, this does remain our most effective treatment for AML. In patients who have favorable, intermediate-risk karyotypes and who are fit, and would like to have the opportunity to achieve remission and possibly curative stem cell transplant should still be offered intensive induction chemotherapy as the standard of care because in this day and age, we don’t have anything that will produce higher remission rates than the 7+3 intensive therapy.

Other options have recently arisen over last several years. These include the use of hypomethylating or epigenetic agents. Two agents, decitabine and azacitidine, were approved for use with myelodysplastic syndrome in the mid-2000s and since have been adopted for the treatment of older patients with AML. We don’t have a comparison of intensive chemotherapy vs hypomethylating therapies for upfront treatment of AML, particularly in these older individuals. However, retrospective studies have suggested that, particularly for that more at-risk older patient, that the survival rates achieved with each of these modalities may be equivalent. Patients who achieve remission typically will have a higher chance of doing so after induction chemotherapy than treatment with hypomethylating agents, but that overall amount of time that the disease can be controlled and that the patient lives with their disease looks to be, in retrospective studies, almost equivalent. Now, obviously, we need to wait for prospective studies to determine this.

We are also very intrigued by emerging data suggesting that particular biologic subsets of elderly AML patients may benefit preferentially from the administration of epigenetic agents as opposed to cytotoxic chemotherapy, but in the current era, the major benefit of using these hypomethylating agents is that the perception that patients with AML should not receive treatment is really starting to go away a bit. In the past, many of these elderly patients were not offered definitive therapy for their cancer because of the fear of all of the treatment-related toxicity with intensive chemo. The presence, tolerability, and availability of these hypomethylating agents as an option for these older patients has made clinicians much more likely to administer them for individuals who, in the past, might have just been offered best supportive or palliative care.

Cancer Network: What, in your opinion, are the key factors to keep in mind when approaching treatment of acute myeloid leukemia in an elderly patient?

Dr. Wang: It is important to realize that almost all these older AML patients, even those above the age of 80, can be considered for definitive treatment of their disease. These are patients that, in the past, although they may have been offered hospice or supportive care, in current era, the consensus is that these patients do benefit from some type of definitive therapy. One must keep in mind at all times that AML will be a life-ending disease for the majority of these patients. It is important, given the heterogeneity of this population this day and age, to tailor the therapy that you offer to these patients to the individual patient and their priorities, life, comorbidities, and underling tumor biology.