Acute myeloid leukemia (AML) is a disease of the elderly, with the majority of patients diagnosed in their 6th and 7th decade of life. Older patients with AML are less likely to achieve complete remission after induction chemotherapy, and they suffer from higher rates of leukemia relapse compared to younger cohorts. Suboptimal outcomes are the result of adverse biologic characteristics of leukemia in the elderly, as well as the presence of medical comorbidities and patient or physician preferences as to initiating treatment. In addition, there is a distinct lack of randomized, prospective data to guide management decisions for the treatment of AML in the elderly. Patients who are over age 75, with poor performance status, multiple comorbidities, or poor prognostic features, should be considered for a clinical trial or palliative therapy. Elderly patients who are candidates for standard induction chemotherapy and achieve complete remission are unlikely to benefit from intensive postremission therapy and should be referred to a clinical trial when possible. Further prospective trials are needed to identify a tolerable, effective treatment regimen for older patients with AML.
In this issue of ONCOLOGY, Dr. Melchert makes an earnest attempt to highlight many of the obstacles faced in treating elderly patients for acute myeloid leukemia (AML) and summarizes the disappointing results that follow. She points out the important biologic differences between AML in younger and older patients. Also emphasized is the reality that elderly patients frequently present with decreased performance status and increased comorbidities (the two are not the same), and that both of these lead to significantly decreased tolerance to chemotherapy. The underrepresentation of older patients on clinical trials is also noted. All of these points are important and worth emphasis. A key omission, however, is that nowhere in the paper does the author attempt to define the subject of the discussion.
Maybe I'm particularly touchy, sensitive, and irritable about the issue of age because I just turned 60. I'll admit I'm gray and bald, but I still ski down the black diamond slopes, sometimes hit my drives over 250 yards, and run my 3 miles daily. I'm certainly older, but am I elderly? Of course, this rant isn't about my health, but rather to make the point that a patient's performance status and comorbidities as well as the biologic characteristics of the individual's leukemia are not determined by age alone. We probably do both our patients and our research a disservice if we continue to use age as the single defining characteristic for protocol eligibility and selection of treatment.
Considering first the issue of performance status, in a recent analysis of 968 patients with AML treated on Southwest Oncology Group trials, we found that age by itself did not have a major impact on the ability of patients to tolerate induction chemotherapy. If patients had an excellent performance status (Eastern Cooperative Oncology Group [ECOG] 0), the risk of early death (defined as within 30 days of induction chemotherapy) was not increased even in patients over age 75. In contrast, if patients were younger than age 55, performance status had no impact on the risk of early death.
We did observe a powerful interaction between age and performance status so that if patients had a poor performance status (ECOG 2 or 3) and were over age 65, the risk of early death approached 50%. Thus, when considering tolerance to intensive induction chemotherapy, age by itself is not the issue, rather it is the combination of age and performance status or extent of comorbidities.
In our study, we did note an increased likelihood of adverse biologic characteristics in the AML cases affecting older patients, with a higher rate of multidrug resistance and an increased incidence of unfavorable cytogenetics. However, even in patients over age 65, some cases with favorable-risk cytogenetics were seen and over 50% had intermediate-risk karyotypes. These results are very similar to those recently reported by the German-Austrian AML Study Group. As we have previously noted, high complete response rates (approximately 80%) can be expected in older (even elderly) patients with a decent performance status, intermediate- or good-risk cytogenetics, and lack of P-glycoprotein. In contrast, for patients in the same age group with poor performance status, poor-risk cytogenetics and P-glycoprotein-expressing AML blasts, there is almost no hope for a remission using standard induction therapy.
It does seem to be the case that age may affect the duration of remission, independent of the cytogenetic risk group. While older patients with favorable-risk core-binding-factor (CBF) AML have a high complete response rate, the duration of remission is significantly shorter than in younger patients. The explanation for this is uncertain, and at least two general hypotheses have been offered. One argument is that AML in the older patient is more often a multistep process, and perhaps the CBF mutations occur in an already malignant, disordered hematopoietic progenitor. A slightly different hypothesis is that the nature and behavior of the malignancy may be determined in part by the age of the hematopoietic stem cell in which it occurs.
Even if the duration of remission is adversely affected by age, this does not mean that obtaining a complete remission in older individuals is without benefit. The ability to resume a normal life, even for relatively brief periods of time, can be of great value to the older patient. Further, obtaining a complete remission is a vital first step if allogeneic transplantation is to be considered. Although Melchert is correct that data remain limited, she failed to discuss a reasonably large series of 122 older AML patients who underwent nonmyeloablative allogeneic transplants from related or unrelated donors. The 2-year disease-free survival rate is 44% for related and 63% for unrelated donor transplant recipients-better results than one would expect for a group of AML patients with a median age of 60. Granted, these results may be influenced by patient selection issues, and it is now the responsibility of the research community to verify these results in prospective comparative studies.
Just as there are elderly patients who should not be denied the benefits of standard intensive induction therapies, there are those for whom current therapies are futile. Such patients are those with poor performance status, advanced age, and unfavorable molecular characteristics. For these patients, we need entirely new approaches. It would be useful if we could agree on an objective, reproducible definition of this group. A number of clinical trials, some hoping to be the basis for drug approval by the US Food and Drug Administration, have been designed as single-arm studies for "elderly patients who are not candidates for standard induction chemotherapy." Without a clear definition for such patients based on large historical databases, such studies will inevitably be difficult to interpret.
-Frederick R. Appelbaum, MD
Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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