Treatment of AML Based on Age
Abstract & Commentary
By William B. Ershler, MD
Synopsis:In a retrospective review of 2276 patients with acute myeloid leukemia (AML) treated on one of three consecutive Phase 3 studies using non-age based, standard intensive chemotherapy conducted by the Japan Adult Leukemia Study Group between 1995 and 2005, there was a significant decline in overall survival in patients aged ≥ 50 years when compared to those < 50 years. However, there was no difference in survival for patients aged 50 through 64 years. Although older patients with AML are often treated with less intensive therapy than younger patients, this analysis suggests that intensive chemotherapy without dose modification based on age may be considered for otherwise healthy patients with AML up to age 64.
Source: Yanada M, et al. The demarcation between younger and older acute myeloid leukemia patients. Cancer 2013;119:3326-3333.
Because of both biological and clinical factors, age is known to be an important prognostic factor in adult acute myeloid leukemia (AML).1,2With increasing age, there is a higher prevalence of adverse disease characteristics such as unfavorable cytogenetics and prior myelodysplastic syndrome (MDS).3,4In addition, older patients are more likely to have comorbid medical conditions and a worse performance status. As a result, current treatment regimens are typically based on age, with older patients, frequently defined as those ≥ 55 or 60 years of age, receiving less intense treatment than younger patients. However, it remains unknown if older patients who are generally in good health require this treatment modification.
To investigate the correlation between age and outcomes in patients with AML treated with intensive chemotherapy, Yanada and colleagues reviewed data from three consecutive prospective Phase 3 studies conducted by the Japan Adult Leukemia Study Group between 1995 and 2005. In these studies, there were no dose modifications made based on age, and all patients received the standard intensive cytarabine-based chemotherapy. All of the studies had the same inclusion criteria, which were as follows: newly diagnosed AML (excluding acute promyelocytic leukemia), age 15-64 years, an ECOG performance status of ≤ 3, and adequate liver (serum bilirubin < 2.0 mg/L), renal (serum creatinine < 2.0 mg/dL), pulmonary (PaO2 ≥ 60 Torr or SpO2 ≥ 93%), and cardiovascular function (normal EKG and ECHO). Exclusion criteria included AML secondary to myelodysplastic syndrome or previous cytotoxic therapy. Data on 2276 patients aged < 65 years who met these criteria and were enrolled on one of these studies were retrospectively analyzed.
Initially, patients were divided into four subgroups based on age for data analysis: age 15-29, 30-39, 40-49, 50-64 years. However, because initial analysis revealed a significant difference in overall survival between patients aged 40-49 and 50-64, subsequent analyses focused on two further-defined comparisons: 1) age < 50 (n = 1339) vs ≥ 50 (n = 937) years, and 2) age 50-54 (n = 334) vs 55-59 (n = 322) vs 60-64 (n = 281) years. There were no significant differences in performance status between the groups.
There was a significant decline in overall survival in patients aged ≥ 50 years when compared to those < 50 years (37.0% and 49.6% at 5 years, P < 0.001). However, there were no significant differences in overall survival in patients aged 50-54, 55-59, and 60-64, with overall survival rates of 38.2%, 35.1%, and 38.0%, respectively (P = 0.934).
In addition, differences were noted in cytogenetic profiles and subsequent risk between the two age groups. Specifically, favorable cytogenetics including t(8;21) and inv(16)/t(16;16) occurred more frequently in patients < 50 years (P < 0.001 and P = 0.043, respectively), and less favorable cytogenetics including add(5q)/del(5q)/-5, add(7q)/del(7q)/-7, complex karyotype, and monosomal karyotype were more frequent in patients ≥ 50 years (P = 0.002, P = 0.021, P < 0.001, and P < 0.001, respectively). However, there were no significant differences in the cytogenetic profiles in patients aged 50-54, 54-59, and 60-64.
Of the 2276 patients evaluated, 1788 achieved complete remission (CR). Patients < 50 years appeared to have a higher rate of CR than those ≥ 50 years (79.8% vs 76.7%). However, this difference was not statistically significant (P = 0.078). There was no difference in CR rate among patients aged 50-54, 54-59, and 60-64 (P = 0.829). Patients ≥ 50 years were more likely to experience relapse than those < 50 years (61.1% vs 53.4%, P = 0.008). There was no difference in relapse rate among patients aged 50-54, 54-59, and 60-64 (P = 0.196). There were no significant differences in early death or non-relapsed mortality among any of the age groups.
Those of us with a focused interest on cancer in older people might understandably be drawn to the title of the current paper, only to learn that "old" was defined as 50-plus. Although we all understand that AML is different, the median age for this disease is 70 years5and, thus, the majority of patients with AML would not be included in an analysis that restricts discussion to those 65 years and younger. That stated, the data from Japan are both notable and interesting. There seems to be an age-associated hinge point at age 50 years with a deflection downward in treatment response and survival thereafter. What is particularly curious is that beyond age 50 through age 64 years, response rates and survival did not show incremental declines but were stable. One possible explanation is that AML when it occurs in late middle age as opposed to earlier is somewhat different, with less favorable prognostic features including cytogenetic changes and markers of drug resistance. Beyond age 65, host factors such as prevalent comorbidities and functional declines contribute to the more dismal outcomes associated with AML observed.
To further explain the Japanese data, it should be remembered that these were patients enrolled on clinical trials and thus may not represent the general AML population. If data were available for all patients in the selected age groups, it is quite possible an incremental decline in response rates and survival would be observed, as described in the epidemiologic study from England6also reviewed in this issue of Clinical Oncology Alert.
- Estey E, Dohner H. Acute myeloid leukaemia. Lancet 2006;368:1894-1907.
- Yanada M, Naoe T. Acute myeloid leukemia in older adults. Int J Hematol 2012;96:186-193.
- Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol 2007;25:1908-1915.
- Schoch C, et al. The influence of age on prognosis of de novo acute myeloid leukemia differs according to cytogenetic subgroups. Haematologica 2004;89:1082-1090.
- Siegel R, et al. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.
- Shah A, et al. Survival and cure of acute myeloid leukaemia in England, 1971-2006: A population-based study. Br J Haematol 2013;162:509-516.