ABSTRACT: 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.
Older adults represent the fastest-growing segment of the population in the United States. Within the next 25 years, 20% of the US population is expected to be older than age 60. Acute myeloid leukemia (AML) is a hematologic malignancy more commonly diagnosed in the older adult, with the median age of diagnosis being 67 years. For older individuals with acute leukemia, the mortality rate closely parallels incidence, thus highlighting the lethal nature of this disease. Several unique challenges in treating leukemia in the elderly ultimately contribute to the significantly inferior clinical outcomes seen in this group compared to younger cohorts. This article will discuss obstacles to treating elderly patients with acute leukemia, the biologic characteristics of AML in the elderly that lead to adverse outcomes, and treatment strategies aimed at improving overall survival.
The optimal chemotherapeutic regimen for patients younger than age 60 has been studied extensively in clinical trials of AML. Despite the fact that the majority of patients with acute leukemia are elderly, relatively few clinical trials have investigated treatment strategies in these patients for either curative or palliative intent.
The Southwest Oncology Group (SWOG) reported that the number of patients enrolled on clinical trials over age 65 between 1993 and 1996 were significantly underrepresented. While only 25% of patients aged 65 years or older were enrolled in SWOG trials in the mid-1990s, this age cohort represented 63% of the cancer population in the United States during the same period. One explanation is that several trials simply excluded elderly patients from enrolling. However, even trials that did not exclude elderly patients had lower enrollment rates, which could be attributed to either patient or physician perception of decreased tolerance of cytotoxic chemotherapy or investigational agents. In fact, up to half of oncologists questioned have reported not enrolling patients on clinical trials based on age alone.
Furthermore, older patients who are enrolled in clinical trials may not be representative of the elderly population at large. Restrictive exclusion criteria of many clinical trials select for patients with fewer comorbidities, less advanced age, and a higher baseline performance status. Subsequently, our knowledge of the optimum treatment strategy in the older adult is limited by a distinct lack of reliable clinical trial data.
Biologic Characteristics of AML in the Elderly
AML is a clonal disorder that is characterized by an unregulated proliferation of undifferentiated myeloid progenitor cells in the bone marrow and peripheral blood. The classification of AML is based on both morphologic and cytogenetic criteria. A comparison of the French-American-British (FAB) classification system and the more recent World Health Organization (WHO) system is shown in Table 1.
Molecular and cytogenetic abnormalities are common in leukemia, and are of particular importance in elderly patients with AML (Table 2). The presence of unfavorable karyotypes such as monosomy 5, monosomy 7, chromosome 11q23 abnormalities, and complex karyotype are much more commonly detected in elderly patients. Furthermore, cytogenetic abnormalities associated with favorable outcomes, such as inversion of chromosome 16, a translocation of chromosomes 15 and 17, or a translocation of chromosomes 8 and 21, are seen with considerably less frequency in older adults.
In a review of the Medical Research Council trials AML 10 (for patients younger than age 55) and AML 11 (for patients older than age 55), a distinct discrepancy was seen in karyotype distribution between the two age groups. Favorable cytogenetic profiles were detected in 24% vs 7% and unfavorable cytogenetic profiles in 6% vs 13% in younger vs older cohorts, respectively. Furthermore, the presence of poor-risk karyotype profiles appears to continually increase with age. A recent report of five SWOG trials conducted between 1998 and 2006 indicated that the percentage of patients with favorable cytogenetics declined and the percentage with unfavorable cytogenetics rose precipitously for age groups less than 55, between 55 and 65, between 65 and 75, and greater than 75. Thus, the presence of poor-risk cytogenetics increases with age and is associated with adverse outcomes in elderly patients with AML.
Antecedent hematologic malignancies are also associated with poor outcomes in patients with AML. Elderly patients are more likely to have a diagnosis of myelodysplastic syndrome (MDS) or a myeloproliferative disorder preceding the development of AML, and these patients consistently respond poorly to chemotherapy. Systemic exposure to chemotherapeutics that are known to induce a secondary AML, such as alkylating agents and topoisomerase II inhibitors are also more commonly experienced in elderly patients. Furthermore, adverse cytogenetic profiles are present in higher frequency in patients with preceding MDS and those with exposure to alkylating agents (chromosome 5 or 7 abnormalities) and topoisomerase II inhibitors (chromosome 11q23 abnormalities). Together, these two factors contribute to inferior responses to standard treatment protocols.
In more recent years, the presence of a multidrug resistance phenotype has been identified as a negative prognostic finding in AML. The gene responsible for this phenotype (MDR-1) is located on the long arm of chromosome 7, and encodes a 170-kD glycoprotein or P-glycoprotein (PgP), which functions as an ATP-dependent efflux pump. In vitro models have shown that PgP overexpression has led to increased cellular export of antineoplastic drugs, including vinca alkaloids, anthracyclines, epipodophyllotoxins, and paclitaxel(Drug information on paclitaxel).
MDR-1 is more commonly expressed in elderly patients and is associated with an increased resistance to anthracycline chemotherapy, with an associated decreased rate of complete remission and an inferior disease-free survival and overall survival. In a comparison of patients younger than age 55 enrolled on the SWOG 8600 trial to patients older than age 55 enrolled on the SWOG 9031 trial, MDR-1 overexpression was detected in 30% vs 71% of younger and older patients, respectively. Thus, MDR-1 overexpression is a significant contributor to the likelihood of an adverse clinical outcome for elderly patients with AML.
Numerous additional molecular markers have been identified in AML that affect response to chemotherapy and overall clinical outcomes. One example is the presence of fms-like tyrosine kinase (FLT-3) internal tandem duplications or point mutations, which have been shown in multiple studies to result in adverse outcomes. While these mutations are not unique to elderly patients with AML, they appear to confer an inferior response to chemotherapy in both younger and older patients.
In contrast, the presence of nucleophosmin gene mutations (NPM1) has recently been linked to chemo-responsiveness in patients with AML.[13,14] The NPM1 gene encodes nucleophosmin, a nucleocytoplasmic shuttling protein that is normally present in the nucleolus and is responsible for maintaining genomic integrity. Mutations in exon 12 of the NPM1 gene result in cytoplasmic translocation of the protein and subsequent inhibition of the ARF/p53 tumor-suppressor pathway. The presence of cytoplasmic nucleophosmin in leukemic blasts of patients with AML has been linked to a normal karyotype, increased frequency of FLT-3 mutations, and a favorable response to induction chemotherapy.
While these molecular characteristics are not unique to elderly patients with AML, the presence of these, along with karyotype analysis and MDR-1 expression, can help determine a gene-expression profile that may guide therapeutic decisions.