Acute myeloid leukemia in older adults

Authors: Masamitsu Yanada Tomoki Naoe

Publish Date: 2012/07/13

Volume: 96, Issue: 2, Pages: 186-193

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Abstract

Acute myeloid leukemia AML is predominantly a disease of older adults with a median age at diagnosis of over 65 years AML in older adults differs biologically and clinically from that in younger ones and is characterized by stronger intrinsic resistance and lower tolerance to chemotherapy The effects of age on both patient and diseaserelated factors result in a higher incidence of early death during chemotherapy a lower rate of complete remission and a reduced chance of longterm survival Treatment options for older adults with AML include intensive chemotherapy lessintensive chemotherapy best supportive care or enrolment in clinical trials Given the heterogeneous nature of AML in older adults therapeutic decisions need to be individualized after systematic assessment of disease biology and patient characteristics Regardless of treatment however outcomes for older AML patients remain in general unsatisfactory In contrast with the progress made for younger adults the treatment of AML in older adults has not improved significantly in recent decades Development of less toxic and more targeted agents may well provide treatment alternatives for a majority of these patients The overall dismal outcome with currently available treatment approaches has encouraged older AML patients to participate in prospective clinical trialsAcute myeloid leukemia AML is a disease that primarily affects older adults and the median age at diagnosis is over 65 years 1 2 3 The cutoff age for differentiating younger from older AML is arbitrary age 65 or older has traditionally been used as the eligibility criterion for previous studies of elderly AML by the Japan Adult Leukemia Study Group whereas other study groups have chosen among others 60 or older 70 or older or 50–70 years For practical purposes however age 60 or over is generally used to define elderly AML 4 5 Elderly AML is a biologically and clinically distinct disease with a diminished response to chemotherapy Previous clinical trials of intensive chemotherapy showed rates of complete remission CR around 50  and of longterm survival at less than 10  which are much worse than for younger patients 1 2 3 Furthermore such data likely overestimate the true outcome for elderly AML as patients entered into clinical trials are screened using criteria such that they often do not represent the general patient population In contrast with the progress made for younger adults the outcome of treatment of elderly AML has improved little if at all in recent decades 6 7 The adverse prognostic impact of older age is attributable to differences both in diseaserelated factors ie cytogenetics secondary AML and expression of the multidrug resistance phenotype and patientrelated factors ie general condition organ dysfunctions and comorbidities In addition to these therapeutic drawbacks the net incidence of elderly AML is expected to increase as the population continues to age making the management of elderly AML an even more critical issueThe unfavorable biologic characteristics of AML amplified in older adults such as a higher proportion of unfavorable cytogenetics higher frequency of antecedent hematologic disorders or previous treatment for one or more other malignancies and more frequent expression of the multidrug resistance phenotype Cytogenetic findings at diagnosis have important prognostic implications for both younger and older patients 8 9 10 Favorable cytogenetic characteristics eg core binding factor CBF abnormalities as defined by t821 or inv16/t1616 are relatively uncommon in older adults and are seen in less than 5  of patients aged over 60 years 8 9 10 In contrast unfavorable cytogenetics represented by complex karyotype is predominant in older patients Secondary AML arising from myelodysplastic syndrome MDS or myeloproliferative neoplasm MPN or AML related to prior chemotherapy for previous malignancies both of which are known as subtypes with increased resistance to chemotherapy is also common in this age group 1 2 3 Response to chemotherapy is affected by the expression of genes that confer drug resistance such as the multidrug resistance 1 MDR1 gene that encodes the chemotherapy efflux pump Pglycoprotein Overexpression of Pglycoprotein reportedly occurs in 71  of older patients compared to only 35  of younger patients 11Patientrelated factors such as poor general condition significant comorbidities and diminished functional reserves also contribute to the poorer outcomes for older patients Moreover because of their reduced performance status PS and increased prevalence of significant comorbidities older patients are less tolerant of complications associated with chemotherapy These conditions often make physicians reluctant to administer intensive chemotherapy to older patients Indeed according to a survey conducted in the United States chemotherapy was administered to only 30  of patients over the age of 65 years 12 Although selected patients can tolerate and benefit from intensive chemotherapy older adults as a whole are more likely to experience treatmentrelated mortality TRM and less likely to benefit from standard induction and postremission therapiesTaken together these findings indicate that the effects of age in terms of both patient and diseaserelated factors result in a higher incidence of early death during induction therapy a lower rate of CR and a reduced chance of longterm survivalThe prognosis of AML worsens with age When treated with intensive chemotherapy CR rates for older adults range between 40 and 60  1 2 3 which is much lower than those for younger adults Even if CR is achieved older adults are more likely to experience relapse leading to an extremely low expectation for longterm survival Such a poor chance of treatment success is combined with a high risk of TRM which ranges from 10 to 40  even for selected older adults 1 2 3

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