Subsets of Elderly AML Patients Respond Well to Chemotherapy
Subsets of Elderly AML Patients Respond Well to Chemotherapy
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Approximately 5% of elderly patients will have translocation (8;21) or inversion (16) upon cytogenetic evaluation. In a retrospective review of the outcomes for 147 elderly (> 60 years), patients with one or the other of these changes, complete remission after aggressive induction therapy was achieved in 88%. Aggressive postremission therapy was associated with better leukemia-free survival, but optimal strategies for this subset of patients remain to be developed.
Source: Prebet T, et al. Acute myeloid leukemia with translocation (8;21) or inversion (16) in elderly patients treated with conventional chemotherapy: A collaborative study of the French CBF-AML Intergroup. J Clin Oncol. 2009;27:4747-4753.
Treatment of acute myeloid leukemia (AML) in the elderly with aggressive regimens is often avoided due to the high risk or toxicity but also because of limited success.1 One reason for the lack of success is that the elderly are more likely to present with unfavorable prognostic factors, including a history of myelodysplastic syndrome or an unfavorable cytogenetic profile. However, for the uncommon elderly patient with favorable cytogenetics, aggressive treatment may well result in successful outcomes.
For example, AML with translocation (t) (8;21) or inversion (inv) (16) is associated with a favorable prognosis when treated with intensive chemotherapy. These changes are associated rearrangements of the core binding factor (CBF) genes (CBFA and CBFB), and the rearrangements result in impaired transcription of genes involved in myeloid differentiation.2 In general, patients with AML who are shown to have one or the other of these cytogenetic changes have a favorable prognosis when treated with aggressive strategies, including both induction and consolidation chemotherapy.3 However, among patients 60 years and older, these changes are observed only in approximately 5% of patients.3,4
In the current report, Prebet et al, throughout France, conducted a retrospective study to evaluate the characteristics and outcomes of AML with t(8;21) or inv(16) in elderly patients. For this, 147 patients with t(8;21) or inv(16) AML, who were age 60 years or older and who received at least one course of induction chemotherapy, were included. All patients had been treated on one of several clinical-trial protocols but, at a mininum, all included induction chemotherapy with an anthracycline and cytarabine. Once in remission, additional therapy consisted of low-dose maintenance chemotherapy (n = 72) or intensive consolidation (n = 56). The median age was 67 years. Sixty patients had t(8;21) and 87 patients had inv(16). A total of 129 patients (88%) achieved complete response (CR) after one or two induction courses, and 15 patients (10%) experienced early death (within eight weeks of induction therapy). During a median follow-up of 48 months, the five-year probabilities of overall survival (OS) and leukemia-free survival (LFS) were 31% and 27%, respectively. Multivariate analysis showed a negative impact of high WBC, impaired performance status, and deletion (9q) on OS and LFS. Administration of intensive consolidation was associated with better LFS only in patients with t(8;21). In addition, the need for critical care during induction independently predicted lower LFS.
Commentary
All of the patients considered in this retrospective review received aggressive induction therapy and, for patients over the age of 60 years, there is likely to have been a selection factor, as those with significant comorbidities or functional impairments may have not been included. Nonetheless, the observed high CR rate (88%) was comparable to that observed in young patients with the same cytogenetic features and, thus, strengthens the rationale for providing aggressive induction chemotherapy to the elderly with these cytogenetic changes. However, postremission therapy remains unclear. Although intermediate- to high-dose cytarabine is a particularly effective consolidation regimen for patients with these cytogenetic changes (particularly t(8,21)), this approach is problematic in elderly patients, particularly those older than age 70.5 For these patients, and perhaps for all elderly patients in remission from AML, new maintenance strategies employing novel agents such as multi-hit tyrosine kinase inhibitors, which target Kit, Ras, and Flt3, demethylating agents or histone deacetylase inhibitors are candidates for investigation. However, it will take a large intergroup effort to recruit sufficient numbers of patients to demonstrate the value of any of these approaches.
In summary, aggressive systemic therapy should be strongly considered for elderly patients who have AML with t(8;21) or inv(16). However, despite the high remission rate, the high risk of relapse suggests that alternative strategies of postremission therapy are warranted.
References
1. Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol. 2007; 25:1908-1915.
2. Niebuhr B, et al. Gatekeeper function of the RUNX1 transcription factor in acute leukemia. Blood Cells Mol Dis. 2008;40:211-218.
3. Appelbaum FR, et al. The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations. Br J Haematol. 2006;135:165-173.
4. Marcucci G, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol. 2005;23:5705-5717.
5. Buchner T, et al. Treatment of older patients with AML. Crit Rev Oncol Hematol. 2005;56:247-259.
Approximately 5% of elderly patients will have translocation (8;21) or inversion (16) upon cytogenetic evaluation. In a retrospective review of the outcomes for 147 elderly (> 60 years), patients with one or the other of these changes, complete remission after aggressive induction therapy was achieved in 88%. Aggressive postremission therapy was associated with better leukemia-free survival, but optimal strategies for this subset of patients remain to be developed.Subscribe Now for Access
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