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Treatment of AML and MDS in Older Adults
Abstract & Commentary
By Andrew S. Artz, MD
Synopsis: The prognosis of older adults with AML even after intensive chemotherapy is poor. Kantarjian and colleagues evaluated 446 AML patients 70 years and older who underwent cytarabine-based intensive chemotherapy between 1900 and 2008. After excluding the small subset with favorable cytogenetic profiles, they found the complete response rate was 45%. However, 8 week mortality was 36% and median survival was 4.6 month. Adverse prognostic factors included age 80 or older, complex karyotype, creatinine > 1.3 mg/dL, and ECOG PS 2 or more. Eight week mortality for patients with 2 or more risk factors was over 50%. For AML patients 70 years or older harboring these adverse risk factors, early death is high with standard induction, warranting alternative approaches.
Source: Kantarjia H, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116:4422-4429.
a.ute myeloid leukemia (AML) is primarily a disease of the elderly, with the median age around 68 years. Registry data of all elderly AML patients indicate a median survival of less than 3 months after diagnosis. The prognosis remains poor even for adults 60 years and older with AML who are deemed fit enough to undergo standard chemotherapy alone.1 Outcomes deteriorate for each decade of age, if performance status limitations exist1 such that the value of intensive chemotherapy in many older AML patients may be questioned. The reason for poor outcomes relates not only to resistant leukemia but also to decreased physiologic reserve, as measured by comorbid burden, performance status, or other measures. Early death represents a good marker for poor tolerance to treatment. A host of new therapies have emerged, threatening to supplant the historical standard of cytarabine and an anthracylcine.2-6
Investigators at MD Anderson Cancer Center reviewed data on 446 AML (excluding APL) patients 70 years and older who were initially treated with cytarabine-based intensive chemotherapy regimens from 1990 to 2008. The median age was 74 years, ranging from 70 to 88 years. Karotypes were unfavorable in 54%, normal karotype in 39%, and favorable in 4%. The majority (63%) received idarubicin and the rest received another chemotherapy agent (e.g., fludarabine, topotecan, clofarabine, etc.) in combination with cytarabine. Of the 16 patients with favorable karyotypes (i.e., inversion 16 or translocation 8;21), the response rate was 63%; the remaining 430 patients achieved a 45% CR rate. The median duration of CR lasted 10.8 months. However, in those without favorable karyotypes, early death at 4 and 8 weeks was 26% and 36%, respectively. Median survival was 4.6 months, and 3-year survival was 10% in the cohort lacking a favorable karyotype. CR rate and survival did not differ by decade of treatment.
Independent factors predicting 8-week mortality included age 80 years and older, ECOG performance status of 2-4, complex karyotype, and creatinine greater than1.3 mg/dL. The investigators constructed a risk score from these four components. Eight-week mortality for patients with 0, 1, or ≥ 2 factors was 20%, 31%, and > 50%, respectively. Prevalence of adverse features was evenly spread: 28% showed no adverse features, 31% exhibited one adverse factor, and 32% revealed two or more adverse features. The prognostic model discriminated well in a separate cohort of patients treated from 1980 to 1989.
a.L in the elderly presents significant challenges in determining what, if any, treatment should be administered. The historical gold standard has been induction chemotherapy, employing an anthracycline and cytarabine for those deemed fit enough for treatment. The paradigm is problematic, as objective measures to assess fitness are limited and outcomes are still quite poor, with < 10% long-term survivors with optimal therapy. Therefore, we need to readdress the benefits and risks of this historical standard.
Kantarjian and colleagues take advantage of the large leukemia service at the MD Anderson Cancer Center to amass results on 446 adults 70 years and older undergoing intensive chemotherapy with cytarabine and at least one other agent. Only 16 patients showed the favorable karyotypes of inversion 16 or translocation 8;21. The analysis focused primarily on the remaining 430 patients, of whom 54% had unfavorable karotypes. Complete response rates were around 40%-50%. However, median survival was 4.6 months and eight-week mortality was 36% among these selected older adults, again depicting the limitations of standard therapy. A frustrating truth was that survival did not differ in the 1990 to 1999 time period, compared to 2000 to 2008.
To address which adults 70 years and older with AML might realize some benefit from standard chemotherapy, they created a prognostic model for early death. The four independent factors found were age 80 years or older, complex karyotype, poor performance status of two or more, and serum creatinine > 1.3 mg/dL. Eight-week mortality for patients with 0, 1, or ≥ 2 factors was 20%, 31%, and > 50%, respectively. In short, based on these data, the presence of two or more adverse features would strongly argue against standard induction, and one can debate the merits of an early death rate of 20%-31% in patients with 0-1 adverse features.
While this model is helpful for prognostication and decision making, applying this to clinical practice mandates incorporating additional information. Of the 18 or so factors analyzed, it is interesting that three of the four measures (i.e., age, creatinine and PS) can be considered surrogates of physiologic reserve rather than disease-based parameters. Thus, one would expect more precise measures such as comorbid scores, functional tests (i.e., get up and go), or biomarkers might prove useful in the future. Some data from the same group suggest comorbidity scores can stratify for early death after induction.7 A comorbidity score would have been invaluable. Disease-based prognostication has developed rapidly. Unfortunately, outcomes for older adults are worse for any given prognostic factor relative to younger adults. In this series, a fairly large number (36%) had a normal karotype, probably because such patients were more likely to be offered chemotherapy compared to those with more adverse disease features. Molecular abnormalities among normal karyotype AML enable risk stratifying this homogenous group. For example, the presence of a nucleophosmin 1 mutation has been associated with better prognosis. In younger adults, this appears to be restricted to the subset without a FLT3-internal tandem duplication; yet in older adults, FLT-3 ITD mutational status may not be as important.8 Thus, the presence of normal karotype AML and a NPM1 mutation may tilt the balance toward using intensive or standard chemotherapy, at least in a relatively fit patient. In the future, more biologically targeted drugs for specific defects (e.g., FLT-3 inhibitors) may well provide more effective if not more tolerable treatments.
Obviously, new therapies, such as clofarabine, azacitidine, decitabine, and others have emerged that rebalance the risk-benefit ratio.2-6 Adverse features for early mortality provide a compelling rationale to avoid standard induction for patients deemed fit enough to receive therapy. One must balance the enthusiasm for new therapies with the recognition that prospective studies have not established that alternative drugs, such as demethylating agents, actually reduce early death. Moreover, an entirely different approach has been intensification of therapy. One major study in AML patients 60 years and older showed that daunorubucin of 90 mg/m2 bested 45 mg/m2 for remission rates, although OS was only affected in the 60- to 65-year-old cohort.5 Similarly, allogeneic hematopoietic transplant continues to expand to older adults, and is starting to be offered to adults 70 years and older. Finally, these data affirm the appropriateness of clinical trials, even as upfront therapy.
In conclusion, intensive cytarabine-based chemotherapy results in a significant eight-week mortality rate in AML patients 70 years and older that may be predicted by certain risk factors. For patients lacking any adverse prognostic features for early death, intensive chemotherapy remains a viable option. For those harboring several adverse features, results after intensive chemotherapy argue strongly against this approach. The benefits of newer, less intensive approaches are being actively investigated.
1. Appelbaum FR, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481-3485.
2. Faderl S, et al. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008;112:1638-1645.
3. Larson RA, et al. Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia. 2002;16:1627-1636.
4. Fenaux P, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 28:562-569.
5. Lowenberg B, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361:1235-1248.
6. Cashen AF, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 28:556-561.
7. Giles FJ, et al. The haematopoietic cell transplantation comorbidity index score is predictive of early death and survival in patients over 60 years of age receiving induction therapy for acute myeloid leukaemia. Br J Haematol. 2007;136:624-647.
8. Rollig C, et al. A novel prognostic model in elderly patients with acute myeloid leukemia: Results of 909 patients entered into the prospective AML96 trial. Blood. 116:971-978.