Acute myeloid leukemia (AML) may occur in people of all ages, but is most common in patients older than 65 years.[Citation1] In the elderly population, AML is associated with several distinctive biological and clinical features compared to younger adults, which correlate with poor outcome.[Citation1–Citation3] Moreover, age has been always identified as a strong independent predictor for overall survival (OS) in AML patients, with a worse outcome as age increases.[Citation1,Citation2]
At present, there is no treatment of choice for older patients with AML.[Citation2,Citation4] This is mainly due to (1) the poor outcome of elderly patients intensively-treated, with long-term survivors being less than 10% [Citation5]; (2) the lack of tolerability of standard chemotherapy, which is frequently associated with high mortality and morbidity rates and a significant decrease in quality of life. Moreover, only a minority of elderly AML patients, aged less than 70 years and with a WHO performance status of 0–2, are suitable for standard, intensive chemotherapy, because a high proportion of them have a low performance status and high comorbidity burden.[Citation6]
Accordingly, we are dealing every day with the dilemma of which therapies may benefit the vast majority of elderly AML patients, being uncertain about the opportunity of administering intensive therapies, complicated by a high rate of treatment-related deaths, or lower-intensity treatments, associated with a high risk of leukemia-related deaths. As a fact, the development of lower-intensity treatment due to the discovery of novel agents has granted to a significant proportion of patients aged >70 years, not eligible for intensive treatment, the access to a disease-specific therapy. This is a major advancement itself, because until 20 years ago the administration of supportive care was the only option for approximately 60% of elderly patients with AML. However, the road to develop and bring novel, targeted, less toxic drugs to the market for elderly AML has been, in the last 30 years, a boulevard of broken dreams,[Citation7] in which approximately all new agents failed to convince the US Food and Drug Administration of their favorable safety and efficacy profile in a population of patients who clearly need additional therapies.
In this issue of the Journal, Thomas and Le Jeune extensively reviewed the safety of treatment options for elderly people with AML.[Citation8] Together with the innovative therapeutic options in development, the authors emphasize the importance of tolerability and quality of life, and suggest a multidisciplinary approach to treat elderly AML patients. After elegantly presenting the most recent advancement with novel agents, and showing the possible new scenarios for both chemical and cell therapies, the authors discuss the relevance of considering the safety of each treatment for each patient. This return to the Socratic philosophy, with an anthropocentric point of view, open new questions about the necessity of an individualized therapy for elderly AML patients, that may take in account not only a (possible) increase in OS, but also the maintenance or improvement of quality of life, the symptom’s management and a maximization of time outside of hospital care.
In this regard, it should be underlined that a major goal when testing new drugs or combinations would be to identify reliable biomarkers able to predict which patients are more likely to achieve clinical responses. This would allow, on one hand, to prevent undesirable toxicity in patients with less chance to obtain a benefit and, on the other hand, to optimize the costs, especially when expensive molecular targeted drugs are employed.
Very recently, our group has shown, for the first time, the prospective use of a gene expression profile (GEP)-driven therapy in a cohort of hard-to-treat AML patients, unfit for standard therapy, with an extremely poor prognosis.[Citation9] We treated 66 very elderly, unfit patients with AML with low-dose lenalidomide plus low-dose cytarabine. By studying the global GEP of AML blasts collected before treatment administration, we identified 5 genes efficiently discriminating patients who obtained or not a CR [9 + Isidori A, unpublished data]. Although this gene signature needs to be validated in an independent cohort of patients and seems to be treatment specific, our study opens a new scenario for drug development in older AML patients, demonstrating that a more accurate biomarkers definition can help discriminate among patients who may or may not benefit from a specific targeted therapy or even intensive chemotherapy. However, there is still a lot of work to do in this field to identify biomarkers predictive of response, because the plethora of novel molecular mutations have represented a prognostic rather than a therapeutic advancement until now, specially in the elderly population. Nevertheless, we have to keep in mind that a significant requirement to treatment development in this field is the need for a randomized proof. In this view, the ‘pick a winner’ design, being used in the United Kingdom and elsewhere, probably still represents the more efficient way to clinically develop and validate new therapeutic options, feasible for unselected patients.
Last but not least, chronologic age cannot be the mainstay for treatment decision-making: studies from real-world practice and experimental clinical trials have documented that age and frailty are prime predictors of outcome in AML.[Citation10] As a consequence, a commonly accepted definition of unfitness to intensive and non-intensive chemotherapy in AML is warranted. Thus, it is time to start to systematically measure patient-specific factors, possibly with the help of geriatricians, to discriminate among fit, unfit, vulnerable and frail patients for a given treatment.
With this in mind, it is time to reappraise thinking of a comprehensive, and at the same time individualized, approach to elderly AML management, which moves from fitness status and biology and attempts to a tailored treatment of every single patient. The development of novel, targeted and less toxic therapeutic options is providing the opportunity to be treated to a large proportion of patients suitable for supportive care only until few years ago. However, the rate of toxic deaths are still unacceptable for elderly AML patients, even with lower-intensity therapies, indicating that we need to better recognize signs (or symptoms) of vulnerability in elderly patients though a multi-geriatric, comprehensive assessment of physical, social, cognitive and psychological parameters.
In conclusion, we think that it is time for a change for the treatment of older and frail patients with AML: the patient, and not the treatment, should be the starting point, and the goal will be more and more to select the right treatment able to keep an accurate balance between efficacy of therapy and avoidance of a decreased quality of life and loss of autonomy feared by elderly patients and their families.
Declaration of interest
A Isidori has received honoraria from Lundbeck Canada. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed
References
- Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–1152.
- Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet. 2013;381:484–495.
- Isidori A, Salvestrini V, Ciciarello M, et al. The role of the immunosuppressive microenvironment in acute myeloid leukemia development and treatment. Expert Rev Hematol. 2014;7(6):807–818.
- Isidori A, Venditti A, Maurillo L, et al. Alternative novel therapies for the treatment of elderly acute myeloid leukemia patients. Expert Rev Hematol. 2013;6(6):767–784.
- Kantarjian HM, Ravandi F, O’Brien S. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116:4422–4429.
- Nazha A, Ravandi F. Acute myeloid leukemia in the elderly: do we know who should be treated and how? Leuk Lymph. 2014;55(5):979–987.
- Sekeres MA, Steensma DP. Boulevard of broken dreams: drug approval for older adults with acute myeloid leukemia. J Clin Oncol. 2012;30(33):4061–4063.
- Thomas X, Le Jeune C. The safety of treatment options for elderly people with acute myeloid leukemia. Expert Opin Drug Saf. 2016 Mar 17:1–11. [Epub ahead of print].
- Visani G, Ferrara F, Di Raimondo F, et al. Low-dose lenalidomide plus cytarabine induce complete remission that can be predicted by genetic profiling in elderly acute myeloid leukemia patients. Leukemia. 2014 Apr;28(4):967–970.
- Ferrara F, Barosi G, Venditti A, et al. Consensus-based definition of unfitness to intensive and non-intensive chemotherapy in acute myeloid leukemia: a project of SIE, SIES and GITMO group on a new tool for therapy decision making. Leukemia. 2013;27(5):997–999.