Acute myeloid leukemia (AML) is a disease of older adults, with a median age at diagnosis over 65 years. Studies from real-world practice1 and experimental clinical trials2, 3, 4 have documented that age and frailty are prime predictors of outcome in AML. Accordingly, a proper assessment of patient’s fitness represents a critical step in the therapeutic decision-making process of AML.5, 6 Notwithstanding, physicians lack a common framework for establishing unfitness to different therapies in AML. A comprehensive evaluation of geriatric domains is time consuming and costly, and it measures characteristics that are not independently predictive of treatment toxicity, early mortality and overall survival in AML patients. More simple indexes, like the adapted Charlson comorbidity index7 and the hematopoietc cell transplantation co-morbidity index,8 have an inherent risk of overemphasizing the measure of frailty of the patient with AML at diagnosis, being developed for patients in advanced stages of the disease.

In view of the clinical relevance of having a uniform and feasible definition of unfitness in AML, we sought to provide such a definition by using the group and consensus methodologies under the auspices of the Italian Society of Hematology, Italian Society of Experimental Hematology (SIES) and Italian Group for Bone Marrow Transplantation (GITMO).

The consensus process

We first recruited a panel of experts, defined as individuals with relevant knowledge, interest and skill in AML. We preferred a small group of dedicated experts than a larger one because of the narrow task, and the method used to reach the consensus.

Three orders of therapies were claimed to be worth to be distinguished in the treatment of patients with AML. Intensive chemotherapy was meant as any chemotherapeutic regimen aimed at achieving complete remission (CR), like combination of cytarabine and anthracyclines; non-intensive chemotherapy was as any therapy aimed at altering the natural course of the disease not necessarily achieving CR, such as low-dose cytarabine or hypomethylating agents; supportive therapy was meant as any therapy aimed at improving patient’s quality of life, including cytoreductive therapies (hydroxyurea) and/or transfusion support.

Figure 1 shows the way the decision for selecting from the possible criteria could be framed as an analytic hierarchy process.9 It was agreed that four motivations should influence the decision of preferring one criterion to another for any definition of unfitness, namely: (a) to avoid therapies that could interfere with the age-dependent frailty of the patients; (b) to avoid therapies that could produce organ intolerance due to organ comorbidities; (c) to avoid therapies that the patient is unable to complain with, due to individual characteristics; and (d) to avoid risky therapies in patients whose life-expectancy is otherwise reduced by a non-AML disease.

Figure 1
figure 1

Analytic hierarchy process model regarding the selection of criteria for unfitness to therapy in patients with AML. At the top is the goal of the decision; at the bottom are the criteria to be decided; and in the middle are three motivations used for evaluating how well the options meet the goal.

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We first aimed at selecting the criteria in their conceptual terms. To achieve this, a questionnaire was mailed to each member of the panel asking them to list candidate critical events they considered crucial for chemotherapy according to existing evidence and personal knowledge and experience. These criteria were further refined in a Delphi process.10 Candidate conceptual criteria were ranked according to their priority votes, with the criteria that ranked highest to be included in the list, forming the core set of conceptual criteria.

Using a bottom-up approach, the criteria were subjected to comparison according to their ability to fulfill one of the four motivations preliminarily selected for the decision according to the preferences of the members of the panel. This part of the process was exploited in a consensus meeting using the nominal group technique.11

We then aimed at selecting the criteria in their operational terms populating them with quantitative or numerical attributes, or by categorizing the critical events that could exploit any conceptual criteria.

The definitions of unfitness

The panel listed 24 conceptual criteria to be included in the core set of candidate criteria for the definition of unfitness to intensive and non-intensive chemotherapy. The members of the panel claimed that the cogent ailments were selected based on research of a number of authors, in which the criteria were selected based on their clinical implications for the newly diagnosed patients with AML. Using the pairwise comparisons, the members of the panel proposed that the definition of unfitness to intensive chemotherapy should require the fulfillment of at least one of nine criteria (Table 1) and that the definition of unfitness to non-intensive chemotherapy should require the fulfillment of at least one of six criteria (Table 2).

Table 1 Conceptual criteria to be used to define patients unfit to conventional intensive chemotherapy
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Table 2 Conceptual criteria to be used to define patients unfit to non-intensive chemotherapy
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Finally, the panel listed the operational criteria to be included in the definitions of unfitness (Tables 3 and 4). The members of the panel claimed having largely derived operational criteria from the definitions of comorbidities from the literature with modifications.

Table 3 Operation criteria to define unfitness to intensive chemotherapy in AML
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Table 4 Operational criteria to define unfitness to non-intensive chemotherapy in AML
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Comments and perspectives

To overcome the cognitive and practical issues inherent to the task of selecting criteria for unfitness to chemotherapy in AML, we used an approach based on analytic hierarchy process with multiple criteria process that reduces complex problems into small manageable parts. We provided definitions that consist in establishing the criteria widely used in different definitions of unfitness to therapies, but not in this precise combination and not as mutually exclusive categories.

An age older than 75 years was selected, reasoning that age is a strong determinant of host-specific clinical characteristics, such as cognitive, emotional and physical function, that predict vulnerability to toxicity.

Critical organs for comorbidity were selected among those scrutinized in the most used indices of comorbidities developed and evaluated in the effort to predict whether a patient is likely to do well after intensive chemotherapies.

Cognitive impairment may increase the risk of morbidity and mortality during therapy.12 In addition, it severely precludes patient/doctor interaction in the assessment of risk/benefit ratio and can motivate withholding of chemotherapy for the risk of treatment non-compliance.

Infections are an important cause of morbidity and mortality for patients with AML; therefore, the panel considered unresolved bacterial or fungal infections in the definition of unfitness in both intensive and, although at a lesser extent, non-intensive chemotherapy.13

The performance status at AML presentation is associated with mortality within 30 days from induction.1, 14 In the panelists’ opinion, making a realistic judgment about patient’s unfitness requires a careful performance status reassessment after adequate intensive supportive treatment. The threshold of performance status chosen for defining unfitness to intensive chemotherapy was a value >2 and the decision was in accordance with the results of the literature.1, 15

Patient’s financial and socioeconomic status, presence of a caregiver and distance from the caring center are further critical factors allowing care of AML to be delivered and follow-up to be performed. However, our panelists agreed that these dimensions should not entail a relevance, in the frame of the Italian perspective of social security and welfare, in that patients may trust in a number of facilities and supports (that is, home care, free transportation, social assistance).

In conclusion, we propose the use of novel definitions of unfitness to intensive and non-intensive chemotherapy in AML patients, which were developed using a analytic hierarchy process-based consensus process. We hope that adoption of these definitions will help the physician in the clinical practice of AML, and will improve conduct and reporting of clinical trials. To enforce the purpose and aim of being a novel tool for improving the decision on chemotherapy in AML, the results of this consensus work must be externally validated.