Finding the right fit: assessment of fitness in AML

In this issue of Blood Advances, Venditti et al¹ detail a set of recommendations from the European Leukemia Network (ELN) on fitness assessment in acute myeloid leukemia (AML). Based on the Grading of Recommendations Assessment, Development, and Evaluation methodology, statements² were assigned an evidence level and grade, followed by a 2-round Delphi consensus process on the level of agreement involving 31 hematologists with disease-specific expertise and patient representatives. In the last decade, both the complexity of AML treatment and potential considerations for fitness assessments have grown, with a lack of consensus on the required components. The development of both targeted and nonintensive therapies has shifted the thinking of treatment eligibility from a binary “fit” or “unfit” for intensive chemotherapy (IC) to a position where many patients may be eligible for at least lower-intensity treatment. These ELN guidelines therefore provide a critical tool to help define fitness/unfitness and support efforts to identify and categorize individual factors that contribute to these definitions.

These guidelines complement the recently published International Society of Geriatric Oncology statement on the treatment of AML in patients ≥70 years³ and the existing older adult AML treatment guidelines.⁴ The key paradigm outlined in the present manuscript is a dynamic and context-specific fitness assessment. Patients are considered “eligible” rather than “fit,” “unfit,” or “frail” for a given therapy. Fitness in this framework is specific to the intensity of therapeutic intervention and can improve or worsen during treatment, thereby influencing subsequent therapeutic decisions. The authors also define the components of fitness as including a “comprehensive evaluation of age, performance status, comorbidities, and functional capacity,” emphasizing that no single item, including age, can make this determination.

The uptake of less intensive regimens (eg, azacitidine plus venetoclax) and targeted therapies (eg, isocitrate dehydrogenase inhibitors) has improved outcomes and changed how treatment eligibility is considered, especially for older adults. Many of these options are less intensive and can be administered as an outpatient, and in some cases, are as efficacious as standard IC,⁵ with at least 1 ongoing prospective randomized clinical trial evaluating the comparison (ClinicalTrials.gov identifier: NCT04801797; NCT05554393). The evaluation of patients with AML is increasingly complex, and it is imperative that there be an assessment of fitness alongside disease biology to determine optimal therapy. Delaying treatment for complete characterization of cytogenetic and targeted mutational status in stable patients has been demonstrated to not adversely affect outcomes.⁶ Noting this, the authors also suggest using this time to complete a comprehensive fitness evaluation, such as a comprehensive geriatric assessment, alongside the classification of disease biology to determine the most appropriate treatment.

The dynamic nature of fitness from 1 therapy to the next for specific treatments is another key consideration. The guideline recognizes this with a specific recommendation on fitness eligibility for IC being distinct from allogeneic stem cell transplant (alloSCT) eligibility and importantly endorses the consideration of alloSCT after initial nonintensive treatment in appropriate patients. The latter suggestion has increasing relevancy for patients who may be borderline in their initial eligibility for IC and is a strategy that has been associated with reasonable disease outcomes.⁷ 

Importantly, the recommendations presented in the article include input from patient and caregiver representatives of the Acute Leukemia Advocates Network. It has been described that the level of social support in leukemia has a stronger association with survival compared with other cancers.⁸ Treatment choices can have substantial financial and social burdens on patients. Therefore, the current ELN recommendations incorporate additional patient-centered components, such as quality of life (QoL) and shared decision-making, as considerations for treatment selection. QoL and patient-reported outcomes are recognized as important considerations in the assessment of premorbid function and treatment outcomes, providing a more comprehensive understanding of patients’ experiences and perspectives. In addition to QoL assessment, the present work also emphasizes the importance of caregivers and optimizes both social support and psychiatric comorbidities that may impact adherence to treatment. Overall, the fitness assessment recommendations differ in these aspects from prior guidelines, which are more focused on geriatric assessments and do not provide explicit recommendations in these domains. The incorporation of these additional aspects of social support and QoL is likely to improve leukemia care.

There were areas in which no consensus was reached. Notably, this included a recommendation on whether early palliative care (EPC) should be considered in patients receiving IC. Although some studies have demonstrated improved QoL and symptom burden in patients with AML receiving EPC,⁹ the optimal time for palliative care intervention is unclear, and several panelists prioritized life-saving interventions. The panel also did not reach a consensus on whether an adverse disease risk profile was a contraindication to IC in older fit patients, a population where the impact of IC compared with nonintensive strategies remains controversial, and complications of IC may impact fitness for alloSCT. The complex interplay between patient fitness and disease biology will also likely pose a challenge in applying some of these recommendations to clinical practice. Additionally, the comprehensive geriatric assessment suggested by the authors may not be practical in routine practice. Prospective collection of fitness information in clinical trials would allow the identification of factors to be prioritized and the examination of these factors along the disease and treatment continuum.

In summary, as the therapeutic options for AML continue to expand, there are available treatments that vary in intensity. Fitness-level characterization now extends beyond conventional categories of “fit,” “unfit,” and “frail” and instead shifts to an approach where eligibility for a given treatment considers patient/disease-specific factors that are individualized and aligned with patient preferences. These guidelines recognize this substantial clinical challenge and provide a much-needed framework for these considerations.

Conflict-of-interest disclosure: L.M. reports advisory board participation for AbbVie. N.C. declares no competing financial interests.