Discussion

The role of physical performance measures as predictors of survival has been controversial in intensively treated older adults with AML. Klepin et al^[12] reported the first prospective data to investigate the predictive value of GA measures in older adults with AML (median age, 69 years; 10.8% were age 80 years or older; 78.1% had an ECOG PS ≤1) showing physical function as a predictor for survival. However, another prospective study by Timilshina et al^[13] of selected older adults with AML (median age, 68 years; none were age 80 years or older; 85.6% had ECOG PS ≤1) showed that physical performance measures were not good predictors of OS. Those studies had differences in patient selection and were limited by relatively small cohorts and lack of information about mutational status (which requires further validation). Given that previous studies for GA measures in older adults with AML pertain to Western countries, GA must be validated in non-Western countries on the basis of varied outcomes by region because of differences in referral systems,^[31] genetic background,^[32,33] and socioeconomic status.^[34,35] Our Korean cohort was characterized by relatively younger age (median age, 64 years; none were age 80 years or older), good performance status (ECOG PS ≤1; 93.3%), and data about mutational status compared with the aforementioned prospective studies.^[12,13] Among the GA measures, objectively measured physical dysfunction by SPPB was significantly associated with worse OS and NRM, suggesting that physical function is a good predictor for survival, even in relatively younger patients with better ECOG PS. Of note, gait speed among the SPPB battery was the single measure associated with worse OS and NRM in our cohort, which is in line with a recent prospective study in patients with hematologic malignancies age 75 years or older who had treatment of various intensities.^[36] In addition, sit-and-stand speed, another component of SPPB, had a prognostic impact on OS and NRM similar to that of gait speed. These results clarified the role of physical function as survival predictors in intensively treated older adults with AML and highlighted the potential of gait speed and sit-and-stand speed as simple measures for frailty.

Our study also highlights the prognostic significance of depressive symptoms for survival. There were reports of an association between depression and mortality in various cancer types, but few in AML.^[37,38] Klepin et al^[39] reported that depressive symptom burdens at remission were associated with functional decline after induction chemotherapy and also mortality.^[40] However, they did not find an association between depression before treatment and mortality partly because of the small cohort.^[12,39,40] In our cohort, baseline depressive symptoms measured by SGDS-K were associated with worse survival. SGDS-K is a screening tool specialized for measuring depression in the elderly population. To the best of our knowledge, this is the first prospective study demonstrating the prognostic value of baseline emotional health in older adults with AML. Our data showed that patients with increased depressive symptom burden measured by SGDS-K were more frequently diagnosed with MDD during the postremission treatment course. Indeed, all patients diagnosed with MDD during the treatment course died, mostly as a result of NRM. Depression could influence cancer mortality through a pathophysiological effect via neuroendocrine and immunologic functions or from weakening adherence to preventive screening procedures, AML treatments, or recommendations for maintaining health.^[37] Depressive symptoms can be a proxy for disease severity because of similarity to the adverse effects of treatment or cancer symptoms. Therefore, screening for depression should be conducted routinely, and referrals to mental health specialists should be considered. Prognostic significance of dynamic changes in depressive symptoms should be evaluated further by repeat GA at each step of the treatment course in larger cohorts. Moreover, our data suggest the necessity for further studies to determine whether interventions targeting emotional as well as functional health can improve survival outcomes.

It is notable that cognitive impairment was not associated with worse survival in our cohort, in contrast to data from Klepin et al.^[12] The proportion of patients with cognitive dysfunction was similar between the 2 studies despite the difference in age distribution. Cognitive test scores can identify patients who either have or are at risk for delirium, which is a known risk factor for mortality among hospitalized older patients with other medical conditions.^[41] Our data showed the relationship between baseline cognitive performance and subsequent development of delirium during the treatment course. However, delirium was not associated with survival outcomes in our cohort. Given the inclusion of an older population with worse ECOG PS in the cohort of Klepin et al, the influence of baseline cognitive impairment on survival might be more significant in older populations with AML, suggesting heterogeneity among the older AML population, which should be confirmed through a large-scale study. Conversely, our data suggest that cognitive impairment was associated with treatment tolerance or resilience. We observed that patients with cognitive impairment were exposed to increased risk for grade 3 to 4 infectious complications and had prolonged hospitalization during induction chemotherapy, which might be related to increased incidence of delirium during induction chemotherapy. In addition, impaired physical function measured by SPPB was associated with grade 3 to 4 acute renal failure and infection. The association between these nonfatal toxicities and patient characteristics has received little attention.^[8] Our data suggest that cognitive and functional measures by GAs are available to identify patients at risk of severe toxicities after intensive chemotherapy in older adults with AML, with those patients possibly being preferred candidates for low-intensity combined therapies.^[42] Additional large studies are warranted to confirm the feasibility of GA measures as predictors of nonfatal toxicities.

Among existing survival prediction models,^{[14-16] [43]} AML scores^[14] and the Wheatley index^[16] were useful in our cohort. Of note, our data showed that the addition of SPPB and SGDS-K, gait speed and SGDS-K, or sit-and-stand speed and SGDS-K significantly improved the predictive power of those survival prediction models, with 10% to 23% of absolute additional variability. These results are strong evidence for the need to incorporate GA into validated survival prediction models to determine initial treatment, such as intensive induction chemotherapy or low-intensity therapies, in practice and in clinical trials with older adults with AML. For example, older adults with AML may be offered combination therapy with venetoclax and hypomethylating agents with its proven safety profile and outcome^[42] rather than intensive chemotherapy if the GA combined model-based risk of death is high.

The strengths of our study include its prospective nature, a high participation rate, and the scarcity of GA research conducted in Asian cohorts. In particular, our cohort included patients with AML between age 60 and 75 years who were the main subjects of intensive induction chemotherapy. Such a cohort is more practical and applicable than those in previous prospective studies that included patients with AML older than age 75 years, even as old as 80 years or older.^[10,11] In addition, we reassessed the existing prognostic models with a cohort of mutational profiles representing recent advances in supportive care, and we objectively demonstrated how much the GA measures improved predictability. Nonetheless, the modest size of the cohort and data from a single institution could limit its generalizability, warranting larger prospective studies from multiple institutions.

In summary, we prospectively demonstrated the prognostic value of physical and psychological GAs for survival outcomes in intensively treated older adults with AML. Particularly, gait speed or sit-and-stand speed were the most powerful measures for identifying frailty and predicting survival. Measurements of cognitive and physical impairments helped identify nonfatal toxicities during intensive chemotherapy. Our data will facilitate incorporation of GA measures into validated survival prediction models for determining the initial treatment of older adults with AML in routine clinical care and clinical trials. Further studies are warranted to determine the best ways to adjust the care provided for frail patients to improve treatment tolerance and outcomes.