Integrating Assessment of Sarcopenia into Decision-making for Allogeneic Hematopoietic Cell Transplantation: Ready for Prime Time?

The term sarcopenia, derived from the Greek words sarx meaning “flesh” and penia meaning “loss,” was initially utilized to describe age-associated muscle loss and function observed in the older population (1,2). Sarcopenia can occur in concert with biologic aging or can be secondary to inactivity or various disease processes such as chronic obstructive pulmonary disease, acquired immunodeficiency syndrome, or cancer (3). In 2010, a consensus definition of sarcopenia was developed by the European Working Group on Sarcopenia and Older People to include depletion in both muscle mass and muscle function, which was defined as reduced physical performance or muscle strength (4). The consensus noted that muscle strength can be preserved in those with reduced muscle mass and that the relationship between muscle mass and muscle function is not linear (1). The European consensus definition was updated in 2018 and places more emphasis on muscle strength over muscle mass citing reduced strength as a better predictor of adverse outcomes when compared to mass (5).

Muscle wasting has many clinically significant implications in cancer care because loss of lean body mass and muscle has been associated with increased chemotherapy toxicity, shorter time to disease progression, and poorer survival (6,7). In patients suffering from cancer-associated sarcopenia, the loss of muscle mass and function is compounded by the effects of chemotherapy that can lead to further inactivity, and decreased oral intake and malnutrition as well as direct negative effects on muscle such as protein breakdown in muscle, inflammation, and reduction of myocyte cross-sectional area (8,9). Given the importance of patient selection in a population that has typically been heavily pretreated, understanding the relationships between sarcopenia and prognosis is particularly relevant for patients undergoing hematopoietic cell transplantation (HCT). In the current issue of the Journal, Armenian et al. (10) appropriately convey that there is limited information in regards to the impact of sarcopenia on outcomes of patients undergoing HCT. Two studies, the largest being of 315 patients, previously have demonstrated that sarcopenia is present in 35%–55% of patients pre-HCT (11,12). Muscle wasting was found at baseline in 43% of patients about to receive induction chemotherapy for newly diagnosed acute myeloid leukemia (13), and a depletion in muscle mass was seen in 100% of children after they underwent chemotherapy for acute lymphoblastic leukemia (14).

Armenian et al. (10) adds to our knowledge by reporting findings from a single-center retrospective study of the association of sarcopenia with several clinically relevant outcomes in 859 patients (mean age = 51 years, range = 18–74 years) with acute myeloid/lymphoid leukemia or myelodysplastic syndrome who underwent a first allogeneic HCT; 51.1% had myeloablative conditioning and 43.5% had matched sibling donors. All patients underwent computed tomography (CT) scans of the chest, abdomen, and pelvis as part of institutional routine care to rule out occult infection prior to HCT. Cross-sectional muscle area was measured from the lumbar vertebra (L3) and stringent criteria were used (a priori definition for sarcopenia, observers were blinded, and interobserver coefficient was <1.5%). Sarcopenia was found in 33.7% of patients. After adjusting for covariates, sarcopenia was associated with higher two-year nonrelapse mortality (NRM; hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.16 to 2.16); the higher risk of death was due to infection and organ failure (HR = 2.34, 95% CI = 1.19 to 4.34). In addition, sarcopenia was associated with higher all-cause mortality (HR = 1.42, 95% CI = 1.09 to 1.78), but it was not associated with relapse-related mortality. Length of stay was also longer for those with sarcopenia (37.2 vs 31.5 days, P < 0.001). Of particular importance to consider is that the two-year incidence of NRM approached 30% in patients who had both sarcopenia and high HCT comorbidity-age index.

In healthy adults at least age 60 years, the prevalence of sarcopenia is approximately 10% (15). Therefore, it is remarkable that one-third of the patients in the study had sarcopenia, despite a young median age of 51 years (11,12). The causes are likely multifactorial secondary to aging, prior chemotherapy, and poor nutrition; older patients with comorbidity are likely the most vulnerable to sarcopenia (2). The higher risk of infection and organ failure associated with sarcopenia are consistent with prior studies (16,17). Although the exact mechanism of how sarcopenia leads to higher risk of infection and organ failure is unclear, it may be due to higher exposure to pre-HCT chemotherapy.

The work by Armenian et al. (10) has some limitations. The study population is rather heterogeneous and included multiple types of hematologic malignancies, pre-HCT therapies, and conditioning regimens. It is also unclear what and how many lines of therapies patients had received prior to HCT. It is possible that sarcopenia may be a surrogate of exposure to prior therapy leading to immunosuppression and organ damage, thereby increasing NRM.

Nevertheless, this study is the first to demonstrate sarcopenia as a prognostic marker in the setting of allogeneic HCT, consistent with studies in autologous HCT and other cancer types (18,19). Sarcopenia and frailty (defined as decreased physiological reserve and function across multiple organ systems leading to increased vulnerability to stressors and adverse outcomes (20)) are closely related but represent distinct entities. Several studies have shown that frailty measured by geriatric assessment may predict adverse outcomes. In a prospective study of 203 patients aged 50 years and older who underwent allogeneic HCT, Muffly et al. (21) demonstrated that overall survival (OS) was worse in those with limitations in instrumental activities of daily living (HR = 2.38, 95% CI = 1.59 to 3.56), slow walking speed (HR = 1.80, 95% CI = 1.14 to 2.83), high hematopoietic cell transplantation-specific comorbidity index (HR = 1.56, 95% CI = 1.07 to 2.28), and low mental health (HR = 1.67, 95% CI = 1.13–2.48). In a separate prospective study of 106 patients ages 60 years and older, Deschler et al. (22) also demonstrated that those with comorbidities had worse progression-free survival (HR = 1.13, 95% CI = 1.00 to 1.27), and those with poor baseline physical functioning had worse overall survival (HR = 3.26, 95% CI = 1.00 to 10.6). Now in this study, Armenian et al. (10) have demonstrated that the sarcopenia led to poor outcomes above and beyond that which could be attributed to comorbidity. Together, these factors can be used to predict post-transplantation adverse outcomes (16,17), to better select transplant candidates, and to guide the need for increased monitoring during and post-transplant, thereby reducing morbidity and mortality associated with HCT. In addition, sarcopenia may guide interventions such as exercise that may improve post-transplantation outcomes (23,24).

Although CT scans were used in this study, it is worth noting that there are alternative methods of assessing sarcopenia that may be more cost-effective, such as the use of patient-reported outcomes and objective measures of physical function like those incorporated in geriatric assessment (25,26). For example, the patient-reported outcome for sarcopenia (SarcoPRO) measure has been shown to be associated with functional impairment (25). Although physical and functional outcomes in relation to muscle mass have been better incorporated in geriatric and geriatric oncology research (27), the term sarcopenia has loosely and widely been used to describe purely a loss in muscle mass or lean body mass (without a functional assessment) in cancer research. This is in part because of the rise in research evaluating muscle and fat mass as predictive and prognostic tools; access to thoughtfully selected key physical performance or patient-reported outcomes are limited. Although the European consensus definition of sarcopenia was developed primarily for older adults, it will be crucial to develop methods that incorporate strength, performance, and functional measures to cancer-associated sarcopenia research going forward. These patient-reported and objective measures of function should be evaluated in conjunction with CT scans or other imaging of muscle mass in clinical studies evaluating outcomes of patients with cancer, including those undergoing HCT, moving forward.

Notes

Affiliation of authors: Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY (KPL, RFD, JWF, SGM).

SGM and KP have no disclosures. RD is on the advisory board for Exelixis, and JF is a consultant for Bayer and Astellas and received funding for travel from Roche.