Background
CAR T-cell therapy is an effective treatment for patients with relapsed/refractory large B-cell lymphoma (LBCL) or other B-lineage lymphomas.1–5 However, CAR T-cell therapy has been associated with potentially life-threatening toxicities, such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).1–4 Additionally, there is considerable prognostic variability after CAR T-cell therapy, including length of progression-free survival (PFS) or overall survival (OS) due to the heterogeneous features of disease biology and broad range of clinical comorbid conditions in the relapsed/refractory setting.1,6–8 In this context, identifying appropriate prognostic biomarkers of response to CAR T-cell therapy is of major clinical importance.
Abnormal skeletal muscle measurements at baseline such as low muscle mass and resultant fat infiltration (myosteatosis) have been associated with adverse cancer-related outcomes and all-cause mortality in patients with solid and hematologic malignancies,9–12 including in those undergoing hematopoietic cell transplantation (HCT).13–15 For patients undergoing CAR T-cell therapy, abnormally low skeletal muscle prior to CAR T-cell infusion may be of particular clinical relevance, given the increasing recognition of the role of muscle as a regulator of immune response.5,16,17 Skeletal muscle cells can modify immune-mediated responses through muscle cell–derived cytokines (myokines), cell surface molecules, and cell-to-cell interactions, which alter T-cell homeostasis.5,17 In this context, poor muscle health may adversely impact outcomes after CAR T-cell therapy.18 There is a paucity of information on the impact of abnormal skeletal muscle measurements at baseline on outcomes after CAR T-cell therapy, including the interaction between these measurements and established prognostic factors, such as elevated lactate dehydrogenase (LDH) levels at baseline.19–21 Previous studies have noted worse outcomes after CAR T-cell therapy in patients with poor performance status and elevated LDH levels at baseline.19–21 As such, understanding the relationship between objective measurements of skeletal muscle health and biomarkers such as LDH level is an important step toward establishing clinical utility.
Recent advances in software technology have facilitated the near real-time integration of body muscle and fat measurements into CT imaging obtained for standard clinical care, setting the stage for risk stratification for primary or secondary prevention.22–25 The overall aims of this study were to describe the association between skeletal muscle measurements obtained from pretreatment CT images and postinfusion acute toxicities (eg, CRS, ICANS) as well as 1-year PFS and OS after CAR T-cell therapy, and to identify individuals at highest risk for worse outcomes after treatment.
Patients and Methods
Patient Cohort and Definitions
This was a retrospective cohort study of patients who underwent CAR T-cell therapy as adults (age ≥18 years) for large B-cell (LBCL) or B-lineage lymphoma at City of Hope (COH) between February 2015 and February 2021. The institutional review board at COH approved the protocol and written informed consent was obtained from study participants in accordance with the Declaration of Helsinki. Medical records were abstracted for patient demographics (age at CAR T-cell therapy, sex, race/ethnicity), diagnosis (LBCL, low-grade lymphoma, transformed low-grade lymphoma, other), number of prior lines of therapy, disease status26 (complete remission, stable disease, partial response, progressive disease), prelymphodepletion largest lesion diameter, prelymphodepletion (<2 days) blood LDH level (normal: <271 U/L; abnormal: ≥271 U/L), health status (Karnofsky performance status score), and CAR T-cell therapy–related variables (lymphodepletion regimen, treatment on clinical trial, T-cell product).
Outcomes of interest included length of hospitalization, ICU admission during the initial hospitalization for CAR T-cell infusion, development of CRS or ICANS, disease progression, and cause-specific mortality. CRS and ICANS were graded according to established consensus criteria.27 Toxicity monitoring and management were conducted per institutional guidelines. Disease response was obtained from chart review, and vital status was obtained from the National Death Index and institutional medical records.
Body Composition at CAR T-Cell Therapy
Body composition was assessed from existent CT scans for pre–CAR T-cell disease response. CT scans completed ≤60 days prior to CAR T-cell infusion were deemed to accurately represent patients’ body composition and were selected for analysis. Three adjacent cross-sectional images were used to quantify muscle area at the level of the third lumbar vertebra (L3).13 Muscle and adipose tissues were quantified with Automatic Body composition Analyzer using Computed tomography image Segmentation (ABACS),22 which is a commercially available software that automatically segments skeletal muscle and adipose tissue. To maintain quality assurance, ABACS segmentation for each patient was manually reviewed by members of the research team (A. Iukuridze and L. Atencio), who were blinded to patient characteristics and outcomes. Muscle area was normalized for height (cm2/m2)28 and reported as lumbar skeletal muscle index (SMI). Skeletal muscle radiodensity (SMD), typically used to determine myosteatosis, was measured in Hounsfield units (HU). Skeletal muscle gauge (SMG), which combines skeletal muscle index and density (SMI × SMD), with arbitrary units (AU),29–31 was also determined for all participants. Due to a lack of well-established definitions for adiposity and skeletal muscle measures, we used a priori–determined lowest sex-specific tertile cutoffs for abnormal SMI (<35 cm2/m2 [female]; <46 cm2/m2 [male]), SMD (<25.7 HU [female]; <27.7 HU [male]), and SMG (<934 AU [female]; <1,203 AU [male]). Abnormal skeletal muscle was defined as having an abnormally low SMG, because the index represents a composite measure (quantity and quality) of skeletal muscle health,29–31 including in patients undergoing HCT.25 Individuals were considered to have abnormal visceral adipose tissue (VAT) according to sex-based VAT tertile cutoffs (>100 cm2 [female]; >168 cm2 [male]).
Statistical Analysis
Patient, disease, and CAR T-cell characteristics were summarized with median and range for continuous variables, and frequencies and percentages for categorical variables. Length of hospitalization, rates of ICU admission, CRS, and ICANS by body composition parameters (abnormal skeletal muscle, visceral adiposity) were compared using the chi-square test for categorical or 2-sided Student t tests for continuous variables. Univariable Cox proportional hazards regression was used to characterize the association between patient, disease, and CAR T-cell–related risk factors and 1-year PFS or OS. For PFS, time was calculated from CAR T-cell infusion to relapse/progression, start of conditioning for HCT, or last contact, whichever occurred first. For OS, time was calculated from CAR T-cell infusion to date of death or last contact, censored at 1-year. The Kaplan-Meier (KM) method was used to examine the association between selected variables and PFS and OS, and log-rank tests were used to compare the KM curves.
Variables with P value ≤.10 in univariable analyses for PFS and OS were included in the multivariable model. Backward stepwise elimination was used to remove nonsignificant variables one at a time, starting with the least significant with P>.05, and the model re-estimated. This was repeated until no more variables could be removed. For each outcome (PFS, OS), 2 separate multivariable regression models were created. Model 1 comprised skeletal muscle (normal [ref], abnormal), age at CAR T-cell therapy (continuous), LDH (normal [ref], abnormal), CAR T-cell product (categorical), and largest residual lesion diameter (continuous). Next, we examined the effect of having abnormal skeletal muscle and/or elevated prelymphodepletion LDH, given the well-established prognostic association between LDH and disease response. Model 2 included the following: combined skeletal muscle + LDH variable (normal skeletal muscle, normal LDH level [ref]; abnormal skeletal muscle, normal LDH level; normal skeletal muscle loss, abnormal LDH level; abnormal skeletal muscle, abnormal LDH level), age at CAR T-cell therapy, CAR T-cell product, and largest residual lesion diameter. Variables included in model 1 were also included in the multivariable analysis examining the association between abnormal skeletal muscle and ICANS. All statistical analyses were 2-sided, and a P<.05 was considered statistically significant in the final multivariable models; SPSS Statistics, version 27 (IBM Corp) was used for the analyses.
Results
Patient Characteristics
Of the 280 patients who underwent CAR T-cell therapy for LBCL or B-lineage lymphoma, 54 were excluded because abdominal CT images were obtained >60 days prior to CAR T-cell therapy. Clinical characteristics of the 226 patients (80.7% of the overall cohort) included in the study are detailed in Table 1. Median time from CT scan to CAR T-cell infusion was 10 days (range, 0–60 days), and 190 (84.1%) patients had a CT scan performed within 30 days of CAR T-cell therapy. Before apheresis, 91 (40%) had received >3 lines of therapy, including 39 (17%) who had undergone autologous HCT. Median age was 63.1 years (range, 18.5–82.4 years), and most patients were male (66%), non-Hispanic White (51%), and being treated for de novo LBCL (64%). All patients underwent fludarabine and cyclophosphamide-based lymphodepletion. Median prelymphodepletion LDH was 205 U/L (range, 98–5,693 U/L), and 74 (33%) had an abnormal value (≥271 U/L). Disease status was progressive disease in 172 (76%) patients, followed by stable disease in 42 (19%), partial response in 10 (4%), and complete remission in 2 (1%); 58% had primary refractory disease. Median diameter of the largest residual lesion was 2.3 cm (range, 0–17.2 cm). CAR T-cell products were axicabtagene ciloleucel (51%), lisocabtagene maraleucel (32%), and tisagenlecleucel (17%); 47% of patients were treated on a clinical trial.
Patient Characteristics
The median follow-up time after CAR T-cell infusion was 8.1 months (range, 0.2–62.6 months). CRS of any grade was observed in 141 (62%) patients, with 39 (17%) having grade ≥2 CRS. ICANS was observed in 68 (30%) patients, including 36 (16%) who had grade ≥2 ICANS. Overall, 90 (40%) patients received IL-6 receptor blockade with tocilizumab and 13 (6%) were treated with corticosteroids. Among the 144 patients with available radiographic disease response evaluation on day 28 (±7 days), 57 (37%) and 73 (47%) patients attained a complete remission and partial response, respectively. The 1-year PFS and OS rates for the overall cohort were 50.3% (±3.6%) and 63.5% (±3.6%), respectively; relapse or disease progression accounted for 82% of deaths within the first year. In unadjusted analyses, prelymphodepletion LDH level, residual lesion diameter, CAR T-cell product, and abnormal skeletal muscle were each associated with disease progression and all-cause mortality within 1 year of infusion (Table 2).
Univariate Analysis: Risk Factors for Poor Outcomes After CAR T-Cell Therapy
Health Outcomes by Body Composition Measures
Average length of hospitalization was statistically significantly longer for patients who had abnormal skeletal muscle compared with those who did not (mean [SD], 27.8 [16.6] vs 22.9 [17.9] days; P=.047) (supplemental eTable 1, available with this article at JNCCN.org). Patients with abnormal skeletal muscle also had a greater likelihood of developing any ICANS (38.7% vs 25.8%; P=.048), corresponding to a 1.7-fold risk (HR, 1.74; 95% CI, 1.05–2.87) in the multivariable model. On the other hand, there were no statistically significant differences in ICU admission or CRS rates, including CRS severity, between those with and without abnormal skeletal muscle. Adiposity measures such as VAT were not associated with any of the outcomes examined.
Patients with abnormal skeletal muscle had significantly worse 1-year PFS (35.2% [±6.0%] vs 58.0% [±4.4%]; P=.002) and OS (43.8% [±6.4%] vs 73.8% [±4.0%]; P<.014) compared with those with normal skeletal muscle (Figure 1A, B; Table 3). In adjusted analyses, abnormal skeletal muscle was associated with 1.7-fold (HR, 1.70; 95% CI, 1.11–2.57) risk of disease progression and a >2-fold (HR, 2.44; 95% CI, 1.49–4.00) risk of death within the first year compared with normal skeletal muscle.
Kaplan-Meier plots of (A) PFS rates and (B) OS rates within 1 year of CAR T-cell therapy according to skeletal muscle status at baseline.
Abbreviations: OS, overall survival; PFS, progression-free survival.
Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7100
Cumulative Incidence and Risk of Worse Outcomes After CAR T-Cell Therapy
Among patients with abnormal skeletal muscle, we identified a subgroup of patients with abnormal blood LDH level (n=31; 13.7% of the overall cohort) who had especially poor outcomes. In these patients, 1-year PFS and OS were 17.0% (±7.5%) and 11.7% (±7.5%), respectively. On the other hand, patients with normal LDH level and normal skeletal muscle (n=108; 47.8% of the cohort) had the highest PFS (72.4% [±4.7%]) and OS rates (82.3% [±4.3%]) (Figure 2A, B; Table 3). In adjusted analyses, having both abnormal skeletal muscle and abnormal LDH level was associated with a >5-fold (HR, 5.34; 95% CI, 2.97–9.62) risk of disease progression and a nearly 10-fold (HR, 9.73; 95% CI, 4.81–19.70) risk of death by 1 year (ref: normal LDH level and skeletal muscle) (Table 3).
Kaplan-Meier plots of (A) PFS rates and (B) OS rates within 1 year of CAR T-cell therapy according to baseline muscle status and LDH level.
Abbreviations: LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival.
Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7100
Discussion
In this contemporary cohort of patients who underwent CAR T-cell therapy for B-cell lymphoma as adults, we found significant associations between abnormal skeletal muscle at baseline and clinically relevant outcomes such as ICANS and prolonged length of hospitalization. After adjusting for well-established modifiers of disease response such as extent of residual disease or treatment intensity of CAR T-cell therapy, patients with abnormal skeletal muscle had a nearly 2-fold risk of disease progression and worse OS compared with those with normal skeletal muscle. Importantly, we identified a subgroup of patients with abnormal skeletal muscle and abnormal LDH level at baseline in whom OS was 12% at 1 year, which is in stark contrast to the sizeable proportion of patients with normal LDH level and normal skeletal muscle, for whom OS exceeded 80%. Taken together, the findings from this study speak to the need for more comprehensive strategies to optimize risk stratification prior to consideration of CAR T-cell therapy, and the need to explore alternative management approaches in the subset of patients likely to have acute treatment-related toxicity and poor disease response.
Body composition measures for the current study were acquired from CT images that were obtained as part of pretreatment clinical evaluation, a strategy that has been successfully used in other populations.32 To date, studies that have linked these CT-based measurements to outcomes after cancer treatment have largely been in patients with solid malignancies,9–12,33 including those with gastrointestinal cancers, because of the association between nutritional deficiencies and availability of abdominal imaging. We recently reported on the association between pretreatment skeletal muscle health and increased risk of acute toxicities in patients undergoing HCT for hematologic malignancies, including a higher risk of all-cause mortality.13,14 Others have reported on the association between skeletal muscle loss and worse outcomes after conventional therapy in adults with newly diagnosed B-cell malignancies.34 To our knowledge, our study is the first to highlight the association between abnormal skeletal muscle and adverse outcomes in patients undergoing CAR T-cell therapy, a population that will continue to grow in the foreseeable future. We leveraged advances in software technologies, including use of automated body composition measurements, to determine muscle loss in our patients.35 This may provide a platform for rapid real-time integration of this information into decision-making in the clinical setting, prior to the start of CAR T-cell therapy.
The mechanism by which patients undergoing CAR T-cell therapy develop abnormal skeletal muscle is likely multifactorial given the number of modifiers of muscle health in these patients, including lifestyle changes (eg, nutritional imbalance, physical inactivity) and comorbid health conditions that emerge after systemic antineoplastic therapy.36,37 Relevant to CAR T-cell therapy, skeletal muscle cells can regulate immune function through myokines such as IL-6, IL-7, and IL-15 that modulate CD8+ T-cell homeostasis and promote proliferation of naïve T cells and B cells.5,16–18 Studies in older nononcology populations have highlighted the bidirectionality of skeletal muscle and the immune system.5,16,17 On the one hand, chronic low-grade inflammation contributes to muscle catabolism via pleiotropic mechanisms mediated by the inflammatory secrotome,5,38 whereas skeletal muscle loss can contribute to insufficient myokine signaling and impaired regenerative capacities of immune cells with time.5,16–18 These observations speak to the importance of muscle health in response to CAR T-cell therapy, and highlight the need for additional mechanistic and longitudinal studies to interrogate the association between muscle and the immune system vis-à-vis disease response after CAR T-cell treatment.
Separate from disease response, we also found a significant association between baseline abnormal skeletal muscle and ICANS, which may have contributed to longer hospitalization in these patients. On the other hand, we did not see a difference in the rate or severity of CRS, including tocilizumab use between the 2 groups. Although previous reports have considered CRS and neurotoxicity in aggregate,39,40 it is increasingly recognized that CRS and neurotoxicity may occur exclusive of one another, with potentially different underlying mechanisms.41 A recent systematic review evaluating risk factors for CAR T-cell–related neurotoxicity highlighted the association between older patient age at treatment as well as baseline blood biomarkers and risk of ICANS.42 In the current study, having baseline abnormal skeletal muscle was associated with a nearly 2-fold risk of ICANS, independent of age and blood biomarkers such as LDH level. In the absence of available functional assessments, it is possible that the abnormalities in skeletal muscle seen in our patients reflected baseline physiologic frailty, a condition characterized by the inability to manage acute stressors associated with treatment.43,44 Complementary assessment of physiologic reserves in patients with muscle loss prior to CAR T-cell therapy may allow for risk-based resource allocation (eg, inpatient vs outpatient toxicity monitoring) and consideration of early interventions such as prophylactic corticosteroid administration to mitigate ICANS-associated acute toxicity.45
The strengths of the current study are the large and ethnically diverse patient population included in our analyses, the consideration of well-established patient and disease-related prognostic risk factors in our multivariable models, and inclusion of a broad range of B-cell diagnoses and CAR T-cell products that speak to the generalizability of our findings. We acknowledge that the CT images used in this study were not initially intended for measuring muscle or adipose tissue, and for some patients we relied on the CT component of the PET/CT scan instead of higher-resolution CT. However, previous studies have consistently shown excellent correlation between CT-based abdominal muscle and adiposity measurements and whole-body composition,34,35 as well as robust concordance between high-resolution CT and PET/CT-based imaging.14,46 Given the lack of well-established definitions for adiposity and skeletal muscle measures, clinicians may need to contextualize their interpretation of body composition measures according to the populations of interest, because the thresholds used to define abnormal skeletal muscle or high adiposity in the current study may not be applicable to other patient populations. Moreover, the findings from this study should be considered as preliminary, due to the smaller sample sizes in some of the combined categories, such as abnormal skeletal muscle and LDH level, and the reliance on a single-institution cohort, which may impact generalizability. Prospective studies are needed to validate our findings and to examine the utility of integrating more time-intensive clinical assessments (eg, short physical performance battery, geriatric assessment)47 prior to CAR T-cell therapy in the setting of more readily accessible automated body composition measurements such as those used in the current study.
Conclusions
We found a strong association between skeletal muscle health and a range of outcomes in patients undergoing CAR T-cell therapy, including the morbidity associated with ICANS and disease response. These associations speak to the multidimensionality of information obtained from readily available skeletal muscle assessments. Ultimately, the findings from the current study may facilitate the development of targeted interventions to improve outcomes, given the long latency between apheresis and autologous CAR T-cell delivery. This may include prehabilitation and nutritional optimization prior to the start of lymphodepletion as well as tailored medical approaches shortly thereafter. These efforts will be complementary to ongoing efforts toward sustained efficacy after CAR T-cell therapy.
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