CD3+ T cells as biomarkers of frailty in elderly patients with hematologic malignancies

Older patients with hematologic malignancies often receive lower intensity treatment regimens due to frailty, influenced by malnutrition, comorbidities, decreased physical performance status, and difficulty tolerating the side effects of treatment.^1,2 However, a small subset of older patients are less frail, with this “robust” group often benefitting from improved clinical outcomes, especially when they receive more intense treatments, which has been covered previously on the Multiple Myeloma Hub.

Frailty assessments can guide treatment decisions; to be comprehensive these should use validated assessment scales and tools that cover cognition, physical function, general health, and comorbidities.¹ Increasingly, biological markers of ageing are being identified (e.g., p16^INK4a is a marker of senescence), which have the potential to be incorporated into clinical practice and future research for patient stratification.² Here, we summarize a study by Fell et al.² published in the British Journal of Haematology, which explored novel expression signatures associated with clinical frailty in elderly patients with hematologic malignancies.

Study design

Patients with hematologic malignancies were recruited from two treatment programs at two medical centers. In total, 74 mRNAs (including cell function, ageing, and senescence genes) from peripheral blood CD3⁺ T cells were quantified and compared in patients graded as robust or non‑robust (corresponding to pre-frail and frail). Frailty was assessed using measurements based on the five categories of Fried's frailty phenotype; unintentional weight loss, fatigue and exhaustion, weakness assessed using grip strength, slow walking speed, and reduced physical activity.³

Key findings  

Overall, 69 patients were recruited. The demographic information of these patients is presented in Table 1.

Table 1. Demographics of patients recruited to study*

DFCI, Dana-Farber Cancer Institute; OSU, Ohio State University. *Adapted from Fell, et al.2
Characteristic	All patients (N = 69)	DFCI cohort (n = 45)	OSU cohort (n = 24)	p value
Median age (range), years	76 (36–92)	79 (75–92)	57 (36–80)	<0.01
On treatment, %				<0.01
Yes	55	40	83
No	45	60	17
Frailty, %				0.57
Robust	25	22	29
Non-robust	75	78	71
Sex, %				0.30
Male	39	44	29
Female	61	56	71
Disease, %				<0.01
Myeloma	69	53	100
Leukemia	19	29	0
Lymphoma	12	18	0

Of the mRNAs analyzed, reduced expression of the following four genes was associated with frailty:

• CD27 (odds ratio [OR], 4.18; 95% confidence interval [CI], 1.51–15.19)
  • CD27 is associated with T-cell activation and robustness
• AHR (OR, 3.14; 95% CI, 1.16–9.54)
  • Loss of function of AHR is associated with premature aging
• CD28 (OR, 2.85; 95% CI, 1.18–8.18)
  • Loss of function of CD28 is associated with T-cell exhaustion and senescence
• IL2RA (OR, 2.85; 95% CI, 1.17–8.27)
  • IL2RA is associated with immunity and immune surveillance⁴

Conclusion

Clinical frailty assessments require clinical training and experience, can yield variable results, and are inconsistently conducted at different centers. The results of this study suggest that there are molecular markers of frailty that, alongside clinical assessments, could facilitate the classification of elderly patients as frail with greater ease and consistency. These biomarkers need to be assessed in larger clinical trials to be validated as screening or diagnostic tools