T‐cell clonality testing for the diagnosis of T‐cell large granular lymphocytic leukemia: Are we identifying pathology or incidental clones?

Abstract

Introduction: T-cell clonality testing by T-cell receptor (TCR) gene rearrangement is key to the diagnosis of T-cell lymphoproliferative disorders such as T-cell large granular lymphocytic (T-LGL) leukemia. Benign clonal T-cell expansions, however, are commonly found in patients without identifiable disease, a condition referred to as T-cell clones of uncertain significance (T-CUS). In practice, T-cell clonality testing is performed for a range of reasons and results are often challenging to interpret given the overlap between benign and malignant clonal T-cell proliferations and uncertainties in the management of T-CUS. Methods: We conducted a 5-year retrospective cohort study of 211 consecutive patients who underwent PCR-based T-cell clonality testing for suspected T-LGL leukemia at our institution to characterize the use of T-cell clonality testing and its impact on patient management. Results: Overall, 46.4% (n = 98) of individuals tested had a clonal T-cell population identified. Patients with a monoclonal T-cell population were more likely to be older, have rheumatoid arthritis and have higher lymphocyte counts compared to patients with polyclonal populations. The majority of patients eventually diagnosed and treated for T-LGL leukemia had rheumatoid arthritis and lower neutrophil counts compared to untreated patients with monoclonal T-cell populations. A diagnosis of T-LGL leukemia was made in only a minority of patients (n = 48, 22.7%), and only a small proportion were treated (n = 17, 8.1%). Conclusion: Our study suggests that T-cell clonality testing most commonly identifies incidental T-cell clones with only a minority of patients receiving a diagnosis of T-LGL leukemia and fewer requiring active treatment. These finding indicate an opportunity to improve utilization of T-cell clonality testing in clinical practice to better target patients where the results of testing would impact clinical management.

TRBC1 in flow cytometry: Assay development, validation, and reporting considerations

“…Given that several studies have demonstrated that clones constituting less than 20% of total lymphocytes or 400 cells/μL of blood are highly prevalent in patients without T‐cell malignancy and show no particular disease association, it is unclear if reporting these populations is necessary or even harmful (Chin‐Yee et al, 2022; Kroft & Harrington, 2022; Shi et al, 2020). The risk of overdiagnosis of a T‐cell malignancy is particularly higher in older patients presenting with unexplained cytopenia or post‐transplant patients who present with oligoclonal reactive cytotoxic T‐cell proliferations (Chin‐Yee et al, 2022; Kroft & Harrington, 2022). Most reactive T‐CUS cases are CD8+ or CD4+/CD8+ double‐positive, hence the decision to report these populations must be balanced with the risk of triggering unnecessary laboratory workup and misdiagnosis (Shi et al, 2020).…”

“…The incidence of T-CUS rises with age and given the normal function of T-cells, T-CUS is favored to represent reactive T immunoclones as they commonly exhibit features of activation and terminal differentiation including downregulation of CD5, CD2, CD3, and CD7 or upregulation of CD57 and CD56 (Case #12; Case #13).Given that several studies have demonstrated that clones constituting less than 20% of total lymphocytes or 400 cells/μL of blood are highly prevalent in patients without T-cell malignancy and show no particular disease association, it is unclear if reporting these populations is necessary or even harmful(Chin-Yee et al, 2022;Kroft & Harrington, 2022;Shi et al, 2020). The risk of overdiagnosis of a T-cell malignancy is particularly higher in older patients presenting with unexplained or post-transplant patients who present with oligoclonal reactive cytotoxic T-cell proliferations(Chin-Yee et al, 2022;Kroft & Harrington, 2022). Most reactive T-CUS cases are CD8+ or CD4+/CD8+ double-positive, hence the decision to report these populations must be balanced with the risk of triggering unnecessary laboratory workup and misdiagnosis(Shi et al, 2020).…”