Serum TARC: a biomarker for early detection or exclusion of relapse in classic Hodgkin lymphoma Open Access

TO THE EDITOR:

Classic Hodgkin lymphoma (cHL) is characterized by a small percentage of tumor cells, known as Hodgkin Reed-Sternberg cells, admixed with many inflammatory cells. The Hodgkin Reed-Sternberg cells secrete various chemokines that shape their microenvironment, thereby promoting tumor survival.^1,2 Thymus and activation-regulated chemokine (TARC or CCL17) is secreted in remarkably high quantities. TARC can be measured in serum (sTARC) in which it has proven to be a specific biomarker for cHL. Previous studies have shown that ∼90% of patients exhibit elevated levels at diagnosis, up to 400 times higher than healthy controls.^3-7 Furthermore, sTARC levels correlate with total metabolic tumor volume (TMTV).⁸ Recent studies have highlighted the use of sTARC measurements for diagnosis and evaluating treatment response, but its potential for early detection or exclusion of relapse during follow-up remains largely unexplored.^6,7,9-13 

Currently, monitoring disease relapse relies solely on clinical evaluation, whereas surveillance imaging using ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)–computed tomography (CT) is discouraged in the Lugano classification because of a lack of survival benefit and false-positive rates exceeding 20%.^14-17 A specific and sensitive biomarker would be the most optimal diagnostic tool to detect relapse and could reduce imaging use in case of nonspecific symptoms during follow-up. In this study, we aimed to determine the sensitivity, specificity, and positive and negative predictive value (PPV and NPV) of sTARC during follow-up of patients with cHL in complete remission.

We studied 204 patients who were in complete remission after first- or second-line treatment for cHL at the University Medical Centre Groningen between 2005 and 2022. Permission was obtained from the institutional review board of the University Medical Centre Groningen, and all participating patients signed informed consent. Patients with sTARC values below the predefined cutoff of 1000 pg/mL at diagnosis¹⁰ or patients with <2 serum samples during follow-up were excluded (n = 30), leading to a total of 174 eligible patients (supplemental Table 1). Patients with negative baseline sTARC more often had stage 1 or Epstein-Barr virus–positive disease. For patients who were treated between 2005 and 2016, samples were measured retrospectively (n = 82), whereas patients treated from 2016 onward were monitored in real-time as part of routine clinical care (n = 92). Follow-up and sampling were generally conducted according to local guidelines every 3, 4, and 6 months during the first, second, and third years, respectively, and annually in the fourth and fifth years. The median follow-up was 36 months (range, 3-60), with a median of 6 available serum samples (range, 2-14) per patient. Relapse was diagnosed in 16 patients (9.2%) with a median time to relapse of 16 months (range, 3-48).

At initial diagnosis, the median sTARC level was 28 748 pg/mL (range, 1117-2 327 328) among all patients. Despite a negative FDG-PET/CT, 10 patients had an sTARC level that exceeded 1000 pg/mL at the end of treatment. The 5-year progression-free survival of patients with a positive posttherapy sTARC level was 50% as opposed to 93% among patients who had a negative posttherapy sTARC level, aligning with the previous observations of Hsi et al.¹⁸ A diagnosis of clinical relapse was made within 6 months in 4 patients, and a single patient relapsed after 20 months and had persistently elevated sTARC measurements in between. These findings emphasize the important clinical utility of sTARC monitoring during and directly after treatment in identifying patients at high risk for early relapse.

To determine the sensitivity, we focused on the 16 patients who experienced a relapse. Of these, 13 had elevated levels of sTARC (Figure 1A), thus indicating that sTARC has a sensitivity of 81% to detect disease relapse. The median sTARC level at relapse was 4919 pg/mL (range, 1098-397 56). Interestingly, 8 of the 13 patients had no clinical symptoms suggestive of disease activity at the time of their first positive sTARC test. In 3 patients, the measurements were performed retrospectively, and sTARC elevation was observed up to 16 months before diagnosis. The measurements of the other 10 patients were analyzed prospectively. In 6 of these patients, relapse was not suspected based on routine follow-up, and the indication for an FDG-PET/biopsy was solely based upon elevated sTARC. The median time from the first sTARC elevation to the relapse diagnosis was 4 months in the prospective cohort. See the supplemental Sensitivity analysis for detailed patient descriptions.

To determine the specificity, we investigated the sTARC results among 158 patients who remained in remission. The median follow-up was 36 months in this cohort. In total, 969 of 1009 samples (96%) were below the cutoff of 1000 pg/mL. In 145 of 158 (92%) patients, sTARC remained below 1000 pg/mL (Figure 1B). Twelve patients in remission had at least 1 minor (<2500 pg/mL) sTARC elevation. In 6 patients, this was linked to activity of a concomitant disease known to cause sTARC elevation, mainly active atopic eczema (range, 1000-2197 pg/mL). In 6 patients, the elevation was not explained by a concomitant condition, but levels were only moderately elevated (range, 1030-2240 pg/mL), which was consistent during all timepoints or was followed by a spontaneous decrease. Only 1 patient exhibited sTARC levels above 2500 pg/mL (up to 29 546 pg/mL), which was attributed to severe eczema for which hospitalization was required. Therefore, sTARC analysis during routine follow-up demonstrated a specificity of 92%. After excluding patients with concomitant conditions, the specificity increased to 96%.

The PPV and NPV of sTARC during the follow-up were 50% and 98%, respectively. When the 7 patients with concomitant conditions were excluded, the PPV increased to 68%. The total accuracy of sTARC during the follow-up was 91%.

Of the 13 patients with a positive sTARC level at relapse, 12 patients had a tumor lesion with a quantifiable uptake above the standardized uptake value of 4 and were eligible for TMTV analysis.¹⁹ The median TMTV at relapse was 20.6 mL (range, 0.202-798), measured by semiautomatic segmentation using a 3D Slicer with multiple SUV threshold (MUST)-segmenter.²⁰ The sTARC level at relapse strongly correlated with the TMTV (Spearman’s rank correlation coefficient of 0.73; P = .009; Figure 2).

To evaluate our predefined sTARC cutoff of 1000 pg/mL, which was based on the upper limit of sTARC levels in healthy controls, we conducted a receiver operating characteristic curve analysis.¹⁰ This demonstrated a slightly higher optimal level of 1329 pg/mL (supplemental Figure 1) for detecting disease relapse, likely because of the slightly elevated sTARC levels observed in patients with eczema.

To our knowledge, this is the first study to investigate routine sTARC measurements as a screening tool for disease activity during follow-up in patients with cHL in remission. Our findings show that sTARC can be used as a biomarker to detect relapse early with an accuracy of 91%. Importantly, most patients with positive sTARC levels were asymptomatic, and sTARC elevation preceded the diagnosis of relapse by up to 16 months. The correlation of sTARC with TMTV at relapse supports its role in early relapse detection, which is becoming more and more important with the development of novel treatment strategies with radiotherapy and/or checkpoint inhibitors for patients in their first relapse. These strategies are only applicable to or mainly effective in patients with limited disease at relapse and might bypass the need for high-dose chemotherapy and autologous stem cell transplant.^21,22 In addition to its role in the early detection of relapse, the high specificity and NPV make it possible to virtually rule out disease activity, thereby reducing the use of FDG-PET/CT imaging in patients with nonspecific symptoms. Other favorable characteristics of sTARC are its noninvasive nature, the applicability as a commercially available test, a low turnaround time, and low analysis costs. Because the use of routine imaging is discouraged in clinical practice, sTARC enables clinicians, for the first time, to rely on a specific, cheap, and readily accessible diagnostic tool to detect an impending relapse. Some caution is advised in patients with atopic eczema or other diseases that might lead to slightly elevated sTARC levels. Especially in these cases, it is important to interpret the dynamics of sTARC in serial measurements. In conclusion, we showed that using sTARC in routine monitoring can lead to the early detection of relapse in 81% of patients, often before the onset of clinical symptoms. Especially now that less intensive treatment regimens are being developed for patients with limited-stage relapse, we advocate for the integration of sTARC into clinical follow-up of patients with cHL.

Contribution: S.A.T., W.J.P., A.D., L.V., A.v.d.B., and M.N. designed the study; S.A.T., W.J.P., K.K., B.-J.K., M.N., and A.G.H.N. were responsible for patients and data collection; S.A.T., L.V., M.N., A.G.H.N., B.-J.K., A.v.d.B., A.D., and W.J.P. interpreted the results; S.A.T. drafted the manuscript; W.J.P., A.D., L.V., A.v.d.B., M.N., K.K., B.-J.K., and A.G.H.N. were responsible for the revision of manuscript and comments; and all authors read and approved the final manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Wouter J. Plattel, Department of Haematology, University Medical Center Groningen, PO BOX 30 001, Hanzeplein 1 (EA 10), 9700 RB Groningen, The Netherlands; email: w.j.plattel@umcg.nl.