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Letters to the Editor
levels did not differ according to subtype (Online Supplementary Figure S1D). In the 71 patients with paired pre-treatment and post-treatment samples in complete response, sCD163 levels declined significantly (median 2,510 ng/mL [range 870-30,000] to 2,120 ng/mL [range 670-5,000], P=0.018) (Figure 1B, Online Supplementary Figure S1F). In 30 patients with paired pre- and mid-treat- ment samples, levels also declined, although not statisti- cally significantly (Figure 1B, Online Supplementary Figure S1F, H). sCD163 levels in 11 patients with primary pro- gressive or relapsing disease did not differ from the paired pre-treatment levels (Figure 1B). The distribution of pre- treatment sCD163 levels in groups of patients stratified by their later response to treatment are presented in Online Supplementary Figure S1J.
The outcomes in the subgroup with pre-treatment sCD163 levels above the median were worse than those with levels below the median (Figure 2C, D). The relative risks of death and progression were, respectively, 2.2-fold (95% CI: 0.99-4.94; P=0.052) and 2.2-fold (95% CI: 1.05- 4.48; P=0.037) higher. In Cox regression analysis, sCD163 remained an independent prognostic factor for poor progression-free survival (HR=2.16, 95% CI: 1.05- 4.48; P=0.037) (Online Supplementary Table S2) together with age, poor performance status, elevated lactate dehy- drogenase concentration and male gender. A similar trend was seen for poor overall survival (HR=2.21, 95% CI: 0.99-4.94, P=0.052) (Online Supplementary Table S2).
Taken together, we measured sCD163 levels in two independent DLBCL cohorts. Pre-treatment sCD163 lev- els correlated with CD163+ TAM and CD163 mRNA lev- els in the lymphoma tissue, while no correlation with monocyte counts was seen, suggesting that circulating sCD163 predominantly arises from the lymphoma tissue and that the elevated levels reflect host response to an aggressive lymphoma presentation. Pre-treatment sCD163 levels were elevated compared to those in healthy controls, and high levels were associated with unfavorable outcomes. We observed a decline in sCD163 levels in response to therapy, which in turn suggests that sCD163 could be used as a disease response biomarker in DLBCL. Similar observations have been previously made in chronic lymphocytic leukemia and multiple myelo- ma.6,7 The few samples at relapse prevented us from drawing firm conclusions, but the levels seemed in line with diagnostic values.
The two different ELISA methods implemented in the cohorts have been compared in2the past and their results showed a strong correlation (r =0.97), but a systematic bias due to different calibration levels.12 This likely explains the difference in sCD163 levels between the two subsets, with higher levels observed in the popula- tion-based cohort even though the trial cohort had a larg- er number of patients with advanced disease. Another contributing factor may be the larger number of patients >60 years in the population-based cohort.
An advantage of sCD163 as a potential biomarker is its stability in plasma, simplifying sample collection and handling.12 While absolute levels might differ between individuals for reasons other than tumor burden, levels could also be used as a patient-specific measure of response, indicated by declining levels in patients achiev- ing complete remission. Indeed, the intraindividual bio- logical variation in sCD163 is low, supporting the use of sCD163 for monitoring.12 While several prognostic fac- tors are already used in clinical routine, disease monitor- ing tools in DLBCL are less common. Interim fluo- rodeoxyglucose positron emission tomography/comput- ed tomography13 and down-modulation of circulating
tumor DNA14 are useful and promising for disease moni- toring, but the impact of host-related factors such as the tumor microenvironment should not be ignored.
Our results show that sCD163 is an indicator of biolog- ically aggressive DLBCL. The findings were similar in two independent cohorts despite differences in clinical variables, implying that the prognostic impact of sCD163 is not limited to a particular population of patients. Therefore, these results suggest that sCD163 represents a useful and easily assessable biomarker for therapeutic monitoring of patients with DLBCL.
Heli Vajavaara,1,2,3* Frida Ekeblad,4* Harald Holte,5
Judit Jørgensen,6 Suvi-Katri Leivonen,1,2,3 Mattias Berglund,4 Peter Kamper,6 Holger J. Møller,7,8 Francesco d’Amore,6,8 Daniel Molin,4 Gunilla Enblad,4 Maja Ludvigsen,6,8
Ingrid Glimelius4,9# and Sirpa Leppä1,2,3#
*HV and FE contributed equally as co-first authors.
#IG and SL contributed equally as co-senior authors.
1Research Program Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 2Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; 3iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland; 4Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; 5Department of Oncology and KG Jebsen center for B-cell malignancies, Oslo University Hospital, Oslo, Norway; 6Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 7Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; 8Department of Clinical Medicine, Aarhus University, Aarhus, Denmark and 9Department of Medicine, division of clinical epidemiology, Karolinska Institutet, Solna, Sweden
Correspondence: SIRPA LEPPA - sirpa.leppa@helsinki.fi INGRID GLIMELIUS - ingrid.glimelius@igp.uu.se doi:10.3324/haematol.2020.278182
Received: December 15, 2020.
Accepted: March 17, 2021.
Pre-published: March 25, 2021.
Disclosures: HV has received honoraria from Roche (not related to this study). SL has received honoraria and research funding from Celgene/BMS, Cho Pharma USA, Incyte, GILEAD, Novartis, Roche, Takeda, Bayer and Janssen-Cilag (not related to this study). IG has received honoraria from Janssen-Cilag (not related to this study).
DM received honoraria from Roche, Merck, Bristol-Myers Squibb, and Takeda (not related to this study). Other authors declare no conflicts of interest pertinent to the topic of this manuscript.
Contributions: HV and FE designed and conceived the study, ana- lyzed the data, and wrote the manuscript; JJ, HH, MB, DM, GE, IG and SL provided samples and clinical data; S-KL analyzed the data; PK, FdA, ML, DM and GE designed the study; HJM performed laboratory analyses; IG and SL designed and supervised the study and wrote the manuscript. All authors read, critically reviewed and approved the manuscript.
Acknowledgments: the authors would like to thank Anne Aarnio and Marika Tuukkanen for technical assistance and Sara Ekberg
for statistical support.
Funding: the study was supported by grants from the Academy
of Finland (to SL), Finnish Cancer Foundation (to SL), Juselius Foundation (to SL), Ida Montin Foundation (to HV), Finnish Society for Oncology (to HV), University of Helsinki (to SL), Helsinki University Hospital (to SL), Swedish Cancer Society (19 0123 Pj 01 H and 19 0109 SCIA) (to IG), Swedish Society of Medicine (to IG) and Lions Research Cancer Fund, Uppsala Sweden (to IG).
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