ORIGINAL RESEARCH published: 15 April 2020 doi: 10.3389/fimmu.2020.00586 Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT – A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party Olaf Penack 1* , Christophe Peczynski 2 , Steffie van der Werf 3 , Jürgen Finke 4 , Edited by: Arnold Ganser 5 , Helene Schoemans 6 , Jiri Pavlu 7 , Riitta Niittyvuopio 8 , Aurore Saudemont, Wilfried Schroyens 9 , Leylagül Kaynar 10 , Igor W. Blau 1 , Walter J. F. M. van der Velden 11 , GlaxoSmithKline, United Kingdom Jorge Sierra 12 , Agostino Cortelezzi 13 , Gerald Wulf 14 , Pascal Turlure 15 , Reviewed by: Montserrat Rovira 16 , Zubeydenur Ozkurt 17 , Maria J. Pascual-Cascon 18 , Luca Castagna, Maria C. Moreira 19 , Johannes Clausen 20 , Hildegard Greinix 21 , Rafael F. Duarte 22† and Humanitas Research Hospital, Italy Grzegorz W. Basak 23† Frederic Baron, 1 University of Liège, Belgium Department of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany, 2 EBMT Statistical Unit, Paris, France, 3 EBMT Data Office, Leiden, Netherlands, 4 Department of Medicine I, Medical Center, *Correspondence: Faculty of Medicine, University of Freiburg, Freiburg, Germany, 5 Hannover Medical School, Hanover, Germany, 6 Department Olaf Penack of Hematology, University Hospital Leuven, KU Leuven, Leuven, Belgium, 7 Imperial College London, London, olaf.penack@charite.de United Kingdom, 8 HUCH Comprehensive Cancer Center, Helsinki, Finland, 9 Antwerp University Hospital, Antwerp, Belgium, † These authors have contributed 10 Medical Faculty, Erciyes University, Kayseri, Turkey, 11 Medical Centre, Radboud University, Nijmegen, Netherlands, equally to this work 12 Hospital de la Santa Creu I Sant Pau, Barcelona, Spain, 13 Fondazione IRCCS Ca’ Granda, University of Milan, Milan, Italy, 14 Department of Hematology and Medical Oncology, Universitätsklinikum Göttingen, Göttingen, Germany, 15 CHRU Limoges, Specialty section: Limoges, France, 16 Hospital Clinic, Barcelona, Spain, 17 Faculty of Medicine, Gazi University, Ankara, Turkey, 18 Hospital This article was submitted to Regional de Málaga, Málaga, Spain, 19 Instituto National do Cancer, Rio de Janeiro, Brazil, 20 Elisabethinen Hospital, Linz, Alloimmunity and Transplantation, Austria, 21 Department of Hematology and Oncology, Medical University of Graz, Graz, Austria, 22 Hospital Universitario a section of the journal Puerta de Hierro, Madrid, Spain, 23 Department of Hematology and Oncology, Medical University of Warsaw, Warsaw, Poland Frontiers in Immunology Received: 09 January 2020 Elevated serum ferritin levels occur due to iron overload or during inflammation Accepted: 13 March 2020 Published: 15 April 2020 and macrophage activation. A correlation of high serum ferritin levels with increased Citation: mortality after alloSCT has been suggested by several retrospective analyses as well Penack O, Peczynski C, as by two smaller prospective studies. This prospective multicentric study aimed to van der Werf S, Finke J, Ganser A, Schoemans H, Pavlu J, study the association of ferritin serum levels before start of conditioning with alloSCT Niittyvuopio R, Schroyens W, outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling Kaynar L, Blau IW, alloSCT for the first time were considered for inclusion, regardless of conditioning. van der Velden WJFM, Sierra J, Cortelezzi A, Wulf G, Turlure P, A comparison of outcomes between patients with high and low ferritin level was Rovira M, Ozkurt Z, performed using univariate analysis and multivariate analysis using cause-specific Cox Pascual-Cascon MJ, Moreira MC, Clausen J, Greinix H, Duarte RF and model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point Basak GW (2020) Association of was determined at 1500 µg/l (median of measured ferritin levels). In alloSCT recipients Serum Ferritin Levels Before Start of with ferritin levels above cut off measured before the start of conditioning, overall survival Conditioning With Mortality After alloSCT – A Prospective, (HR = 2.5, CI = 1.5–4.1, p = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6– Non-interventional Study of the EBMT 3.8, p < 0.0001) were inferior. Excess mortality in the high ferritin group was due to both Transplant Complications Working Party. Front. Immunol. 11:586. higher relapse incidence (HR = 2.2, CI = 1.2–3.8, p = 0.007) and increased non-relapse doi: 10.3389/fimmu.2020.00586 mortality (NRM) (HR = 3.1, CI = 1.5–6.4, p = 0.002). NRM was driven by significantly Frontiers in Immunology | www.frontiersin.org 1 April 2020 | Volume 11 | Article 586 Penack et al. Ferritin and alloSCT Outcome higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6–9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT. Keywords: transplantation, stem cell, immunology, biomarker, iron metabolism, ferritin INTRODUCTION up was taken from minimal essential data (MED-A) forms, which are submitted from all consecutive patients to the central Allogeneic stem cell transplantation (alloSCT) is a curative EBMT registry. In addition, we designed registration and MED- treatment option for patients suffering from hematological B/C forms that were prospectively collected and specific to malignancies and some other diseases. High treatment-associated this study. Treatment teams completed specific forms (MED- mortality is a major difficulty of this procedure and predicting B/C) forms at the time of registration and at day + 100 after mortality is a clinical challenge. The current standard for alloSCT alloSCT. The MED-B/C form contained detailed information risk assessment is the use of clinical scores, such as the European on ferritin serum levels prior to alloSCT, patient characteristics, Society for Blood and Marrow Transplantation (EBMT)-score infectious- as well as non-infectious complications, GVHD (1), the Hematopoietic Cell Transplantation-Comorbidity Index staging, morbidity and mortality. Ferritin levels were determined (HCT-CI) (2), the Dana-Farber Cancer Institute (DFCI)-score at time of hospital admission for alloSCT directly before start of (3), and a combination of such scores (4). conditioning therapy. The use of biomarkers to further improve alloSCT risk assessment is an attractive option (5). Mortality in the first months/years after alloSCT is mainly due to leukemia relapse, ENDPOINTS AND STATISTICAL infections or graft-versus-host disease (GVHD). In all these ANALYSES clinical situations serum ferritin, an acute phase and iron binding protein, has been demonstrated to be elevated (6–13). Based on Patient, disease, and transplant-related characteristics for the two this background results, several retrospective studies and meta- cohorts (ferritin levels prior to alloSCT above median/ferritin analyses have suggested that serum ferritin may be of use as a levels below median) were compared by using χ2 statistics for biomarker during alloSCT (7, 14–18). categorical variables and the Mann-Whitney test for continuous Based on these preliminary results and on the fact that variables. Primary endpoint was the incidence of acute GVHD. ferritin is a routine laboratory parameter assessed in patients Acute GVHD was picked as a primary endpoint because of undergoing alloSCT, we saw a strong rationale for investigating our previous observation on a correlation of maximum Ferritin serum ferritin as a biomarker. The Transplant Complications levels after alloSCT with acute GVHD severity (12). Secondary Working Party (TCWP) of the EBMT performed a prospective, endpoints were relapse incidence (RI), non-relapse mortality multicenter and non-interventional study to test whether the (NRM), overall survival (OS), progression free survival (PFS), ferritin level evaluated prior to the start of conditioning therapy is and the incidence of chronic GVHD. PFS was defined as an independent risk factor for increased mortality after alloSCT. survival with no evidence of relapse or progression. RI was defined as the probability of having had a relapse during follow up time. Death without experiencing a relapse was MATERIALS AND METHODS a competing event. NRM was defined as death without evidence of relapse or progression. OS was defined as the Data Source, Study Design, and Data time from alloSCT to death, regardless of the cause. To Collection define acute GVHD during the consensus process, we used We asked EBMT centers performing more than 50 alloSCT the criteria established by the MAGIC group (19–21). To per year if they were willing to participate in this prospective define chronic GVHD, we used the NIH 2014 criteria (20– study. Twenty centers in ten countries agreed to participate. 22). Cumulative incidence was used to estimate the endpoints Data collection for the EBMT registry was approved by the of NRM, RI, acute, and chronic GVHD to accommodate European Society for Blood and Marrow Transplantation and by for competing risks. To study acute and chronic GVHD, the IRB of Charité Universitätsmedizin Berlin as well as by IRBs we considered relapse and death to be competing events. of the participating centers. Data were prospectively collected Probabilities of OS and PFS were calculated using the Kaplan– between 8/2014 and 2/2018. Consecutive alloSCT recipients with Meier method. Univariate analyses were done using the Gray acute leukemia, lymphoma or myelodysplastic syndrome (MDS) test for cumulative incidence functions and the log rank receiving a first matched sibling alloSCT from peripheral blood, test for OS and PFS. A Cox proportional hazards model regardless of conditioning, were eligible, provided they had was used for multivariate regression. All variables differing signed an informed consent document that permitted sharing significantly between the 2 groups or factors associated with of clinical data according to national rules. Basic data on one outcome in univariate analysis were included in the patient and disease characteristics as well as longer term follow Cox model. The following variables entered the multivariate Frontiers in Immunology | www.frontiersin.org 2 April 2020 | Volume 11 | Article 586 Penack et al. Ferritin and alloSCT Outcome models as possible confounders: age, sex mismatch between computing. R Foundation for Statistical Computing, Vienna, recipient and donor, diagnosis, disease status, Karnofsky score, Austria1 ). number of CD34 cells given, intensity of conditioning (EBMT definition: myeloablative conditioning (MAC) was defined as TBI > 6 gray or oral busulfan > 8 mg/kg or intravenous RESULTS busulfan > 6.4 mg/kg), type of GVHD prophylaxis, ATG use, time from diagnosis to transplant, year of transplant and CMV Patients and Transplant Characteristics status. As the number of variables was too high regarding the The entry criteria for analysis of OS were fulfilled in 298 number of events, a stepwise selection using Akaike information patients. The main patients and transplant characteristics that criterion (AIC) was run for all the confounding factors. The were included in the analysis of OS are described in Table 1. Most difference between the two cohorts was then assessed in the parameters were balanced between the two cohorts. However, a final selected model. higher percentage of sex mismatch transplants in the direction Results were expressed as the hazard ratio (HR) with of female to male were observed in the group of patients with the 95% confidence interval (95% CI). Proportional hazards ferritin above cut off before alloSCT. The ferritin cut off point was assumptions were checked systematically for all proposed determined at 1500 µg/l (median of measured ferritin levels). models using the Grambsch-Therneau residual-based test. All tests were 2-sided. The type I error rate was Endpoints fixed at 0.05 for the determination of factors associated In the present study, the incidence of acute GVHD grades with time-to-event outcomes. Statistical analyses were II–IV and grades III–IV in the whole population at performed in November 2018 with R 3.4.2 (R Core Team (2017). R: A language and environment for statistical 1 https://www.R-project.org/ TABLE 1 | Population characteristics. Ferritin <=1500 µ G/L (N = 153) Ferritin > 1500 µ G/L (N = 145) P-value Year of transplant median (range) [IQR] 2016 (2014–2018)[2015–2017] 2015 (2014–2018)[2015–2016] 0.6 Patient age (years) Median (range) [IQR] 52 (17.1–71.3) [38.1–60.2] 53.2 (19–70.9) [42.9–62.3] 0.3 Time from diagnosis to transplant (months) median (range) [IQR] 5 (1–71) [3–8] 4 (1–61) [3–6] 0.05 Number of CD34 + cells infused (E + 06) median (range) [IQR] 5.9 (0.9–10.7) [4.5–7.2] 5.5 (0.6–10.2) [4.2–6.7] 0.1 Sex mismatch 0.012 Female to male 27 (18%) 43 (30%) Other combination 123 (82%) 98 (70%) Diagnosis 0.058 Acute leukemia 93 (61%) 107 (74%) Lymphoma 19 (12%) 12 (8%) MDS 41 (27%) 26 (18%) Disease status 0.2 CR 94 (64%) 98 (70%) Not in CR 54 (36%) 42 (30%) ATG 0.5 No 77 (50%) 79 (54%) Yes 76 (50%) 66 (46%) Conditioning intensity 0.9 MAC/CHEMO 30 (20%) 32 (22%) MAC/TBI 26 (17%) 25 (17%) RIC 95 (63%) 87 (61%) Karnovsky Score 0.8 < = 80 23 (16%) 21 (15%) 90–100 125 (85%) 122 (85%) Missing 5 2 Disease risk index 0.8 Low 6 (4%) 4 (3%) Intermediate 86 (59%) 88 (65%) High 48 (33%) 39 (29%) Very high 5 (3%) 5 (4%) Missing 8 9 Frontiers in Immunology | www.frontiersin.org 3 April 2020 | Volume 11 | Article 586 Penack et al. Ferritin and alloSCT Outcome FIGURE 1 | Survival after alloSCT in both cohorts according to ferritin serum levels prior to alloSCT. Overall survival (OS) (A) as well as progression free survival (PFS) (B) were significantly inferior in patients with high ferritin serum levels (blue line) as compared to patients with low ferritin levels (red line). FIGURE 2 | Relapse incidence (RI) after alloSCT in both cohorts according to ferritin serum levels prior to alloSCT. Relapse incidence was increased in patients with high ferritin serum levels (blue line) as compared to patients with low ferritin levels (red line). Frontiers in Immunology | www.frontiersin.org 4 April 2020 | Volume 11 | Article 586 Penack et al. Ferritin and alloSCT Outcome FIGURE 3 | Non-relapse mortality (NRM) after alloSCT in both cohorts according to ferritin serum levels prior to alloSCT. NRM was increased in patients with high ferritin serum levels (blue line) as compared to patients with low ferritin levels (red line). 100 days was 25% and 11%, respectively. The incidence of Patients in the ferritin high group had significantly more chronic GVHD and severe chronic GVHD at last follow NRM (Figure 3, univariate HR = 3.1, CI = 1.5–6.3, p = 0.002; up was 25.8% and 15.1%, respectively. We observed no multivariate HR = 3.1, CI = 1.5–6.4, p = 0.002). NRM was differences in incidence and severity of acute GVHD as driven by significantly higher infection-related mortality in the well as chronic GVHD in between the two cohorts. As high ferritin group (Figure 4, univariate HR = 3.9, CI = 1.6– expected, chronic GVHD incidence was significantly lower 9.7, p = 0.003; multivariate HR = 3.9, CI = 1.6–9.7, p = 0.003). in alloSCT recipients receiving anti-T-cell globulin as part of A descriptive analysis of causes of death is given in Table 2. the conditioning regimen (ATG, HR = 0.25, CI = 0.13–0.5, We conclude that serum ferritin levels prior to alloSCT are an p < 0.0001). independent risk factor for OS, relapse, and NRM at one year. We found that OS and PFS of alloSCT recipients with ferritin levels above cut off measured before start of conditioning were significantly shorter as compared with the low ferritin cohort DISCUSSION (Figure 1A, OS univariate HR = 2.3, CI = 1.4–3.6, p = 0.00041; multivariate HR = 2.5, CI = 1.5–4.1, p = 0.0005) (Figure 1B, Our results from this prospective study indicate that serum PFS univariate HR = 2.1, CI = 1.4–3.2, p = 0.00014; multivariate ferritin prior to alloSCT is associated to mortality after alloSCT. HR = 2.4, CI = 1.6–3.8, p < 0.0001). This trial served as confirmation of previous retrospective Mortality was 29% at last follow up and with distribution of studies, which delivered preliminary results pointing in the same 15.0% relapse/progression as well as 14% NRM. Excess mortality direction (7, 14–18). Of note, the Center for International Blood in the high ferritin group was driven by higher relapse incidence and Marrow Transplantation Research (CIBMTR) published an as well as by higher NRM. We found that the incidence of evaluation on different biomarkers and found that ferritin levels relapse after alloSCT was 24.2% till the end of follow up. AlloSCT above 2500µg/ml were not associated with inferior alloSCT recipients with ferritin levels above cut off had significantly more outcome (23) contrasting previously published studies (7, 14–18) relapses as compared with the low ferritin group (Figure 2, and our results. univariate HR = 1.7, CI = 1–2.8, p = 0.03; multivariate HR = 2.2, A limitation of our clinical study is the lack of mechanistic CI = 1.2–3.8, p = 0.007). insight on the role of ferritin in development of complications Frontiers in Immunology | www.frontiersin.org 5 April 2020 | Volume 11 | Article 586 Penack et al. Ferritin and alloSCT Outcome FIGURE 4 | Infection-related mortality after alloSCT in both cohorts according to ferritin serum levels prior to alloSCT. Infection-related mortality was increased in patients with high ferritin serum levels (blue line) as compared to patients with low ferritin levels (red line). TABLE 2 | Mortality and cause of death in both cohorts. ferritin levels. First, high ferritin is related to iron overload although those factors are not always closely associated (10). Status at last follow up Ferritin <= 1500 µ Ferritin > 1500 µ G/L G/L (N = 153) (N = 145) Iron overload due to multiple pre-transplant red blood cell transfusion has been described to have negative impact on Alive 126 (82%) 92 (63%) alloSCT outcome (7, 8, 11, 13). Second, ferritin levels are Dead 26 (18%) 53 (37%) very high during severe graft-versus-host disease and during Death due to relapse or 15 (10%) 27 (19%) macrophage activation syndromes after alloSCT (12). Third, progression ferritin is an acute phase protein that is regularly elevated Death without relapse 11 (7%) 26 (18%) during acute and chronic infections (24, 25). Ferritin has NRM infection related 5 (3%) 14 (10%) been implicated in fungal growth and high ferritin levels have NRM due to other causes 6 (4%) 12 (8%) previously been suggested to be a risk factor for infections after alloSCT (26–28). In line with these data, our results indicated increased infection-related mortality in the group after alloSCT. In addition, our patient population was restricted with higher ferritin levels. Fourth, ferritin levels have been to alloSCT from HLA-identical sibling donors. We are therefore associated with increased growth of acute myeloid leukemia unable to draw definite conclusions from these results regarding (AML) (9, 16). So, taken together ferritin is elevated during the association of ferritin levels with outcome in matched tumor relapse and major infectious as well as non-infectious unrelated donor alloSCT or in haploidentical alloSCT, which are complications after alloSCT. Based on these considerations, increasingly used. ferritin might be a surrogate marker for organ dysfunction An attractive feature of using ferritin as a biomarker and it is understandable that it can serve as a biomarker for alloSCT outcome is that many severe clinical conditions for alloSCT mortality with significant prediction of tumor occurring in the peri-transplant period are associated to high relapses as well as NRM. Frontiers in Immunology | www.frontiersin.org 6 April 2020 | Volume 11 | Article 586 Penack et al. Ferritin and alloSCT Outcome In our study ferritin levels were not associated to a higher ETHICS STATEMENT disease stage (CR/non-CR) or a longer time between diagnosis and alloSCT. In line with these findings, high ferritin levels Ethical review and approval was not required for the study on were not associated to the diagnosis of MDS, where patients human participants in accordance with the local legislation and often receive multiple blood transfusions prior to alloSCT. There institutional requirements. The patients/participants provided are two likely explanations: (1) Patients with multiple blood their written informed consent to participate in this study. transfusions often receive drug treatment to reduce iron overload, and (2) The ferritin levels may not primarily reflect iron overload as discussed in the previous paragraph. Interestingly, a recent AUTHOR CONTRIBUTIONS prospective study in patients with MDS and CMML undergoing alloSCT reported that administration of iron chelation therapy OP wrote the manuscript. CP analyzed the data. All authors read, prior to HSCT was not associated to outcome. However, early edited, and approved the manuscript. iron reduction after alloSCT (started before d + 180) was associated to improved relapse free survival (29). In conclusion, we found that high serum ferritin is an FUNDING independent risk factor for increased mortality after alloSCT. The perspective of the future use of ferritin as biomarker will be likely JP acknowledges the support of the Imperial NIHR-BCR. OP a combination with clinical parameters such as the EBMT-score acknowledges the support of José Carreras Leukämie-Stiftung or the HCT-CI. However, to investigate such a combination or (11R2016 and 3R2019), Deutsche Krebshilfe (70113519), and a combination with alternative biomarkers was not within the Deutsche Forschungsgemeinschaft (PE 1450/7-1). scope of our study and remains to be analyzed in the future. ACKNOWLEDGMENTS DATA AVAILABILITY STATEMENT A part of the presented work (<30%) has been previously The datasets generated for this study are available on request to presented at the EBMT annual (30) in Frankfurt, Germany. The the corresponding author. authors hold copyright. REFERENCES 10. Jarisch A, Salzmann-Manrique E, Cario H, Grosse R, Soerensen J, Fischer R, et al. Serum ferritin is not a reliable predictor to determine iron overload in 1. Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A, thalassemia major patients post-hematopoietic stem cell transplantation. Eur J et al. Risk assessment for patients with chronic myeloid leukaemia before Haematol. (2018) 101:791–7. allogeneic blood or marrow transplantation. chronic leukemia working party 11. Leitch HA, Fibach E, Rachmilewitz E. Toxicity of iron overload and iron of the european group for blood and marrow transplantation. Lancet. 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Miranda P, Gil-Santana L, Oliveira MG, Mesquita ED, Silva E, Rauwerdink Copyright © 2020 Penack, Peczynski, van der Werf, Finke, Ganser, Schoemans, Pavlu, A, et al. Sustained elevated levels of C-reactive protein and ferritin Niittyvuopio, Schroyens, Kaynar, Blau, van der Velden, Sierra, Cortelezzi, Wulf, in pulmonary tuberculosis patients remaining culture positive upon Turlure, Rovira, Ozkurt, Pascual-Cascon, Moreira, Clausen, Greinix, Duarte and treatment initiation. PLoS One (2017) 12:e0175278. doi: 10.1371/journal.pone. Basak. This is an open-access article distributed under the terms of the Creative 0175278 Commons Attribution License (CC BY). The use, distribution or reproduction in 26. Almeida RS, Brunke S, Albrecht A, Thewes S, Laue M, Edwards JE, et al. The other forums is permitted, provided the original author(s) and the copyright owner(s) hyphal-associated adhesin and invasin Als3 of Candida albicans mediates iron are credited and that the original publication in this journal is cited, in accordance acquisition from host ferritin. PLoS Pathog. (2008) 4:e1000217. doi: 10.1371/ with accepted academic practice. No use, distribution or reproduction is permitted journal.ppat.1000217 which does not comply with these terms. Frontiers in Immunology | www.frontiersin.org 8 April 2020 | Volume 11 | Article 586