Biology of Blood and Marrow Transplantation
Volume 14, Issue 7 , Pages 759-765, July 2008

Plasma Elevations of Tumor Necrosis Factor-Receptor-1 at Day 7 Postallogeneic Transplant Correlate with Graft-versus-Host Disease Severity and Overall Survival in Pediatric Patients

  • Carrie L. Kitko

      Affiliations

    • Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan
    • Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
    • Corresponding Author InformationCorrespondence and reprint requests: Carrie Kitko, MD, Blood and Marrow Transplant Program, 5303 Cancer Center, 1500 E. Medical Center Drive, SPC 5941, Ann Arbor, MI 48109-5941.
    • ,
  • Sophie Paczesny

      Affiliations

    • Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
    • ,
  • Gregory Yanik

      Affiliations

    • Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan
    • Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
    • ,
  • Thomas Braun

      Affiliations

    • Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan
    • ,
  • Dawn Jones

      Affiliations

    • Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
    • ,
  • Joel Whitfield

      Affiliations

    • Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
    • ,
  • Sung W. Choi

      Affiliations

    • Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan
    • Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
    • ,
  • Raymond J. Hutchinson

      Affiliations

    • Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan
    • ,
  • James L.M. Ferrara

      Affiliations

    • Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan
    • Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
    • ,
  • John E. Levine

      Affiliations

    • Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan
    • Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan

Received 29 November 2007; accepted 9 April 2008.

Article Outline

Abstract 

Tumor necrosis factor-α (TNF-α) is known to play a role in the pathogenesis of graft-versus-host disease (GVHD), a cause of significant morbidity and treatment-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (HCT). We measured the concentration of TNF-Receptor-1 (TNFR1) in the plasma of HCT recipients as a surrogate marker for TNF-α both prior to transplant and at day 7 in 82 children who underwent a myeloablative allogeneic HCT at the University of Michigan between 2000 and 2005. GVHD grade II–IV developed in 39% of patients at a median of 20 days after HCT. Increases in TNFR1 level at day 7 post-HCT, expressed as ratios compared to pretransplant baseline, correlated with the severity of GVHD (P = .02). In addition, day 7 TNFR1 ratios >2.5 baseline were associated with inferior 1-year overall survival (OS 51% versus 74%, P = .04). As an individual biomarker, TNFR1 lacks sufficient precision to be used as a predictor for the development of GVHD. However, increases in the concentration of TNFR1, which are detectable up to 2 weeks in advance of clinical manifestations of GVHD, correlate with survival in pediatric HCT patients.

Key Words: GVHD, Hematopoietic stem cell transplantation, TNF, Pediatrics

 

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Introduction 

Acute graft-versus-host disease (aGVHD) continues to be a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT) in both adults and children 1, 2. Because no laboratory test predicts the development of GVHD, clinical prognostic factors are used to determine the risk of developing this complication. Well-categorized GVHD prognostic factors include donor age [3], donor type [4], and degree of human leukocyte antigen (HLA) match [5]. Historically, GVHD was thought to occur less often in pediatric recipients of HCT than in adult HCT recipients 6, 7. However, more recent large pediatric transplant studies report rates of grade II-IV GVHD ranging from 40%-64%, similar to that seen in adults 8, 9, 10, 11, 12.

The pathophysiology of GVHD involves a complex interaction between cellular immune effectors such as donor T cells and host antigen-presenting cells (APCs), and soluble effectors such as inflammatory cytokines [13]. The role of tumor necrosis factor-alpha (TNF-α) as a critical cytokine mediator of GVHD is well established in murine models 14, 15, 16, 17, 18. TNF-α is produced by activated monocytes and macrophages, as well as activated T cells [19]. Donor T cell-derived TNF-α production appears to be a major contributor to the incidence and severity of experimental GVHD 20, 21, 22. Significant increases in TNF-α levels have been demonstrated in the first week of posttransplant, and correlate with increased severity of GVHD [17]. In clinical allogeneic HCT, Holler and colleagues 23, 24, 25 have shown an association between GVHD and elevated levels of TNF-α during conditioning. Recent evidence also suggests that inhibition of TNF-α may be beneficial in patients as primary treatment for aGVHD as well as in those with steroid refractory aGVHD 24, 26, 27.

Given this data, we hypothesized that the concentration of TNF-α would be elevated early after HCT but prior to the development of GVHD in pediatric recipients. Previous studies have shown that concentrations of TNF-α strongly correlate with concentrations of tumor necrosis factor receptor 1 (TNFR1) 28, 29. TNF-α binds to its receptors, TNFR1 and TNFR2, on the surface of multiple cell types; the receptor-ligand complexes are subsequently shed into the plasma, where they are easily measured [30]. TNFR1 has superior stability than TNF-α in long-term storage [25] and correlates with clinical GVHD activity [26]. Therefore, we used TNFR1 as a surrogate marker for TNF-α. We measured the concentration of TNFR1 in samples obtained pre-HCT and at day 7 post-HCT in 82 pediatric patients who underwent myeloablative allogeneic HCT at the University of Michigan between January 2000 and December 2005.

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Materials and Methods 

Patient Characteristics 

Informed consent was obtained from the parent or guardian of 82 children undergoing HCT under an institutional review board-approved protocol between January 2000 and December 2005. Blood samples were obtained prior to and at day 7 post HCT. The characteristics of these patients are shown in Table 1. All patients received myeloablative conditioning regimens. Donors and recipients were considered matched if their HLA-A, B, and DR loci were identical by midresolution DNA techniques for class I loci and high-resolution techniques for class II loci. Cord blood units were matched at 4 of 6 loci in 3 cases and 6 of 6 loci in 3 cases. Hematologic malignancy was the indication for transplantation in the 78% of patients. Donors included HLA-identical siblings (n = 32), single antigen mismatched related donors (n = 6), matched unrelated donors (n = 35), single antigen mismatched unrelated donors (n = 3), and unrelated cord blood units (n = 6).

Table 1. Characteristics of 82 Pediatric Patients Who Underwent a Myeloablative Allogeneic Transplant at the University of Michigan between January 2000 and December 2005
Donor and Patient Age
Median patient age (range) n = 828.8 years (0.8-17.8)
Median donor age (range) n = 76∗21 years (0.6-55)
Diagnosis
Acute leukemia62 (76%)
JMML2 (2%)
Nonmalignant18 (22%)
Disease stage
Standard risk56 (87%)
High risk8 (13%)
CMV status
Recipient −/Donor −28 (34%)
Recipient −/Donor +6 (7%)
Recipient +/Donor −30 (37%)
Recipient +/Donor +18 (22%)
Risk for CMV reactivation54 (66%)
Conditioning
Busulfan-based†52 (63%)
TBI-based‡23 (28%)
Cy/ATG§7 (9%)
Donor source
Related38 (46%)
Unrelated38 (46%)
Unrelated cord blood6 (8%)
GVHD incidence
Grade 0-I50 (61%)
Grade II18 (22%)
Grade III-IV14 (17%)

GVHD indicates graft-versus-host disease; JMML, juvenile myelomonocytic leukemia; TBI, total body irradiations.

∗Six cord blood donors were excluded.

†Busulfan based: busulfan (12.8 mg/kg i.v.)/cyclophosphamide (120 mg/kg i.v.) ± cytarabine (8 g/m2 i.v.).

‡TBI: (1200 cGy)/cyclophosphamide (120 mg/kg i.v.).

§Cy/ATG: cyclophosphamide (200 mg/kg i.v.)/antithymocyte globulin (7.5 mg/kg i.v.).

Prophylaxis, Diagnosis, and Treatment of GVHD 

For prevention of GVHD, patients received tacrolimus and either minidose methotrexate (5 mg/m2 on days 1, 3, 6, and 11, n = 76) or mycophenolate mofetil (MMF) (500 mg/m2/dose 3 times daily from day 0 to day 28, n = 6). Tacrolimus levels were monitored and the dose adjusted to a target level of 8-12 ng/mL. The diagnosis of aGVHD was based on clinical symptoms with confirmatory biopsies from target organs obtained whenever clinically indicated and appropriate. GVHD was graded on a scale of 0-IV based on the modified Glucksberg criteria [31]. Initial treatment of clinically significant GVHD (overall grade ≥II) included systemic methylprednisolone 2 mg/kg/day. Patients were enrolled in clinical studies whenever possible, and those who did not response to initial GVHD therapy received additional agents at the discretion of the treating physician.

Supportive Care 

All patients were admitted to HEPA filtered rooms. For Pneumocystis jiroveci pneumonia prevention patients received trimethoprim-sulfamethoxazole or pentamidine starting at day 30 post-HCT. Acyclovir was given as prophylaxis for patients seropositive for herpes simplex virus and/or varicella-zoster virus. Serum CMV DNA levels measured by polymerase chain reaction were tested weekly in recipients who were seropositive or received a graft from a seropositive donor. Antifungal prophylaxis consisted of fluconazole or voriconazole starting at the time of conditioning and continuing until the patient was off immunosuppression. Patients received leucoreduced and irradiated blood products to maintain their hemoglobin >8.0 g/dL and platelet counts >20 k/mm3.

TNFR1 Measurement 

On the day of sample acquisition, the plasma component of each blood sample was separated and frozen for later analysis. The concentration of soluble TNFR1 was measured using a cytokine enzyme-linked immunosorbent assay (R&D, Minneapolis, MN). The assays were performed according to manufacturer's protocol, and all samples and standards were run in duplicate. The maximum GVHD scores were blinded to the technician who ran the TNFR1 samples.

Statistical Analysis 

Because of a 50-fold variability in baseline concentrations of TNFR1 (143–7541 pg/mL), we expressed the day 7 value as a ratio to pretransplant baseline. Differences in mean ratios of TNFR1 by GVHD grade were assessed using univariate and multivariate linear regression models. Overall survival (OS) was estimated using Kaplan-Meier methods, and differences in OS among patient subgroups were assessed with a log-rank test. P-Values of .05 or less were considered statistically significant.

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Results 

GVHD grade II-IV developed in 39% (95% confidence interval [CI]: 29%, 50%) of patients at a median of 20 days (range: 8-72). The rate of severe grade III-IV GVHD was 17% (95% CI: 10%, 27%). Baseline TNFR1 concentrations did not correlate with the occurrence or severity of GVHD, nor was there a correlation between day 7 TNFR1 ratios and onset of GVHD (P = .18). However, consistent with our hypothesis, the mean day 7 TNFR1 ratio correlated with increased severity of GVHD (Figure 1). In children who eventually developed a maximum of grade 0-I GVHD, the mean day 7 ratio was 1.7 ± 0.16 (n = 50); those with a maximum of grade II (n = 18) the ratio was 2.4 ± 0.68; and with maximum of grade III-IV (n = 14) the ratio was 3.0 ± 0.62 (test for trend P = .02). Increasing mean day 7 TNFR1 ratios correlated with increasing severity of GVHD; however, the sample size did not permit demonstration of a significant correlation to individual GVHD grades.

  • View full-size image.
  • Figure 1. 

    Mean day 7 ratios are associated with maximum severity of GVHD (P = .02). Mean ± SEM; Grade 0-I, 1.7 ± 0.16; Grade II, 2.4 ± 0.68; Grade III-IV, 3.0 ± 0.62.

Because GVHD severity is an important predictor of mortality 1, 32, we tested whether children with the highest TNFR1 ratios experienced inferior survival. The performance of TNFR1 as an individual biomarker for the prediction of GVHD was assessed using area under the receiver operating characteristic (ROC) curve (AUC) (Figure 2). Multiple ratios between 1.35 and 2.74 demonstrated statistical significance in this regard. We decided that a clinically meaningful threshold should have a specificity of at least 80% and the smaller group should include at least 1/5th of the patients. Using these criteria, we found that a threshold ratio of 2.5 was a useful discriminator between groups (TNFR1 ratio >2.5, n = 19). As an individual biomarker for the prediction of GVHD, a TNFR1 ratio of 2.5 corresponds to a specificity of 82% and a sensitivity of 31%. Despite the low sensitivity of this test, the day 7 TNFR1 ratio significantly correlated with 1-year survival. Children with a day 7 TNFR1 ratio of ≤2.5 experienced 75% survival at 1 year (95% CI: 65%, 84%) compared to patients with a ratio of >2.5 who experienced a statistically inferior survival of 51% (95% CI: 41%, 62%) (Figure 3). As expected, patients with the higher day 7 TNFR1 ratios had a higher incidence of GVHD grade II-IV and 1-year nonrelapse treatment-related mortality (TRM), but these differences did not reach the criteria for statistical significance (Table 2). Rates of chronic GVHD (cGVHD) were similar for patients with a day 7 TNFR1 ratio >2.5 or ≤2.5 (42% versus 38%, P = .75).

  • View full-size image.
  • Figure 2. 

    ROC curve. The AUC of the ROC curve is 0.63, P = .04. The cross indicates a threshold ratio of 2.5 corresponding to a specificity of 82% and a sensitivity of 31%.

Table 2. GVHD Grade II-IV Rates and 1 Year TRM Based on TNFR1 Day 7 Ratios ≤ or >2.5
TNFR1 RatioGVHD II-IV1 Year TRM
TNFR1 ≤2.5 (n = 63)35%8%
TNFR1 >2.5 (n = 19)53%27%
P = .07P = .09

TRM indicates treatment-related mortality; TNFR1, Tumor necrosis factor Receptor-1.

The number of patients in this study was not sufficient to simultaneously estimate the effects on GVHD grade by day 7 TNR1 ratio, donor type, patient age, donor age, CMV status (at risk for reactivation versus no risk for reactivation), indication for transplant (malignancy versus nonmalignancy) or disease status (standard risk-leukemia in remission versus high risk- leukemia not in remission) in a single multivariate model. As an alternative, we fit 5 models using GVHD grade combined separately with each of the other patient characteristics. Thus, we could assess if any of the patient characteristics individually altered the association of the day 7 TNFR1 ratio with GVHD grade. In 5 of these models (patient age, donor age, CMV status, indication for transplant, and disease status), the relationship between day 7 TNFR1 ratio and GVHD remained significant after adjustment for the other variable. However, after adjustment for donor source, the day 7 TNFR1 ratio still correlated with GVHD, but the association was no longer significant, indicating that the presence of confounding between the day 7 ratio and donor source. In fact, children who underwent an unrelated donor HCT had higher mean day 7 TNFR1 ratios then children who underwent a related donor HCT (2.6 versus 1.5, P = .01). To further explore the relationship between donor source and the day 7 TNFR1 ratio on outcomes, we divided the patients into 4 groups ordered from lowest to highest according to expected risk of death: related donor recipients with low day 7 TNFR1 ratios (≤2.5), related donor recipients with high day 7 TNFR1 ratios (>2.5), unrelated donor recipients with low day 7 TNFR1 ratios, and unrelated donor recipients with high day 7 TNFR1 ratios, and compared survival outcomes across these groups. The differences in survival for these groups was statistically significant (P = .01 by log rank analysis for trend), confirming that a high day 7 TNFR1 ratio correlated with inferior survival after stratification by donor source (Figure 4).

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  • Figure 4. 

    Kaplan-Meier plot of OS based on the day 7 TNFR1 threshold of 2.5 by donor source. MRD low = recipients of matched related donor HCT with a day 7 TNFR1 ratio ≤2.5, MRD high = recipients of matched related donor HCT with a day 7 TNFR1 ratio >2.5, MUD low = recipients of matched unrelated donor HCT with a day 7 TNFR1 ratio ≤2.5, MUD high = recipients of matched unrelated donor HCT with a day 7 TNFR1 ratio >2.5. P = .01, log rank test for trend.

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Discussion 

Because donor T cells are known to mediate GVHD, effector mechanisms of GVHD damage initially focused primarily on the role of cytotoxic T lymphocytes. More recent animal models have suggested that the clinical manifestations of GVHD are the culmination of a series of complex interactions between host APCs, donor T cells, and target tissues, all of which are highly influenced by anti- and pro-inflammatory signals [13]. The validity of this model in children has not previously been tested. In this study, we report a significant association between the magnitude of elevation of plasma TNFR1 concentrations at day 7 posttransplant and the subsequent severity of GVHD in a series of 82 children who underwent myeloablative allogeneic HCT. This evidence that a pro-inflammatory environment early posttransplant influences subsequent GVHD in pediatric HCT recipients is strengthened by the finding that the magnitude of change in TNFR1 concentrations correlates with likelihood of death in the first posttransplant year. Day 7 TNFR1 ratios >2.5 correlated with a 25% reduction in survival over the first posttransplant year. Other biologic marker thresholds, such leukemia burden in the pretransplant marrow specimen, have correlated with posttransplant survival probability 33, 34, 35, 36, 37.

In our pediatric patient population, there was a trend toward a higher incidence of TRM in the patients with TNFR1 ratios >2.5. In this study, most of the mortality is explained by GVHD, however, other transplant related complications such as sepsis or veno-occlusive disease (VOD) may contribute to both TRM and elevated inflammatory TNFR1 concentrations. In this study there were 3 cases of sepsis and 8 cases of VOD, resulting in 1 death. Therefore, a larger study will be required to determine the relationship of these less common complications to TNFR1 concentrations and outcomes.

Animal studies show that allogeneic reactions between donor T cells and host APCs are established within 72 hours of HCT [38]. Because the change in day 7 TNFR1 concentrations predicted more severe GVHD grade well in advance of its clinical manifestations, we speculate the TNFR1 ratio at this early time point reflects the magnitude of the systemic alloreaction that eventually culminates in clinical GVHD. Our study was not designed to distinguish the individual contributions of the donor and recipient to TNFR1 concentrations. Because most nucleated cells express TNFR1[19], it is highly probable that both donor and host cellular sources contribute to the concentrations measured. Potential future clinical studies could compare TNFR1 levels in autologous transplant recipients to allogeneic recipients as an indirect assessment of the recipient versus donor contributions of TNFR1. A potential complicating factor may be the downregulation of recipient contributions to TNFR1 concentrations over time by donor T cell eradication of host TNF-α producing cells in the allogeneic setting.

We therefore speculate that the magnitude of increase in TNFR1 concentration over baseline reflects both host changes in response to myeloablative conditioning, as well as donor cell responses to alloantigens in the early posttransplant period. Not surprisingly, these donor cell responses appear to be greater following unrelated donor transplant as evidenced by higher TNFR1 concentrations on day 7, presumably because of increased likelihood of a robust donor-host interaction given the greater number of minor histocompatibility mismatches in the unrelated donor setting. Importantly, our study suggests that although unrelated donor recipients are more likely to have high day 7 TNFR1 concentrations, any patient with a high TNFR1 concentration at day 7 is at greater risk of mortality, regardless of donor source. For example, the expected survival advantage for related donor recipients was offset by a high day 7 TNFR1 ratio as evidenced by the nearly equivalent survival at 1 year for related donor recipients with a high day TNFR1 ratio and unrelated donor recipients with a low day TNFR1 ratio.

Large numbers of children require allogeneic HCT for treatment of high-risk or recurrent malignancy. Because allogeneic HCT carries substantial risk of treatment related morbidity and mortality, further improvement in survival rates in pediatric allogeneic HCT recipients depends in part on further advances in the diagnosis, prevention, and treatment of transplant-related complications such as GVHD. Our findings suggest that it may be possible to develop prognostic biomarkers for GVHD. Validation of these observations in a multicenter setting, perhaps with a larger panel of candidate proteins, should be pursued. Development of a predictive laboratory test for GVHD may allow risk-stratification early after HCT and provide the rationale for more individualized preemptive treatment strategies that may eventually improve OS of these patients.

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Acknowledgments 

This work was supported by the following grants: Doris Duke Charitable Foundation Distinguished Clinical Scientist Award Grant #20020347 (PI: J.L.M. Ferrara), the National Institutes of Health (P01 CA039542-20), and the Child Health Research Career Development Award K12HD028820-15 (PI: C.L. Kitko). Authorship: Carrie L. Kitko, James L.M. Ferrara, and John E. Levine designed the study and wrote the paper. Carrie L. Kitko, Sophie Paczesny, and Dawn Jones gathered the clinical data. Thomas Braun performed the statistical analysis. Joel Whitfield performed all the ELISA tests. All authors reviewed the final version of the manuscript. The authors declare no competing financial interests.

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PII: S1083-8791(08)00148-1

doi:10.1016/j.bbmt.2008.04.002

Biology of Blood and Marrow Transplantation
Volume 14, Issue 7 , Pages 759-765, July 2008

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