Dawn Jones

A biomarker panel for acute graft-versus-host disease.

No validated biomarkers exist for acute graft-versus-host disease (GVHD). We screened plasma with antibody microarrays for 120 proteins in a discovery set of 42 patients who underwent transplantation that revealed 8 potential biomarkers for diagnostic of GVHD. We then measured by enzyme-linked immunosorbent assay (ELISA) the levels of these biomarkers in samples from 424 patients who underwent transplantation randomly divided into training (n = 282) and validation (n = 142) sets. Logistic regression analysis of these 8 proteins determined a composite biomarker panel of 4 proteins (interleukin-2-receptor-alpha, tumor-necrosis-factor-receptor-1, interleukin-8, and hepatocyte growth factor) that optimally discriminated patients with and without GVHD. The area under the receiver operating characteristic curve distinguishing these 2 groups in the training set was 0.91 (95% confidence interval, 0.87-0.94) and 0.86 (95% confidence interval, 0.79-0.92) in the validation set. In patients with GVHD, Cox regression analysis revealed that the biomarker panel predicted survival independently of GVHD severity. A panel of 4 biomarkers can confirm the diagnosis of GVHD in patients at onset of clinical symptoms of GVHD and provide prognostic information independent of GVHD severity.

Frequency of CD4+CD25hiFOXP3+ Regulatory T Cells Has Diagnostic and Prognostic Value as a Biomarker for Acute Graft-versus-Host-Disease

The relationship between regulatory T cells (Tregs) and acute graft-versus-host disease (aGVHD) in clinical allogeneic bone marrow transplantation (BMT) recipients is not well established. We conducted a prospective analysis of peripheral blood Tregs as determined by the frequency of CD4(+)CD25(hi)FOXP3(+) lymphocytes in 215 BMT patients. Autologous BMT patients (N = 90) and allogeneic BMT patients without GVHD (N = 65) had similar Treg frequencies, whereas allogeneic patients with GVHD (N = 60) had Treg frequencies that were 40% less than those without GVHD. Treg frequencies decreased linearly with increasing grades of GVHD at onset, and correlated with eventual maximum grade of GVHD (P < .001). In addition, frequency of Tregs at onset of GVHD predicted the response to GVHD treatment (P = .003). Patients with Treg frequencies less than the median had higher nonrelapse mortality (NRM) than patients with Tregs greater than the median, but experienced equivalent relapse mortality, resulting in an inferior survival at 2 years (38% versus 63%, P = .03). Treg frequency may therefore have important prognostic value as a biomarker of aGVHD.

Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with severity and incidence of GVHD and survival

Acute graft-versus-host disease (GVHD) remains a significant cause of mortality after hematopoietic cell transplantation (HCT). Tumor necrosis factor-alpha (TNF-alpha) mediates GVHD by amplifying donor immune responses to host tissues and by direct toxicity to target organs. We measured TNF receptor 1 (TNFR1) as a surrogate marker for TNF-alpha in 438 recipients of myeloablative HCT before transplantation and at day 7 after transplantation. Increases in TNFR1 levels more than or equal to 2.5 baseline correlated with eventual development of GVHD grade 2 to 4 (58% vs 32%, P < .001) and with treatment-related mortality (39% vs 17%, P < .001). In a multivariate analysis including age, degree of HLA match, donor type, recipient and donor sex, disease, and status at HCT, the increase in TNFR1 level at day 7 remained a significant predictor for outcome. Measurement of TNFR1 levels early after transplantation provides independent information in advance of important clinical outcomes, such as GVHD and death.

The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation

Idiopathic pneumonia syndrome (IPS) refers to a diffuse, noninfectious, acute lung injury after hematopoietic stem cell transplantation. Historically, IPS is associated with respiratory failure and mortality rates exceeding 50%. Preclinical studies have implicated tumor necrosis factor-alpha as an important effector molecule in the development of disease. We studied the tumor necrosis factor-alpha inhibitor, etanercept, combined with corticosteroids in treating 15 patients (median age, 18 years; range, 1-60 years) with IPS. Eight of 15 patients required mechanical ventilation at therapy onset. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum 25 mg) twice weekly, for a maximum of 8 doses. Therapy was well tolerated with no infectious pulmonary complications noted. Ten of 15 patients had a complete response, defined as the ability to discontinue supplemental oxygen support during study therapy. The median time to complete response was 7 days (range, 3-18 days), with a day 28 survival of 73%. IPS onset was associated with elevations of several inflammatory proteins in the bronchoalveolar lavage fluid and plasma, and response to therapy correlated with reductions in pulmonary and systemic inflammation. The combination of etanercept and corticosteroids is safe and is associated with high response rates and improved survival in patients with IPS.

Clofarabine and busulfan conditioning facilitates engraftment and provides significant antitumor activity in nonremission hematologic malignancies

Patients with hematologic malignancies not in remission before allogeneic hematopoietic stem cell transplantation (HSCT) have a poor prognosis. To improve the antitumor activity of conditioning, we combined clofarabine with myeloablative doses of busulfan in a phase 1/2 study in nonremission hematologic malignancies. Forty-six patients were enrolled, including 31 patients with nonremission acute myelogenous leukemia (AML). Patients had a median age of 53 years, with a median comorbidity index of 3. Donors were unrelated, HLA mismatched, or both in 59% of patients. Common grade III to IV nonhematologic toxicities included transient transaminitis (50%), mucositis (24%), hand-foot syndrome (13%), transient hypoxia (13%), nausea/vomiting (9%), and diarrhea (9%). All patients engrafted. Complete remission was achieved in 80% of all patients by day +30 and in 100% of AML patients without prior hematopoietic stem cell transplantation. Two-year nonrelapse mortality for all patients was 31%, and overall survival was 28%. In AML, the overall survival was 48% at 1 year and 35% at 2 years. These data suggest that clofarabine combined with myeloablative doses of busulfan is well tolerated, secures engraftment, and possesses significant antitumor activity, particularly in nonremission AML. This study is registered at www.ClinicalTrials.gov under identifier NCT00556452.

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

Tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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.

Minimal Contact Intervention with Autologous BMT Patients: Impact on QOL and Emotional Distress

Bone marrow transplantation (BMT) is often a last treatment option for individuals who have experienced relapse or treatment failure and is often accompanied by increased levels of distress and reductions in quality of life (QOL). Despite this, few studies have been designed to improve post-BMT QOL and reduce distress. The current study examined the course of distress and QOL in 26 autologus BMT patients and the effect on distress and QOL of providing a minimal contact workbook intervention. Physical well-being decreased following the BMT, but increased at 2- and 6-month follow-up assessments, and distress did not significantly vary over the course of the study for patients in the standard care and workbook intervention groups. Examination of the reasons for the lack of group differences revealed that approximately half of the individuals randomized to the workbook intervention did not look at the material; with those that did reporting higher QOL, decreased anxiety, more adaptive coping, and decreased religiosity. The results argue for the importance of targeting patients at need prior to the transplant procedure, triaging them based on specific characteristics, and providing treatments that match these characteristics.