Acute graft-versus-host disease (GVHD) remains the major cause of non-relapse mortality (NRM) following allogeneic bone marrow transplantation (BMT), yet it has been graded and treated in the same way for almost 40 years. The current grading system uses only clinical symptom severity which imposes major limitations. The grade of acute GVHD at diagnosis does not correlate with outcome sufficiently to guide treatment. Thus, GVHD treatment is not intensified until primary therapy has failed which may be one reason why the treatment of acute GVHD has not advanced. The long term goal of this project is to develop risk-adapted treatment strategies to minimize GVHD-related NRM after transplantation. Laboratory tests that accurately predict GVHD outcomes at its onset are needed to achieve that goal. We have identified and validated plasma biomarkers that predict response to treatment, correlate with overall acute GVHD severity, and are specific for GVHD of the skin or the GI tract. More recently, we showed that at GVHD onset biomarker panels correlate with survival independent of clinical severity or target organ involvement. We have now developed and validated a novel GVHD-biomarker based scoring system that at GVHD onset categorizes patients according to predicted six month NRM, the time period when the majority of NRM attributable to acute GVHD occurs. The new Ann Arbor GVHD scoring system consists of three scores that correspond to <10%, ~25%, and 45% probability of six month NRM, which reflects increasing rates of early treatment failure. The novelty of this scoring system is its ability to identify high risk GVHD at onset independently of initial clinical presentation. For example, >80% of six month NRM is due to steroid-refractory GI GVHD, but not all GI GVHD is high risk. Ann Arbor 3 GVHD (45% six month NRM) enriches for high risk GI GVHD, even though GI symptoms are absent at onset in half of the cases. The objective of this project is to test experimental GVHD treatment based on NRM risk assigned at onset. Our central hypothesis is that risk-adapted GVHD treatment can reduce NRM. Because effector T-cells are required for GVHD mediated tissue damage, blockade of T-cell trafficking to the GI tract at GVHD onset is likely to be beneficial. Natalizumab, an antibody that interferes with T-cell trafficking to the GI tract ameliorates inflammatory bowel disease, and is therefore an attractive drug to study for primary GVHD therapy in high risk patients. We plan to test our central hypothesis and thus accomplish the objective of this application by (1) conducting a clinical trial using natalizumab to improve day 28 complete response rate from 30% to 45% in patients with Ann Arbor 3 GVHD and (2) developing a biomarker algorithm that predicts high risk GVHD prior to onset of symptoms.
PROJECT 3 NARRATIVE Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, GVHD. Strategies that mitigate GVHD will allow for better harnessing of this effective therapeutic modality to treat many patients with hematologic cancers.
| Holtan, Shernan G; DeFor, Todd E; Panoskaltsis-Mortari, Angela et al. (2018) Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802. Blood Adv 2:1882-1888 |
| Ortiz-Velez, Laura; Ortiz-Villalobos, Javiera; Schulman, Abby et al. (2018) Genome alterations associated with improved transformation efficiency in Lactobacillus reuteri. Microb Cell Fact 17:138 |
| Ferrara, James L M; Chaudhry, Mohammed S (2018) GVHD: biology matters. Hematology Am Soc Hematol Educ Program 2018:221-227 |
| Major-Monfried, Hannah; Renteria, Anne S; Pawarode, Attaphol et al. (2018) MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood 131:2846-2855 |
| Naymagon, Steven; Naymagon, Leonard; Wong, Serre-Yu et al. (2017) Acute graft-versus-host disease of the gut: considerations for the gastroenterologist. Nat Rev Gastroenterol Hepatol 14:711-726 |
| Hartwell, Matthew J; Özbek, Umut; Holler, Ernst et al. (2017) An early-biomarker algorithm predicts lethal graft-versus-host disease and survival. JCI Insight 2:e89798 |
| Stickel, N; Hanke, K; Marschner, D et al. (2017) MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia 31:2732-2741 |
| Ferrara, James Lm; Smith, Christopher M; Sheets, Julia et al. (2017) Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis. J Clin Invest 127:2441-2451 |
| Miller, Holly K; Braun, Thomas M; Stillwell, Terri et al. (2017) Infectious Risk after Allogeneic Hematopoietic Cell Transplantation Complicated by Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 23:522-528 |
| Renteria, Anne S; Levine, John E; Ferrara, James L M (2016) Therapeutic targets and emerging treatment options in gastrointestinal acute graft-versus-host disease. Expert Opin Orphan Drugs 4:469-484 |
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