# Project 3: Clinical Trials of High Risk GVHD

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $591,471

## Abstract

PROJECT 3 SUMMARY/ABSTRACT
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.

## Key facts

- **NIH application ID:** 10006012
- **Project number:** 5P01CA039542-32
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** JOHN LEVINE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $591,471
- **Award type:** 5
- **Project period:** 1997-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006012

## Citation

> US National Institutes of Health, RePORTER application 10006012, Project 3: Clinical Trials of High Risk GVHD (5P01CA039542-32). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006012. Licensed CC0.

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