Current and Emerging Targeted Therapies for Acute Graft-Versus-Host Disease
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REVIEW ARTICLE
Current and Emerging Targeted Therapies for Acute Graft‑Versus‑Host Disease Stelios Kasikis1 · Aaron Etra1 · John E. Levine1
© Springer Nature Switzerland AG 2020
Abstract Acute graft-versus-host disease (GVHD), the major complication after allogeneic hematopoietic cell transplant (HCT), develops in approximately 50% of patients. The primary treatment is high-dose systemic steroids, but treatment failure is common, and steroid-refractory (SR) GVHD is the leading cause of non-relapse mortality after allogeneic HCT. Ruxolitinib became the first treatment for SR GVHD to obtain US Food and Drug Administration approval, and other new treatments are actively being studied. We searched the literature using the PubMed database and clinical trials using ClinicalTrials.gov to identify the most promising new treatments for GVHD. In this review, we categorize potential new treatments for GVHD by their mechanism of action (e.g., antibodies that deplete T cells or prevent their trafficking to target tissues, proteasome inhibitors, tyrosine kinase inhibitors, and other agents) and summarize the results from clinical trials.
Key Points Steroid-refractory graft-versus-host disease (SR GVHD) is the main contributor to non-relapse mortality after allogeneic hematopoietic cell transplant. The unmet need posed by SR GVHD has led to multiple clinical trials investigating agents that target biological pathways. Several agents appear promising for SR GVHD, including the recently US Food and Drug Administrationapproved ruxolitinib as well as mesenchymal stem cells.
1 Introduction Allogeneic hematopoetic stem cell transplantation (HCT) can cure hematologic malignancies and other blood disorders, but its main toxicity, graft-versus-host disease
* John E. Levine [email protected] 1
Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA
(GVHD), precludes wider use. Acute graft-versus-host disease (aGVHD) targets the skin, liver, and gastrointestinal (GI) tract, is graded on a scale of I–IV, and typically develops during the weeks to months after HCT [1]. Clinical symptoms are the culmination of a multi-step process that begins with activation of host antigen-presenting cells (APCs) in the setting of tissue damage from conditioning therapy. Donor T cells, activated to recognize host antigens by the activated host APCs, migrate to target tissues and induce apoptosis [2]. Once GVHD develops, high doses of systemic steroids are used for treatment, which results in responses in around 50% of patients [3]. Overall responses include both complete responses (CRs, complete resolution of symptoms) and partial responses (PRs, improvement in at least one target organ without worsening in any other). The overall response rate (ORR) after 28 days of treatment often serves as the primary endpoint in aGVHD clinical trials and is a widely accepted surrogate for non-relapse mortality (NRM) and long-term survival [4–6]. Although overall survival (OS) following the diagnosis of GVHD has improved in recent
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