Stefanie Sarantopoulos

Positions:

Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1998

Boston University

Ph.D. 1998

Boston University School of Medicine

Intern, Internal Medicine

Boston University School of Medicine

Resident, Internal Medicine

Boston University School of Medicine

Chief Resident, Internal Medicine

Boston University School of Medicine

Fellowship, Hematology/ Oncology

Dana-Farber Cancer Institute

Grants:

BAFF Pathology: Novel Therapeutic Targets in Chronic Graft versus Host Disease

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Breaking B-Cell Tolerance to Produce Antibodies that Eradicate Leukemias and Lymphomas

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

The Notch2-BCR Axis: Targeting Drivers of B cell Fate in Chronic GVHD

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Leukemia & Lymphoma Society
Role
Principal Investigator
Start Date
End Date

Understanding Aberrant TLR7 Signaling in B Cells from Patients with Chronic GVHD

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
American Society for Blood and Marrow Transplantation
Role
Principal Investigator
Start Date
End Date

A Phase II of Entospletinib, a SYK Inhibitor, First line cGVHD patients

Administered By
Duke Cancer Institute
Awarded By
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
End Date

Publications:

A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic Graft-Versus-Host Disease: SYK Inhibition in Chronic GVHD.

BACKGROUND: Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells as well as in vivo mouse studies. These and other pre-clinical studies implicated hyper-reactive B cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first-in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. OBJECTIVES: The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD as well as examining alterations in B cell compartments with treatment. STUDY DESIGN: This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was utilized to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. RESULTS: Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over three years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in one patient two years after the end of therapy. In the prophylaxis arm, one of five patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77% with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure free survival was 69% (95% CI, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD-CD38hi plasmablast-like B cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. CONCLUSIONS: Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation.
Authors
Lin, C; DiCioccio, RA; Haykal, T; McManigle, WC; Li, Z; Anand, SM; Poe, JC; Bracken, SJ; Jia, W; Alyea, EP; Cardones, AR; Choi, T; Gasparetto, C; Grunwald, MR; Hennig, T; Kang, Y; Long, GD; Lopez, R; Martin, M; Minor, KK; Quinones, VLP; Sung, AD; Wiggins, K; Chao, NJ; Horwitz, ME; Rizzieri, DA; Sarantopoulos, S
MLA Citation
URI
https://scholars.duke.edu/individual/pub1560448
PMID
36577483
Source
pubmed
Published In
Transplant Cell Ther
Published Date
DOI
10.1016/j.jtct.2022.12.015

Chronic GvHD NIH Consensus Project Biology Task Force: Evolving path to personalized treatment of chronic GvHD.

Chronic GvHD (cGvHD) remains a prominent barrier to allogeneic hematopoietic stem cell transplantion as the leading cause of non-relapse mortality and significant morbidity. Tremendous progress has been achieved in both understanding of pathophysiology and the development of new therapies for cGvHD. While our field has historically approached treatment from an empiric position, research performed at the bedside and bench has elucidated some of the complex pathophysiology of cGvHD. From the clinical perspective, there is significant variability of disease manifestations between individual patients, pointing to diverse biological underpinnings. Capitalizing on progress made to date, the field is now focused on establishing personalized treatment approaches. The manuscript's intent is to concisely review recent knowledge gained and formulate a path towards patient-specific cGvHD therapy.
Authors
Buxbaum, NP; Socié, G; Hill, GR; MacDonald, KP; Tkachev, V; Teshima, T; Lee, SJ; Ritz, J; Sarantopoulos, S; Luznik, L; Zeng, D; Paczesny, S; Martin, PJ; Pavletic, SZ; Schultz, KR; Blazar, BR
MLA Citation
Buxbaum, Nataliya Prokopenko, et al. “Chronic GvHD NIH Consensus Project Biology Task Force: Evolving path to personalized treatment of chronic GvHD.Blood Adv, Nov. 2022. Pubmed, doi:10.1182/bloodadvances.2022007611.
URI
https://scholars.duke.edu/individual/pub1555677
PMID
36322878
Source
pubmed
Published In
Blood Adv
Published Date
DOI
10.1182/bloodadvances.2022007611

Meibomian Gland Dysfunction: A Route of Ocular Graft-Versus-Host Disease Progression That Drives a Vicious Cycle of Ocular Surface Inflammatory Damage.

PURPOSE: To investigate the role of aggressive meibomian gland dysfunction (MGD) in the immune pathogenesis of ocular graft-vs-host disease (GVHD). METHODS: In mice, an allogeneic GVHD model was established by transferring bone marrow (BM) and purified splenic T cells from C57BL/6J mice into irradiated C3-SW.H2b mice (BM+T). Control groups received BM only. Mice were scored clinically across the post-transplantation period. MGD severity was categorized using the degree of atrophy on harvested lids. Immune disease was analyzed using flow cytometry of tissues along with fluorescent tracking of BM cells onto the ocular surface. In humans, parameters from 57 patients with ocular GVHD presenting to the Duke Eye Center were retrospectively reviewed. MGD was categorized using the degree of atrophy on meibographs. Immune analysis was done using high-parameter flow cytometry on tear samples. RESULTS: Compared with BM only, BM+T mice had higher systemic disease scores that correlated with tear fluid loss and eyelid edema. BM+T had higher immune cell infiltration in the ocular tissues and higher CD4+-cell cytokine expression in draining lymph nodes. BM+T mice with worse MGD scores had significantly worse corneal staining. In patients with ocular GVHD, 96% had other organs affected. Patients with ocular GVHD had abnormal parameters on dry eye testing, high matrix metalloproteinase-9 positivity (92%), and abundance of immune cells in tear samples. Ocular surface disease signs were worse in patients with higher MGD severity scores. CONCLUSIONS: Ocular GVHD is driven by a systemic, T-cell-dependent process that causes meibomian gland damage and induces a robust form of ocular surface disease that correlates with MGD severity. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
Authors
Perez, VL; Mousa, HM; Soifer, M; Beatty, C; Sarantopoulos, S; Saban, DR; Levy, RB
MLA Citation
Perez, Victor L., et al. “Meibomian Gland Dysfunction: A Route of Ocular Graft-Versus-Host Disease Progression That Drives a Vicious Cycle of Ocular Surface Inflammatory Damage.Am J Ophthalmol, vol. 247, Sept. 2022, pp. 42–60. Pubmed, doi:10.1016/j.ajo.2022.09.009.
URI
https://scholars.duke.edu/individual/pub1553095
PMID
36162534
Source
pubmed
Published In
American Journal of Ophthalmology
Volume
247
Published Date
Start Page
42
End Page
60
DOI
10.1016/j.ajo.2022.09.009

Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force.

Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.
Authors
Cuvelier, GDE; Schoettler, M; Buxbaum, NP; Pinal-Fernandez, I; Schmalzing, M; Distler, JHW; Penack, O; Santomasso, BD; Zeiser, R; Angstwurm, K; MacDonald, KPA; Kimberly, WT; Taylor, N; Bilic, E; Banas, B; Buettner-Herold, M; Sinha, N; Greinix, HT; Pidala, J; Schultz, KR; Williams, KM; Inamoto, Y; Cutler, C; Griffith, LM; Lee, SJ; Sarantopoulos, S; Pavletic, SZ; Wolff, D
MLA Citation
Cuvelier, Geoffrey D. E., et al. “Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force.Transplant Cell Ther, vol. 28, no. 8, Aug. 2022, pp. 426–45. Pubmed, doi:10.1016/j.jtct.2022.05.038.
URI
https://scholars.duke.edu/individual/pub1524425
PMID
35662591
Source
pubmed
Published In
Transplant Cell Ther
Volume
28
Published Date
Start Page
426
End Page
445
DOI
10.1016/j.jtct.2022.05.038

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.
Authors
Wolff, D; Radojcic, V; Lafyatis, R; Cinar, R; Rosenstein, RK; Cowen, EW; Cheng, G-S; Sheshadri, A; Bergeron, A; Williams, KM; Todd, JL; Teshima, T; Cuvelier, GDE; Holler, E; McCurdy, SR; Jenq, RR; Hanash, AM; Jacobsohn, D; Santomasso, BD; Jain, S; Ogawa, Y; Steven, P; Luo, ZK; Dietrich-Ntoukas, T; Saban, D; Bilic, E; Penack, O; Griffith, LM; Cowden, M; Martin, PJ; Greinix, HT; Sarantopoulos, S; Socie, G; Blazar, BR; Pidala, J; Kitko, CL; Couriel, DR; Cutler, C; Schultz, KR; Pavletic, SZ; Lee, SJ; Paczesny, S
MLA Citation
Wolff, Daniel, et al. “National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report.Transplant Cell Ther, vol. 27, no. 10, Oct. 2021, pp. 817–35. Pubmed, doi:10.1016/j.jtct.2021.06.001.
URI
https://scholars.duke.edu/individual/pub1488122
PMID
34217703
Source
pubmed
Published In
Transplant Cell Ther
Volume
27
Published Date
Start Page
817
End Page
835
DOI
10.1016/j.jtct.2021.06.001