Keith Sullivan

Overview:

Research areas
  • Late effects of cancer treatment and stem cell transplantation 
  • Chronic graft-versus-host disease 
  • Transplantation for sickle cell and autoimmune diseases 
  • Knowledge engineering
Overview
Early on, Dr. Sullivan and the team at Fred Hutchinson Cancer Research Center developed a systematic investigative approach for the diagnosis and treatment of chronic graft-versus-host disease (GVHD), the major cause of late morbidity and non-relapse mortality following allogeneic stem cell transplantation (SCT). As a result of this work, it became clear that blood and marrow transplant recipients require systematic long-term follow-up to evaluate and treat late complications of high-dose chemoradiotherapy and SCT.

The program grew into a large multidisciplinary team, resulting in improvement in patient outcome and quality of life. Through the late events project, he also contributed to outcomes research, computer decision support systems, and knowledge engineering for follow-up care. With quality of life as a focus, research pursued the application of SCT to diseases with high morbidity but little immediate mortality. For young patients with advanced, symptomatic sickle cell disease, myeloablative conditioning and SCT from an HLA-identical sibling has led to an 86% long-term survival free of sickle cell disease. For individuals with autoimmune diseases such as multiple sclerosis, scleroderma, and systemic lupus erythematosus, current therapy is often incomplete and significant morbidity from the disease or its treatment is observed.

Recent preclinical and clinical data suggest that high-dose immunosupression and SCT can halt the progression and, in some settings, reverse the course of autoimmune diseases. Since his arrival at Duke University, over 30 centers nationwide are participating in Duke-led phase II and III trials to test the toxicity, efficacy, and quality of life following autologous and allogeneic stem cell transplantation for autoimmune diseases.

These trials will also serve as platforms to study the immune repertoire and mechanistic pathways before and after SCT to gain greater insight into the basic mechanisms of autoimmunity.

A national repository of tissue and cell specimens is also part of these NIH-supported trials to further promote scientific study from these unique patients.

Positions:

James B. Wyngaarden Distinguished Professor of Medicine, in the School of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1971

Indiana University at Indianapolis

Grants:

Home-Based Tablet Computer Pain Coping Skills Following Stem Cell Transplant

Administered By
Psychiatry & Behavioral Sciences, Behavioral Medicine
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Immunotherapy with Renal Tumor RNA Transfected Dendritic Cells

Awarded By
National Institutes of Health
Role
Consultant
Start Date
End Date

Hematopoietic Stem Cell Transplantation for Young Adults with Sickle Cell Disease

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Emory University
Role
Principal Investigator
Start Date
End Date

Phase II, randomised, observer-blind, placebo-controlled,multicentre study to assess the safety, immunogenicity and efficacy of GSK Bilologicals ' Herpes Zoster HZ/su candidate vaccine to adults aged 18 years and older with haematologic malignancies.

Administered By
Duke Cancer Institute
Awarded By
GlaxoSmithKline
Role
Principal Investigator
Start Date
End Date

Scleroderma Cyclophosphamide or Transplantation (SCOT) Trial-Option 6

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

Publications:

Phase I dose escalation study of naive T-cell depleted donor lymphocyte infusion following allogeneic stem cell transplantation.

Prophylactic donor lymphocyte infusions (DLI) are used to augment post-transplant immune recovery to reduce both infectious complications and disease recurrence. Preclinical studies implicate the naive T-cell subset as the primary driver of graft-versus-host disease (GvHD). In this phase I dose escalation study, we assessed the safety of a DLI that was depleted of CD45RA+ naive T cells. Sixteen adult patients received a prophylactic DLI at a median of 113 days (range 76-280 days) following an HLA-identical, non-myeloablative allogeneic hematopoietic stem cell transplantation. Three patients each received the naive T-cell depleted DLI with a CD3+ dose of 1 × 105/kg, 1 × 106/kg, and 5 × 106/kg. The maximum dose of 1 × 107/kg was expanded to 7 patients. No dose-limiting grade III/IV acute GvHD or adverse events attributable to the DLI were observed at any dose level. One patient developed grade 2 acute GvHD of skin and upper intestines, and another developed moderate chronic GvHD of the lungs following the DLI. With a median follow-up of 2.8 years, 2-year progression-free and overall survival is 50.0% and 68.8%, respectively. In conclusion, these data suggest that a DLI that has been depleted of CD45RA+ naive T cells is feasible and carries a low risk of acute or chronic GvHD.
Authors
Maung, KK; Chen, BJ; Barak, I; Li, Z; Rizzieri, DA; Gasparetto, C; Sullivan, KM; Long, GD; Engemann, AM; Waters-Pick, B; Nichols, KR; Lopez, R; Kang, Y; Sarantopoulos, S; Sung, AD; Chao, NJ; Horwitz, ME
MLA Citation
Maung, Ko K., et al. “Phase I dose escalation study of naive T-cell depleted donor lymphocyte infusion following allogeneic stem cell transplantation.Bone Marrow Transplant, July 2020. Pubmed, doi:10.1038/s41409-020-0991-5.
URI
https://scholars.duke.edu/individual/pub1450672
PMID
32624583
Source
pubmed
Published In
Bone Marrow Transplant
Published Date
DOI
10.1038/s41409-020-0991-5

Allogeneic HSCT for autoimmune disease: a shared decision.

MLA Citation
Sullivan, Keith M., and Stefanie Sarantopoulos. “Allogeneic HSCT for autoimmune disease: a shared decision.Nat Rev Rheumatol, vol. 15, no. 12, Dec. 2019, pp. 701–02. Pubmed, doi:10.1038/s41584-019-0306-7.
URI
https://scholars.duke.edu/individual/pub1412070
PMID
31530942
Source
pubmed
Published In
Nat Rev Rheumatol
Volume
15
Published Date
Start Page
701
End Page
702
DOI
10.1038/s41584-019-0306-7

Application of stem cell transplantation in autoimmune diseases.

PURPOSE OF REVIEW: Autologous hematopoietic stem cell transplantation (HSCT) is a promising therapeutic modality for severe autoimmune diseases. In this review, we will outline the immunological mechanisms and the clinical evidence and experiences for therapeutic HSCT in autoimmune diseases, with particular focus on systemic sclerosis and multiple sclerosis. RECENT FINDINGS: Approximately 3000 patients with autoimmune diseases worldwide have been treated with HSCT. HSCT in systemic sclerosis has been shown in three randomized controlled trials to be associated with significant long-term event-free survival despite some transplant-related mortality in the first year. A recent controlled trial in multiple sclerosis has also show benefit with transplant. SUMMARY: The aim of HSCT is to 'reset' one's immune system into a naïve and self-tolerant state through immune depletion and regulation. HSCT requires careful patient selection, close collaboration between physicians and expertise of transplant team to ensure optimal outcome.
Authors
Ng, S-A; Sullivan, KM
MLA Citation
Ng, Sue-Ann, and Keith M. Sullivan. “Application of stem cell transplantation in autoimmune diseases.Curr Opin Hematol, vol. 26, no. 6, Nov. 2019, pp. 392–98. Pubmed, doi:10.1097/MOH.0000000000000531.
URI
https://scholars.duke.edu/individual/pub1409931
PMID
31490316
Source
pubmed
Published In
Curr Opin Hematol
Volume
26
Published Date
Start Page
392
End Page
398
DOI
10.1097/MOH.0000000000000531

Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures.

OBJECTIVE: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study. METHODS: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples. RESULTS: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score. CONCLUSION: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.
Authors
Assassi, S; Wang, X; Chen, G; Goldmuntz, E; Keyes-Elstein, L; Ying, J; Wallace, PK; Turner, J; Zheng, WJ; Pascual, V; Varga, J; Hinchcliff, ME; Bellocchi, C; McSweeney, P; Furst, DE; Nash, RA; Crofford, LJ; Welch, B; Pinckney, A; Mayes, MD; Sullivan, KM
MLA Citation
Assassi, Shervin, et al. “Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures.Ann Rheum Dis, vol. 78, no. 10, Oct. 2019, pp. 1371–78. Pubmed, doi:10.1136/annrheumdis-2019-215770.
URI
https://scholars.duke.edu/individual/pub1404205
PMID
31391177
Source
pubmed
Published In
Ann Rheum Dis
Volume
78
Published Date
Start Page
1371
End Page
1378
DOI
10.1136/annrheumdis-2019-215770

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial.

Importance: Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster. Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients. Design, Setting, and Participants: Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT. Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter. Main Outcomes and Measures: The primary end point was occurrence of confirmed herpes zoster cases. Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P = .02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points. Conclusions and Relevance: Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months. Trial Registration: ClinicalTrials.gov Identifier: NCT01610414.
Authors
Bastidas, A; de la Serna, J; El Idrissi, M; Oostvogels, L; Quittet, P; López-Jiménez, J; Vural, F; Pohlreich, D; Zuckerman, T; Issa, NC; Gaidano, G; Lee, J-J; Abhyankar, S; Solano, C; Perez de Oteyza, J; Satlin, MJ; Schwartz, S; Campins, M; Rocci, A; Vallejo Llamas, C; Lee, D-G; Tan, SM; Johnston, AM; Grigg, A; Boeckh, MJ; Campora, L; Lopez-Fauqued, M; Heineman, TC; Stadtmauer, EA; Sullivan, KM; ZOE-HSCT Study Group Collaborators,
MLA Citation
Bastidas, Adriana, et al. “Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial.Jama, vol. 322, no. 2, July 2019, pp. 123–33. Pubmed, doi:10.1001/jama.2019.9053.
URI
https://scholars.duke.edu/individual/pub1398097
PMID
31287523
Source
pubmed
Published In
Jama
Volume
322
Published Date
Start Page
123
End Page
133
DOI
10.1001/jama.2019.9053