Publications by authors named "Stefanie Sarantopoulos"

71 Publications

Cognitive impairment in candidates for allogeneic hematopoietic stem cell transplantation.

Bone Marrow Transplant 2021 Oct 19. Epub 2021 Oct 19.

Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC, USA.

Hematopoietic cell transplant (HCT) is an increasingly common and curative treatment strategy to improve survival among individuals with malignant and nonmalignant diseases, with over one million HCTs having been performed worldwide. Neurocognitive dysfunction is a common and untoward consequence of HCT for many recipients, although few studies have examined the profile of neurocognitive impairments in HCT or their association with clinical features, such as frailty, or the incidence of pre-HCT neurocognitive impairments across all ages, which may influence post-HCT neurocognitive impairments. We examined the pattern and correlates of pre-transplant neurocognitive dysfunction in a prospective sample of adults undergoing HCT. Neurocognition was assessed using the Montreal Cognitive Assessment Battery. Frailty was assessed using the Short Physical Performance Battery. Linear regression analysis was used to examine the associations between neurocognitive performance and frailty. Neurocognitive screening profiles were also examined by partitioning MoCA into domain scores, including Executive Function and Memory. We also examined the associations between neurocognition, frailty, and clinical outcomes, including length of transplant hospitalization and survival. One hundred and ten adults were evaluated across a wide age range (range: 19-75; mean age = 54.7 [SD = 14.1]). Neurocognitive performance tended to fall below published normative levels (mean MoCA = 25.5 [SD = 4.1]), with 17% of participants demonstrating impaired performance compared with medical normative data (MoCA ≤ 22) and 34% exhibiting impaired performance relative to healthy samples (MoCA ≤ 25). Mild impairments (MoCA ≤ 25) were common across age ranges, including middle-aged patients (23% for age < 50; 35% for age 50-60, 41% for age ≥ 60), particularly for items assessing Executive Function. Greater levels of frailty associated with lower neurocognitive screening scores (r = -0.29, P < 0.01) and Executive Functioning (r = -0.24, P < 0.01), whereas greater age was associated with poorer Memory performance only (r = -0.33, P < 0.01). Greater levels of frailty prior to transplant associated with longer length of stay (β = 0.10, P = 0.046), but were not associated with survival. Neurocognitive impairments are common among adults undergoing HCT and the pattern of performance varies by age. Pre-transplant frailty is associated with neurocognitive functioning and may portend worse post-transplant early clinical outcomes.
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http://dx.doi.org/10.1038/s41409-021-01470-zDOI Listing
October 2021

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 2021 10 10;27(10):817-835. Epub 2021 Jun 10.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.

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.
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http://dx.doi.org/10.1016/j.jtct.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478861PMC
October 2021

A phase 2 trial of the somatostatin analog pasireotide to prevent GI toxicity and acute GVHD in allogeneic hematopoietic stem cell transplant.

PLoS One 2021 25;16(6):e0252995. Epub 2021 Jun 25.

Division of Hematologic Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, NC, United States of America.

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant contributor to transplant-related mortality. We performed a phase 2 trial of the somatostatin analog pasireotide to prevent gastrointestinal toxicity and GVHD after myeloablative allogeneic HCT.

Methods: Patients received 0.9mg pasireotide every 12 hours from the day prior to conditioning through day +4 after HCT (or a maximum of 14 days). The primary outcomes were grade 3-4 gastrointestinal toxicity through day 30 and acute GVHD. Secondary outcomes were chronic GVHD, overall survival and relapse free survival at one year. Stool and blood samples were collected from before and after HCT for analyses of stool microbiome, local inflammatory markers, and systemic inflammatory and metabolic markers. Results were compared with matched controls.

Results: Twenty-six patients received pasireotide and were compared to 52 matched contemporaneous controls using a 1-2 match. Grade 3-4 GI toxicity occurred in 21 (81%) patients who received pasireotide and 35 (67%) controls (p = 0.33). Acute GVHD occurred in 15 (58%) patients in the pasireotide group and 28 (54%) controls (p = 0.94). Chronic GVHD occurred in 16 patients in the pasireotide group (64%) versus 22 patients in the control group (42%) (p = 0.12). Overall survival at 1 year in the pasireotide group was 63% (95% CI: 47%,86%) versus 82% (95% CI: 72%, 93%) in controls (log-rank p = 0.006). Relapse-free survival rate at one year was 40% (95% CI: 25%, 65%) in the pasireotide group versus 78% (95% CI: 68%, 91%) in controls (log-rank p = 0.002). After controlling for the effect of relevant covariates, patients in the pasireotide group had attenuated post-HCT loss of microbial diversity. Analysis of systemic inflammatory markers and metabolomics demonstrated feasibility of such analyses in patients undergoing allogeneic HCT. Baseline level and pre-to-post transplant changes in several inflammatory markers (including MIP1a, MIP1b, TNFa, IL8Pro, and IL6) correlated with likelihood of survival.

Conclusions: Pasireotide did not prevent gastrointestinal toxicity or acute GVHD compared to contemporaneous controls. Pasireotide was associated with numerically higher chronic GVHD and significantly decreased OS and RFS compared to contemporaneous controls. Pasireotide may provide a locally protective effect in the stool microbiome and in local inflammation as measured by stool calprotectin, stool beta-defensin, and stool diversity index.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252995PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232534PMC
November 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2020 Treatment of Chronic GVHD Report.

Transplant Cell Ther 2021 09 11;27(9):729-737. Epub 2021 Jun 11.

Clinical Division of Hematology, Medical University of Graz, Graz, Austria. Electronic address:

Positive results from recent clinical trials have significantly expanded current therapeutic options for patients with chronic graft-versus-host disease (GVHD). However, new insights into the associations between clinical characteristics of chronic GVHD, pathophysiologic mechanisms of disease, and the clinical and biological effects of novel therapeutic agents are required to allow for a more individualized approach to treatment. The current report is focused on setting research priorities and direction in the treatment of chronic GVHD. Detailed correlative scientific studies should be conducted in the context of clinical trials to evaluate associations between clinical outcomes and the biological effect of systemic therapeutics. For patients who require systemic therapy but not urgent initiation of glucocorticoids, clinical trials for initial systemic treatment of chronic GVHD should investigate novel agents as monotherapy without concurrently starting glucocorticoids, to avoid confounding biological, pathological, and clinical assessments. Clinical trials for treatment-refractory disease should specifically target patients with incomplete or suboptimal responses to most recent therapy who are early in their disease course. Close collaboration between academic medical centers, medical societies, and industry is needed to support an individualized, biology-based strategic approach to chronic GVHD therapy.
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http://dx.doi.org/10.1016/j.jtct.2021.05.004DOI Listing
September 2021

Female Sex Is Associated with Improved Long-Term Survival Following Allogeneic Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 09 17;27(9):784.e1-784.e7. Epub 2021 Jun 17.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina. Electronic address:

Life expectancy for long-term survivors of allogeneic hematopoietic stem cell transplantation (alloHSCT), defined as those living ≥5 years post-transplantation, is significantly lower compared with that of the age-matched general population despite a relatively low primary disease relapse rate at >2 years post-transplantation. Among several factors, patient sex is increasingly recognized as a prognostic indicator of long-term survival. We examined the influence of patient sex and donor-recipient sex matching on overall survival (OS) in a landmark analysis of long-term survivors. Using our institutional database supplemented with individual patient record review, we retrospectively investigated the relative influence of recipient sex and donor-recipient sex matching on outcomes of long-term survivors of alloHSCT between 1994 and 2014. Over this 20-year period, 247 met inclusion criteria for analysis; males and females had similar demographic and treatment characteristics. However, significantly more deaths after the 5-year landmark occurred in male recipients. Interestingly, donor sex did not have a significant impact on OS in multivariate analysis, and differences in OS of donor-recipient sex pairs was driven by recipient sex. In addition to recipient sex, only chronic graft-versus-host disease (cGVHD) retained significance as a covariate with an impact on OS in multivariate analysis. Men experienced slightly higher, but statistically nonsignificant, rates and increased severity of cGVHD, and had higher cGVHD-related mortality compared with females. In this long-term survival analysis of adult alloHSCT recipients, one of the only to include follow-up to 15 years, our results show that women survive significantly longer than men irrespective of their age at transplantation. This outcome is independent of other common pretransplantation prognostic indicators, such as donor sex or performance status at transplantation. The inferior survival in males is consistent with survival outcomes described in the transplantation literature. Increasing evidence suggests a biological basis for long-term sex-determined outcomes, possibly owing to differing rates or severity of cGVHD or sustained alloimmune tolerance in females. Larger studies are warranted to validate these retrospective clinical results.
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http://dx.doi.org/10.1016/j.jtct.2021.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403653PMC
September 2021

Hedgehog blockade in steroid-refractory sclerotic chronic graft-versus-host disease.

Br J Haematol 2021 Oct 17;195(2):e120-e122. Epub 2021 Jun 17.

Department of Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA.

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http://dx.doi.org/10.1111/bjh.17657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511171PMC
October 2021

Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies.

Transplant Cell Ther 2021 08 12;27(8):669.e1-669.e8. Epub 2021 May 12.

Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina. Electronic address:

Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies but is associated with significant morbidity and mortality. Although deaths during the first year after transplantation are often attributable to treatment toxicities and complications, death after the first year may be due to sequelae of accelerated aging caused by cellular senescence. Cytotoxic therapies and radiation used in cancer treatments and conditioning regimens for HCT can induce aging at the molecular level; HCT patients experience time-dependent effects, such as frailty and aging-associated diseases, more rapidly than people who have not been exposed to these treatments. Consistent with this, recipients of younger cells tend to have decreased markers of aging and improved survival, decreased graft-versus-host disease, and lower relapse rates. Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplantation versus matched related donor (MRD) and matched unrelated donor (MUD) transplantation in patients with hematologic malignancies over a 20-year period. In this single-center, retrospective study, we examined the outcomes of all adult patients who underwent their first allogeneic HCT through the Duke Adult Bone Marrow Transplant program from January 1, 1996, to December 31, 2015, to allow for at least 3 years of follow-up. Patients were excluded if they died or were lost to follow-up before day 365 after HCT, received an allogeneic HCT for a disease other than a hematologic malignancy, or received cells from a haploidentical or mismatched adult donor. UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank P = .03, median overall survival: UCB not reached, MRD/MUD 7.4 years). After adjusting for selected covariates, UCB recipients who survived at least 1 year after HCT had a hazard of death that was 31% lower than that of MRD/MUD recipients (hazard ratio, 0.69; 95% confidence interval, 0.47-0.99; P = .049). This trend held true in a subset analysis of subjects with acute leukemia. UCB recipients also experienced lower rates of moderate or severe chronic graft-versus-host disease (GVHD) and nonrelapse mortality, and slower time to relapse. UCB and MRD/MUD recipients experienced similar rates of grade 2-4 acute GVHD, chronic GHVD, secondary malignancy, and subsequent allogeneic HCT. UCB is already widely used as a donor source in pediatric HCT; however, adult outcomes and adoption have historically lagged behind in comparison. Recent advancements in UCB transplantation such as the implementation of lower-intensity conditioning regimens, double unit transplants, and ex vivo expansion have improved early mortality, making UCB an increasingly attractive donor source for adults; furthermore, our findings suggest that UCB may actually be a preferred donor source for mitigating late effects of HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.05.002DOI Listing
August 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report.

Transplant Cell Ther 2021 06 2;27(6):452-466. Epub 2021 Mar 2.

Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Durham, North Carolina. Electronic address:

Preventing chronic graft-versus-host disease (GVHD) remains challenging because the unique cellular and molecular pathways that incite chronic GVHD are poorly understood. One major point of intervention for potential prevention of chronic GVHD occurs at the time of transplantation when acute donor anti-recipient immune responses first set the events in motion that result in chronic GVHD. After transplantation, additional insults causing tissue injury can incite aberrant immune responses and loss of tolerance, further contributing to chronic GVHD. Points of intervention are actively being identified so that chronic GVHD initiation pathways can be targeted without affecting immune function. The major objective in the field is to continue basic studies and to translate what is learned about etiopathology to develop targeted prevention strategies that decrease the risk of morbid chronic GVHD without increasing the risks of cancer relapse or infection. Development of strategies to predict the risk of developing debilitating or deadly chronic GVHD is a high research priority. This working group recommends further interrogation into the mechanisms underpinning chronic GVHD development, and we highlight considerations for future trial design in prevention trials.
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http://dx.doi.org/10.1016/j.jtct.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217141PMC
June 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIb. The 2020 Preemptive Therapy Working Group Report.

Transplant Cell Ther 2021 08 6;27(8):632-641. Epub 2021 Apr 6.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Chronic graft-versus-host disease (GVHD) commonly occurs after allogeneic hematopoietic cell transplantation (HCT) despite standard prophylactic immune suppression. Intensified universal prophylaxis approaches are effective but risk possible overtreatment and may interfere with the graft-versus-malignancy immune response. Here we summarize conceptual and practical considerations regarding preemptive therapy of chronic GVHD, namely interventions applied after HCT based on evidence that the risk of developing chronic GVHD is higher than previously appreciated. This risk may be anticipated by clinical factors or risk assignment biomarkers or may be indicated by early signs and symptoms of chronic GVHD that do not fully meet National Institutes of Health diagnostic criteria. However, truly preemptive, individualized, and targeted chronic GVHD therapies currently do not exist. In this report, we (1) review current knowledge regarding clinical risk factors for chronic GVHD, (2) review what is known about chronic GVHD risk assignment biomarkers, (3) examine how chronic GVHD pathogenesis intersects with available targeted therapeutic agents, and (4) summarize considerations for preemptive therapy for chronic GVHD, emphasizing trial development, including trial design and statistical considerations. We conclude that robust risk assignment models that accurately predict chronic GVHD after HCT and early-phase preemptive therapy trials represent the most urgent priorities for advancing this novel area of research.
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http://dx.doi.org/10.1016/j.jtct.2021.03.029DOI Listing
August 2021

Assessing the Feasibility of a Novel mHealth App in Hematopoietic Stem Cell Transplant Patients.

Transplant Cell Ther 2021 02 13;27(2):181.e1-181.e9. Epub 2020 Dec 13.

Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina. Electronic address:

Hematopoietic stem cell transplantation (HCT) is a curative treatment option for patients with hematologic conditions but presents many complications that must be managed as a complex, chronic condition. Mobile health applications (mHealth apps) may permit tracking of symptoms in HCT. In seeking strategies to manage the complexities of HCT, our team collaborated with Sicklesoft, Inc., to develop an mHealth app specifically for HCT patients to allow for daily evaluation of patient health, Technology Recordings to better Understand Bone Marrow Transplantation (TRU-BMT). The primary value of this application is that of potentially enhancing the monitoring of symptoms and general health of patients undergoing HCT, with the ultimate goal of allowing earlier detection of adverse events, earlier intervention, and improving outcomes. To first evaluate patient interest in mHealth apps, we designed and administered an interest survey to patients at the 2017 BMT-InfoNet reunion. As a follow-up to the positive feedback received, we began testing the TRU-BMT app in a Phase 1 pilot study. Thirty patients were enrolled in this single-arm study and were given the TRU-BMT mHealth app on a smartphone device in addition to a wearable activity tracker. Patients were followed for up to 180 days, all the while receiving daily app monitoring. Adherence to TRU-BMT was approximately 30% daily and 44% weekly, and greater adherence was associated with increased meal completion, decreased heart rate, and shorter hospital stay. TRU-BMT assessments of symptom severity were significantly associated with duration of hospital stay and development of chronic graft-versus-host disease. Our findings suggest that using TRU-BMT throughout HCT is feasible for patients and established a proof-of-concept for a future randomized control trial of the TRU-BMT application in HCT. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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http://dx.doi.org/10.1016/j.jtct.2020.10.017DOI Listing
February 2021

Chlorhexidine Gluconate Bathing Reduces the Incidence of Bloodstream Infections in Adults Undergoing Inpatient Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 03 7;27(3):262.e1-262.e11. Epub 2021 Jan 7.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina. Electronic address:

Bloodstream infections (BSIs) occur in 20% to 45% of inpatient autologous and allogeneic hematopoietic cell transplant (HCT) patients. Daily bathing with the antiseptic chlorhexidine gluconate (CHG) has been shown to reduce the incidence of BSIs in critically ill patients, although very few studies include HCT patients or have evaluated the impact of compliance on effectiveness. We conducted a prospective cohort study with historical controls to assess the impact of CHG bathing on the rate of BSIs and gut microbiota composition among adults undergoing inpatient HCT at the Duke University Medical Center. We present 1 year of data without CHG bathing (2016) and 2 years of data when CHG was used on the HCT unit (2017 and 2018). Because not all patients adhered to CHG, patients were grouped into four categories by rate of daily CHG usage: high (>75%), medium (50% to 75%), low (1% to 49%), and none (0%). Among 192 patients, univariate trend analysis demonstrated that increased CHG usage was associated with decreased incidence of clinically significant BSI, defined as any BSI requiring treatment by the medical team (high, 8% BSI; medium, 15.2%; low, 15.6%; no CHG, 30.3%; P = .003), laboratory-confirmed BSI (LCBI; P = .03), central line-associated BSI (P = .04), and mucosal barrier injury LCBI (MBI-LCBI; P = .002). Multivariate analysis confirmed a significant effect of CHG bathing on clinically significant BSI (P = .023) and MBI-LCBI (P = .007), without consistently impacting gut microbial diversity. Benefits of CHG bathing were most pronounced with >75% daily usage, and there were no adverse effects attributable to CHG. Adherence to daily CHG bathing significantly decreases the rate of bloodstream infection following HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010223PMC
March 2021

BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation.

Blood 2021 05;137(18):2544-2557

Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.

Patients with chronic graft-versus-host disease (cGVHD) have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major histocompatibility complex-mismatched model with cGVHD-like manifestations, we first examined B-lymphopenic μMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B-cell number. Mice that later developed cGVHD had significantly increased numbers of recipient fibroblastic reticular cells with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD, because BAFF transcript in CD4+ T cells from diseased mice and patients was increased. cGVHD manifestations in mice were associated with high BAFF/B-cell ratios and persistence of B-cell receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR responsiveness to surrogate antigen and NOTCH ligand. BAFF Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR activation or when alloantigen was present in vivo. Using T cell-depleted (BM only) BAFF Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells, and alloantibody production. We demonstrate that pathologic production of BAFF promotes an altered B-cell compartment and augments BCR responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in patients with cGVHD.
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http://dx.doi.org/10.1182/blood.2020008040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109011PMC
May 2021

Selective ERBB2 and BCL2 Inhibition Is Synergistic for Mitochondrial-Mediated Apoptosis in MDS and AML Cells.

Mol Cancer Res 2021 05 29;19(5):886-899. Epub 2021 Jan 29.

Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina.

The proto-oncogene is associated with an aggressive phenotype in breast cancer. Its role in hematologic malignancies is incompletely defined, in part because is not readily detected on the surface of cancer cells. We demonstrate that truncated ERBB2, which lacks the extracellular domain, is overexpressed on primary CD34 myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells compared with healthy hematopoietic cells. This overexpression of ERBB2 is associated with aberrant, oncogenic signaling with autophosphorylation of multiple tyrosine sites. Like in breast cancers, ERBB2 can exist as truncated isoforms p95 and p110 in MDS and AML. Neutralization of ERBB2 signaling with ERBB2 tyrosine kinase inhibitors (i.e., lapatinib, afatinib, and neratinib) increases apoptotic cell death and reduces human engraftment of MDS cells in mice at 21 weeks posttransplantation. Inhibition of ERBB2 modulates the expression of multiple pro- and anti-apoptotic mitochondrial proteins, including B-cell lymphoma 2 (BCL2). Dual blockade with ERBB2 and BCL2 inhibitors triggers additional reductions of BCL2 phosphorylation and myeloid cell leukemia-1 (MCL1) expression compared with single drug treatment. Dual therapy was synergistic at all tested doses, with a dose reduction index of up to 29 for lapatinib + venetoclax compared with venetoclax alone. Notably, these agents operated together and shifted cancer cells to a pro-apoptotic phenotype, resulting in increased mitochondrial cytochrome release and activated caspase-3-mediated cell death. IMPLICATIONS: These findings warrant study of ERBB2 and BCL2 combination therapy in patients with MDS and AML. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/5/886/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137592PMC
May 2021

Clinical and Neuroimaging Correlates of Post-Transplant Delirium.

Biol Blood Marrow Transplant 2020 12 19;26(12):2323-2328. Epub 2020 Sep 19.

Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina.

Delirium is common among adults undergoing hematopoietic stem cell transplantation (HCT), although the clinical and neuroimaging correlates of post-HCT delirium have not been adequately delineated. We therefore examined the frequency of delirium and neuroimaging correlates of post-transplant delirium in a retrospective cohort of 115 adults undergoing neuroimaging after allogeneic HCT. Delirium was established using previously validated methods for retrospective identification of chart-assessed postprocedural delirium. Chart reviews were independently conducted by a multidisciplinary team with expertise in HCT, psychiatry, and psychology on consecutive allogeneic HCT patients who underwent neuroimaging assessments and transplantation at a single center between January 2009 and December 2016. Neuroimaging markers of white matter damage and brain volume loss were also recorded. In total, 115 patients were included, ranging in age from 20 to 74 years (mean [SD] age, 49 [13]). Fifty-three patients (46%) developed post-HCT delirium. In an adjusted model, delirium incidence was associated with older age (odds ratio [OR], 1.92 [1.28, 2.87] per decade, P = .002), greater severity of white matter hyperintensities (OR, 1.95 [1.06, 3.57], P = .031), and conditioning intensity (OR, 6.37 [2.20, 18.45], P < .001) but was unrelated to cortical atrophy (P = .777). Delirium was associated with fewer hospital-free days (P = .023) but was not associated with overall survival (hazard ratio, 0.95 [0.56, 1.61], P = .844). Greater incidence of delirium following HCT was associated with greater age, microvascular burden, and conditioning intensity. Pre-HCT consideration of microvascular burden and other neuroimaging biomarkers of risk may be warranted.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977594PMC
December 2020

Pre-transplant hepatic steatosis (fatty liver) is associated with chronic graft-vs-host disease but not mortality.

PLoS One 2020 11;15(9):e0238824. Epub 2020 Sep 11.

Division of Hematologic Malignancies and Cell Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.

Allogeneic-HCT (allo-HCT), while potentially curative, can result in significant complications including graft versus host disease (GVHD). Prior studies suggest that metabolic syndrome may be one risk factor for GVHD. We hypothesized that hepatic steatosis on pre-HCT computed tomography (CT) scans may be a marker for development of GVHD and poor outcomes in allo-HCT. In this retrospective study, we reviewed the pre-HCT CT scans and transplant outcome data of patients who underwent allo-HCT at Duke University Medical Center from 2009 to 2017. The presence of steatosis was confirmed using CT attenuation measurements. We then assessed the association between pre-HCT hepatic steatosis and HCT-related outcomes including GVHD. 80 patients who had pre-HCT CT scans were included in the study. Pre-transplant hepatic steatosis was associated with the development of chronic GVHD (OR 4.2, p = 0.02), but was not associated with acute GVHD (OR 1.3, p = 0.7), non-relapse mortality (p = 0.81) or overall survival (p = 0.74). Based on this single center retrospective study, pre-transplant hepatic steatosis is associated with development of chronic GVHD. Further, prospective study with other imaging modalities including non-contrasted CT scans is needed to determine if this association is reproducible.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485815PMC
November 2020

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

Bone Marrow Transplant 2021 01 5;56(1):137-143. Epub 2020 Jul 5.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, USA.

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 × 10/kg, 1 × 10/kg, and 5 × 10/kg. The maximum dose of 1 × 10/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.
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http://dx.doi.org/10.1038/s41409-020-0991-5DOI Listing
January 2021

Allogeneic HSCT for autoimmune disease: a shared decision.

Nat Rev Rheumatol 2019 12;15(12):701-702

Duke University Medical Center, Durham, NC, USA.

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http://dx.doi.org/10.1038/s41584-019-0306-7DOI Listing
December 2019

Interrater Reliability of Clinical Grading Measures for Cutaneous Chronic Graft-vs-Host Disease.

JAMA Dermatol 2019 07;155(7):833-837

Department of Dermatology, Duke University, Durham, North Carolina.

Importance: Cutaneous chronic graft-vs-host disease (cGVHD) is common after allogeneic hematopoietic stem cell transplant and is often associated with poor patient outcomes. A reliable and practical method for assessing disease severity and response to therapy among these patients is urgently needed.

Objective: To evaluate the interrater agreement and reliability of skin-specific and range of motion (ROM) variables of the 2014 National Institutes of Health (NIH) response criteria for cGVHD and a skin sclerosis grading scale (SSG).

Design, Setting, And Participants: In this observational study performed at a single tertiary academic center, 6 academic blood and marrow transplant specialists and 4 medical dermatologists examined 8 patients with diagnosed cutaneous cGVHD on July 10, 2015. The patient cohort was enriched for patients with sclerotic features. Each patient was evaluated by using the skin-specific and ROM criteria of the 2014 NIH response criteria for cGVHD and an SSG ranging from 0 to 3. Each patient was also asked to complete quality-of-life scoring instruments. Interrater agreement and reliability were estimated by calculating the Krippendorff α and Cohen κ statistics. Data were analyzed from September 29, 2015, through November 22, 2018.

Main Outcomes And Measures: Estimation of interrater agreement by interclass coefficient (Krippendorff α and Cohen κ statistics) for the skin-specific and ROM components of the 2014 NIH Response Criteria for Chronic GVHD and for the SSG.

Results: The median age of the patients evaluated was 54 years (range, 46-58 years). Patients were predominantly male (6 [75%]). Six of the 8 patients had a predominantly sclerotic cutaneous phenotype. Interrater agreement among our experts was acceptable for NIH skin feature score (0.68; 95% CI, 0.30-0.86) and good for NIH ROM scoring (0.80; 95% CI, 0.68-0.86). Dermatologists had acceptable agreement for NIH skin GVHD score (0.69; 95% CI, 0.25-0.82) and skin feature score (0.78; 95% CI, 0.17-0.98), good agreement in ROM grading (0.85; 95% CI, 0.69-0.90), and near perfect agreement in identifying sclerosis (0.82; 95% CI, 0.27-0.97).

Conclusions And Relevance: Although dermatologists had acceptable agreement in NIH skin GVHD score and skin features score, near perfect agreement in identifying cutaneous sclerosis, better agreement in grading severity of cutaneous cGVHD, especially in the intermediate grades, appears to be needed.
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http://dx.doi.org/10.1001/jamadermatol.2018.5459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583829PMC
July 2019

B cells in chronic graft-versus-host disease.

Hum Immunol 2019 Jun 5;80(6):393-399. Epub 2019 Mar 5.

Department of Medicine, Duke University, Durham, NC, USA; Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC, USA; Duke Cancer Institute, Duke University, Durham, NC, USA. Electronic address:

Allogeneic hematopoietic stem cell transplantation (alloHCT) is the definitive therapy for numerous otherwise incurable hematologic malignancies and non-malignant diseases. The genetic disparity between donor and recipient both underpins therapeutic effects and confers donor immune system-mediated damage in the recipient, called graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) is a major cause of late post-transplant morbidity and mortality. B cells have a substantiated role in cGVHD pathogenesis, as first demonstrated by clinical response to the anti-CD20 monoclonal antibody, rituximab. Initiation of CD20 blockade is met at times with limited therapeutic success that has been associated with altered peripheral B cell homeostasis and excess B Cell Activating Factor of the TNF family (BAFF). Increased BAFF to B cell ratios are associated with the presence of circulating, constitutively activated B cells in patients with cGVHD. These cGVHD patient B cells have increased survival capacity and signal through both BAFF-associated and B Cell Receptor (BCR) signaling pathways. Proximal BCR signaling molecules, Syk and BTK, appear to be hyper-activated in cGVHD B cells and can be targeted with small molecule inhibitors. Murine studies have confirmed roles for Syk and BTK in development of cGVHD. Emerging evidence has prompted investigation of several small molecule inhibitors in an attempt to restore B cell homeostasis and potentially target rare, pathologic B cell populations.
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http://dx.doi.org/10.1016/j.humimm.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049519PMC
June 2019

Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2019 05 19;25(5):845-854. Epub 2019 Feb 19.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.
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http://dx.doi.org/10.1016/j.bbmt.2019.02.014DOI Listing
May 2019

How I treat refractory chronic graft-versus-host disease.

Blood 2019 03 23;133(11):1191-1200. Epub 2019 Jan 23.

Division of Hematological Malignancies and Cellular Therapy, Department of Medicine.

Approximately 35% to 50% of patients otherwise cured of hematologic malignancies after allogeneic hematopoietic stem cell transplantation will develop the pleomorphic autoimmune-like syndrome known as chronic graft-versus-host disease (cGVHD). Since in 2005, National Institutes of Health (NIH) consensus panels have proposed definitions and classifications of disease to standardize treatment trials. Recently, the first agent was approved by the US Food and Drug Administration for steroid-refractory cGVHD. Despite these advances, most individuals do not achieve durable resolution of disease activity with initial treatment. Moreover, standardized recommendations on how to best implement existing and novel immunomodulatory agents and taper salvage agents are often lacking. Given the potential life-threatening nature of cGVHD, we employ in our practice patient assessment templates at each clinic visit to elucidate known prognostic indicators and red flags. We find NIH scoring templates practical for ongoing assessments of these complex patient cases and determination of when changes in immunosuppressive therapy are warranted. Patients not eligible or suitable for clinical trials have systemic and organ-directed adjunctive treatments crafted in a multidisciplinary clinic. Herein, we review these treatment options and offer a management and monitoring scaffold for representative patients with cGVHD not responding to initial therapy.
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http://dx.doi.org/10.1182/blood-2018-04-785899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418480PMC
March 2019

Employment, Insurance, and Financial Experiences of Patients with Chronic Graft-versus-Host Disease in North America.

Biol Blood Marrow Transplant 2019 03 5;25(3):599-605. Epub 2018 Oct 5.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Understanding the socioeconomic impact of chronic graft-versus-host disease (GVHD) on affected patients is essential to help improve their overall well-being. Using data from the Chronic GVHD Consortium, we describe the insurance, employment, and financial challenges faced by these patients and the factors associated with the ability to work/attend school and associated financial burdens. A 15-item cross-sectional questionnaire designed to measure financial concerns, income, employment, and insurance was completed by 190 patients (response rate, 68%; 10 centers) enrolled on a multicenter Chronic GVHD Consortium Response Measures Validation Study. Multivariable logistic regression models examined the factors associated with financial burden and ability to work/attend school. The median age of respondents was 56years, and 87% of the patients were white. A higher proportion of nonrespondents had lower income before hematopoietic cell transplantation and less than a college degree. All but 1 patient had insurance, 34% had faced delayed/denied insurance coverage for chronic GVHD treatments, and 66% reported a financial burden. Patients with a financial burden had greater depression/anxiety and difficulty sleeping. Nonwhite race, lower mental functioning, and lower activity score were associated with a greater likelihood of financial burden. Younger age, early risk disease, and higher mental functioning were associated with a greater likelihood of being able to work/attend school. In this multicenter cohort of patients with chronic GVHD, significant negative effects on finances were observed even with health insurance coverage. Future research should investigate potential interventions to provide optimal and affordable care to at-risk patients and prevent long-term adverse financial outcomes in this vulnerable group.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445749PMC
March 2019

SYK inhibitor entospletinib prevents ocular and skin GVHD in mice.

JCI Insight 2018 10 4;3(19). Epub 2018 Oct 4.

Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA.

Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HCT). The tyrosine kinase SYK contributes to both acute and chronic GVHD development, making it an attractive target for GVHD prevention. Entospletinib (ENTO) is a second-generation highly selective SYK inhibitor with a high safety profile. Potential utility of ENTO as GVHD prophylaxis in patients was examined using a preclinical mouse model of eye and skin GVHD and ENTO-compounded chow. We found that early SYK inhibition improved blood immune cell reconstitution in GVHD mice and prolonged survival, with 60% of mice surviving to day +120 compared with 10% of mice treated with placebo. Compared with mice receiving placebo, mice receiving ENTO had dramatic improvements in clinical eye scores, alopecia scores, and skin scores. Infiltrating SYK+ cells expressing B220 or F4/80, resembling SYK+ cells found in lichenoid skin lesions of chronic GVHD patients, were abundant in the skin of placebo mice but were rare in ENTO-treated mice. Thus, ENTO given early after HCT safely prevented GVHD.
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http://dx.doi.org/10.1172/jci.insight.122430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237454PMC
October 2018

Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD.

Blood Adv 2018 09 18;2(18):2307-2319. Epub 2018 Sep 18.

UNC Lineberger Comprehensive Cancer Center.

Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients after allogeneic bone marrow (BM) or stem cell transplantation (allo-SCT). Recent work has indicated that both T and B lymphocytes play an important role in the pathophysiology of cGVHD. Previously, our group showed a critical role for the germinal center response in the function of B cells using a bronchiolitis obliterans (BO) model of cGVHD. Here, we demonstrated for the first time that cGVHD is associated with severe defects in the generation of BM B lymphoid and uncommitted common lymphoid progenitor cells. We found an increase in the number of donor CD4 T cells in the BM of mice with cGVHD that was negatively correlated with B-cell development and the frequency of osteoblasts and Prrx-1-expressing perivascular stromal cells, which are present in the B-cell niche. Use of anti-DR3 monoclonal antibodies to enhance the number of donor regulatory T cells (T) in the donor T-cell inoculum ameliorated the pathology associated with BO in this model. This correlated with an increased number of endosteal osteoblastic cells and significantly improved the generation of B-cell precursors in the BM after allo-SCT. Our work indicates that donor T play a critical role in preserving the generation of B-cell precursors in the BM after allo-SCT. Approaches to enhance the number and/or function of donor T that do not enhance conventional T-cell activity may be important to decrease the incidence and severity of cGVHD in part through normal B-cell lymphopoiesis.
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http://dx.doi.org/10.1182/bloodadvances.2017014977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156893PMC
September 2018

Notch signaling mediated by Delta-like ligands 1 and 4 controls the pathogenesis of chronic GVHD in mice.

Blood 2018 11 4;132(20):2188-2200. Epub 2018 Sep 4.

Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) and remains an area of unmet clinical need with few treatment options available. Notch blockade prevents acute GVHD in multiple mouse models, but the impact of Notch signaling on cGVHD remains unknown. Using genetic and antibody-mediated strategies of Notch inhibition, we investigated the role of Notch signaling in complementary mouse cGVHD models that mimic several aspects of human cGVHD in search of candidate therapeutics. In the B10.D2→BALB/c model of sclerodermatous cGVHD, Delta-like ligand 4 (Dll4)-driven Notch signaling was essential for disease development. Antibody-mediated Dll4 inhibition conferred maximum benefits when pursued early in a preventative fashion, with anti-Dll1 enhancing early protection. Notch-deficient alloantigen-specific T cells showed no early defects in proliferation or helper polarization in vivo but subsequently exhibited markedly decreased cytokine secretion and enhanced accumulation of FoxP3 regulatory T cells. In the B6→B10.BR major histocompatibility complex-mismatched model with multi-organ system cGVHD and prominent bronchiolitis obliterans (BO), but not skin manifestations, absence of Notch signaling in T cells provided long-lasting disease protection that was replicated by systemic targeting of Dll1, Dll4, or both Notch ligands, even during established disease. Notch inhibition decreased target organ damage and germinal center formation. Moreover, decreased BO-cGVHD was observed upon inactivation of and/or in T cells. Systemic targeting of Notch2 alone was safe and conferred therapeutic benefits. Altogether, Notch ligands and receptors regulate key pathogenic steps in cGVHD and emerge as novel druggable targets to prevent or treat different forms of cGVHD.
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http://dx.doi.org/10.1182/blood-2018-03-841155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238189PMC
November 2018

A phase II/III randomized, multicenter trial of prednisone/sirolimus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft--host disease: BMT CTN 0801.

Haematologica 2018 11 28;103(11):1915-1924. Epub 2018 Jun 28.

University of Minnesota, Minneapolis, MN.

Initial therapy of chronic graft--host disease is prednisone ± a calcineurin-inhibitor, but most patients respond inadequately. In a randomized, adaptive, phase II/III, multicenter trial we studied whether prednisone/sirolimus or prednisone/sirolimus/photopheresis was more effective than prednisone/sirolimus/calcineurin-inhibitor for treating chronic graft--host disease in treatment-naïve or early inadequate responders. Primary endpoints of this study were proportions of subjects alive without relapse or secondary therapy with 6-month complete or partial response in phase II, or with 2-year complete response in phase III. The prednisone/sirolimus/photopheresis arm closed prematurely because of slow accrual and the remaining two-drug three-drug study ended in phase II due to statistical futility with 138 evaluable subjects. The two-drug and three-drug arms did not differ in rates of 6-month complete or partial response (48.6% 50.0%, =0.87), or 2-year complete response (14.7% 15.5%, =0.90). Serum creatinine values >1.5 times baseline were less frequent in the calcineurin-inhibitor-free arm at 2 months (1.5% 11.7%, =0.025) and 6 months (7.8% 24.0%, =0.016). Higher adjusted Short Form-36 Physical Component Summary and Physical Functioning scores were seen in the two-drug arm at both 2 months (=0.02 and =0.04, respectively) and 6 months (=0.007 and =0.001, respectively). Failure-free survival and overall survival rates at 2 years were similar for patients in the the two-drug and three-drug arms (48.6% 46.2%, =0.78; 81.5% 74%, =0.28). Based on similar long-term outcomes, prednisone/sirolimus is a therapeutic alternative to prednisone/sirolimus/calcineurin-inhibitor for chronic graft--host disease, being easier to administer and better tolerated.
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http://dx.doi.org/10.3324/haematol.2018.195123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278959PMC
November 2018

Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2018 10 25;24(10):1961-1964. Epub 2018 Jun 25.

Department of Rheumatology and Immunology, Duke University School of Medicine, Durham, North Carolina.

Systemic sclerosis is a progressive inflammatory disease that is frequently fatal and has limited treatment options. High-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT) has been evaluated as treatment for this disease in observational studies, multicenter randomized controlled clinical trials, and meta-analyses. On behalf of the American Society for Blood and Marrow Transplantation (ASBMT), a panel of experts in transplantation and rheumatology was convened to review available evidence and make a recommendation on AHCT as an indication for systemic sclerosis. Three randomized trials have compared the efficacy of AHCT with cyclophosphamide only, and all demonstrated benefit for the AHCT arm for their primary endpoint (improvement in the American Scleroderma Stem Cell versus Immune Suppression Trial, event-free survival in Autologous Stem Cell Transplantation International Scleroderma trial, and change in global rank composite score in Scleroderma: Cyclophosphamide or Transplantation trial). AHCT recipients also had better overall survival and a lower rate of disease progression. These findings have been confirmed in subsequent meta-analyses. Based on this high-quality evidence, the ASBMT recommends systemic sclerosis should be considered as a "standard of care" indication for AHCT. Close collaboration between rheumatologists and transplant clinicians is critical for optimizing patient selection and patient outcomes. Transplant centers in the United States are strongly encouraged to report patient and outcomes data to the Center for International Blood and Marrow Transplant Research on their patients receiving AHCT for this indication.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239926PMC
October 2018

B-cell targeting in chronic graft-versus-host disease.

Blood 2018 03 1;131(13):1399-1405. Epub 2018 Feb 1.

Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN.

Over the last decade, our understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) has improved considerably. In this spotlight, we discuss emerging insights into the pathophysiology of cGVHD with a focus on B cells. First, we summarize supporting evidence derived from mouse and human studies. Next, novel cGVHD therapy approaches that target B cells will be covered to provide treating physicians with an overview of the rationale behind the emerging armamentarium against cGVHD.
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http://dx.doi.org/10.1182/blood-2017-11-784017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031308PMC
March 2018

Allogeneic Stem-Cell Transplantation - A T-Cell Balancing ACT.

N Engl J Med 2018 Feb;378(5):480-482

From the Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke Cancer Institute, Duke University Medical Center, Durham, NC.

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http://dx.doi.org/10.1056/NEJMcibr1713238DOI Listing
February 2018
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