Publications by authors named "Gwynn Long"

49 Publications

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252995PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232534PMC
June 2021

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

Transplant Cell Ther 2021 Sep 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403653PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.05.002DOI 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010223PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0991-5DOI Listing
January 2021

Phase 2 Study of Anti-Human Cytomegalovirus Monoclonal Antibodies for Prophylaxis in Hematopoietic Cell Transplantation.

Antimicrob Agents Chemother 2020 03 24;64(4). Epub 2020 Mar 24.

USA Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.02467-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179282PMC
March 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamadermatol.2018.5459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583829PMC
July 2019

Adult Umbilical Cord Blood Transplantation Using Myeloablative Thiotepa, Total Body Irradiation, and Fludarabine Conditioning.

Biol Blood Marrow Transplant 2017 Nov 17;23(11):1949-1954. Epub 2017 Jul 17.

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

Treatment-related mortality (TRM) remains elevated in adult patients undergoing umbilical cord blood transplantation (UCBT), including an early rise in TRM suggestive of excessive toxicity associated with the standard myeloablative total body irradiation (TBI), fludarabine, and cyclophosphamide regimen. In an attempt to reduce regimen-related toxicity, we previously studied a modified myeloablative regimen with TBI (1350 cGy) and fludarabine (160 mg/m); TRM was decreased, but neutrophil engraftment was suboptimal. Therefore, to improve engraftment while still minimizing regimen-related toxicity, we piloted a myeloablative regimen with the addition of thiotepa (10 mg/kg) to TBI and fludarabine conditioning. Thirty-one adult patients (median age, 46 years; range, 19 to 65) with hematologic malignancies (acute leukemia/myelodysplastic syndrome, 77%; lymphoid malignancy, 23%) underwent single (n = 1) or double (n = 30) UCBT from 2010 to 2015 at our institution. The cumulative incidence of neutrophil engraftment was 90% (95% confidence interval [CI], 70% to 97%) by 60 days, with a median time to engraftment of 21 days (95% CI, 19 to 26). The cumulative incidence of platelet engraftment was 77% (95% CI, 57% to 89%) by 100 days, with a median time to engraftment of 47 days (95% CI, 37 to 73). Cumulative incidences of grades II to IV and grades III to IV acute graft-versus-host disease (GVHD) at day 100 were 45% (95% CI, 27% to 62%) and 10% (95% CI, 2% to 23%), respectively. The overall incidence of chronic GVHD at 2 years was 40% (95% CI, 22% to 57%), with 17% of patients (95% CI, 6% to 33%) experiencing moderate to severe chronic GVHD by 2 years. TRM at 180 days was 13% (95% CI, 4% to 27%), at 1 year 24% (95% CI, 10% to 41%), and at 3 years 30% (95% CI, 13% to 49%). Relapse at 1 year was 13% (95% CI, 4% to 27%) and at 3 years 19% (95% CI, 6% to 38%). With a median follow-up of 35.5 months (95% CI, 12.7 to 52.2), disease-free and overall survival at 3 years were 51% (95% CI, 29% to 69%) and 57% (95% CI, 36% to 73%), respectively. This regimen represents a reasonable alternative to myeloablative conditioning with TBI, fludarabine, and cyclophosphamide and warrants further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2017.06.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831160PMC
November 2017

Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization.

Biol Blood Marrow Transplant 2017 Jul 6;23(7):1151-1157. Epub 2017 Apr 6.

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

Delayed hematopoietic recovery contributes to increased infection risk following umbilical cord blood (UCB) transplantation. In a Phase 1 study, adult recipients of UCB stem cells cultured ex vivo for 3 weeks with nicotinamide (NiCord) had earlier median neutrophil recovery compared with historical controls. To evaluate the impact of faster neutrophil recovery on clinically relevant early outcomes, we reviewed infection episodes and hospitalization during the first 100 days in an enlarged cohort of 18 NiCord recipients compared with 86 standard UCB recipients at our institution. The median time to neutrophil engraftment was shorter in NiCord recipients compared with standard UCB recipients (12.5 days versus 26 days; P < .001). Compared with standard UCB recipients, NiCord recipients had a significantly reduced risk for total infection (RR, 0.69; P = .01), grade 2-3 (moderate to severe) infection (RR, 0.36; P < .001), bacterial infection (RR, 0.39; P = .003), and grade 2-3 bacterial infection (RR, 0.21; P = .003) by Poisson regression analysis; this effect persisted after adjustment for age, disease stage, and grade II-IV acute GVHD. NiCord recipients also had significantly more time out of the hospital in the first 100 days post-transplantation after adjustment for age and Karnofsky Performance Status (69.9 days versus 49.7 days; P = .005). Overall, transplantation of NiCord was associated with faster neutrophil engraftment, fewer total and bacterial infections, and shorter hospitalization in the first 100 days compared with standard UCB transplantation. In conclusion, rapid hematopoietic recovery from an ex vivo expanded UCB transplantation approach is associated with early clinical benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2017.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846194PMC
July 2017

Phase II study of dose-attenuated bortezomib, cyclophosphamide and dexamethasone ("VCD-Lite") in very old or otherwise toxicity-vulnerable adults with newly diagnosed multiple myeloma.

J Geriatr Oncol 2017 May 28;8(3):165-169. Epub 2017 Feb 28.

Division of Hematological Malignancies and Cellular Therapy, Duke Cancer Institute, Durham, NC, United States.

Objectives: Multiple myeloma (MM) primarily strikes older adults, but full-dose chemotherapy such as bortezomib (Velcade), cyclophosphamide and dexamethasone (VCD) is often excessively toxic to very old or frail adults and those with substantial comorbidities. We piloted dose-attenuated VCD ("VCD-Lite") in such vulnerable adults with newly diagnosed MM (NDMM).

Materials And Methods: Subjects with NDMM and a high risk of therapy-related toxicity due to factors above received bortezomib 1.3mg/m subcutaneously, cyclophosphamide 300mg/m and dexamethasone 40mg orally, all on days 1, 8, and 15 of a 28day cycle for eight cycles, followed by indefinite, alternating bortezomib and lenalidomide maintenance. Toxicity, overall response rate (ORR), progression-free and overall survival (PFS and OS) were determined. The Cancer and Aging Research Group geriatric assessment (CARG GA) was administered at baseline in an exploratory manner as a predictor of severe toxicity.

Results: 14 patients went on the study, which was closed early due to slow accrual. Intention-to-treat ORR was 64%. 64% of patients experienced grade ≥3 adverse events, the majority of which were unlikely therapy-related. Median PFS was 24.2months and OS 29.7months, with 14%, 36% and 29% of patients discontinuing study drugs due to toxicity, MM progression and other reasons respectively. Baseline CARG GA was successfully completed by all subjects but one.

Conclusion: VCD-Lite is a viable option for vulnerable adults with NDMM. CARG GA is feasible. Further studies to optimize therapy and to explore CARG GA as a toxicity predictor are vital.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jgo.2017.02.004DOI Listing
May 2017

Efficacy and safety of high-dose chemotherapy with autologous stem cell transplantation in senior versus younger adults with newly diagnosed multiple myeloma.

Hematol Oncol 2017 Dec 19;35(4):752-759. Epub 2017 Jan 19.

Department of Internal Medicine, Duke University Medical Center, Durham, NC, USA.

We retrospectively studied 340 fit patients with multiple myeloma (MM) who underwent autologous stem cell transplantation (ASCT). We hypothesized that progression-free survival (PFS) of older patients was non-inferior to that of younger patients after ASCT. Our null hypothesis was that the PFS hazard ratio (HR) for a 5-year increase in age was ≥1.05; the alternative (non-inferiority) hypothesis was that the HR was ≤1. The observed HR was 0.94 (95% confidence interval [CI] 0.86-1.03); since the CI upper bound was <1.05, we reject the null hypothesis and conclude that PFS in older patients was at least as good as in younger patients. We cannot reject an analogous null hypothesis for overall survival (HR 1.06 [95% CI 0.94-1.19]), since the CI upper bound >1.05. Toxicity was similar across ages and transplant-related mortality was minimal. 28% of subjects <65 versus 45% of those ≥65 received maintenance therapy. In summary, ASCT prolongs PFS equally well in older vs. younger adults. Although we cannot exclude maintenance as a confounder, these data support ASCT for fit seniors with MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949235PMC
December 2017

Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.

Biol Blood Marrow Transplant 2017 Feb 14;23(2):262-268. Epub 2016 Nov 14.

Division of Cellular Therapy, Duke University, Durham, North Carolina.

Comprehensive recommendations for maintenance therapy after autologous stem cell transplantation (ASCT) for patients with multiple myeloma (MM) have yet to be defined. Bortezomib has been utilized as maintenance therapy after ASCT, but data attesting to the safety and efficacy of this agent compared with lenalidomide in the post-ASCT setting are limited. Therefore, we retrospectively analyzed the outcomes of 102 patients with MM who received maintenance therapy with bortezomib after ASCT at Duke University's adult bone marrow transplant clinic between 2005 and 2015. Maintenance with bortezomib was initiated between 60 and 90 days after ASCT as a single agent 1.3 mg/m once every 2 weeks (n = 92) or in combination with lenalidomide (10 mg/day) (n = 10). The median age at ASCT was 64 (range, 31 to 78). Of the 99 patients with molecular data available, 42% had high-risk cytogenetics (including d17p, t(4;14), +1q, and t(14;16) by fluorescein in situ hybridization). Overall, 46% of patients experienced side effects from maintenance therapy, with 31% of all patients experiencing peripheral neuropathy. In total, 2% of patients required discontinuation of bortezomib maintenance because of adverse events. No secondary malignancies were reported from the therapy. The median progression-free survival (PFS) for patients receiving maintenance therapy with bortezomib after ASCT was 36.5 months (95% confidence interval [CI], 21.3 to not available) and median overall survival was 72.7 months (95% CI, 63.9 to not available). The PFS of patients with high-risk cytogenetics was not statistically significantly different from those with standard-risk cytogenetics, suggesting that maintenance with bortezomib may help overcome the impact of high-risk cytogenetics on early progression. These results indicate that maintenance therapy with bortezomib represents a safe, well-tolerated, and efficacious option for patients with high-risk cytogenetics, renal insufficiency, an inability to tolerate lenalidomide, or a previous history of another cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2016.11.010DOI Listing
February 2017

Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

J Hematol Oncol 2016 08 17;9(1):71. Epub 2016 Aug 17.

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

Background: The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.

Methods: We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis.

Results: Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls.

Conclusions: Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted.

Trial Registration: ClinicalTrials.gov NCT01280955.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-016-0301-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989381PMC
August 2016

Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial.

Clin Infect Dis 2016 10 1;63(8):999-1006. Epub 2016 Aug 1.

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

Background: Respiratory viral infections (RVIs) are frequent complications of hematopoietic stem cell transplant (HSCT). Surgical masks are a simple and inexpensive intervention that may reduce nosocomial spread.

Methods: In this prospective single-center study, we instituted a universal surgical mask policy requiring all individuals with direct contact with HSCT patients to wear a surgical mask, regardless of symptoms or season. The primary endpoint was the incidence of RVIs in the mask period (2010-2014) compared with the premask period (2003-2009).

Results: RVIs decreased from 10.3% (95/920 patients) in the premask period to 4.4% (40/911) in the mask period (P < .001). Significant decreases occurred after both allogeneic (64/378 [16.9%] to 24/289 [8.3%], P = .001) and autologous (31/542 [5.7%] to 16/622 [2.6%], P = .007) transplants. After adjusting for multiple covariates including season and year in a segmented longitudinal analysis, the decrease in RVIs remained significant, with risk of RVI of 0.4 in patients in the mask group compared with the premask group (0.19-0.85, P = .02). In contrast, no decrease was observed during this same period in an adjacent hematologic malignancy unit, which followed the same infection control practices except for the mask policy. The majority of this decrease was in parainfluenza virus 3 (PIV3) (8.3% to 2.2%, P < .001).

Conclusions: Requiring all individuals with direct patient contact to wear a surgical mask is associated with a reduction in RVIs, particularly PIV3, during the most vulnerable period following HSCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciw451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036914PMC
October 2016

Quantitative measures of physical functioning after autologous hematopoietic stem cell transplantation in multiple myeloma: a feasibility study.

Clin Lymphoma Myeloma Leuk 2015 Feb 28;15(2):103-9. Epub 2014 Sep 28.

Duke University Medical Center, Durham, NC. Electronic address:

Background: The safety and feasibility of the symptom-limited cardiopulmonary exercise test (CPET) and the 6-minute walk test (6MWT) has not been rigorously tested in patients with multiple myeloma (MM) after high-dose chemotherapy with autologous stem cell transplantation (ASCT), nor have correlations with patient-reported outcomes (PROs) been explored.

Patients And Methods: We undertook CPET, 6MWT, and PRO assessments using standardized measurements and questionnaires in patients with MM in remission after ASCT.

Results: A total of 22 patients who were a median of 17 months after ASCT underwent assessment. No severe adverse events were observed. Exercise capacity, measured during CPET as the peak oxygen consumption, was 17.5 ± 5.9 mL/kg/min, the equivalent of 38% ± 18% less than that for age- and sex-predicted sedentary normative values. During the 6MWT, the mean 6-minute walk distance was 500 m, or 25% ± 13% less than the predicted values. Additional analysis using Pearson's correlation revealed no significant univariate associations between exercise or functional capacity and any PROs.

Conclusion: Patients with MM have marked and significant reductions in quantitative measures of physical function for years after the initial therapy, although that did not correlate with PROs in the present pilot study. Larger prospective studies are required to determine the clinical ramifications of these findings and to mechanistically dissect them, as well to test interventions aimed at mitigating them.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2014.09.002DOI Listing
February 2015

Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma.

J Clin Apher 2015 Jun 8;30(3):176-82. Epub 2014 Oct 8.

Division of Hematologic Malignancies and Cellular Therapy, Duke Cancer Institute, Durham, North Carolina.

High-dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony-stimulating factor; G-CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy-three patients were mobilized with G-CSF alone, and 94 patients with Cy plus G-CSF (Cy+G-CSF). We retrospectively analyzed Cy's impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 × 10(6) CD34+ cells/kg were collected from patients mobilized with Cy+G-CSF versus G-CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization-related toxicity was also, however, augmented by Cy; 14% of Cy+G-CSF patients were hospitalized because of complications versus none receiving G-CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long-term outcomes, multivariate analysis revealed no difference for Cy+G-CSF versus G-CSF (hazard ratio 0.8 for event-free survival [95% confidence interval {CI} 0.57-1.25] and 0.96 for overall survival [95% CI 0.61-1.54]). In summary, we show that mobilization with Cy increases toxicity without positively impacting long-term outcomes in MM. Our findings place into question Cy's benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jca.21360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523145PMC
June 2015

Evaluation of the spectra Optia® mononuclear cell collection procedure in multiple myeloma patients.

J Clin Apher 2015 Feb 19;30(1):1-7. Epub 2014 Jun 19.

Department of Medicine, Division of Cellular Therapy, Duke University School of Medicine, Durham, North Carolina.

Background: Peripheral blood stem cell (PBSC) rescue following myeloablative therapy is a mainstay of cancer therapy. To evaluate the ability of the Spectra Optia Apheresis System (SO), a newly developed apheresis device, the device was studied in multiple myeloma patients undergoing a first autologous PBSC transplant.

Aim: To demonstrate that neutrophil recovery was not inferior to historical controls when SO harvested PBSCs were reinfused following myeloablative therapy.

Methods: Multiple myeloma patients were mobilized according to the standard practice at four clinical sites. Following mobilization, MNC collections were performed on the SO. The collected cells were cryopreserved and reinfused following myeloablative chemotherapy. Neutrophil recovery defined by an absolute neutrophil count exceeding 500/μL (ANC500) was compared to historical data for patients transplanted following apheresis using the COBE Spectra (CS) device.

Results: The median day to neutrophil recovery was 12 days (range 10-14 days), with no significant difference in engraftment comparing patients transplanted with stem cells collected using the SO versus historical cohort of patients collected with the CS. CD34+ cell and MNC collection efficiency (CE) were 69.3% and 65.0% for the SO and CS, respectively. Platelet CE, product hematocrit and product granulocytes (as % of WBCs) using the SO were 21%, 2.3% and 28%, respectively. There were no device-related severe adverse events.

Conclusions: The study's results confirm that the Spectra Optia Apheresis System's MNC Collection Protocol is safe and effective for its intended use and that engraftment kinetics of cells collected by SO is not inferior to the CS System.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jca.21341DOI Listing
February 2015

Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.

J Clin Invest 2014 Jul 9;124(7):3121-8. Epub 2014 Jun 9.

Background: Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.

Methods: In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.

Results: No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.

Conclusion: UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.

Trial Registration: Clinicaltrials.gov NCT01221857.

Funding: Gamida Cell Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI74556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071379PMC
July 2014

Reduced-intensity allogeneic transplantation using alemtuzumab from HLA-matched related, unrelated, or haploidentical related donors for patients with hematologic malignancies.

Biol Blood Marrow Transplant 2014 Feb 20;20(2):257-63. Epub 2013 Nov 20.

Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.

We present a comparative study on 124 patients with hematologic malignancies who had undergone reduced-intensity conditioning and then received a transplant from an HLA-matched related (MRD), an HLA-matched unrelated (MUD), or an HLA-haploidentical related (HAPLO) donor. The conditioning regimen, which consisted of fludarabine, melphalan or busulfan, and alemtuzumab was administered to patients with lymphoid (n = 62) or myeloid disease (n = 62). Mycophenolate mofetil was used as prophylaxis for graft-versus-host disease (GVHD), and 38, 58, and 33 patients received transplants from MRD, MUD, and HAPLO donors, respectively. Only 2 patients experienced primary graft failure (GF) after melphalan-based regimen, whereas 8 of the 17 patients who received a transplant from HAPLO donors experienced a primary GF after busulfan-based regimen. The cumulative incidence of grade III to IV acute GVHD in engrafted patients who had received transplants from MRD, MUD, or HAPLO donors was 3%, 11%, and 27%, respectively, and the 2-year overall survival (OS) rates were 51%, 22%, and 23%, respectively. According to multivariate analysis, transplantation from either MUD or HAPLO donors compared with MRD were adverse factors that affected the OS (P = .006 and P = .002, respectively). In conclusion, the reduced-intensity regimen that included fludarabine, busulfan, or melphalan and alemtuzumab using only mycophenolate mofetil as the GVHD prophylaxis conferred favorable outcomes in the MRD group but lower survival rates in the MUD and HAPLO groups. The busulfan-based regimen led to a high incidence of GF in the HAPLO group, suggesting the need for modification or intensification of immunosuppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2013.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140655PMC
February 2014

A Phase I study of arsenic trioxide (Trisenox), ascorbic acid, and bortezomib (Velcade) combination therapy in patients with relapsed/refractory multiple myeloma.

Cancer Invest 2013 Mar 13;31(3):172-6. Epub 2013 Feb 13.

Division of Cellular Therapy, Duke University Medical Center, Durham, North Carolina 27710, USA.

Purpose: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade™) (AAV) for patients with relapsed/refractory multiple myeloma.

Experimental Design: ATO (0.25 mg/kg) and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m(2) or 1.3 mg/m(2) IV bolus on days 1 and 8 of a 21-day cycle).

Results: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered.

Conclusion: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/07357907.2012.756109DOI Listing
March 2013

Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation.

Biol Blood Marrow Transplant 2012 Nov 12;18(11):1664-1676.e1. Epub 2012 Jun 12.

Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27705, USA.

Immunologic reconstitution after allogeneic hematopoietic cell transplantation is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients after a dual UCB (n = 29) and matched sibling donor (n = 33) or matched unrelated donor (n = 33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of matched sibling donor and matched unrelated donor recipients. Significantly lower levels of CD3+, CD4+, and CD8+ T cells were observed in UCB recipients until 6 months after transplantation. Lower levels of regulatory T cells persisted until 1 year after transplantation. Thymopoiesis as measured by TCR rearrangement excision circle was comparable among all recipients by 6 months after transplantation. In a subset of patients 1 year after transplantation with similar levels of circulating T cells and TCR rearrangement excision circle, there was no difference in TCR diversity. Compared to HLA-identical matched sibling donor and matched unrelated donor adult hematopoietic cell transplantation recipients, quantitative lymphoid recovery in UCB transplantation recipients is slower in the first 3 months, but these differences disappeared by 6 to 12 months after transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2012.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472115PMC
November 2012

Feasibility of low-dose interleukin-2 therapy following T-cell-depleted nonmyeloablative allogeneic hematopoietic stem cell transplantation from HLA-matched or -mismatched family member donors.

Cancer Invest 2011 Jan;29(1):56-61

Department of Medicine, Division of Cellular Therapy, Duke University Medical Center, Durham, North Carolina 27710, USA.

Introduction: High relapse rates and infections remain primary causes of failure in nonmyeloablative transplantation. Interleukin-2 (IL-2) may stimulate the immune system and improve outcomes. The primary objective of this pilot study was to evaluate the feasibility of administering IL-2 following a T-cell-depleted nonmyeloablative hematopoietic stem cell transplant.

Methods: Patients received T-cell-depleted nonmyeloablative transplant from a matched or mismatched related donor. Those with allogeneic engraftment,
Results: Eight patients aged 28-69 years were treated. Significant toxicities were limited to GVHD of the skin ≤grade 2 in 3 patients and severe fatigue in 4 patients, limiting the duration of therapy. Two of the 8 patients died of relapsed disease and 1 from CMV. With a median overall duration of follow-up of survivors of 48 months, 5 patients (63%) remain alive and in continuous complete remission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/07357907.2010.535055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619422PMC
January 2011

Adult dual umbilical cord blood transplantation using myeloablative total body irradiation (1350 cGy) and fludarabine conditioning.

Biol Blood Marrow Transplant 2011 Jun 22;17(6):867-74. Epub 2010 Sep 22.

Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27705, USA.

High treatment-related mortality (TRM) and high graft failure rate are serious concerns in HLA-mismatched umbilical cord blood (UCB) transplantation with myeloablative conditioning. We conducted a prospective trial of dual UCB transplantation using modified myeloablation consisting of total-body irradiation (TBI; 1350 cGy) and fludarabine (Flu) (160 mg/m(2)). Twenty-seven patients (median age, 33 years; range: 20-58 years) with hematologic malignancies were enrolled. The median combined cryopreserved total nucleated cell (TNC) dose was 4.3 × 10(7)/kg (range: 3.2-7.7 × 10(7)/kg). The cumulative incidences of neutrophil (≥500/μL) and platelet (≥50,000/μL) engraftment were 80% (95% confidence interval [CI], 58%-91%) and 68% (95% CI, 46%-83%), respectively. Among engrafted patients, a single cord blood unit was predominant by 100 days posttransplantation. A higher cryopreserved and infused TNC dose and infused CD3(+) cell dose were significant factors associated with the predominant UCB unit (P = .032, .020, and .042, respectively). TRM and relapse rates at 2 years were 28% (95% CI, 12%-47%) and 20% (95% CI, 7%-37%), respectively. Cumulative incidences of grades II-IV and grades III-IV acute graft-versus-host disease (aGVHD) were 37% (95% CI, 20%-55%) and 11% (95% CI, 3%-26%), respectively, and that of chronic GVHD was 31% (95% CI, 15%-49%). With a median follow-up of 23 months, overall survival and disease-free survival rates at 2 years were 58% (95% CI, 34%-75%) and 52% (95% CI, 29%-70%), respectively. This study supports the use of TBI 1350 cGy/Flu as an alternative to conventional myeloablative conditioning for dual UCB transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2010.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877679PMC
June 2011

Renal shielding and dosimetry for patients with severe systemic sclerosis receiving immunoablation with total body irradiation in the scleroderma: cyclophosphamide or transplantation trial.

Int J Radiat Oncol Biol Phys 2011 Mar 26;79(4):1248-55. Epub 2010 Aug 26.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: To describe renal shielding techniques and dosimetry in delivering total body irradiation (TBI) to patients with severe systemic sclerosis (SSc) enrolled in a hematopoietic stem cell transplant protocol.

Methods And Materials: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) protocol uses a lymphoablative preparative regimen including 800 cGy TBI delivered in two 200-cGy fractions twice a day before CD34(+) selected autologous hematopoietic stem cell transplantation. Lung and kidney doses are limited to 200 cGy to protect organs damaged by SSc. Kidney block proximity to the spinal cord was investigated, and guidelines were developed for acceptable lumbar area TBI dosing. Information about kidney size and the organ shifts from supine to standing positions were recorded using diagnostic ultrasound (US). Minimum distance between the kidney blocks (dkB) and the lumbar spine region dose was recorded, and in vivo dosimetry was performed at several locations to determine the radiation doses delivered.

Results: Eleven patients were treated at our center with an anteroposterior (AP)/posteroanterior (PA) TBI technique. A 10% to 20% dose inhomogeneity in the lumbar spine region was achieved with a minimum kidney block separation of 4 to 5 cm. The average lumbar spine dose was 179.6 ± 18.1 cGy, with an average dkB of 5.0 ± 1.0 cm. Kidney block shield design was accomplished using a combination of US and noncontrast computerized tomography (CT) or CT imaging alone. The renal US revealed a wide range of kidney displacement from upright to supine positions. Overall, the average in vivo dose for the kidney prescription point was 193.4 ± 5.1 cGy.

Conclusions: The dose to the kidneys can be attenuated while maintaining a 10% to 20% dose inhomogeneity in the lumbar spine area. Kidneys were localized more accurately using both US and CT imaging. With this technique, renal function has been preserved, and the study continues to enroll patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2010.05.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995833PMC
March 2011
-->