Publications by authors named "Mitchell E Horwitz"

62 Publications

Lymphoid and myeloid immune cell reconstitution after nicotinamide-expanded cord blood transplantation.

Bone Marrow Transplant 2021 Jul 26. Epub 2021 Jul 26.

University Medical Center Utrecht, Utrecht, The Netherlands.

Omidubicel (nicotinamide-expanded cord blood) is a potential alternative source for allogeneic hematopoietic cell transplantation (HCT) when an HLA-identical donor is lacking. A phase I/II trial with standalone omidubicel HCT showed rapid and robust neutrophil and platelet engraftment. In this study, we evaluated the immune reconstitution (IR) of patients receiving omidubicel grafts during the first 6 months post-transplant, as IR is critical for favorable outcomes of the procedure. Data was collected from the omidubicel phase I-II international, multicenter trial. The primary endpoint was the probability of achieving adequate CD4+ T-cell IR (CD4IR: > 50 × 10/L within 100 days). Secondary endpoints were the recovery of T-cells, natural killer (NK)-cells, B-cells, dendritic cells (DC), and monocytes as determined with multicolor flow cytometry. LOESS-regression curves and cumulative incidence plots were used for data description. Thirty-six omidubicel recipients (median 44; 13-63 years) were included, and IR data was available from 28 recipients. Of these patients, 90% achieved adequate CD4IR. Overall, IR was complete and consisted of T-cell, monocyte, DC, and notably fast NK- and B-cell reconstitution, compared to conventional grafts. Our data show that transplantation of adolescent and adult patients with omidubicel results in full and broad IR, which is comparable with IR after HCT with conventional graft sources.
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http://dx.doi.org/10.1038/s41409-021-01417-4DOI Listing
July 2021

Guidelines for the Prevention and Management of Graft-versus-Host Disease after Cord Blood Transplantation.

Transplant Cell Ther 2021 07;27(7):540-544

Hematologic Malignancies and Cellular Therapies, Department of Medicine, Duke Cancer Institute, Durham, North Carolina.

The incidence of graft-versus-host disease (GVHD) after cord blood (CB) transplantation (CBT) is lower than expected given the marked degree of human leukocyte antigen (HLA)-mismatch of CB grafts. While the exact mechanism that underlies this biology remains unclear, it is hypothesized to be due to the low number of mostly immature T-cells infused as part of the graft1,2, and increased tolerance of CB-derived lymphocytes induced by the state of pregnancy. Nevertheless, acute GVHD (aGVHD) is a significant complication of CBT. In contrast, the incidence of chronic GVHD (cGVHD) following CBT is lower than what is observed following matched related or unrelated donor HSC transplantation (HSCT)3-6. This review outlines the guidelines for the prevention and management of acute and chronic GVHD following CBT.
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http://dx.doi.org/10.1016/j.jtct.2021.03.012DOI Listing
July 2021

Omidubicel Versus Standard Myeloablative Umbilical Cord Blood Transplantation: Results of a Phase III Randomized Study.

Blood 2021 06 22. Epub 2021 Jun 22.

Hospital Universitario y Politécnico La Fe, Valencia, Spain and CIBERONC, Instituto de Salud Carlos III, Madrid, Spain, Valencia, Spain.

Omidubicel is an ex vivo expanded hematopoietic progenitor cell, and non-expanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase III trial to evaluate the efficacy of omidubicel compared to standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients aged 13-65 with hematologic malignancies were randomized to omidubicel versus standard UCBT. Patients received myeloablative conditioning and graft versus host disease (GvHD) prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The primary endpoint was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% CI 10-14 days) and 22 days (95% CI 19-25 days) (p<0.001) for the omidubicel and control arms, respectively. The cumulative incidence of neutrophil engraftment was 96% and 89% for patients receiving omidubicel and control transplants, respectively. The omidubicel arm had faster platelet recovery (55% vs. 35% recovery by 42 days, p=0.028), a lower incidence of first grade 2/3 bacterial or invasive fungal infections (37% vs. 57%, p=0.027), and spent more time out of hospital during the first 100 days following transplant (median 61 vs. 48 days, p=0.005) than controls. Differences in GvHD and survival between the two arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduced early transplant-related complications as compared to standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT.
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http://dx.doi.org/10.1182/blood.2021011719DOI Listing
June 2021

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

Transplant Cell Ther 2021 Jun 17. 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
June 2021

Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome.

JCO Precis Oncol 2021 25;5. Epub 2021 Jan 25.

Laboratory of Myeloid Malignancies, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.

Purpose: Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown.

Methods: Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died.

Results: Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% 11%; = .022) and decreased OS (3-year OS, 55% 79%, = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% 17%; = .003) and RFS was lower (3-year RFS, 13% 49%; = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication.

Conclusion: This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk.
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http://dx.doi.org/10.1200/PO.20.00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140814PMC
January 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

Myeloablative versus Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation in Acute Myelogenous Leukemia and Myelodysplastic Syndromes-Long-Term Follow-Up of the BMT CTN 0901 Clinical Trial.

Transplant Cell Ther 2021 06 26;27(6):483.e1-483.e6. Epub 2021 Feb 26.

Duke University, Durham, North Carolina.

Several prospective randomized trials comparing conditioning intensity before allogeneic hematopoietic cell transplantation (HCT) have been performed, with conflicting results. Although reduced-intensity conditioning (RIC) leads to lower treatment-related mortality (TRM), this is offset by higher rates of relapse. Long-term follow-up of randomized comparative trials are limited. Here we present long-term follow-up of a randomized comparison of myeloablative conditioning (MAC) compared with RIC before HCT for acute myelogenous leukemia (AML) or myelodysplasia (MDS). Long-term comparative analyses of overall survival, relapse, and relapse-free survival were performed. Patients age 18 to 65 years with <5% marrow myeloblasts were randomized to receive MAC (n = 135) or RIC (n = 137), followed by HCT from an HLA-matched donor. The primary endpoint of the trial was an 18-month pointwise comparison of overall survival. The analyses were performed using a proportional hazards model. The median follow-up of the entire cohort was 51 months. At 4 years, the transplant-related mortality (TRM) was 25.1% for MAC, compared with 9.9% for RIC (P < .001). Patients who received RIC had a significantly higher risk of relapse compared to those who received MAC (hazard ratio [HR], 4.06; 95% CI, 2.59 to 6.35; P < 0.001). Among the patients who relapsed after HCT, postrelapse survival was similar at 3 years (24% for MAC and 26% for RIC). Overall survival was superior for patients who received MAC compared to those who received RIC (HR, 1.54; 95% CI, 1.07 to 2.2; P = .03). Our data show that patients who received MAC were at higher risk of late TRM compared with those who received RIC; however, because of the exceedingly high rates of relapse in the RIC arm, overall survival remained significantly better for patients who received MAC. Among patients with MDS or AML eligible for either MAC or RIC regimens, long-term follow up demonstrates a survival advantage for patients who received MAC.
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http://dx.doi.org/10.1016/j.jtct.2021.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217373PMC
June 2021

Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial.

Blood 2021 01;137(3):420-428

Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN.

Results of 2 parallel phase 2 trials of transplantation of unrelated umbilical cord blood (UCB) or bone marrow (BM) from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo UCB (n = 186) or haploidentical (n = 182) transplant. Reduced-intensity conditioning comprised total-body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for UCB transplantation was cyclosporine and mycophenolate mofetil (MMF) and for haploidentical transplantation, posttransplant cyclophosphamide, tacrolimus, and MMF. The primary end point was 2-year progression-free survival (PFS). Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease, and disease status at randomization. Two-year PFS was 35% (95% confidence interval [CI], 28% to 42%) compared with 41% (95% CI, 34% to 48%) after UCB and haploidentical transplants, respectively (P = .41). Prespecified analysis of secondary end points recorded higher 2-year nonrelapse mortality after UCB, 18% (95% CI, 13% to 24%), compared with haploidentical transplantation, 11% (95% CI, 6% to 16%), P = .04. This led to lower 2-year overall survival (OS) after UCB compared with haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49% to 64%), respectively (P = .04). The trial did not demonstrate a statistically significant difference in the primary end point, 2-year PFS, between the donor sources. Although both donor sources extend access to reduced-intensity transplantation, analyses of secondary end points, including OS, favor haploidentical BM donors. This trial was registered at www.clinicaltrials.gov as #NCT01597778.
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http://dx.doi.org/10.1182/blood.2020007535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819761PMC
January 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

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

Guidelines for Cord Blood Unit Thaw and Infusion.

Biol Blood Marrow Transplant 2020 10 27;26(10):1780-1783. Epub 2020 Jun 27.

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1016/j.bbmt.2020.06.018DOI Listing
October 2020

Impact of Conditioning Intensity of Allogeneic Transplantation for Acute Myeloid Leukemia With Genomic Evidence of Residual Disease.

J Clin Oncol 2020 04 20;38(12):1273-1283. Epub 2019 Dec 20.

Duke University, Durham, NC.

Purpose: Patients with acute myeloid leukemia (AML) in remission remain at risk for relapse even after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status before alloHCT has been shown to be prognostic. Whether modulation of the intensity of the alloHCT conditioning regimen in patients with AML who test positive for MRD can prevent relapse and improve survival is unknown.

Methods: Ultra-deep, error-corrected sequencing for 13 commonly mutated genes in AML was performed on preconditioning blood from patients treated in a phase III clinical trial that randomly assigned adult patients with myeloid malignancy in morphologic complete remission to myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC).

Results: No mutations were detected in 32% of MAC and 37% of RIC recipients; these groups had similar survival (3-year overall survival [OS], 56% 63%; = .96). In patients with a detectable mutation (next-generation sequencing [NGS] positive), relapse (3-year cumulative incidence, 19% 67%; < .001) and survival (3-year OS, 61% 43%; = .02) was significantly different between the MAC and RIC arms, respectively. In multivariable analysis for NGS-positive patients, adjusting for disease risk and donor group, RIC was significantly associated with increased relapse (hazard ratio [HR], 6.38; 95% CI, 3.37 to 12.10; < .001), decreased relapse-free survival (HR, 2.94; 95% CI, 1.84 to 4.69; < .001), and decreased OS (HR, 1.97; 95% CI, 1.17 to 3.30; = .01) compared with MAC. Models of AML MRD also showed benefit for MAC over RIC for those who tested positive.

Conclusion: This study provides evidence that MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival.
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http://dx.doi.org/10.1200/JCO.19.03011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164487PMC
April 2020

Small-molecule nicotinamide for ex vivo expansion of umbilical cord blood.

Exp Hematol 2019 12 28;80:11-15. Epub 2019 Nov 28.

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

Umbilical cord blood transplant is an alternative graft source for patients lacking a human leukocyte antigen-matched donor; however, delayed engraftment times have historically resulted in transplant-related morbidity and mortality from complications such as infections and ineffective hematopoiesis. Recent advances in ex vivo expansion techniques have successfully augmented the initial cell dose delivered from an umbilical cord blood graft, leading to improved immune reconstitution, durable hematopoiesis, decreased transplant-related morbidity and mortality, and better outcomes. Herein we review the data for existing and developing ex vivo expansion techniques, with a focus on the preclinical and clinical data for nicotinamide-mediated cord blood expansion across both malignant and benign hematologic indications.
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http://dx.doi.org/10.1016/j.exphem.2019.11.006DOI Listing
December 2019

Cytomegalovirus in Allogeneic Hematopoietic Transplantation: Impact on Costs and Clinical Outcomes Using a Preemptive Strategy.

Biol Blood Marrow Transplant 2020 03 9;26(3):568-580. Epub 2019 Nov 9.

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

Cytomegalovirus (CMV) results in significant morbidity and mortality following hematopoietic cell transplantation (HCT). Establishing the cost and clinical impact is imperative to the selection of appropriate CMV preventative strategies. This is a retrospective cohort study of consecutive patients undergoing their first allogeneic HCT between January 1, 2009, and December 31, 2013. Detailed clinical and institutional cost data were obtained from the start of conditioning through 1-year post-transplantation. Baseline characteristics, resource utilization, costs, and outcomes were compared between patients with and without clinically significant CMV infection (csCMVi). One hundred seventy out of 388 patients (44%) developed csCMVi within 1 year after HCT. Within the first year post-HCT, patients with csCMVi had a significantly longer transplantation-related length of stay (mean, 91.7 days versus 78.3 days; P < .0001) and more frequent and prolonged hospitalizations (mean, 2.4 versus 1.7 admissions [P < .0001]; mean, 39.1 versus 31.5 inpatient days [P = .001]) without significantly more admissions to the intensive care unit (28.2% versus 21.6%; P = .408). The use of granulocyte colony-stimulating factor was greater in patients with csCMVi (73.5% versus 54.1%; P = .0001), although no significant differences were demonstrated in mean platelet or red blood cell (RBC) transfusions. Total costs were also higher in patients with csCMVi (mean cost difference, $45,811; 95% CI, $26,385 to $67,544). However, the incidence of graft-versus-host disease (GVHD) and selected infectious complications was not significantly different between the 2 groups. There were no significant differences in 1-year and 5-year post-transplantation overall survival (OS) or nonrelapse mortality (NRM) between those with and those without csCMVi, although relapse of underlying disease was significantly lower in the csCMVi group. Overall, our data show that allogeneic HCT recipients with csCMVi had significantly greater medical resource utilization and costs than those without csCMVi. However, clinical outcomes, including GVHD, infections, and mortality, were similar in the 2 groups. Further study is needed to determine the cost-effectiveness of CMV preventive modalities.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418947PMC
March 2020

Intestinal Acute Graft-versus-Host Disease: A Bug Highway to the Bloodstream.

Biol Blood Marrow Transplant 2019 08 19;25(8):e250-e251. Epub 2019 Jun 19.

Duke University School of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Durham, NC, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bbmt.2019.06.011DOI Listing
August 2019

Current and future perspectives on allogeneic transplantation using ex vivo expansion or manipulation of umbilical cord blood cells.

Int J Hematol 2019 Jul 23;110(1):50-58. Epub 2019 May 23.

Adult Blood and Marrow Transplant Program, Duke University School of Medicine, 2400 Pratt St. DUMC 3961, Durham, NC, 27710, USA.

In patients with hematologic malignancies, the outcome of umbilical cord blood transplantation has improved and is now comparable to that of matched unrelated donor transplantation. However, the limitation of using umbilical cord blood has been a delay in both hematopoietic and immunologic recovery. Strategies have been proposed to overcome these limitations. One strategy involves ex vivo expansion of the umbilical cord blood unit prior to transplantation. A second strategy involves exposure of the umbilical cord blood graft to compounds aimed at improving homing and engraftment following transplantation. Many of these strategies are now being tested in late phase multi-center clinical trials. If proven cost effective and efficacious, they may alter the landscape of donor options for allogeneic stem cell transplantation.
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http://dx.doi.org/10.1007/s12185-019-02670-6DOI Listing
July 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

Plerixafor alone for the mobilization and transplantation of HLA-matched sibling donor hematopoietic stem cells.

Blood Adv 2019 03;3(6):875-883

Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, MN.

Plerixafor, a direct antagonist of CXCR4/stromal-derived factor 1, can safely and rapidly mobilize allografts without the use of granulocyte colony-stimulating factor (G-CSF). We conducted a phase 2, multicenter, prospective study of plerixafor-mobilized HLA-identical sibling allografts for allogeneic hematopoietic cell transplantation in recipients with hematological malignancies. Donors (n = 64) were treated with subcutaneous plerixafor (240 µg/kg) and started leukapheresis (LP) 4 hours later. The primary objective was to determine the proportion of donors who were successfully mobilized: defined as collection of ≥2.0 × 10 CD34 cells per kilogram recipient weight in ≤2 LP sessions. Recipients subsequently received reduced intensity (RIC; n = 33) or myeloablative (MAC; n = 30) conditioning. Sixty-three of 64 (98%) donors achieved the primary objective. The median CD34 cell dose per kilogram recipient weight collected within 2 days was 4.7 (0.9-9.6). Plerixafor was well tolerated with only grade 1 or 2 drug-related adverse events noted. Bone pain was not observed. Plerixafor-mobilized grafts engrafted promptly. One-year progression-free and overall survivals were 53% (95% confidence interval [CI], 36% to 71%) and 63% (95% CI, 46% to 79%) for MAC and 64% (95% CI, 47% to 79%) and 70% (95% CI, 53% to 84%) for RIC recipients, respectively. Donor toxicity was reduced relative to G-CSF mobilized related donors. This is the first multicenter trial to demonstrate that, as an alternative to G-CSF, plerixafor rapidly and safely mobilizes sufficient numbers of CD34 cells from matched sibling donors for HCT. Engraftment was prompt, and outcomes in recipients were encouraging. This trial was registered at clinicaltrials.gov as #NCT01696461.
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http://dx.doi.org/10.1182/bloodadvances.2018027599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436017PMC
March 2019

Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide.

J Clin Oncol 2019 02 4;37(5):367-374. Epub 2018 Dec 4.

3 University Hospital Vall d'Hebron, Barcelona, Spain.

Purpose: Increasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft.

Methods: Thirty-six patients with hematologic malignancies underwent transplantation at 11 sites.

Results: The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator ( P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively ( P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively.

Conclusion: UCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft.
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http://dx.doi.org/10.1200/JCO.18.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368416PMC
February 2019

HSCT-GAVE as a Manifestation of Chronic Graft versus Host Disease: A Case Report and Review of the Existing Literature.

Case Rep Transplant 2018 12;2018:2376483. Epub 2018 Mar 12.

Adult Blood and Marrow Transplant Program, Duke University Medical Center, Durham, NC, USA.

Gastric antral vascular ectasia or "watermelon stomach" is a significant cause of nonvariceal upper GI bleeding and is characterized by red, tortuous ectatic vessels along longitudinal folds in the gastric antrum. The existing literature links GAVE to patients with cirrhosis, scleroderma, bone marrow transplantation, and chronic renal failure among other associations, but its pathophysiology remains ill-defined. Over 30 cases of hematopoietic stem cell transplant-related GAVE (HSCT-GAVE) have been reported in the literature to date and there are likely many more that go undiagnosed or are attributed to another cause of upper gastrointestinal bleeding. Interestingly, a busulfan-containing conditioning regimen has been the primary factor implicated in the etiology of HSCT-GAVE because this was common to all cases in the literature to date. Here, we present the first case of HSCT-GAVE in a patient that was treated with a non-busulfan-containing conditioning regimen. We propose a link between chronic GVHD and the development of HSCT-GAVE that is supported by a similar development of GAVE in patients with systemic sclerosis.
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http://dx.doi.org/10.1155/2018/2376483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867646PMC
March 2018

Plerixafor Plus Granulocyte Colony-Stimulating Factor for Patients with Non-Hodgkin Lymphoma and Multiple Myeloma: Long-Term Follow-Up Report.

Biol Blood Marrow Transplant 2018 06 2;24(6):1187-1195. Epub 2018 Feb 2.

Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

The purpose of this report is to analyze long-term clinical outcomes of patients exposed to plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization. This was a study of patients with non-Hodgkin lymphoma (NHL; n = 167) and multiple myeloma (MM; n = 163) who were enrolled in the long-term follow-up of 2 pivotal phase III studies (NCT00741325 and NCT00741780) of 240 µg/kg plerixafor plus 10 µg/kg G-CSF, or placebo plus 10 µg/kg G-CSF to mobilize and collect CD34 cells for autologous hematopoietic stem cell transplantation. Overall survival (OS) and progression-free survival (PFS) were evaluated over a 5-year period following the first dose of plerixafor or placebo. The probability of OS was not significantly different in patients with NHL or MM treated with plerixafor or placebo (NHL: 64%; 95% confidence interval [CI], 56% to 71% versus 56%; 95% CI, 44% to 67%, respectively; MM: 64%; 95% CI, 54% to 72% versus 64%; 95% CI, 53% to 73%, respectively). In addition, there was no statistically significant difference in the probability of PFS over 5 years between treatment groups in patients with NHL (50%; 95% CI, 44% to 67% for plerixafor versus 43%; 95% CI, 31% to 54% for placebo) or those with MM (17%; 95% CI, 10% to 24% for plerixafor versus 30%; 95% CI, 21% to 40% for placebo). In this long-term follow-up study, the addition of plerixafor to G-CSF for stem cell mobilization did not affect 5-year survival in patients with NHL or patients with MM.
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http://dx.doi.org/10.1016/j.bbmt.2018.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091693PMC
June 2018

Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation.

J Clin Oncol 2017 Dec 17;35(36):4003-4011. Epub 2017 Oct 17.

Robert J. Soiffer, Haesook T. Kim, Vincent T. Ho, Edwin P. Alyea, and Jerome Ritz, Dana-Farber Cancer Institute; James D. Levine, Beth Israel Deaconess Medical Center and Harvard Medical School; Yi-Bin Chen, Massachusetts General Hospital, Boston; Frank Glavin, Neovii Biotech, Lexington, MA; Joseph McGuirk, University of Kansas Medical Center, Kansas City, KS; Mitchell E. Horwitz, Duke University Medical Center, Durham; Thomas C. Shea, University of North Carolina School of Medicine, Chapel Hill, NC; Laura Johnston, Stanford University, Stanford, CA; Mrinal M. Patnaik, Mayo Clinic, Rochester, MN; Witold Rybka, Penn State College of Medicine, Hershey; David L. Porter, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Andrew Artz, University of Chicago, Chicago; Patrick J. Stiff, Loyola University Medical Center, Maywood, IL; Michael W. Boyer, University of Utah, Salt Lake City, UT; Richard T. Maziarz, Oregon Health & Science University, Portland, OR; Paul J. Shaughnessy, Texas Transplant Institute, San Antonio; Madhuri Vusirikala, University of Texas Southwestern Medical Center, Dallas, TX; Usama Gergis, Weill Cornell Medical College; Ran Reshef, Columbia University Medical Center, New York, NY; Hana Safah, Tulane University, New Orleans, LA; John F. DiPersio and Peter Westervelt, Washington University School of Medicine, St Louis, MO; Jeff Szer, Royal Melbourne Hospital, Parkville, Victoria; Ian D. Lewis, Royal Adelaide Hospital, Adelaide, South Australia, Australia; Jennifer Holter, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Paul J. Martin, Fred Hutchinson Cancer Research Center, Seattle, WA; Joseph A. Pidala, H. Lee Moffitt Cancer Center, Tampa, FL; and Madan H. Jagasia, Vanderbilt University Medical Center, Nashville, TN.

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.
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http://dx.doi.org/10.1200/JCO.2017.75.8177DOI Listing
December 2017

An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD.

Blood 2017 11 29;130(19):2131-2145. Epub 2017 Aug 29.

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

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors and , each critical to B-cell differentiation and fate. All- retinoic acid (ATRA) increased expression, restored the -to- ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated and , but not (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity.
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http://dx.doi.org/10.1182/blood-2017-05-782466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680609PMC
November 2017

Myeloablative conditioning with total body irradiation for AML: Balancing survival and pulmonary toxicity.

Adv Radiat Oncol 2016 Oct-Dec;1(4):272-280. Epub 2016 Jul 15.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Purpose: The purpose of this study was to compare leukemia-free survival (LFS) and other clinical outcomes in patients with acute myelogenous leukemia who underwent a myeloablative allogeneic stem cell transplant with and without total body irradiation (TBI).

Methods And Materials: Adult patients with acute myelogenous leukemia undergoing myeloablative allogeneic stem cell transplant at Duke University Medical Center between 1995 and 2012 were included. The primary endpoint was LFS. Secondary outcomes included overall survival (OS), nonrelapse mortality, and the risk of pulmonary toxicity. Kaplan-Meier survival estimates and Cox proportional hazards multivariate analyses were performed.

Results: A total of 206 patients were evaluated: 90 received TBI-based conditioning regimens and 116 received chemotherapy alone. Median follow-up was 36 months. For all patients, 2-year LFS and OS were 36% (95% confidence interval [CI], 29-43) and 39% (95% CI, 32-46), respectively. After adjusting for known prognostic factors using a multivariate analysis, TBI was associated with improved LFS (hazard ratio: 0.63; 95% CI: 0.44-0.91) and OS (hazard ratio: 0.63; 95% CI, 0.43-0.91). There was no difference in nonrelapse mortality between cohorts, but pulmonary toxicity was significantly more common with TBI (2-year incidence 42% vs 12%, < .001). High-grade pulmonary toxicity predominated with both conditioning strategies (70% and 93% of cases were grade 3-5 with TBI and chemotherapy alone, respectively).

Conclusions: TBI-based regimens were associated with superior LFS and OS but at the cost of increased pulmonary toxicity.
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http://dx.doi.org/10.1016/j.adro.2016.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514157PMC
July 2016

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

Evaluation of Hematopoietic Stem Cell Mobilization Rates with Early Plerixafor Administration for Adult Stem Cell Transplantation.

Biol Blood Marrow Transplant 2017 Aug 11;23(8):1290-1294. Epub 2017 Apr 11.

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

The addition of plerixafor to high-dose colony-stimulating growth factor has been shown to improve stem cell mobilization rates in autologous transplant patients with multiple myeloma and non-Hodgkin lymphoma. This study evaluates the change in administration time of plerixafor to determine if cell mobilization rates are similar between the US Food and Drug Administration-approved administration time of 11 hours before apheresis and an earlier administration time of 16 hours before apheresis. Medical records of patients age ≥ 18 years undergoing autologous stem cell transplantation requiring the use of plerixafor after at least 4 days of granulocyte colony-stimulating factor therapy to complete stem cell mobilization from January 1, 2010 through September 30, 2014 were retrospectively reviewed. The primary outcome was CD34 cell mobilization success rates when plerixafor was administered 11 ± 2 hours (standard administration group) compared with 16 ± 2 hours before cell apheresis (early administration group), as defined as collection of  ≥2 × 10 CD34 cells/kg. Secondary outcomes included the number of plerixafor therapy days required to collect a total of ≥2 × 10 CD34 cells/kg, the number of apheresis cycles required to achieve ≥2 × 10 CD34 cells/kg, the median CD34 cells/kg collected in each apheresis session, and the rates of reported adverse events that occurred in the standard administration time group compared with the early administration time group. Of the 197 patients included, 114 patients received plerixafor 11 ± 2 hours before apheresis and 83 patients received plerixafor 16 hours ± 2 hours before apheresis. Ninety-four percent of patients in the early administration group achieved successful stem cell mobilization compared with 81.6% in the standard administration group (P = .0111). The median number of plerixafor days to reach the collection goal of  ≥2 × 10 CD34 cells/kg was 1 day for each group (P = .323), and the median number of apheresis days to reach the collection goal was 2 days for the standard administration group compared with 1 day for the early administration group (P = .0156). Most adverse events were similar between the 2 groups except for fever, which occurred in 4.8% of the patients in the early administration group and none of the patients in the standard administration group. This study demonstrates plerixafor effectively mobilizes peripheral blood stem cells when given at an early administration time of 16 hours before apheresis compared with standard administration of 11 hours before apheresis. However, further prospective studies could strengthen these results.
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http://dx.doi.org/10.1016/j.bbmt.2017.04.007DOI Listing
August 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.
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http://dx.doi.org/10.1016/j.bbmt.2017.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846194PMC
July 2017

Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes.

J Clin Oncol 2017 Apr 13;35(11):1154-1161. Epub 2017 Feb 13.

Bart L. Scott and H. Joachim Deeg, Fred Hutchinson Cancer Research Center, Seattle, WA; Marcelo C. Pasquini, Brent R. Logan, Mehdi Hamadani, and Mary M. Horowitz, Medical College of Wisconsin, Milwaukee, WI; Juan Wu and Adam M. Mendizabal, Emmes Corporation, Rockville, MD; Steven M. Devine, Ohio State University Comprehensive Cancer Center, Columbus, OH; David L. Porter, University of Pennsylvania, Philadelphia, PA; Richard T. Maziarz, Oregon Health and Science University, Portland, OR; Erica D. Warlick, University of Minnesota, Minneapolis; Jennifer Le-Rademacher, Mayo Clinic, Rochester, MN; Hugo F. Fernandez, Moffitt Cancer Center, Tampa, FL; Edwin P. Alyea, Dana Farber Cancer Institute, Boston, MA; Asad Bashey, Northside Hospital Cancer Institute, Atlanta, GA; Sergio Giralt, Memorial Sloan Kettering Cancer Center, New York, NY; Nancy L. Geller and Eric Leifer, National Heart, Lung, and Blood Institute, Bethesda, MD; and Mitchell E. Horwitz, Duke University, Durham, NC.

Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.
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http://dx.doi.org/10.1200/JCO.2016.70.7091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455603PMC
April 2017
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