John E Wagner

Indiana Blood and Marrow Transplantation, Indianapolis, Indiana, United States

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Publications (243)

  • [Show abstract] [Hide abstract] ABSTRACT: The use of calcineurin inhibitors (CNIs) to reduce the risk of graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) requires intensive post-transplant toxicity monitoring. Sirolimus-based GVHD prophylaxis is associated with a favorable toxicity profile and requires less intensive monitoring. However, the efficacy of sirolimus-based regimen as compared to CNI-based regimen has not been evaluated in the setting of reduced-intensity conditioning (RIC) double umbilical cord blood (UCB) HCT. We compared outcomes of patients receiving sirolimus/mycophenolate mofetil (MMF; n=37) or cyclosporine (CSA)/MMF (n=123) in an ongoing phase II study of RIC UCB transplantation. In multiple regression analysis, sirolimus/MMF did not influence the risk of grade II-IV or grade III-IV acute GVHD. In addition, there was no association between type of GVHD prophylaxis and hematopoietic engraftment. Infection density analysis found a significantly lower risk of infections with sirolimus/MMF between days +46 and +180 post-HCT as compared to CSA/MMF (3.4 vs. 6.3 per 1000 patient-days, p=0.03); however, no difference was observed before day +45. Sirolimus/MMF use resulted in no thrombotic microangiopathy, fewer instances of elevated serum creatinine >2mg/dL (14% vs. 45%; p<0.01), and similar rates of sinusoidal obstruction syndrome (2.7% vs. 4%; p=0.68) as compared to CSA/MMF. Disease-free survival at 1 year was 51% for sirolimus/MMF and 41% for CSA/MMF (p=0.41), and sirolimus/MMF use did not influence the risk of non-relapse mortality or survival. In conclusion, sirolimus/MMF GVHD prophylaxis was better tolerated and resulted in similar rates of GVHD and survival as compared to CSA/MMF after RIC double UCB transplant.
    Article · Aug 2016 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract] ABSTRACT: A number of endocrinopathies have been described after hematopoietic cell transplantation (HCT), but data are limited in patients with Fanconi anemia (FA). We report several endocrine-based disorders in a cohort of 44 patients with FA after HCT, compared to 74 patients who received HCT for hematologic malignancies and 275 healthy controls. Endocrinopathies assessed included hypothyroidism, hypogonadism, short stature, dyslipidemia, insulin resistance, abnormalities in body composition and bone health. Most (86%) patients with FA had at least one endocrinopathy with 11% having 3 or more. Hypothyroidism was seen in 57%, hypogonadism in 27%, short stature in 50%, reduced total body and lumbar spine BMD (height adjusted Z-score < -1) in 57% and 21%, respectively. Vitamin D deficiency was seen in 71%. Short stature was associated with younger age at HCT and gonadal failure with older age at HCT. Insulin resistance was associated with increased percent fat mass and increased android/gynoid ratio by dual energy X-ray absorptiometry (DXA). Hypothyroidism, short stature, and reduced total body BMD were more prevalent in patients with FA compared to patients with hematologic malignancies. We recommend an assessment prior to transplant and close follow up afterwards to ensure proper clinical management. Future studies should continue to explore the impact of HCT on endocrinopathies in FA patients.
    Article · May 2016 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    Full-text Article · Apr 2016 · Haematologica
  • Article · Mar 2016
  • Article · Mar 2016
  • Article · Mar 2016
  • [Show abstract] [Hide abstract] ABSTRACT: A 3-year-old child with recessive dystrophic epidermolysis bullosa treated with bone marrow transplantation subsequently developed body-wide epidermal detachment distinct from his epidermolysis bullosa. Toxic epidermal necrolysis was diagnosed by examination and skin biopsy. Although graft-vs-host disease was considered, he had no features of this diagnosis by laboratory studies or skin biopsy, and he improved without addition of further immune suppressants. Throughout the episode, the patient was maintained on cyclosporine A, a component of his transplant regimen, and also a reported therapy for toxic epidermal necrolysis. He had full recovery. Re-epithelialization occurred in a unique folliculocentric pattern, which we postulate was related to the patient's mesenchymal stem cell infusion, received as an adjunct to his marrow transplantation.
    Article · Mar 2016 · The Journal of pediatrics
  • [Show abstract] [Hide abstract] ABSTRACT: Fanconi anemia (FA) is a rare inherited disorder caused by pathogenic variants in one of 19 FANC genes. FA patients display congenital abnormalities, and develop bone marrow failure, and cancer susceptibility. We identified homozygous mutations in four FA patients and, in each case, only one parent carried the obligate mutant allele. FANCA and FANCP/SLX4 genes, both located on chromosome 16, were the affected recessive FA genes in three and one family respectively. Genotyping with short tandem repeat markers and single nucleotide polymorphism (SNP) arrays revealed uniparental disomy (UPD) of the entire mutation-carrying chromosome 16 in all four patients. One FANCA patient had paternal UPD, whereas FA in the other three patients resulted from maternal UPD. These are the first reported cases of UPD as a cause of FA. UPD indicates a reduced risk of having another child with FA in the family and has implications in prenatal diagnosis. This article is protected by copyright. All rights reserved.
    Article · Feb 2016 · Human Mutation
  • [Show abstract] [Hide abstract] ABSTRACT: B cell anti-host antibody production plays a central role in chronic graft-vs-host disease (cGVHD). T follicular helper (TFH) cells drive B cell responses and are implicated in this process. Given differences in cGVHD incidence between umbilical cord blood (UCB) and adult donor transplant recipients, we evaluated TFH cell reconstitution kinetics to define graft source differences and their potential pathogenic role in cGVHD. Although we observed significantly fewer TFH cells in the blood of UCB recipients (vs. matched related donors (MRD)) early after transplantation, by 1 year the numbers of TFH cells were similar. Additionally, at both early (day 60) and late (1 year) time points, TFH cell phenotype was predominantly central memory cells in both cohorts. TFH cells were functional and able to produce multiple cytokines (INF-γ, TNF-α, IL-2, IL-17 and IL-21) following stimulation. In contrast to mouse models where an enhanced frequency of splenic TFH cells contributes to cGVHD, patients with cGVHD showed significantly depleted circulating TFH cells following both UCB and MRD transplantation. Low numbers of TFH cells early after UCB transplantation could directly contribute to less cGVHD in this cohort. Additionally, systemic therapy (including steroids and calcineurin inhibitors) may contribute to decreases in TFH cells in patients with cGVHD. These data provide further evidence supporting the importance of TFH cells in cGVHD pathogenesis.
    Article · Jan 2016 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract] ABSTRACT: This chapter reviews the pathogenesis and pathology, diagnosis and treatment of Fanconi anemia (FA) with particular emphasis on the expected results of allogeneic hematopoietic cell transplantation (HCT). Children and adults with FA have an extraordinary predisposition for the development of marrow failure and leukemia. Understanding the pathophysiology of FA marrow failure and leukemogenesis could help to find ways to ameliorate the disease progression as well as explain certain clinical observations. The presence of somatic mosaicism may be of important predictive value regarding the clinical course of the patient with FA. As molecular data have become increasingly available, the authors explore the possibility of genotype-phenotype correlations. Fewer patients with an HLA-identical sibling donor receive radiation in an attempt to reduce the late effects commonly associated with radiation. The possibility of using gene transfer methods for correcting genetic diseases of hematopoietic stem cells (HSCs) has received much attention.
    Chapter · Jan 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Fatal myocarditis is a rare complication in immunosuppressed children. Recent reports have linked human herpesvirus 6 (HHV-6) infection, typically a benign infection in childhood, with myocarditis. HHV-6 can reactivate during periods of immunosuppression. Here, we report 2 cases in which children were immunosuppressed, one for treatment of Evans syndrome and the other post hematopoietic stem cell transplantation, who developed rapid and fatal HHV-6-associated myocarditis. These cases suggest that HHV-6 infection should be considered as an etiology of myocarditis in immunosuppressed patients regardless of correlating blood levels. Early treatment of HHV-6 in patients with myocarditis could improve morbidity and mortality.
    Article · Dec 2015 · PEDIATRICS
  • John E. Wagner · Claudio G. Brunstein · Anthony E. Boitano · [...] · Conrad C. Bleul
    [Show abstract] [Hide abstract] ABSTRACT: Clinical application of umbilical cord blood (UCB) as a source of hematopoietic stem cells for transplantation is limited by low CD34+ cell dose, increased risk of graft failure, and slow hematopoietic recovery. While the cell dose limitation is partially mitigated by using two UCB units, larger-dosed single units would be preferable. We have evaluated the feasibility and safety of StemRegenin-1 (SR-1), an aryl hydrocarbon receptor antagonist that expands CD34+ cells, by placing one of the two units in expansion culture. SR-1 produced a 330-fold increase in CD34+ cells and led to engraftment in 17/17 patients at a median of 15 days for neutrophils and 49 days for platelets, significantly faster than in patients treated with unmanipulated UCB. Taken together, the marked expansion, absence of graft failure, and enhanced hematopoietic recovery support testing of SR-1 expansion as a stand-alone graft and suggest it may ameliorate a limitation of UCB transplant.
    Article · Dec 2015 · Cell stem cell
  • Claudio G Brunstein · Jeffrey S Miller · David H McKenna · [...] · John E Wagner
    [Show abstract] [Hide abstract] ABSTRACT: We studied the safety and clinical outcomes of patients treated with umbilical cord blood (UCB) derived regulatory T cells that expanded in cultures stimulated with K562 cells modified to express the high affinity Fc receptor (CD64) and CD86, the natural ligand of CD28 (KT64/86). Eleven patients were treated with Treg doses from 3 to 100 x 10(6) Treg/kg. The median proportion of CD4+FoxP3+CD127- in the infused product was 87% (r, 78-95%) and we observed no dose limiting infusional adverse events. Clinical outcomes were compared to contemporary controls (n=22) who received the same conditioning regimen with sirolimus and mycophenolate mofetil immune suppression. The incidence of grade II-IV acute graft-vs.-host disease (GVHD) at 100 days was 9% (95%CI, 0-25%) vs. 45% (95%CI, 24-67%) in controls (p=.05). Chronic GVHD at 1 year was zero in Tregs and 14% in controls. Hematopoietic recovery and chimerism, cumulative density of infections, non-relapse mortality, relapse and disease-free survival were similar in the Treg recipients and controls. KT64/86 expanded UCB Tregs were safe and resulted in low risk of acute GVHD.
    Article · Nov 2015 · Blood
  • Claudio G Brunstein · Effie W Petersdorf · Todd E DeFor · [...] · John E Wagner
    [Show abstract] [Hide abstract] ABSTRACT: The impact of allele level HLA mismatch is uncertain in recipients of double umbilical cord blood transplantation (dUCBT). We report a single center retrospective study of the clinical effect of using allele-level HLA mismatch HLA-A, -B, -C, -DRB1 and -DQB1 of the two UCB units. We studied 342 patients with hematological malignancy. Donor-recipient pairs were grouped according to the number of matched HLA alleles with 32 matched at 9-10/10, 202 at 6-8/10 and 108 at 2-5/10 alleles. The incidence of hematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), and non-relapse mortality (NRM) and treatment failure was similar between groups. In an exploratory analysis of 174 patients with acute leukemia, after adjusting for length of first remission and cytogenetic risk group, 2-5/10 HLA match was associated with lower risk of relapse and treatment failure. These data indicate that a high degree of allele level HLA mismatch does not adversely affect transplant outcomes and may be associated with reduced relapse risk in patients with acute leukemia.
    Article · Oct 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract] ABSTRACT: Allogeneic hematopoietic cell transplantation is often complicated by graft-versus-host disease (GVHD). We analyzed the incidence and risk factors for acute and chronic graft-versus-host disease (GVHD), and their impact on disease relapse and survival, among recipients of single umbilical cord blood (sUCB, n=295), double umbilical cord blood (dUCB, n=416), and matched sibling donor (MSD, n=469) allografts. The incidence of grade II-IV aGVHD and chronic GVHD among dUCB, sUCB, and MSD was 56%, 26% and 37% and 26%, 7%, and 40%, respectively. Development of acute GVHD had no effect on relapse, non-relapse mortality, or overall survival among UCB recipients, but was associated with worse non-relapse mortality and survival in MSD recipients. Development of cGVHD was only associated with lower relapse in dUCBT. In multivariate analysis of GVHD incidence, age > 18 years was associated with higher incidence of aGVHD and cGVHD across all cohorts, while worse HLA match and prior aGVHD were associated with higher risks of aGVHD in both UCB cohorts. Non-myeloablative conditioning limited the risk of aGVHD compared to myeloablative conditioning in dUCB recipients. Cyclosporine A and mycophenolate mofetil as GVHD prophylaxis lowered the risk of cGVHD compared to steroids with cyclosporine A among sUCB recipients. This large contemporary analysis suggests similarity of risks and consequences of GVHD for UCB and MSD recipients. Limiting the severity of aGVHD remains important in all groups. Increasing the UCB inventory or developing strategies that reduce the cell-dose threshold and thereby increase the chance of identifying an adequately dosed, better HLA-matched single UCB unit may further limit risks of acute GVHD after UCB transplantation.
    Article · Sep 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    Anderson T Wang · Taeho Kim · John E Wagner · [...] · Agata Smogorzewska
    [Show abstract] [Hide abstract] ABSTRACT: Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text Article · Aug 2015 · Molecular cell
  • [Show abstract] [Hide abstract] ABSTRACT: The inclusion of anti-thymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation-based conditioning and either single (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidence of day-100 grade II-IV acute GVHD (30% versus 54%, p = 0.0002), and chronic GVHD (22% versus 43%, p = 0.0008) were lower with ATG compared to non-ATG regimens. However, day 100 grade III-IV acute GVHD was comparable (11% versus 17%, p = 0.15). The 3-year incidences of transplant-related mortality (16% versus 17%, p = 0.98) and relapse (17% versus 27%, p = 0.12), and leukemia-free survival (66% versus 55%, p = 0.23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, p=0.83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse or leukemia-free survival in children and adolescents with ALL. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Article · Aug 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract] ABSTRACT: Second allogeneic hematopoietic cell transplantation (HCT) is the only salvage option for those for develop graft failure after their first HCT. Data on outcomes after second HCT in Fanconi anemia (FA) are scarce. We report outcomes after second allogeneic HCT for FA (n=81). The indication for second HCT was graft failure after the first HCT. Transplants occurred between 1990 and 2012. The timing of second transplantation predicted subsequent graft failure and survival. Graft failure was high when the second transplant occurred less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between first and second transplant was less than 3 months compared to 23% when the interval was longer (p<0.001). Consequently, survival rates were substantially lower when the interval between first and second transplant was less than 3 months, 23% at 1-year compared to 58%, when the interval was longer (p=0.001). The corresponding 5-year probabilities of survival were 16% and 45%, respectively (p=0.006). Taken together, these data suggest that fewer than half of FA patients undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to lower graft failure after first HCT. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Article · Jun 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract] ABSTRACT: Cytomegalovirus (CMV) reactivates in >30% of CMV seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of NK cells expressing NKG2C, CD57 and inhibitory killer-cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation post-HCT. These NK cells persist after the resolution of infection and display 'adaptive' or memory properties. Despite these findings, the differential impact of persistent/inactive vs. reactivated CMV on NK vs. T cell maturation following HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pre-transplant CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an 'adaptive' phenotype (NKG2C(+)CD57(+)). Compared to CMV seronegative recipients, those who reactivated CMV (React(+)) had the highest adaptive cell frequencies, while intermediate frequencies were observed in CMV seropositive recipients harboring persistent/non-replicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV seropositive recipients of sibling, but not UCB grafts, and correlated with lower rates of CMV reactivation (sibling 33% vs. UCB 51%; p<0.01). These data suggest that persistent/non-replicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling, but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Article · Jun 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • Margaret L MacMillan · Todd E DeFor · Jo-Anne H Young · [...] · John E Wagner
    [Show abstract] [Hide abstract] ABSTRACT: Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential changes to the HCT conditioning regimen. One-hundred-and-thirty FA patients (median age 9.0 years, range 1-48) underwent alternative donor HCT at the University of Minnesota between 1995-2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell depleted bone marrow (BM) or unmanipulated umbilical cord blood (UCB) transplantation. The addition of FLU enhanced engraftment three-fold. The incidence of grades II-IV acute and chronic graft-versus-host disease (GVHD) was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age, or with a history of opportunistic infections or transfusions prior to HCT. Mortality was lowest in patients without a prior history of opportunistic infection or transfusions, and who received conditioning with TBI 300 cGy, CY, FLU and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. Copyright © 2015 American Society of Hematology.
    Article · Mar 2015 · Blood

Publication Stats

14k Citations

Institutions

  • 2014
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
  • 2004-2007
    • The Rockefeller University
      New York, New York, United States
  • 2001-2007
    • University of Minnesota Twin Cities
      • Division of Hematology, Oncology and Transplantation
      Minneapolis, MN, United States
  • 2001-2006
    • Columbia University
      • Department of Pediatrics
      New York, New York, United States
  • 2005
    • Medical College of Wisconsin
      • Center for International Blood & Marrow Transplant Research
      Milwaukee, WI, United States
  • 1995-2002
    • University of Minnesota Duluth
      • Medical School
      Duluth, Minnesota, United States