Publications by authors named "Margaret L MacMillan"

114 Publications

Chronic Graft-Versus-Host Disease, Non-Relapse Mortality and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A CIBMTR Analysis.

Transplant Cell Ther 2021 Oct 9. Epub 2021 Oct 9.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; Fred Hutchinson Cancer Research Center, Seattle, WA.

Background: The effect of chronic graft-versus-host disease (cGVHD) on the risk of non-relapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (≥60 years).

Methods: We included 4429 adults ≥40 years who received first HLA-matched peripheral blood alloHCT for acute myeloid leukemia or myelodysplastic syndrome between the years 2008-2017. We compared outcomes of 4 groups: older adults (≥60 years) and younger adults (40-59 years) with or without cGVHD to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse and overall survival (OS). We treated cGVHD as a time-dependent covariate. Severity of cGVHD was based on the CIBMTR clinical definitions.

Results: cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher among older versus younger adults. Adults who developed cGVHD as a group had longer OS, compared to age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild and moderate cGVHD were associated with longer OS.

Conclusions: Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse and longer OS. Older adults had a higher risk of NRM but the increased risk of NRM associated with cGVHD did not differ based on age. Development of mild-moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing relapses. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important.
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http://dx.doi.org/10.1016/j.jtct.2021.10.002DOI Listing
October 2021

Detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post-allogeneic hematopoietic cell transplant patient: a case report.

BMC Infect Dis 2021 Sep 10;21(1):941. Epub 2021 Sep 10.

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

Background: Cerebral toxoplasmosis infection presents with non-specific neurologic symptoms in immunocompromised patients. With lack of measurable adaptive immune responses and reluctance to sample affected brain tissue, expedient diagnosis to guide directed treatment is often delayed.

Case Presentation: We describe the use of cerebrospinal fluid polymerase chain reaction and plasma cell-free DNA technologies to supplement neuroimaging in the diagnosis of cerebral toxoplasmosis in an immunocompromised pediatric patient following allogeneic hematopoietic cell transplantation for idiopathic severe aplastic anemia. Successful cerebral toxoplasmosis treatment included antibiotic therapy for 1 year following restoration of cellular immunity with an allogeneic stem cell boost.

Conclusions: Plasma cell-free DNA technology provides a non-invasive method of rapid diagnosis, improving the likelihood of survival from often lethal opportunistic infection in a high risk, immunocompromised patient population.
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http://dx.doi.org/10.1186/s12879-021-06650-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434744PMC
September 2021

A Review of Infections After Hematopoietic Cell Transplantation Requiring PICU Care: Transplant Timeline Is Key.

Front Pediatr 2021 27;9:634449. Epub 2021 Jul 27.

Department of Pediatrics, Division of Blood and Marrow Transplantation and Cellular Therapy, University of Minnesota, Minneapolis, MN, United States.

Despite major advances in antimicrobial prophylaxis and therapy, opportunistic infections remain a major cause of morbidity and mortality after pediatric hematopoietic cell transplant (HCT). Risk factors associated with the development of opportunistic infections include the patient's underlying disease, previous infection history, co-morbidities, source of the donor graft, preparative therapy prior to the graft infusion, immunosuppressive agents, early and late toxicities after transplant, and graft-vs.-host disease (GVHD). Additionally, the risk for and type of infection changes throughout the HCT course and is greatly influenced by the degree and duration of immunosuppression of the HCT recipient. Hematopoietic cell transplant recipients are at high risk for rapid clinical decompensation from infections. The pediatric intensivist must remain abreast of the status of the timeline from HCT to understand the risk for different infections. This review will serve to highlight the infection risks over the year-long course of the HCT process and to provide key clinical considerations for the pediatric intensivist by presenting a series of hypothetical HCT cases.
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http://dx.doi.org/10.3389/fped.2021.634449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353083PMC
July 2021

Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy.

Transplant Cell Ther 2021 08;27(8):642-649

West Virginia University, Morgantown, West Virginia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized.
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http://dx.doi.org/10.1016/j.jtct.2021.04.007DOI Listing
August 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

Late-Onset Acute and Chronic Graft-versus-Host Disease in Children: Clinical Features and Response to Therapy.

Transplant Cell Ther 2021 08 30;27(8):667.e1-667.e5. Epub 2021 May 30.

Blood and Marrow Transplantation and Cellular Therapy Program, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota; Department of Pediatrics, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota. Electronic address:

Although acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) are known causes of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), the syndrome of late aGVHD is less well understood, particularly in children. We aimed to characterize the clinical features and response to therapy of late aGVHD and cGVHD by retrospectively reviewing 573 consecutive patients age <18 years who underwent their first allogeneic HCT at the University of Minnesota. We included patients with de novo late aGVHD (ie, first occurrence of aGVHD after day +100 post-HCT) and cGVHD. We retrospectively scored cGVHD cases based on the 2014 National Institutes of Health guidelines. At 3 years, 9 patients (2%) had developed late aGVHD, 16 (3%) had overlap cGVHD, and 7 had (1%) classic cGVHD. No cases of joint or genital cGVHD were observed. The overall response to therapy at 6 months was 78% (95% confidence interval [CI], 40% to 97%) after late aGVHD and 43% (95% CI, 23% to 66%) after cGVHD. Higher nonrelapse mortality from day +100 was seen in patients with cGVHD but not in those with late aGVHD compared with patients without GVHD (hazard ratio, 3.6 [95% CI, 1.3 to 10.0] and 1.6 [95% CI, 0.2 to 11.7], respectively). We found variable organ involvement and treatment responses between patients with late aGVHD and those with cGVHD in a single-center pediatric cohort. Further research is needed to investigate the risks and clinical features of late aGVHD and cGVHD in larger cohorts to better understand how to tailor even more effective GVHD preventive and therapeutic approaches in children.
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http://dx.doi.org/10.1016/j.jtct.2021.05.022DOI Listing
August 2021

High incidence of thromboembolism in patients with chronic GVHD: association with severity of GVHD and donor-recipient ABO blood group.

Blood Cancer J 2021 05 18;11(5):96. Epub 2021 May 18.

Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with systemic inflammation and endothelial dysfunction, increasing risk for thromboembolic events (TEE). In 145 adult recipients who developed cGVHD after a matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 32(22%) developed at least 1 TEE event, and 14(10%) developed 2 TEE events. The 5-year cumulative incidence of TEE was 22% (95% CI, 15-29%) with a median time from cGVHD to TEE of 234 days (range, 12-2050). Median time to the development of LE DVT or PE was 107 (range, 12-1925) compared to 450 days (range, 158-1300) for UE DVT. Cumulative incidence of TEE was 9% (95% CI, 0-20%), 17% (95% CI, 9-25%), and 38% (95% CI, 22-55%) in those with mild, moderate, and severe GVHD, respectively. Higher risk for TEE was associated with cGVHD severity (hazard ratio [HR] 4.9, [95% CI, 1.1-22.0]; p = 0.03), non-O-donor to recipient ABO match compared to O-donor to O-recipient match (HR 2.7, [95% CI, 1.0-7.5]; p = 0.053), and personal history of coronary artery disease (HR 2.4, [95% CI, 1.1-5.3]; p = 0.03). TEE was not associated with 2-year non-relapse mortality or 5-year overall survival.
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http://dx.doi.org/10.1038/s41408-021-00488-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131386PMC
May 2021

Multiply restimulated human thymic regulatory T cells express distinct signature regulatory T-cell transcription factors without evidence of exhaustion.

Cytotherapy 2021 08 20;23(8):704-714. Epub 2021 Apr 20.

Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, Minnesota, USA. Electronic address:

Background Aims: Adoptive transfer of suppressive CD4+CD25+ thymic regulatory T cells (tTregs) can control auto- and alloimmune responses but typically requires in vitro expansion to reach the target cell number for efficacy. Although the adoptive transfer of expanded tTregs purified from umbilical cord blood ameliorates graft-versus-host disease in patients receiving hematopoietic stem cell transplantation for lymphohematopoietic malignancy, individual Treg products of 100 × 10 cells/kg are manufactured over an extended 19-day time period using a process that yields variable products and is both laborious and costly. These limitations could be overcome with the availability of 'off the shelf' Treg.

Results: Previously, the authors reported a repetitive restimulation expansion protocol that maintains Treg phenotype (CD4+25++127-Foxp3+), potentially providing hundreds to thousands of patient infusions. However, repetitive stimulation of effector T cells induces a well-defined program of exhaustion that leads to reduced T-cell survival and function. Unexpectedly, the authors found that multiply stimulated human tTregs do not develop an exhaustion signature and instead maintain their Treg gene expression pattern. The authors also found that tTregs expanded with one or two rounds of stimulation and tTregs expanded with three or five rounds of stimulation preferentially express distinct subsets of a group of five transcription factors that lock in Treg Foxp3expression, Treg stability and suppressor function. Multiply restimulated Tregs also had increased transcripts characteristic of T follicular regulatory cells, a Treg subset.

Discussion: These data demonstrate that repetitively expanded human tTregs have a Treg-locking transcription factor with stable FoxP3 and without the classical T-cell exhaustion gene expression profile-desirable properties that support the possibility of off-the-shelf Treg therapeutics.
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http://dx.doi.org/10.1016/j.jcyt.2021.02.118DOI Listing
August 2021

Broad-Spectrum Antibiotics and Risk of Graft-versus-Host Disease in Pediatric Patients Undergoing Transplantation for Acute Leukemia: Association of Carbapenem Use with the Risk of Acute Graft-versus-Host Disease

Transplant Cell Ther 2021 02 21;27(2):177.e1-177.e8. Epub 2020 Dec 21.

Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, PA.

Variation in the gastrointestinal (GI) microbiota after hematopoietic cell transplantation (HCT) has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD risk in pediatric patients undergoing HCT for acute leukemia. We performed a retrospective analysis in a dataset merged from 2 sources: (1) the Center for International Blood and Marrow Transplant Research, an observational transplantation registry, and (2) the Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to 3 classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) antipseudomonal penicillins, and (3) carbapenems. The primary outcome was grade II-IV aGVHD; secondary outcomes were grade III-IV aGVHD and lower GI GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (subcohort) included transplantation characteristics, GVHD risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2550 patients at 36 centers; the subcohort included 1174 patients. In adjusted models, carbapenems were associated with an increased risk of grade II-IV aGVHD in the full cohort (adjusted odds ratio [aOR], 1.24; 95% confidence interval [CI], 1.02 to 1.51) and subcohort (sub hazard ratio [HR], 1.31; 95% CI, 0.99 to 1.72), as well as with an increased risk of grade III-IV aGVHD (subHR, 1.77; 95% CI, 1.25 to 2.52). Early carbapenem exposure (before day 0) especially impacted aGVHD risk. For antipseudomonal penicillins, the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad-spectrum antibiotics, should be used judiciously in pediatric HCT recipients to minimize aGVHD risk. Further research is needed to clarify the mechanism underlying this association.
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http://dx.doi.org/10.1016/j.jtct.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946150PMC
February 2021

First-in-human phase 1 trial of induced regulatory T cells for graft-versus-host disease prophylaxis in HLA-matched siblings.

Blood Adv 2021 03;5(5):1425-1436

Blood and Marrow Transplant Program.

Human CD4+25- T cells cultured in interleukin 2 (IL-2), rapamycin, and transforming growth factor β (TGFβ) along with anti-CD3 monoclonal antibody-loaded artificial antigen-presenting cells generate FoxP3+ induced regulatory T cells (iTregs) with potent suppressive function. We performed a phase 1, single-center, dose-escalation study to determine the safety profile of iTregs in adults with high-risk malignancy treated with reduced-intensity conditioning and mobilized peripheral blood stem cells (PBSCs) from HLA-identical sibling donors. Sixteen patients were enrolled and 14 were treated (2 productions failed to meet desired doses). One patient each received 3.0 × 106/kg, 3.0 × 107/kg, and 3.0 × 108/kg iTregs with corresponding T-conventional-to-iTreg ratios of 86:1, 8:1, and 1:2. After 3 patients received 3.0 × 108/kg in the presence of cyclosporine (CSA) and mycophenolate mofetil (MMF) with no dose-limiting toxicities, subsequent patients were to receive iTregs in the presence of sirolimus/MMF that favors Foxp3 stability based on preclinical modeling. However, 2 of 2 developed grade 3 acute graft-versus-host disease (GVHD), resulting in suspension of the sirolimus/MMF. An additional 7 patients received 3.0 × 108/kg iTregs with CSA/MMF. In the 14 patients treated with iTregs and CSA/MMF, there were no severe infusional toxicities with all achieving neutrophil recovery (median, day 13). Of 10 patients who received 3.0 × 108/kg iTregs and CSA/MMF, 7 had no aGVHD, 2 had grade 2, and 1 had grade 3. Circulating Foxp3+ iTregs were detectable through day 14. In summary, iTregs in the context of CSA/MMF can be delivered safely at doses as high as 3 × 108/kg. This trial was registered at www.clinicaltrials.gov as #NCT01634217.
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http://dx.doi.org/10.1182/bloodadvances.2020003219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948291PMC
March 2021

Steroid-dependent acute GVHD after allogeneic hematopoietic cell transplantation: risk factors and clinical outcomes.

Blood Adv 2021 03;5(5):1352-1359

Blood and Marrow Transplant Program.

Acute graft-versus-host disease (aGVHD) has various risk factors and outcomes. We defined distinct aGVHD treatment response groups based on response to first-line corticosteroids: steroid sensitive (SS), steroid resistant (SR), and the rarely studied steroid dependent (SD) aGVHD. In 1143 consecutive adult and pediatric allogeneic hematopoietic cell transplant recipients, 385 (34%) developed aGVHD, with 10% having SS aGVHD, 9% SD aGVHD, and 14% SR aGVHD. The only factor significantly associated with SD in comparison with SS was older age (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.4-11.3, when comparing 18- to 60-year-olds with <18-year-olds). Factors significantly associated with SR in comparison with SS were unrelated donor (OR, 3.0; 95% CI, 1.2-7.4) and Minnesota high-risk aGVHD (OR, 2.4; 95% CI, 1.3-4.6). SR aGVHD was independently associated with higher risk for 2-year overall mortality (hazards ratio [HR], 1.8; 95% CI, 1.2-2.8) and nonrelapse mortality (NRM; HR, 2.1; 95% CI, 1.2-3.9). SS and SD GVHD groups had similar overall survival and NRM. The cumulative incidence of chronic GVHD was highest in the SD group, followed by the SR and SS groups (46%, 41%, and 29%, respectively). SD and SS GVHD had similar prognoses, both markedly better than those of the SR groups.
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http://dx.doi.org/10.1182/bloodadvances.2020003937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948274PMC
March 2021

Low 5-year health care burden after umbilical cord blood transplantation.

Blood Adv 2021 02;5(3):853-860

Division of Hematology, Oncology and Transplantation, Department of Medicine, and.

Recipients of allogeneic hematopoietic cell transplantation (HCT) experience a substantial health care burden, with potentially differing patterns of long-term health care requirements using peripheral blood stem cells, bone marrow, and umbilical cord blood (UCB) grafts. We analyzed data from 1077 consecutive adult allogeneic HCT recipients who underwent transplant at the University of Minnesota between 2000 and 2016. To estimate health care burden over time, we compared the number of visits, laboratory studies, medications, and relative value units billed. Health care elements were analyzed both individually and together (ie, total health care elements used per patient days into a density composite score). UCB had the lowest density health care burden composite score from the time of transplant through year 5 (median score 64.0 vs 70.5 for peripheral blood stem cells and 88.0 for bone marrow; P < .01). In multivariate analysis of health care burden between years 1 and 5, recipients of either bone marrow (odds ratio [OR] 0.49 [95% confidence interval (CI) 0.29-0.84]) or peripheral blood stem cells (OR 0.49 [95% CI 0.36-0.67]) were half as likely to experience low health care burden compared with UCB. Adult recipients of UCB have a lower long-term health care burden compared with other graft sources, possibly reflecting a better quality of life.
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http://dx.doi.org/10.1182/bloodadvances.2020003369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876878PMC
February 2021

Outcomes of chronic graft-versus-host disease following matched sibling donor versus umbilical cord blood transplant.

Bone Marrow Transplant 2021 06 8;56(6):1373-1380. Epub 2021 Jan 8.

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

We compared chronic graft-versus-host disease (cGvHD) following umbilical cord blood (UCBT) and matched sibling donor peripheral blood transplant (MSD). 145 patients (2010-2017) with cGvHD after MSD (n = 104) and UCBT (n = 41) were included. Prior acute GvHD was less frequent in MSD (55% vs. 85%; p = 0.01). Severe cGvHD (32% vs. 15%, p = 0.01) and de-novo onset (45% vs. 15%, p < 0.01) were more frequent following MSD. Liver was more frequently involved in MSD recipients (38% vs. 6%); and GI in UCBT (33% vs. 63%), both p < 0.01. Overall response (CR + PR) was similar between both cohorts. 2-year CR was higher in UCBT (14% vs 33%, p = 0.02). Karnofsky score (KPS) ≥ 90 at cGvHD diagnosis was associated with higher odds of response (95%CI: 1.42-10, p < 0.01). The cumulative incidence of durable discontinuation of immune-suppressive therapy, failure-free survival (FFS) and NRM at 2-years were similar between cohorts. KPS < 90 (95%CI: 3.1-24.9, p < 0.01) and platelets <100 × 10e9/L (95%CI: 1.25-10, p = 0.01) were associated with higher risk of NRM. UCBT patients were more likely to have a prior acute GvHD, less severe cGvHD and more likely to attain CR. Despite differences, both cohorts had similar NRM and FFS. High-risk groups, including those with platelets <100 × 10e9/L and KPS < 90, need careful monitoring and intensified therapy.
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http://dx.doi.org/10.1038/s41409-020-01195-5DOI Listing
June 2021

Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia.

Haematologica 2020 12 30;Online ahead of print. Epub 2020 Dec 30.

Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco.

Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.
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http://dx.doi.org/10.3324/haematol.2020.270595DOI Listing
December 2020

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Biol Blood Marrow Transplant 2020 08 17;26(8):1459-1468. Epub 2020 May 17.

(7)Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
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http://dx.doi.org/10.1016/j.bbmt.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391266PMC
August 2020

Hematopoietic Stem Cell Transplantation for Shwachman-Diamond Syndrome.

Biol Blood Marrow Transplant 2020 08 16;26(8):1446-1451. Epub 2020 May 16.

Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

We report the outcomes of hematopoietic stem cell transplantation (HSCT) for 52 patients with Shwachman-Diamond syndrome (SDS) who underwent transplantation between 2000 and 2017. The median age at transplantation was 11 years, and the median duration of follow-up was 60 months. The indication for HSCT was bone marrow failure (BMF; cytopenia or aplastic anemia) in 39 patients and myelodysplasia (MDS)/acute myelogenous leukemia (AML) in 13 patients. The donor type was an HLA-matched sibling for 18 patients, an HLA-matched or mismatched relative for 6 patients, and an HLA-matched or mismatched unrelated donor for 28 patients. Preparative regimens for BMF were myeloablative in 13 patients and reduced intensity in 26. At the time of this report, 29 of the 39 patients with BMF were alive, and the 5-year overall survival was 72% (95% confidence interval, 57% to 86%). Graft failure and graft-versus-host disease were the predominant causes of death. Preparative regimens for patients with MDS/AML were myeloablative in 8 and reduced intensity in 5. At the time of this report, only 2 of 13 patients were alive (15%), with relapse the predominant cause of death. Survival after transplantation for SDS-related BMF is better compared with historical reports, but strategies are needed to overcome graft failure and graft-versus-host disease. For SDS- related MDS or AML, transplantation does not extend survival. Rigorous surveillance and novel treatments for leukemia are urgently needed.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371524PMC
August 2020

Facilitating resolution of life-threatening acute GVHD with human chorionic gonadotropin and epidermal growth factor.

Blood Adv 2020 04;4(7):1284-1295

Blood and Marrow Transplant Program, Department of Medicine.

Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation that fails to improve with intense immunosuppression in some patients. We hypothesized that urinary-derived human chorionic gonadotropin (uhCG) could help facilitate resolution of life-threatening aGVHD when added as supportive care via 2 potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF; to aid in epithelial repair). In a phase 1 study, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 receiving initial therapy for high-risk aGVHD [according to the Minnesota criteria] and 13 receiving second-line therapy). Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study. uhCG was well tolerated, with no dose-limiting toxicities. Sixty-two percent of patients in the high-risk cohort and 54% of patients in the second-line cohort had a complete response at study day 28. Plasma EGF was elevated sixfold (from 4 to 24 pg/mL; P = .02) at 6 hours postdose in the high-risk cohort, in contrast to no peak in plasma EGF in the more severe second-line cohort. After 1 week of uhCG, patients reported a twofold increase in the regulatory T cell to conventional T-cell ratio, suggesting immune modulation despite high-dose steroids. Responding patients reported significantly lower plasma amphiregulin and higher plasma butyrate levels at study completion, suggesting improvement in mucosal damage over time. uhCG is a novel, safe, supportive therapy, proceeding to phase 2 testing at 2000 units/m2 in high-risk aGVHD. This study was registered at www.clinicaltrials.gov as #NCT02525029.
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http://dx.doi.org/10.1182/bloodadvances.2019001259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160256PMC
April 2020

Author Correction: Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity.

Sci Rep 2020 Feb 19;10(1):3317. Epub 2020 Feb 19.

Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-60485-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031276PMC
February 2020

Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial.

Blood 2020 01;135(2):97-107

Blood and Marrow Transplant Program, Departments of Pediatrics and Medicine, University of Minnesota Medical School, Minneapolis, MN.

Clinical- and biomarker-based tools may identify a lower-risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced-intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted a National Heart, Lung, and Blood Institute/National Cancer Institute-funded Blood and Marrow Transplant Clinical Trials Network multicenter, open-label, randomized phase 2 trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs prednisone as initial treatment of patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus, n = 58; prednisone, n = 64). Others were AA3 (n = 4), or AA status missing (n = 1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% confidence interval [CI], 54.1%-75.5%) vs 73% (90% CI, 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone ≤0.25 mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs 31.7%; P < .001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, nonrelapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2 to 3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based SR acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. In addition, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life. This trial was registered at www.clinicaltrials.gov as #NCT02806947.
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http://dx.doi.org/10.1182/blood.2019003125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952830PMC
January 2020

Follistatin and Soluble Endoglin Predict 1-Year Nonrelapse Mortality after Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 03 10;26(3):606-611. Epub 2019 Nov 10.

Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.

Damage-associated angiogenic factors (AFs), including follistatin (FS) and soluble endoglin (sEng), are elevated in circulation at the onset of acute graft-versus-host disease (GVHD). We hypothesized that regimen-related tissue injury also might be associated with aberrant AF levels and sought to determine the relevance of these AF on nonrelapse mortality (NRM) in patients with acute GVHD and those without acute GVHD. To test our hypothesis, we analyzed circulating levels of FS, sEng, angiopoietin-2 (Ang2), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) A and B, placental growth factor (PlGF), and soluble VEGF receptor (sVEGFR)-1 and -2, in plasma samples from patients enrolled on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 (n = 221), which tested GVHD prophylaxis after myeloablative hematopoietic stem cell transplantation (HCT). We found that the interaction between FS and sEng had an additive effect in their association with 1-year NRM. In multivariate analysis, patients with the highest levels of day +28 FS and sEng had a 14.9-fold greater hazard ratio (HR) of NRM (95% confidence interval, 3.2 to 69.4; P < .01) when compared with low levels of FS and sEng. We validated these findings using an external cohort of patients (n = 106). Pre-HCT measurements of FS and sEng were not associated with NRM, suggesting that elevations in these factors early post-HCT may be consequences of early regimen-related toxicity. Determining the mechanisms responsible for patient-specific vulnerability to treatment toxicities and endothelial damage associated with specific AF elevation may guide interventions to reduce NRM post-HCT.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219549PMC
March 2020

Pediatric acute GVHD: clinical phenotype and response to upfront steroids.

Bone Marrow Transplant 2020 01 2;55(1):165-171. Epub 2019 Sep 2.

Blood and Marrow Transplant Program, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA.

To better understand the clinical phenotype of acute graft-versus-host disease (GVHD) in children, we examined the GVHD clinical stage, grade, and response to prednisone 60 mg/m/day PO in a diverse group of 370 pediatric patients with acute GVHD treated from 1990 to 2016 at a single institution. Overall response [complete response (CR) + partial response (PR)] at day 28 occurred in 65%, (CR 52%; PR 13%). Initial GVHD grade did not predict day 28 response. However, the Minnesota GVHD Risk Score predicted response with 68% standard risk (SR)-GVHD patients achieving CR/PR at day 28 versus 48% high risk (HR)-GVHD patients (p < 0.01). Multivariable analysis confirmed that response rates were lower in patients with HR-GVHD [odds ratio (OR), 0.4, p < 0.01] and in recipients of HLA mismatched URD (OR 0.4, p = 0.03). Transplant-related mortality (TRM) at 2 years was greater in HR-GVHD patients, recipients of HLA-partially matched or mismatched unrelated donor (URD) grafts, but not umbilical cord blood (UCB). These data highlight the importance of including children in novel acute GVHD treatment trials. Compared with initial GVHD grade, the Minnesota GVHD Risk Score better demarcates risk of steroid failure and TRM in children and could be used for risk stratification in pediatric acute GVHD studies.
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http://dx.doi.org/10.1038/s41409-019-0651-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940525PMC
January 2020

Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease.

JCI Insight 2019 08 8;5. Epub 2019 Aug 8.

Cancer Bioinformatics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.

Steroid-refractory intestinal acute graft-versus-host disease (aGVHD) is a frequently fatal condition with little known about mechanisms driving failed steroid responses in gut mucosa. To uncover novel molecular insights in steroid-refractory aGVHD, we compared gene expression profiles of rectosigmoid biopsies from patients at diagnosis of clinical stage 3-4 lower intestinal aGVHD (N=22), to repeat biopsies when the patients became steroid refractory (N=22), and normal controls (N=10). We also performed single gene analyses of factors associated with tolerance (programmed death ligand-1 [PDL1], indoleamine 2,3 dioxygenase [IDO1], and T cell immunoreceptor with Ig and ITIM domains [TIGIT]) and found that significantly higher expression levels of these aGVHD inhibitory genes (PDL1, IDO1, TIGIT) at aGVHD onset became decreased in the steroid-refractory state. We examined genes triggered by microbial ligands to stimulate gut repair, amphiregulin (AREG) and the aryl hydrocarbon receptor (AhR), and found that both AREG and AhR gene expression levels were increased at aGVHD onset and remained elevated in steroid-refractory aGVHD. We also identified higher expression levels of metallothioneines, metal-binding enzymes induced in stress responses, and M2 macrophage genes in steroid-refractory aGVHD. We observed no differences in T-cell subsets between onset and steroid-refractory aGVHD. Patients with a rapidly fatal course showed greater DNA damage and a distinct microbial signature at aGVHD onset, whereas patients with more prolonged survival exhibited a gene expression profile consistent with activation of Smoothened. Our results extend the paradigm beyond T cell-centric therapies for steroid-refractory GI aGVHD and highlight new mechanisms for therapeutic exploration.
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http://dx.doi.org/10.1172/jci.insight.129762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777917PMC
August 2019

Outcomes and Predictors of Response in Steroid-Refractory Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2019 11 17;25(11):2297-2302. Epub 2019 Jul 17.

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

The prognosis of steroid-refractory acute graft-versus-host disease (aGVHD) is poor, and predictors of response and survival are unclear. In an exploratory analysis of 203 steroid-refractory aGVHD patients with prospectively collected GVHD data who received antithymocyte globulin, etanercept, or mycophenolate mofetil (MMF) as second-line treatment, we determined the predictors of day 28 response, 2-year overall survival, and 2-year nonrelapse mortality (NRM). To minimize the risk of finding false-positive results, we used least absolute shrinkage and selection operator regression, aggressively eliminating variables that are unlikely to be associated with outcome. Day 28 response to second-line therapy was 38% (complete response, 23%), with a 2-year overall survival of 25% and a 2-year NRM of 62%. Factors associated with response were GVHD prophylaxis, organ involvement, and initial aGVHD to steroid-refractory aGVHD interval. Specifically, compared with cyclosporine/MMF as GVHD prophylaxis, the odds ratio (OR) for calcineurin inhibitor/methotrexate was .8 and for cyclosporine/prednisone .6. The OR for aGVHD to steroid-refractory aGVHD interval ≥ 14 versus <14 days was 1.3. The ORs for skin only involvement and gut or liver only involvement when compared with multiorgan involvement were 1.4 and 1.2, respectively. The only variable associated with worse survival was age, with a hazard ratio (HR) per decade of 1.04 for overall mortality. Similarly, age was the only variable associated with NRM (HR per decade, 1.02). When compared with complete response, no response at day 28 increased the risk of death (HR, 2.4; 95% confidence interval, 1.5 to 3.7). In conclusion, by means of an underused statistical technique in the field of transplantation, we identified predictors of response and survival in steroid-refractory aGVHD. Our results highlight the importance of developing novel treatment strategies because current treatments yield poor outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861661PMC
November 2019

Validation of Minnesota acute graft--host disease Risk Score.

Haematologica 2020 31;105(2):519-524. Epub 2020 Jan 31.

Blood and Marrow Transplant Program, University of Minnesota Medical School, Minneapolis, MN.

Using multicenter data, we developed a novel acute graft--host disease Risk Score which more accurately predicts response to steroid treatment, survival and transplant related mortality than other published risk scores based upon clinical grading criteria. To validate this Risk Score in a contemporary cohort, we examined 355 recent University of Minnesota patients (2007-2016) diagnosed with acute graft--host disease and treated with prednisone 60 mg/m/day for 14 days, followed by an 8-week taper. Overall response [complete response + partial response] was higher in the 276 standard risk 79 high risk graft--host disease patients at day 14 (71% 56%, <0.01), day 28 (74% versus 59%, =0.02) and day 56 (68% 49%, <0.01) after steroid initiation. Day 28 response did not differ by the initial graft--host disease grade. In multiple regression analysis, patients with high risk graft--host disease were less likely to respond at day 28 (odds ratio 0.5, 95% CI 0.3-0.9, <0.01) and had higher risks of 2 year transplant related mortality (Hazard Ratio 1.8, 95% CI, 1.0-2.1, =0.03) and overall mortality (Hazard Ratio 1.7, 95% CI, 1.2-2.4, <0.01) than patients with a standard risk graft--host disease. This analysis confirms the Minnesota graft--host disease Risk Score as a valuable bedside tool to define risk in patients with acute graft--host disease. A tailored approach to upfront acute graft--host disease therapy based upon the Minnesota Risk Score may improve outcomes and facilitate testing of novel treatments in these patients.
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http://dx.doi.org/10.3324/haematol.2019.220970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012472PMC
April 2021

Dynamic Graft-versus-Host Disease-Free, Relapse-Free Survival: Multistate Modeling of the Morbidity and Mortality of Allotransplantation.

Biol Blood Marrow Transplant 2019 09 22;25(9):1884-1889. Epub 2019 May 22.

Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.

Graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents complete, ideal recovery after allogeneic hematopoietic cell transplantation (HCT). However, as originally proposed, this composite endpoint does not account for the possibility that HCT complications may improve after treatment. To more accurately estimate survival with response to GVHD and relapse after HCT, we developed a dynamic multistate GRFS (dGRFS) model with outcomes data from 949 patients undergoing their first allogeneic HCT for hematologic malignancy at the University of Minnesota. Because some patients were successfully treated for GVHD and relapse, dGRFS was higher than the originally defined time-to-event GRFS at 1 year (37.0 versus 27.6%) through 4 years (37.4% versus 22.2%). Mean survival without failure events was .52 years (95% confidence interval, .45 to .58 year) greater in dGRFS compared with the originally defined GRFS. Patient age (P< .001), disease risk (P < .001), conditioning intensity (P = .007), and donor type (P = .003) all significantly influenced dGRFS. The multistate model of dGRFS closely estimates the continuing and prevalent severe morbidity and mortality of allogeneic HCT. To serve the greater HCT community in more accurately modeling recovery from transplantation, we provide our R code for determination of dGRFS with annotations in Supplementary Materials.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755055PMC
September 2019

GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia.

Blood Adv 2019 05;3(9):1441-1449

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB ( < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.
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http://dx.doi.org/10.1182/bloodadvances.2018030171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517657PMC
May 2019

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203).

Lancet Haematol 2019 Mar;6(3):e132-e143

Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.

Background: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial.

Methods: In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m intravenous bolus on day 1 and 10 mg/m intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037.

Findings: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively).

Interpretation: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial.

Funding: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.
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http://dx.doi.org/10.1016/S2352-3026(18)30221-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503965PMC
March 2019

Pretransplant Serum Citrulline Predicts Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2018 11 7;24(11):2190-2196. Epub 2018 Jul 7.

Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.

Post-transplant biomarkers of acute graft-versus-host disease (aGVHD) and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) have been extensively studied. However, pretransplant biomarkers may provide a greater window of opportunity to intervene. We measured serum biomarkers of various aspects of gut barrier physiology before HCT (median, day -7) and 7 and 28 days post-HCT in 95 consecutive allo-HCT recipients enrolled in an open-label biorepository protocol. Biomarkers included citrulline for total functional enterocyte mass, Reg3a for antibacterial activity of the gut, and intestinal fatty acid binding protein (I-FABP) for enterocyte turnover. Compared to 16 healthy control subjects, we demonstrated that patients came to transplant with abnormal levels of all 3 biomarkers (P < .05), reflecting residual damage from prior chemotherapy. All 3 biomarkers initially declined from pre-HCT to day +7 (more pronounced after myeloablative than reduced-intensive conditioning) followed by a recovery phase and return toward pre-HCT values by day +28. A lower pre-HCT citrulline was independently associated with a higher risk of aGVHD grades II to IV (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.69; P = .02), and this association was not specific to gut GVHD. The strongest correlate of NRM was a higher level of Reg3a at day +7 (P < .001). I-FABP did not predict transplant outcomes. In conclusion, pre-HCT serum citrulline levels identify patients at high risk for developing aGVHD. Our results suggest that pre-HCT interventions to augment the gut barrier may decrease the risk of aGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251308PMC
November 2018

Amphiregulin in intestinal acute graft-versus-host disease: a possible diagnostic and prognostic aid.

Mod Pathol 2019 04 13;32(4):560-567. Epub 2018 Nov 13.

Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, MN, USA.

Amphiregulin, a weak epidermal growth factor receptor agonist, is elevated, while epidermal growth factor, a strong epidermal growth factor receptor agonist, is low in the blood of patients with severe acute graft-versus-host disease. However, the tissue expression and function of these epidermal growth factor receptor ligands in acute graft-versus-host disease target organs is unknown. We compared by immunohistochemistry expression of amphiregulin and epidermal growth factor in archived, formalin-fixed, paraffin-embedded intestinal tissues of 48 patients with biopsy-proven gastrointestinal acute graft-versus-host disease to 3 groups: (1) 10 non-hematopoietic cell transplant normal controls, (2) 11 patients with newly diagnosed ulcerative colitis (ulcerative colitis), (3) 8 patients with a clinical diagnosis of acute graft-versus-host disease despite pathologically non-diagnostic biopsies, (4) and 10 cases of cytomegalovirus colitis. We used a semi-quantitative score of 0 (absent) through 3 (strong) to describe the intensity of immunohistochemical staining. We correlated serum and tissue amphiregulin and epidermal growth factor in patients with acute graft-versus-host disease. Gastrointestinal amphiregulin was significantly lower in acute graft-versus-host disease biopsies (median score 1), ulcerative colitis (median score 1.5), and cytomegalovirus colitis (median score 1) than in normal colon (median score 2, p = 0.004, p = 0.03, p = 0.009 respectively). Amphiregulin expression in was low in 74% of acute graft-versus-host disease cases with or without significant apoptosis. Patients with acute graft-versus-host disease exhibiting the pattern of high gastrointestinal amphiregulin but low serum amphiregulin (n = 14) had the best 1-year survival at 71%, but patients with high serum amphiregulin had poorer survival (<30%) regardless of gastrointestinal amphiregulin expression. Overall, our results lead to the hypothesis that amphiregulin is released into the circulation from damaged intestinal epithelium and stroma, although contributions from other cellular sources are likely. Low gastrointestinal amphiregulin expression by immunohistochemistry may be further studied for its utility in the pathologic acute graft-versus-host disease diagnosis without classic apoptotic changes.
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http://dx.doi.org/10.1038/s41379-018-0170-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941942PMC
April 2019
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