Publications by authors named "Michael R Verneris"

173 Publications

Indirect comparison of tisagenlecleucel and blinatumomab in pediatric relapsed/refractory acute lymphoblastic leukemia.

Blood Adv 2021 Oct 1. Epub 2021 Oct 1.

Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, United States.

In the absence of head-to-head trials, an indirect-treatment comparison can estimate the treatment effect of tisagenlecleucel in comparison with blinatumomab on rates of complete remission (CR) and overall survival (OS) in patients with relapsed or primary refractory (R/R) acute lymphoblastic leukemia (ALL). Patient-level data from two pivotal trials, ELIANA (tisagenlecleucel; n = 79) and MT103-205 (blinatumomab; n = 70), were used in comparisons of CR and OS, controlling for cross-trial difference in available patient characteristics. Five different adjustment approaches were implemented: stabilized inverse probability of treatment weight (sIPTW); trimmed sIPTW; stratification by propensity score quintiles; adjustment for prognostic factors; and adjustment for both prognostic factors and propensity score. Comparative analyses indicate that treatment with tisagenlecleucel was associated with a statistically significant higher likelihood of achieving CR and lower hazard of death than treatment with blinatumomab. The tisagenlecleucel group exhibited a higher likelihood of CR than the blinatumomab group in every analysis regardless of adjustment approach (odds ratios: 6.71-9.76). Tisagenlecleucel was also associated with a lower hazard of death than blinatumomab in every analysis, ranging from 68% to 74% lower hazard of death than with blinatumomab, determined using multiple adjustment approaches (hazard ratios: 0.26-0.32). These findings support the growing body of clinical trial and real-world evidence demonstrating that tisagenlecleucel is an important treatment option for children and young adults with R/R ALL.
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http://dx.doi.org/10.1182/bloodadvances.2020004045DOI Listing
October 2021

Comparison of haploidentical and umbilical cord blood transplantation after myeloablative conditioning.

Blood Adv 2021 Oct;5(20):4064-4072

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

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has emerged as an important treatment modality. Most reports comparing haplo-HSCT with posttransplant cyclophosphamide (PTCy) and other donor sources have focused on outcomes in older adults treated with reduced intensity conditioning. Therefore, in the current study, we evaluated outcomes in patients with hematological malignancy treated with myeloablative conditioning prior to haplo- (n = 375) or umbilical cord blood (UCB; n = 333) HSCT. All haplo recipients received a 4 of 8 HLA-matched graft, whereas recipients of UCB were matched at 6-8/8 (n = 145) or ≤5/8 (n = 188) HLA antigens. Recipients of 6-8/8 UCB transplants were younger (14 years vs 21 and 29 years) and more likely to have lower comorbidity scores compared with recipients of ≤5/8 UCB and haplo-HSCT (81% vs 69% and 63%, respectively). UCB recipients were more likely to have acute lymphoblastic leukemia and transplanted in second complete remission (CR), whereas haplo-HSCT recipients were more likely to have acute myeloid leukemia in the first CR. Other characteristics, including cytogenetic risk, were similar. Survival at 3 years was similar for the donor sources (66% haplo- and 61% after ≤5/8 and 58% after 6-8/8 UCB). Notably, relapse at 3 years was lower in recipients of ≤5/8 UCB (21%, P = .03) compared with haplo- (36%) and 6-8/8 UCB (30%). However, nonrelapse mortality was higher in ≤5/8 UCB (21%) compared with other groups (P < .0001). These data suggest that haplo-HSCT with PTCy after myeloablative conditioning provides an overall survival outcome comparable to that after UCB regardless HLA match group.
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http://dx.doi.org/10.1182/bloodadvances.2021004462DOI Listing
October 2021

Donor Killer Immunoglobulin Receptor Gene Content and Ligand Matching and Outcomes of Pediatric Patients with Juvenile Myelomonocytic Leukemia Following Unrelated Donor Transplantation.

Transplant Cell Ther 2021 Aug 15. Epub 2021 Aug 15.

Division of Pediatric Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio; Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio.

Natural killer (NK) cell determinants predict relapse-free survival after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia, and previous studies have shown a beneficial graft-versus-leukemia effect in patients with juvenile myelomonocytic leukemia (JMML). However, whether NK cell determinants predict protection against relapse for JMML patients undergoing HCT is unknown. Therefore, we investigated NK cell-related donor and recipient immunogenetics as determinants of HCT outcomes in patients with JMML. Patients with JMML (age 0 to <19 years) who underwent a first allogeneic HCT from an unrelated donor between 2000 and 2017 and had available donor samples from the Center for International Blood and Marrow Transplant Research Repository were included. Donor killer immunoglobulin receptor (KIR) typing was performed on pre-HCT samples. The primary endpoint was disease-free survival (DFS); secondary endpoints included relapse, grade II-IV acute graft versus-host-disease (aGVHD), chronic GVHD (cGVHD), GVHD-free relapse-free survival, transplantation-related mortality, and overall survival (OS). Donor KIR models tested included KIR genotype (AA versus Bx), B content (0-1 versus ≥2), centromeric and telomeric region score (AA versus AB versus BB), B content score (best, better, or neutral), composite score (2 versus 3 versus 4), activating KIR content, and the presence of KIR2DS4. Ligand-ligand and KIR-ligand mismatch effects on outcomes were analyzed in HLA-mismatched donors (≤7/8; n = 74) only. Univariate analyses were performed for primary and secondary outcomes of interest, with a P value <.05 considered significant. One hundred sixty-five patients (113 males), with a median follow-up of 85 months (range, 6 to 216 months) met the study criteria. Of these, 111 underwent an unrelated donor HCT and 54 underwent a UCB HCT. Almost all (n = 161; 98%) received a myeloablative conditioning regimen. After exclusion of recipients of reduced-intensity/nonmyeloablative conditioning regimens and ex vivo T cell-depleted grafts (n = 8), there were 42 AA donors and 115 Bx donors, respectively. Three-year DFS, OS, relapse, and GRFS for the entire cohort were 58% (95% confidence interval [CI], 50% to 66%), 67% (95% CI, 59% to 74%), 26% (95% CI, 19% to 33%), and 27% (95% CI, 19% to 35%), respectively. The cumulative incidence of grade II-IV aGVHD at 100 days was 36% (95% CI, 27% to 44%), and that of cGVHD at 1 year was 23% (95% CI, 17% to 30%). There were no differences between AA donors and Bx donors for any recipient survival outcomes. The risk of grade II-IV aGVHD was lower in patients with donors with a B content score of ≥2 (hazard ratio [HR], 0.46; 95% CI, 0.26 to 0.83; P = .01), an activating KIR content score of >3 (HR, 0.52; 95% CI, 0.29 to 0.95; P = .032), centromeric A/B score (HR, 0.57; 95% CI, 033 to 0.98; P = .041), and telomeric A/B score (HR, 0.58; 95% CI, 0.34 to 1.00; P = .048). To our knowledge, this is the first study analyzing the association of NK cell determinants and outcomes in JMML HCT recipients. This study identifies potential benefits of donor KIR-B genotypes in reducing aGVHD. Our findings warrant further study of the role of NK cells in enhancing the graft-versus-leukemia effect via recognition of JMML blasts.
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http://dx.doi.org/10.1016/j.jtct.2021.08.009DOI Listing
August 2021

Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia.

J Immunother Cancer 2021 Aug;9(8)

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse.

Methods: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel.

Results: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion.

Conclusions: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.
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http://dx.doi.org/10.1136/jitc-2020-002287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344270PMC
August 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

Neither Donor nor Recipient Mitochondrial Haplotypes Are Associated with Unrelated Donor Transplant Outcomes: A Validation Study from the CIBMTR.

Transplant Cell Ther 2021 10 23;27(10):836.e1-836.e7. Epub 2021 Jun 23.

University of Colorado Denver, Children's Cancer and Blood Disorders, Denver, Colorado.

Graft-versus-host-disease (GVHD) is a multistep process that involves T-cell recognition and priming toward alloantigen, expansion, acquisition of effector function, and repeated tissue injury, resulting in clinical manifestations of the disease. All of these processes have considerable metabolic demands and understanding the key role of mitochondria in cellular metabolism as it relates to GVHD has increased significantly. Mitochondrial DNA (mtDNA) haplotypes have been linked to functional differences in vitro, suggesting they have functional differences at an organismal level. We previously used mtDNA typing to assess the impact of mtDNA haplotypes on outcomes of ~400 allo-HCT patients. This pilot study identified uncommon mtDNA haplotypes potentially associated with inferior outcomes. We sought to validate pilot findings of associations between donor and recipient mitochondrial haplotypes and transplant outcome. We examined a cohort of 4143 donor-recipient pairs obtained from the Center for International Blood and Marrow Transplant Research. MtDNA was extracted from whole blood or peripheral blood mononuclear cells from donors and recipients and sequenced to discern haplotype. We used multiple regression analysis to examine the independent association of mtDNA haplotype with overall survival and grade III-IV acute GVHD (aGVHD) adjusting for known risk factors for poor transplant outcome. Neither recipient nor donor mtDNA haplotype reached groupwise significance for overall survival (P =.26 and .39, respectively) or grade III-IV aGVHD (P = .68 and.57, respectively). Adjustment for genomically determined ancestry in the subset of donor-recipient pairs for which this was available did not materially change results. We conclude that our original finding was due to chance in a small sample size and that there is essentially no evidence that mtDNA haplotype or haplotype mismatch contributes to risk of serious outcomes after allogeneic transplantation.
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http://dx.doi.org/10.1016/j.jtct.2021.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478819PMC
October 2021

Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes.

Front Immunol 2021 29;12:607282. Epub 2021 Mar 29.

Division of Medical Oncology, School of Medicine, University of Colorado, Aurora, CO, United States.

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2Il2rγSIRPα (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of "responding" patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.
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http://dx.doi.org/10.3389/fimmu.2021.607282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040953PMC
July 2021

Perspectives on outpatient administration of CAR-T cell therapy in aggressive B-cell lymphoma and acute lymphoblastic leukemia.

J Immunother Cancer 2021 04;9(4)

BMT & Cell Therapy Program, Division of Hematology/Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.

Chimeric antigen receptor (CAR) T-cell therapies that specifically target the CD19 antigen have emerged as a highly effective treatment option in patients with refractory B-cell hematological malignancies. Safety and efficacy outcomes from the pivotal prospective clinical trials of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel and the retrospective, postmarketing, real-world analyses have confirmed high response rates and durable remissions in patients who had failed multiple lines of therapy and had no meaningful treatment options. Although initially administered in the inpatient setting, there has been a growing interest in delivering CAR-T cell therapy in the outpatient setting; however, this has not been adopted as standard clinical practice for multiple reasons, including logistic and reimbursement issues. CAR-T cell therapy requires a multidisciplinary approach and coordination, particularly if given in an outpatient setting. The ability to monitor patients closely is necessary and proper protocols must be established to respond to clinical changes to ensure efficient, effective and rapid evaluation either in the clinic or emergency department for management decisions regarding fever, sepsis, cytokine release syndrome and neurological events, specifically immune effector cell-associated neurotoxicity syndrome. This review presents the authors' institutional experience with the preparation and delivery of outpatient CD19-directed CAR-T cell therapy.
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http://dx.doi.org/10.1136/jitc-2020-002056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047987PMC
April 2021

An Immune Recovery-Based Revaccination Protocol for Pediatric Hematopoietic Stem Cell Transplant Recipients: Revaccination Outcomes Following Pediatric HSCT.

Transplant Cell Ther 2021 04 28;27(4):317-326. Epub 2021 Jan 28.

Division of Pediatric Infectious Diseases, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, Colorado.

Following hematopoietic stem cell transplant (HSCT), patients are at increased risk of vaccine-preventable diseases (VPDs) and experience worse outcomes of VPDs compared to immunocompetent patients. Therefore, patients are routinely vaccinated post-HSCT to restore VPD immunity. Published guidelines recommend revaccination based on time post-HSCT, although optimal revaccination timing and the value of using other clinical and laboratory variables to guide revaccination remain unclear. An institutional immune recovery-based protocol to guide timing of revaccination is used at Children's Hospital Colorado. This protocol incorporates time from transplant, time off immunosuppressive therapy and intravenous immunoglobulin replacement, absence of active graft-versus-host disease (GVHD), and minimum absolute CD4 count, absolute lymphocyte count (ALC), and immunoglobulin G (IgG) levels. The objective of this study is to evaluate the performance of this immune recovery-based revaccination protocol by determining rates of seroprotective vaccine responses achieved and describing demographic, clinical, and laboratory markers associated with protective antibody titers post-revaccination. Rates of seroprotection following revaccination were retrospectively determined for patients who received autologous or allogeneic HSCTs at Children's Hospital Colorado from 2007 to 2017. Percent seropositivity after revaccination was determined for ten VPDs: measles, mumps, rubella, varicella, tetanus, diphtheria, Haemophilus influenzae type B (Hib), poliovirus, hepatitis B virus (HBV), and Streptococcus pneumoniae. The impact of covariates, including post-HSCT vaccine timing, patient demographics, clinical features (diagnosis, donor and conditioning regimen data, GVHD, cytomegalovirus disease), and laboratory parameters (CD4 count, ALC, IgG level), on rates of seroprotection post-revaccination was determined using Wilcoxon rank sum, Fisher's exact, or chi-square tests, as appropriate. One hundred-twelve unique patients among 427 HSCT recipients had available data for both revaccination timing and vaccine titers. Among these, high rates of seroprotection were achieved after revaccination for rubella (100%), diphtheria (100%), tetanus (100%), and Hib (98%). More modest rates of seroprotection were achieved after revaccination with HBV (87%) and pneumococcal conjugate (85%) vaccines. Seroprotection was lower after revaccination with measles (76%), pneumococcal polysaccharide (72%), mumps (67%), and varicella (25%) vaccines. Greater rates of seroprotection were associated with younger age (hepatitis B vaccine, P = .04), lack of prior rituximab treatment (pneumococcal conjugate vaccine, P = .005), lack of total body irradiation (pneumococcal conjugate vaccine, P = .03), and receipt of a non-cord blood transplant (pneumococcal polysaccharide vaccine, P = .04). These results suggest that a revaccination protocol that incorporates both time post-HSCT and patient-specific indicators of immunologic recovery can achieve high rates of seroprotection against most VPDs. Seroprotection rates for HBV and PCV were notably among the highest reported in children post-HSCT, suggesting that an immune recovery-based protocol may improve seroprotection for some VPDs that frequently are associated with lower vaccine responses post-HSCT. Seroprotection rates for other VPDs remained suboptimal after revaccination. Therefore, evaluation of additional strategies, such as the use of novel markers of immune competence and new vaccines, to further optimize protection against VPDs in this population is warranted.
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http://dx.doi.org/10.1016/j.jtct.2021.01.017DOI Listing
April 2021

Phase I Dose-Finding, Safety, and Tolerability Trial of Romiplostim to Improve Platelet Recovery After UCB Transplantation.

Transplant Cell Ther 2021 06 2;27(6):497.e1-497.e6. Epub 2021 Mar 2.

Division of Pediatric Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota. Electronic address:

Platelet recovery is delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that has the potential to improve platelet engraftment after UCBT. The purpose of this study was to determine the safety profile and maximum tolerated dose (MTD) of romiplostim and to investigate whether romiplostim accelerates platelet recovery post-UCBT. It was a single-center, dose-finding, safety and tolerability phase I trial of weekly romiplostim in 20 adult patients who failed to achieve an un-transfused platelet count of 20 × 10/L by day +28 post-UCBT. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post-UCBT. Four dose levels (4, 6, 8, and 10 µg/kg per dose) were evaluated. The MTD of romiplostim was determined by the continual reassessment method, with a goal to identify a dose level with desired toxicity rate of ≤20%. Median age of the patients was 59.5 years, and 60% were female. Eleven patients received nonmyeloablative (NMA) double UCBT, seven patients received myeloablative single UCBT, and two patients received NMA single UCBT. Two patients received 4 µg/kg per dose, two received 6 µg/kg per dose, four received 8 µg/kg per dose, and the remaining 12 received 10 µg/kg per dose. Only five patients completed the full six doses of treatment. Of the 15 patients who received fewer than six doses, 12 were due to a platelet count of >100 × 10/L, two were due to platelet count of >400 × 10/L, and one was due to right upper extremity edema without thrombosis. All romiplostim-treated patients achieved platelet engraftment to 20 × 10/L at a median of 45 days post-UCBT compared to 90% of controls at a median of 45 days (P = .08). Similarly, 90% of romiplostim-treated patients achieved platelet engraftment to 50 × 10/L at a median of 48 days compared to 75% of controls at a median of 52 days (P = .09). All dose levels were effective with low toxicity; therefore, the MTD of romiplostim was 10 µg/kg per dose, and romiplostim is a safe and potentially effective therapy to counter delayed platelet recovery post-UCBT.
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http://dx.doi.org/10.1016/j.jtct.2021.02.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217114PMC
June 2021

Therapeutic manipulation of innate lymphoid cells.

JCI Insight 2021 03 22;6(6). Epub 2021 Mar 22.

Since their relatively recent discovery, innate lymphoid cells (ILCs) have been shown to be tissue-resident lymphocytes that are critical mediators of tissue homeostasis, regeneration, and pathogen response. However, ILC dysregulation contributes to a diverse spectrum of human diseases, spanning virtually every organ system. ILCs rapidly respond to environmental cues by altering their own phenotype and function as well as influencing the behavior of other local tissue-resident cells. With a growing understanding of ILC biology, investigators continue to elucidate mechanisms that expand our ability to phenotype, isolate, target, and expand ILCs ex vivo. With mounting preclinical data and clinical correlates, the role of ILCs in both disease pathogenesis and resolution is evident, justifying ILC manipulation for clinical benefit. This Review will highlight areas of ongoing translational research and critical questions for future study that will enable us to harness the full therapeutic potential of these captivating cells.
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http://dx.doi.org/10.1172/jci.insight.146006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026185PMC
March 2021

Glycemic variability is associated with poor outcomes in pediatric hematopoietic stem cell transplant patients.

Pediatr Blood Cancer 2020 11 16;67(11):e28626. Epub 2020 Aug 16.

Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Colorado.

Background: Among pediatric hematopoietic stem cell transplant (HSCT) recipients, abnormal glycemic control is shown to be associated with increased risk of transplant-related mortality, death from any cause, risk of infection, increased hospitalized, and intensive care days. Independent effects of higher glycemic variability, a component of glycemic control, have not been described. This study aimed to characterize risk factors for, and consequences of, higher glycemic variability in HSCT patients.

Procedure: Medical records for a cohort of 344 patients, age 0-30 years, who underwent first HSCT from 2007 to 2016 at Children's Hospital Colorado were retrospectively reviewed. Glucose coefficients of variation (CV) were analyzed for HSCT days -14 to 0 and 0-30, and patients were assessed for potential risk factors and outcomes.

Results: Roughly one-third of patients had pre-HSCT and day 0-30 glucose CV above the reported healthy adult range. Independent of HSCT type, doubling of pre-HSCT glucose CV was associated with a 4.91-fold (95% confidence interval [CI], 1.40-17.24) increased hazard of infection, as well as increased risk for intensive care hospitalization for allogenic HSCT patients. Multivariable analysis demonstrated that allogeneic HSCT patients had a 1.40- and 1.38-fold (95% CI, 0.98-1.99 and 1.00-1.91) increased hazard of death for every doubling of pre-HSCT and day 0-30 glucose CV, respectively.

Conclusions: Just as with higher mean glucose, higher glycemic variability in the pediatric HSCT population is independently associated with significantly increased morbidity. Additional research is required to evaluate the utility of glucose control to mitigate these relationships and improve HSCT outcomes.
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http://dx.doi.org/10.1002/pbc.28626DOI Listing
November 2020

Targeting Tumor-Associated Macrophages in the Pediatric Sarcoma Tumor Microenvironment.

Front Oncol 2020 14;10:581107. Epub 2020 Dec 14.

Department of Pediatric Hematology/Oncology/Bone Marrow Transplant, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO, United States.

For many pediatric sarcoma patients, multi-modal therapy including chemotherapy, radiation, and surgery is sufficient to cure their disease. However, event-free and overall survival rates for patients with more advanced disease are grim, necessitating the development of novel therapeutic approaches. Within many pediatric sarcomas, the normal immune response, including recognition and destruction of cancer cells, is lost due to the highly immune suppressive tumor microenvironment (TME). In this setting, tumor cells evade immune detection and capitalize on the immune suppressed microenvironment, leading to unchecked proliferation and metastasis. Recent preclinical and clinical approaches are aimed at understanding this immune suppressive microenvironment and employing cancer immunotherapy in an attempt to overcome this, by renewing the ability of the immune system to recognize and destroy cancer cells. While there are several factors that drive the attenuation of immune responses in the sarcoma TME, one of the most remarkable are tumor associated macrophage (TAMs). TAMs suppress immune cytolytic function, promote tumor growth and metastases, and are generally associated with a poor prognosis in most pediatric sarcoma subtypes. In this review, we summarize the mechanisms underlying TAM-facilitated immune evasion and tumorigenesis and discuss the potential therapeutic application of TAM-focused drugs in the treatment of pediatric sarcomas.
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http://dx.doi.org/10.3389/fonc.2020.581107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769312PMC
December 2020

Human innate lymphoid cell precursors express CD48 that modulates ILC differentiation through 2B4 signaling.

Sci Immunol 2020 11;5(53)

Department of Pediatric, Division of Children's Cancer and Blood Disorders, University of Colorado and Children's Hospital of Colorado, Research Complex 1, North Tower, 12800 E. 19th Ave., Mail Stop 8302, Room P18-4108, Aurora, CO 80045, USA.

Innate lymphoid cells (ILCs) develop from common lymphoid progenitors (CLPs), which further differentiate into the common ILC progenitor (CILP) that can give rise to both ILCs and natural killer (NK) cells. Murine ILC intermediates have recently been characterized, but the human counterparts and their developmental trajectories have not yet been identified, largely due to the lack of homologous surface receptors in both organisms. Here, we show that human CILPs (CD34CD117α4β7Lin) acquire CD48 and CD52, which define NK progenitors (NKPs) and ILC precursors (ILCPs). Two distinct NK cell subsets were generated in vitro from CD34CD117α4β7LinCD48CD52 and CD34CD117α4β7LinCD48CD52 NKPs, respectively. Independent of NKPs, ILCPs exist in the CD34CD117α4β7LinCD48CD52 subset and give rise to ILC1s, ILC2s, and NCR ILC3s, whereas CD34CD117α4β7LinCD48CD52 ILCPs give rise to a distinct subset of ILC3s that have lymphoid tissue inducer (LTi)-like properties. In addition, CD48-expressing CD34CD117α4β7Lin precursors give rise to tissue-associated ILCs in vivo. We also observed that the interaction of 2B4 with CD48 induced differentiation of ILC2s, and together, these findings show that expression of CD48 by human ILCPs modulates ILC differentiation.
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http://dx.doi.org/10.1126/sciimmunol.aay4218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294935PMC
November 2020

A validated pediatric disease risk index for allogeneic hematopoietic cell transplantation.

Blood 2021 02;137(7):983-993

Center for International Blood and Marrow Transplant Research, Department of Medicine, and.

A disease risk index (DRI) that was developed for adults with hematologic malignancy who were undergoing hematopoietic cell transplantation is also being used to stratify children and adolescents by disease risk. Therefore, to develop and validate a DRI that can be used to stratify those with AML and ALL by their disease risk, we analyzed 2569 patients aged <18 years with acute myeloid (AML; n = 1224) or lymphoblastic (ALL; n = 1345) leukemia who underwent hematopoietic cell transplantation. Training and validation subsets for each disease were generated randomly with 1:1 assignment to the subsets, and separate prognostic models were derived for each disease. For AML, 4 risk groups were identified based on age, cytogenetic risk, and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2, 3, 5), high (7, 8), and very high (>8) risk groups was 78%, 53%, 40%, and 25%, respectively (P < .0001). For ALL, 3 risk groups were identified based on age and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2-4), and high (≥5) risk groups was 68%, 51%, and 33%, respectively (P < .0001). We confirmed that the risk groups could be applied to overall survival, with 5-year survival ranging from 80% to 33% and 73% to 42% for AML and ALL, respectively (P < .0001). This validated pediatric DRI, which includes age and residual disease status, can be used to facilitate prognostication and stratification of children with AML and ALL for allogeneic transplantation.
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http://dx.doi.org/10.1182/blood.2020009342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918183PMC
February 2021

Therapeutic effect of TRC105 and decitabine combination in AML xenografts.

Heliyon 2020 Oct 13;6(10):e05242. Epub 2020 Oct 13.

Dept. of Medicine, University of Minnesota, Minneapolis, MN, USA.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, often characterized by poor prognosis following standard induction therapy. The hypomethylating agent decitabine (DAC) is an alternative treatment for elderly and relapsed/refractory AML patients, yet responses following DAC monotherapy are still modest. The transforming growth factor-β (TGF-β) receptor CD105 (endoglin) is expressed in various hematopoietic malignancies, and high CD105 expression correlates with poor prognosis in AML patients. Using a xenograft model, we have recently demonstrated that targeting CD105 AML blasts with the TRC105 monoclonal antibody inhibits leukemia progression. Here we investigated whether administration of TRC105 along with DAC could represent a novel therapeutic option for relapsed/refractory AML. Our data show that the DAC/TRC105 combination results in a more durable anti-leukemic effect in AML xenografts compared to DAC monotherapy. Moreover, the DAC/TRC105 combination enhanced reactive oxygen species (ROS) activity, which correlated with reduced leukemia burden. RNA-sequencing studies suggest that TRC105 may alter TGF-β activity in AML blasts. Taken together, these findings provide rationale for the clinical evaluation of TRC105 in combination with DAC in AML patients.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566100PMC
October 2020

Autoimmune cytopenias following allogeneic hematopoietic stem cell transplant in pediatric patients: Response to therapy and late effects.

Pediatr Blood Cancer 2020 09 13;67(9):e28591. Epub 2020 Jul 13.

Children's Hospital Colorado, Division of Pediatric Hematology/Oncology/Bone Marrow Transplant, Colorado, University of Colorado Anschutz Medical Campus, Aurora.

Background: Autoimmune cytopenias (AICs) are rare, but serious complications of allogeneic hematopoietic cell transplantation (allo-HSCT).

Procedure: We performed a case-control study using 20 pediatric AIC cases and 40 controls, matched by stem cell source and primary indication comparing clinical and transplant characteristics, treatment, outcomes, and late effects.

Results: Cases were more likely to be human leukocyte antigen mismatched (P = 0.04). There was no difference in conditioning regimen, serotherapy use, graft-versus-host disease (GVHD) prophylaxis, incidence of acute or chronic GVHD, ABO compatibility, infections, and donor engraftment. The median time to AIC onset was 219 days (range, 97-1205 days) and AIC resolution was 365 days (range, 10 days to 2737.5 days). First-line therapies for AIC patients most commonly included corticosteroids (75%) and rituximab (55%). Only 25% of patients responded to first-line treatment. At a median of 611.5 days from last rituximab dose, 82.5% patients were still receiving intravenous immune globulin for hypogammaglobulinemia compared with 2.5% of controls (P < 0.0001). Iron overload was higher in AIC patients (P = 0.0004), as was avascular necrosis (P = 0.04). There was no difference in overall survival at one year after HSCT (85% vs 82.5%). Two patients with refractory autoimmune hemolytic anemia responded to daratumumab and had resolution of B-cell aplasia.

Conclusions: In this study, we find poor initial responses to AIC-directed therapies and significant late effects.
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http://dx.doi.org/10.1002/pbc.28591DOI Listing
September 2020

Prolactin Acts on Myeloid Progenitors to Modulate SMAD7 Expression and Enhance Hematopoietic Stem Cell Differentiation into the NK Cell Lineage.

Sci Rep 2020 04 14;10(1):6335. Epub 2020 Apr 14.

University of Colorado and Children's Hospital of Colorado, Department of Pediatrics, Center for Cancer and Blood Disorders. Research Complex 1, North Tower, 12800 E. 19th Ave., Mail Stop 8302, Room P18-4108, Aurora, CO, 80045, USA.

Numerous cell types modulate hematopoiesis through soluble and membrane bound molecules. Whether developing hematopoietic progenitors of a particular lineage modulate the differentiation of other hematopoietic lineages is largely unknown. Here we aimed to investigate the influence of myeloid progenitors on CD34 cell differentiation into CD56 innate lymphocytes. Sorted CD34 cells cultured in the presence of stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand (FLT3L) give rise to numerous cell types, including progenitors that expressed the prolactin receptor (PRLR). These CD34PRLR myeloid-lineage progenitors were derived from granulocyte monocyte precursors (GMPs) and could develop into granulocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Moreover, CD34PRLR myeloid progenitors lacked lymphoid developmental potential, but when stimulated with prolactin (PRL) they increased the differentiation of other CD34 cell populations into the NK lineage in a non-contact dependent manner. Both mRNA and protein analyses show that PRL increased mothers against decapentaplegic homolog 7 (SMAD7) in CD34PRLR myeloid cells, which reduced the production of transforming growth factor beta 1 (TGF-β1), a cytokine known to inhibit CD56 cell development. Thus, we uncover an axis whereby CD34PRLR GMPs inhibit CD56 lineage development through TGF-β1 production and PRL stimulation leads to SMAD7 activation, repression of TGF-β1, resulting in CD56 cell development.
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http://dx.doi.org/10.1038/s41598-020-63346-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156717PMC
April 2020

Investigation of donor KIR content and matching in children undergoing hematopoietic cell transplantation for acute leukemia.

Blood Adv 2020 04;4(7):1350-1356

Center for International Blood and Marrow Transplant Research (CIBMTR), Department of Medicine, and.

Multiple models of donor killer immunoglobulin receptor (KIR) alloreactivity or KIR genotype have been reported to be protective against leukemia relapse after allogeneic transplantation. However, few studies have addressed this topic in the pediatric population. Here, we assessed the outcomes of allogeneic transplantation in children with acute lymphoblastic leukemia (ALL; n = 372) or acute myeloid leukemia (AML; n = 344) who received unrelated donor (URD) transplantation and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2005 to 2016. As expected in this pediatric population, most patients underwent myeloablative conditioning while in remission and with bone marrow as a stem cell source. We tested KIR ligand mismatch, KIR gene content (centromeric [Cen] B), KIR2DS1 mismatching, and Cen B/telomeric A using Cox regression models and found that none were significantly associated with either relapse or disease-free survival when considering the entire cohort of patients (ALL and AML), AML, or ALL separately. Moreover, there was no significant association with outcomes in the in vivo T-cell-depleted (ie, serotherapy) cohort. This study, which is the largest analysis of donor KIR in the pediatric acute leukemia population, does not support the use of KIR in the selection of URDs for children undergoing T-replete transplantation.
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http://dx.doi.org/10.1182/bloodadvances.2019001284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160272PMC
April 2020

Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell function.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Department of Medicine, Division of Hematology, Oncology, and Transplantation, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.

Altered BM hematopoiesis and immune suppression are hallmarks of myelodysplastic syndrome (MDS). While the BM microenvironment influences malignant hematopoiesis, the mechanism leading to MDS-associated immune suppression is unknown. We tested whether mesenchymal stromal cells (MSCs) contribute to this process. Here, we developed a model to study cultured MSCs from patients with MDS (MDS-MSCs) compared with those from aged-matched normal controls for regulation of immune function. MDS-MSCs and healthy donor MSCs (HD-MSCs) exhibited a similar in vitro phenotype, and neither had a direct effect on NK cell function. However, when MDS- and HD-MSCs were cultured with monocytes, only the MDS-MSCs acquired phenotypic and metabolic properties of myeloid-derived suppressor cells (MDSCs), with resulting suppression of NK cell function, along with T cell proliferation. A MSC transcriptome was observed in MDS-MSCs compared with HD-MSCs, including increased expression of the ROS regulator, ENC1. High ENC1 expression in MDS-MSCs induced suppressive monocytes with increased INHBA, a gene that encodes for a member of the TGF-β superfamily of proteins. These monocytes also had reduced expression of the TGF-β transcriptional repressor MAB21L2, further adding to their immune-suppressive function. Silencing ENC1 or inhibiting ROS production in MDS-MSCs abrogated the suppressive function of MDS-MSC-conditioned monocytes. In addition, silencing MAB21L2 in healthy MSC-conditioned monocytes mimicked the MDS-MSC-suppressive transformation of monocytes. Our data demonstrate that MDS-MSCs are responsible for inducing an immune-suppressive microenvironment in MDS through an indirect mechanism involving monocytes.
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http://dx.doi.org/10.1172/jci.insight.130155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141401PMC
March 2020

Single-Cell Gene Expression Analyses Reveal Distinct Self-Renewing and Proliferating Subsets in the Leukemia Stem Cell Compartment in Acute Myeloid Leukemia.

Cancer Res 2020 02 29;80(3):458-470. Epub 2019 Nov 29.

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

Standard chemotherapy for acute myeloid leukemia (AML) targets proliferative cells and efficiently induces complete remission; however, many patients relapse and die of their disease. Relapse is caused by leukemia stem cells (LSC), the cells with self-renewal capacity. Self-renewal and proliferation are separate functions in normal hematopoietic stem cells (HSC) in steady-state conditions. If these functions are also separate functions in LSCs, then antiproliferative therapies may fail to target self-renewal, allowing for relapse. We investigated whether proliferation and self-renewal are separate functions in LSCs as they often are in HSCs. Distinct transcriptional profiles within LSCs of / murine AML were identified using single-cell RNA sequencing. Single-cell qPCR revealed that these genes were also differentially expressed in primary human LSCs and normal human HSPCs. A smaller subset of these genes was upregulated in LSCs relative to HSPCs; this subset of genes constitutes "LSC-specific" genes in human AML. To assess the differences between these profiles, we identified cell surface markers, CD69 and CD36, whose genes were differentially expressed between these profiles. mouse reconstitution assays resealed that only CD69 LSCs were capable of self-renewal and were poorly proliferative. In contrast, CD36 LSCs were unable to transplant leukemia but were highly proliferative. These data demonstrate that the transcriptional foundations of self-renewal and proliferation are distinct in LSCs as they often are in normal stem cells and suggest that therapeutic strategies that target self-renewal, in addition to proliferation, are critical to prevent relapse and improve survival in AML. SIGNIFICANCE: These findings define and functionally validate a self-renewal gene profile of leukemia stem cells at the single-cell level and demonstrate that self-renewal and proliferation are distinct in AML. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/3/458/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002190PMC
February 2020

Molecular Correlates of Socioeconomic Status and Clinical Outcomes Following Hematopoietic Cell Transplantation for Leukemia.

JNCI Cancer Spectr 2019 Dec 12;3(4):pkz073. Epub 2019 Sep 12.

See the Notes section for the full list of authors' affiliations.

Background: Clinical outcomes among allogeneic hematopoietic cell transplant (HCT) recipients are negatively affected by low socioeconomic status (SES), yet the biological mechanisms accounting for this health disparity remain to be elucidated. Among unrelated donor HCT recipients with acute myelogenous leukemia, one recent pilot study linked low SES to increased expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA) in peripheral blood mononuclear cells, which involves up-regulation of pro-inflammatory genes and down-regulation of genes involved in type I interferon response and antibody synthesis.

Methods: This study examined these relationships using additional measures in a larger archival sample of 261 adults who received an unrelated donor HCT for acute myelogenous leukemia to 1) identify cellular and molecular mechanisms involved in SES-related differences in pre-transplant leukocyte transcriptome profiles, and 2) evaluate pre-transplant CTRA biology associations with clinical outcomes through multivariable analysis controlling for demographic-, disease-, and transplant-related covariates.

Results: Low SES individuals showed increases in classic monocyte activation and pro-inflammatory transcription control pathways as well as decreases in activation of nonclassic monocytes, all consistent with the CTRA biological pattern. Transplant recipients in the highest or lowest quartiles of the CTRA pro-inflammatory gene component had a more than 2-fold elevated hazard of relapse (hazard ratio [HR] = 2.47, 95% confidence interval [CI] = 1.44 to 4.24),  = .001; HR = 2.52, 95% CI = 1.46 to 4.34,  = .001) and more than 20% reduction in leukemia-free survival (HR = 1.57, 95% CI = 1.08 to 2.28,  = .012; HR = 1.49, 95% CI = 1.04 to 2.15,  = .03) compared with the middle quartiles.

Conclusions: These findings identify SES- and CTRA-associated myeloid- and inflammation-related transcriptome signatures in recipient pre-transplant blood samples as a potential novel predictive biomarker of HCT-related clinical outcomes.
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http://dx.doi.org/10.1093/jncics/pkz073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859844PMC
December 2019

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

More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling.

Blood Adv 2019 11;3(21):3393-3405

Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA.

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.
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http://dx.doi.org/10.1182/bloodadvances.2019000449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855112PMC
November 2019

Donor HLA-E Status Associates with Disease-Free Survival and Transplant-Related Mortality after Non In Vivo T Cell-Depleted HSCT for Acute Leukemia.

Biol Blood Marrow Transplant 2019 12 16;25(12):2357-2365. Epub 2019 Aug 16.

Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, and University Hospital Ulm, Ulm, Germany; Institute of Transfusion Medicine, University of Ulm, Ulm, Germany. Electronic address:

Previous studies have suggested that HLA-E may have a significant role in the outcome of matched unrelated hematopoietic stem cell transplantation (HSCT), especially for patients with acute leukemia. We used Center for International Blood and Marrow Transplant Research data and samples of 1840 adult patients with acute leukemia and their 10/10 HLA-matched unrelated donors to investigate the impact of HLA-E matching status as well as of donor/recipient (D/R) HLA-E genotype on post-HSCT outcome. Both patients and donors were HLA-E genotyped by next-generation sequencing. All patients received their first transplant in complete remission between 2000 and 2015. Median follow-up time was 90 months. Overall survival, disease-free survival (DFS), transplant-related mortality (TRM), and relapse incidence were primary endpoints with statistical significance set at .01. D/R HLA-E genotype analysis revealed a significant association of donor HLA-E*01:03/01:03 genotype with DFS (hazard ratio [HR] = 1.35, P = .0006) and TRM (HR = 1.41, P = .0058) in patients who received T cell replete (ie, without in vivo T cell depletion) transplants (n = 1297). As for D/R HLA-E matching, we did not identify any significant effect on any of the clinical outcome endpoints. In conclusion, this is the largest study to date reporting an improvement of DFS and TRM after matched unrelated HSCT by avoidance of HLA-E*01:03 homozygous donors in patients transplanted with T cell replete grafts for acute leukemia.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050288PMC
December 2019

The Human Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities.

Front Cell Dev Biol 2019 7;7:99. Epub 2019 Jun 7.

Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States.

Tet methylcytosine dioxygenase 2 () is a tumor suppressor gene that is inactivated in a wide range of hematological cancers. TET2 enzymatic activity converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC), an essential step in DNA demethylation. Human TET2 is highly expressed in pluripotent cells and down-regulated in differentiated cells: however, transcriptional regulation of the human gene has not been investigated in detail. Here we define three promoters within a 2.5 kb region located ∼ 87 kb upstream of the first coding exon. The three promoters, designated as Pro1, Pro2, and Pro3, generate three alternative first exons, and their presence in mRNAs varies with cell type and developmental stage. In general, all three transcripts are more highly expressed in human tissues rich in hematopoietic stem cells, such as spleen and bone marrow, compared to other tissues, such as brain and kidney. Transcripts from Pro2 are expressed by a broad range of tissues and at a significantly higher level than Pro1 or Pro3 transcripts. Pro3 transcripts were highly expressed by embryoid bodies generated from the H9 ES cell line, and the major Pro3 transcript is an alternatively spliced mRNA isoform that produces a truncated TET2 protein lacking the catalytic domain. Our study demonstrates distinct tissue-specific mechanisms of transcriptional regulation during early pluripotent states and in differentiated cell types.
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http://dx.doi.org/10.3389/fcell.2019.00099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566030PMC
June 2019
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