Publications by authors named "Timothy S Olson"

66 Publications

Metformin for Treatment of Cytopenias in Children and Young Adults with Fanconi Anemia.

Blood Adv 2022 May 2. Epub 2022 May 2.

Harvard Medical School, United States.

Fanconi anemia (FA), a genetic disorder affecting DNA repair, is characterized by bone marrow failure and cancer susceptibility. In FA mouse models the biguanide metabolic agent metformin improves blood counts and delays tumor development. We conducted a single institution pilot study of metformin in non-diabetic patients with FA to assess feasibility and tolerability of metformin treatment and to determine whether metformin could improve blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin <10g/dL, platelet count <100K cells/µL, or an absolute neutrophil count <1K cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5), and 8/14 were male (57%). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; one subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions due to toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response (HR) based on modified MDS IWG criteria was observed in 4 of 13 evaluable patients (30.8%, 90% CI:11.3 to 57.3). Median time to response was 84.5 days (range 71-128). Responses were noted in neutrophils (n=3), platelets (n=1), and red blood cells (n=1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. We conclude that metformin is safe and tolerable in non-diabetic patients with FA and may provide therapeutic benefit. This trial is registered at www.clinicaltrials.gov as NCT03398824.
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http://dx.doi.org/10.1182/bloodadvances.2021006490DOI Listing
May 2022

Betibeglogene Autotemcel Gene Therapy for Non-β/β Genotype β-Thalassemia.

N Engl J Med 2022 02 11;386(5):415-427. Epub 2021 Dec 11.

From IRCCS Ospedale Pediatrico Bambino Gesù, Sapienza, University of Rome, Rome (F.L., M. Algeri); Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago (A.A.T., J.S.); Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia (J.L.K., T.S.O.); University College London Hospital (J.B.P., B.C.) and University College London Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust (A.J.T., P.J.A.) - all in London; Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (S.H., U.A.); the Department of Pediatric Hematology, Oncology, and Stem Cell Transplantation in Children (M.G.S.) and the Institute of Experimental Hematology (A.S.), Hannover Medical School, Hannover, and GeneWerk, Heidelberg (M.S., I.L.) - both in Germany; Hôpital de la Timone (I.T.) and Institut Paoli-Calmettes Comprehensive Cancer Center (C.C.) - both in Marseille, France; the University of California, San Francisco, Benioff Children's Hospital, Oakland (A.L., M.C.W.); and the Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston (A.S.), and Bluebird Bio, Cambridge (H.E., R.G., M. Asmal, R.A.C.) - all in Massachusetts.

Background: Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the β-globin (β) gene.

Methods: In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-β/β genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months).

Results: A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed.

Conclusions: Treatment with beti-cel resulted in a sustained HbA level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-β/β genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.).
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http://dx.doi.org/10.1056/NEJMoa2113206DOI Listing
February 2022

Unrelated donor α/β T cell- and B cell-depleted HSCT for the treatment of pediatric acute leukemia.

Blood Adv 2022 Feb;6(4):1175-1185

Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.

Unrelated donor (URD) hematopoietic stem cell transplant (HSCT) is associated with an increased risk of severe graft-versus-host disease (GVHD). TCRαβ/CD19 depletion may reduce this risk, whereas maintaining graft-versus-leukemia. Outcome data with TCRαβ/CD19 depletion generally describe haploidentical donors, with relatively few URDs. We hypothesized that TCRαβ/CD19-depletion would attenuate the risks of GVHD and relapse for URD HSCT. Sixty pediatric and young adult (YA) patients with hematologic malignancies who lacked a matched-related donor were enrolled at 2 large pediatric transplantation centers between October 2014 and September 2019. All patients with acute leukemia had minimal residual disease testing, and DP typing was available for 77%. All patients received myeloablative total body irradiation- or busulfan-based conditioning with no posttransplant immune suppression. Engraftment occurred in 98%. Four-year overall survival was 69% (95% confidence interval [CI], 52%-81%), and leukemia-free survival was 64% (95% CI, 48%-76%), with no difference between lymphoid and myeloid malignancies (P = .6297 and P = .5441, respectively). One patient (1.7%) experienced primary graft failure. Relapse occurred in 11 patients (3-year cumulative incidence, 21%; 95% CI, 11-34), and 8 patients (cumulative incidence, 15%; 95% CI, 6.7-26) experienced nonrelapse mortality. Grade III to IV acute GVHD was seen in 8 patients (13%), and 14 patients (26%) developed chronic GVHD, of which 6 (11%) had extensive disease. Nonpermissive DP mismatch was associated with higher likelihood of acute GVHD (odds ratio, 16.50; 95% CI, 1.67-163.42; P = .0166) but not with the development of chronic GVHD. URD TCRαβ/CD19-depleted peripheral HSCT is a safe and effective approach to transplantation for children/YAs with leukemia. This trial was registered at www.clinicaltrials.gov as #NCT02323867.
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http://dx.doi.org/10.1182/bloodadvances.2021005492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864664PMC
February 2022

LNK (SH2B3) inhibition expands healthy and Fanconi anemia human hematopoietic stem and progenitor cells.

Blood Adv 2022 02;6(3):731-745

Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA.

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for a variety of hematological diseases. Allogenic HSCT requires hematopoietic stem cells (HSCs) from matched donors and comes with cytotoxicity and mortality. Recent advances in genome modification of HSCs have demonstrated the possibility of using autologous HSCT-based gene therapy to alleviate hematologic symptoms in monogenic diseases, such as the inherited bone marrow failure (BMF) syndrome Fanconi anemia (FA). However, for FA and other BMF syndromes, insufficient HSC numbers with functional defects results in delayed hematopoietic recovery and increased risk of graft failure. We and others previously identified the adaptor protein LNK (SH2B3) as a critical negative regulator of murine HSC homeostasis. However, whether LNK controls human HSCs has not been studied. Here, we demonstrate that depletion of LNK via lentiviral expression of miR30-based short hairpin RNAs results in robust expansion of transplantable human HSCs that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Importantly, LNK depletion enhances cytokine-mediated JAK/STAT activation in CD34+ hematopoietic stem and progenitor cells (HSPCs). Moreover, we demonstrate that LNK depletion expands primary HSPCs associated with FA. In xenotransplant, engraftment of FANCD2-depleted FA-like HSCs was markedly improved by LNK inhibition. Finally, targeting LNK in primary bone marrow HSPCs from FA patients enhanced their colony forming potential in vitro. Together, these results demonstrate the potential of targeting LNK to expand HSCs to improve HSCT and HSCT-based gene therapy.
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http://dx.doi.org/10.1182/bloodadvances.2021004205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945310PMC
February 2022

Inducible Sbds deletion impairs bone marrow niche capacity to engraft donor bone marrow after transplantation.

Blood Adv 2022 01;6(1):108-120

Cell Therapy and Transplant Section, Division of Oncology, Department of Pediatrics, and.

Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited BM failure syndromes (iBMFSs). Shwachman-Diamond syndrome (SDS) is a rare iBMFS associated with mutations in SBDS. Previous studies have demonstrated that SBDS deficiency in osteolineage niche cells causes BM dysfunction that promotes leukemia development. However, it is unknown whether BM niche defects caused by SBDS deficiency also impair efficient engraftment of healthy donor HSC after HSCT, a hypothesis that could explain morbidity noted after clinical HSCT for patients with SDS. Here, we report a mouse model with inducible Sbds deletion in hematopoietic and osteolineage cells. Primary and secondary BM transplantation (BMT) studies demonstrated that SBDS deficiency within BM niches caused poor donor hematopoietic recovery and specifically poor HSC engraftment after myeloablative BMT. We have also identified multiple molecular and cellular defects within niche populations that are driven by SBDS deficiency and are accentuated by or develop specifically after myeloablative conditioning. These abnormalities include altered frequencies of multiple niche cell subsets, including mesenchymal lineage cells, macrophages, and endothelial cells; disruption of growth factor signaling, chemokine pathway activation, and adhesion molecule expression; and p53 pathway activation and signals involved in cell cycle arrest. Taken together, this study demonstrates that SBDS deficiency profoundly impacts recipient hematopoietic niche function in the setting of HSCT, suggesting that novel therapeutic strategies targeting host niches could improve clinical HSCT outcomes for patients with SDS.
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http://dx.doi.org/10.1182/bloodadvances.2021004640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753223PMC
January 2022

Case Report: Immune Dysregulation Due to Reactivation After Allogeneic Hematopoietic Cell Transplant.

Front Pediatr 2021 10;9:719679. Epub 2021 Aug 10.

Department of Anesthesia and Critical Care Medicine, Division of Critical Care Medicine, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.

Disseminated toxoplasmosis is an uncommon but highly lethal cause of hyperferritinemic sepsis after hematopoietic cell transplantation (HCT). We report two cases of disseminated toxoplasmosis from two centers in critically ill adolescents after HCT: a 19-year-old who developed fever and altered mental status on day +19 after HCT and a 20-year-old who developed fever and diarrhea on day +52 after HCT. Both patients developed hyperferritinemia with multiple organ dysfunction syndrome and profound immune dysregulation, which progressed to death despite maximal medical therapies. Because disseminated toxoplasmosis is both treatable and challenging to diagnose, it is imperative that intensivists maintain a high index of suspicion for infection when managing immunocompromised children, particularly in those with known positive serologies.
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http://dx.doi.org/10.3389/fped.2021.719679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382793PMC
August 2021

The predictive value of PNH clones, 6p CN-LOH, and clonal TCR gene rearrangement for aplastic anemia diagnosis.

Blood Adv 2021 08;5(16):3216-3226

Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia, PA.

Acquired aplastic anemia (AA) is a life-threatening bone marrow aplasia caused by the autoimmune destruction of hematopoietic stem and progenitor cells. There are no existing diagnostic tests that definitively establish AA, and diagnosis is currently made via systematic exclusion of various alternative etiologies, including inherited bone marrow failure syndromes (IBMFSs). The exclusion of IBMFSs, which requires syndrome-specific functional and genetic testing, can substantially delay treatment. AA and IBMFSs can have mimicking clinical presentations, and their distinction has significant implications for treatment and family planning, making accurate and prompt diagnosis imperative to optimal patient outcomes. We hypothesized that AA could be distinguished from IBMFSs using 3 laboratory findings specific to the autoimmune pathogenesis of AA: paroxysmal nocturnal hemoglobinuria (PNH) clones, copy-number-neutral loss of heterozygosity in chromosome arm 6p (6p CN-LOH), and clonal T-cell receptor (TCR) γ gene (TRG) rearrangement. To test our hypothesis, we determined the prevalence of PNH, acquired 6p CN-LOH, and clonal TRG rearrangement in 454 consecutive pediatric and adult patients diagnosed with AA, IBMFSs, and other hematologic diseases. Our results indicated that PNH and acquired 6p CN-LOH clones encompassing HLA genes have ∽100% positive predictive value for AA, and they can facilitate diagnosis in approximately one-half of AA patients. In contrast, clonal TRG rearrangement is not specific for AA. Our analysis demonstrates that PNH and 6p CN-LOH clones effectively distinguish AA from IBMFSs, and both measures should be incorporated early in the diagnostic evaluation of suspected AA using the included Bayesian nomogram to inform clinical application.
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http://dx.doi.org/10.1182/bloodadvances.2021004201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405198PMC
August 2021

Comparison of hematopoietic cell transplant conditioning regimens for hemophagocytic lymphohistiocytosis disorders.

J Allergy Clin Immunol 2022 03 8;149(3):1097-1104.e2. Epub 2021 Aug 8.

Center for International Blood and Marrow Transplant Research, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisc.

Background: Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.

Objective: The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.

Methods: We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.

Results: Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001).

Conclusions: Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.
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http://dx.doi.org/10.1016/j.jaci.2021.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8821728PMC
March 2022

Diagnostic work-up for severe aplastic anemia in children: Consensus of the North American Pediatric Aplastic Anemia Consortium.

Am J Hematol 2021 11 20;96(11):1491-1504. Epub 2021 Aug 20.

Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.

The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.
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http://dx.doi.org/10.1002/ajh.26310DOI Listing
November 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

SLC25A38 congenital sideroblastic anemia: Phenotypes and genotypes of 31 individuals from 24 families, including 11 novel mutations, and a review of the literature.

Hum Mutat 2021 11 5;42(11):1367-1383. Epub 2021 Aug 5.

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders of erythropoiesis characterized by pathologic deposits of iron in the mitochondria of developing erythroblasts. Mutations in the mitochondrial glycine carrier SLC25A38 cause the most common recessive form of CSA. Nonetheless, the disease is still rare, there being fewer than 70 reported families. Here we describe the clinical phenotype and genotypes of 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of reported mutations and genotypes associated with the disease, describe the unique localization of missense mutations in transmembrane domains and account for the presence of several alleles in different populations.
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http://dx.doi.org/10.1002/humu.24267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511274PMC
November 2021

Incidence of CMV Infection and Disease and Adverse Events Associated with Antiviral Therapy in a Retrospective Cohort of Allogeneic Hematopoietic Cell Transplant Recipients at an Academic Children's Hospital.

J Pediatric Infect Dis Soc 2021 Oct;10(9):910-918

Division of Infectious Diseases, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.

Background: Cytomegalovirus (CMV) is a significant source of morbidity and mortality among transplant recipients; the epidemiology is less understood in pediatric hematopoietic cell transplantation (HCT) cohorts. Furthermore, there is a paucity of data related to CMV prophylactic and preemptive strategies.

Methods: A single-center retrospective observational cohort of allogeneic HCT recipients at the Children's Hospital of Philadelphia January 1, 2004-December 31, 2017 was constructed. Subjects were followed for 180 days after transplant to determine whether they had CMV infection or disease. Data on antiviral therapy were collected as were outcomes of CMV disease and adverse events (AEs) related to the antiviral therapy.

Results: Between January 2004 and March 2017, 345 allogeneic HCTs in 333 patients undergoing CMV surveillance testing were identified. CMV DNAemia was detected during the 180-day follow-up in 89 (25.8%) HCTs. CMV recipient-positive transplants were most likely to have CMV infection (47%). Infection rates were high for those receiving a CMV-specific prophylaxis regimen (50%). CMV DNAemia progressed to CMV disease 11.2% of the time. Of 224 subjects receiving CMV-specific prophylaxis, 19.2% experienced ≥1 AE. Of 53 receiving preemptive therapy during any CMV DNAemia episode, 32.1% experienced ≥1 AE.

Conclusions: CMV infection is common in pediatric allogeneic HCT recipients. The CMV-specific prophylaxis regimen employed in this cohort did not effectively prevent DNAemia, progression to CMV disease was uncommon, and AEs from prophylaxis and preemptive therapy were frequent. Novel approaches that reduce the impact of CMV on pediatric allogeneic HCT recipients are needed.
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http://dx.doi.org/10.1093/jpids/piab041DOI Listing
October 2021

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

J Exp Med 2021 07 5;218(7). Epub 2021 May 5.

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
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http://dx.doi.org/10.1084/jem.20201750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105723PMC
July 2021

Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells.

Nat Rev Clin Oncol 2021 06 25;18(6):363-378. Epub 2021 Jan 25.

Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.

As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.
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http://dx.doi.org/10.1038/s41571-020-00456-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335746PMC
June 2021

Paediatric severe aplastic anaemia treatment: where to start?

Authors:
Timothy S Olson

Br J Haematol 2021 02 5;192(3):417-419. Epub 2021 Jan 5.

Division of Oncology, Cell Therapy and Transplant Section, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

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http://dx.doi.org/10.1111/bjh.17233DOI Listing
February 2021

Human mutational constraint as a tool to understand biology of rare and emerging bone marrow failure syndromes.

Blood Adv 2020 10;4(20):5232-5245

Comprehensive Bone Marrow Failure Center, Division of Hematology, and.

Inherited bone marrow failure (IBMF) syndromes are rare blood disorders characterized by hematopoietic cell dysfunction and predisposition to hematologic malignancies. Despite advances in the understanding of molecular pathogenesis of these heterogeneous diseases, genetic variant interpretation, genotype-phenotype correlation, and outcome prognostication remain difficult. As new IBMF and other myelodysplastic syndrome (MDS) predisposition genes continue to be discovered (frequently in small kindred studies), there is an increasing need for a systematic framework to evaluate penetrance and prevalence of mutations in genes associated with IBMF phenotypes. To address this need, we analyzed population-based genomic data from >125 000 individuals in the Genome Aggregation Database for loss-of-function (LoF) variants in 100 genes associated with IBMF. LoF variants in genes associated with IBMF/MDS were present in 0.426% of individuals. Heterozygous LoF variants in genes in which haploinsufficiency is associated with IBMF/MDS were identified in 0.422% of the population; homozygous LoF variants associated with autosomal recessive IBMF/MDS diseases were identified in only .004% of the cohort. Using age distribution of LoF variants and 2 measures of mutational constraint, LOEUF ("loss-of-function observed/expected upper bound fraction") and pLI ("probability of being loss-of-function intolerance"), we evaluated the pathogenicity, tolerance, and age-related penetrance of LoF mutations in specific genes associated with IBMF syndromes. This analysis led to insights into rare IBMF diseases, including syndromes associated with DHX34, MDM4, RAD51, SRP54, and WIPF1. Our results provide an important population-based framework for the interpretation of LoF variant pathogenicity in rare and emerging IBMF syndromes.
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http://dx.doi.org/10.1182/bloodadvances.2020002687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594375PMC
October 2020

Diagnosis and treatment of pediatric myelodysplastic syndromes: A survey of the North American Pediatric Aplastic Anemia Consortium.

Pediatr Blood Cancer 2020 10 11;67(10):e28652. Epub 2020 Aug 11.

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic stem cell disorders that commonly progress to acute myeloid leukemia (AML). The diagnostics, prognostics, and treatment of adult MDS are established but do not directly translate to children and adolescents. Pediatric MDS is a rare disease, characterized by unique cytogenetics and histology compared with adult MDS, and often arises secondary to germline predisposition or cytotoxic exposures. Our objective was to highlight aspects of diagnosis/management that would benefit from further systematic review toward the development of clinical practice guidelines for pediatric MDS.

Procedure: The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is composed of collaborative institutions with a strong interest in pediatric bone marrow failure syndromes and hematologic malignancies. The NAPAAC MDS working group developed a national survey distributed to 35 NAPAAC institutions to assess data on (1) clinical presentation of pediatric MDS, (2) diagnostic evaluation, (3) criteria for diagnosis, (4) supportive care and treatment decisions, and (5) role of hematopoietic stem cell transplantation (HSCT).

Results: Twenty-eight of 35 institutions returned the survey. Most centers agreed on a common diagnostic workup, though there was considerable variation regarding the criteria for diagnosis. Although there was consensus on supportive care, treatment strategies, including the role of cytoreduction and HSCT, varied across centers surveyed.

Conclusions: There is lack of national consensus on diagnosis and treatment of pediatric MDS. This survey identified key aspects of MDS management that will warrant systematic review toward the goal of developing national clinical practice guidelines for pediatric MDS.
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http://dx.doi.org/10.1002/pbc.28652DOI Listing
October 2020

Evolution of histomorphologic, cytogenetic, and genetic abnormalities in an untreated patient with MIRAGE syndrome.

Cancer Genet 2020 07 14;245:42-48. Epub 2020 Jun 14.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Abramson Research Center, Room 716D, 3615 Civic Center Blvd., Philadelphia, PA 19104, United States; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address:

Gain of function variants in SAMD9 cause MIRAGE syndrome, a rare Mendelian disorder that results in myeloid dysplastic syndrome (MDS), poor immune response, restricted growth, adrenal insufficiency, ambiguous genitalia, feeding difficulties and most often significantly reduced lifespan. In this study, we describe histomorphologic and genetic changes occurring in serial bone marrow measurements in a patient with MIRAGE syndrome and untreated MDS of 9 years. Histomorphological analysis during childhood showed progressive hypocellularity with erythroid and megakaryocytic dysplasia and cytogenetic testing demonstrated monosomy 7. Serial leukemia gene panel testing performed over a seven year period revealed multiple pre-leukemic clones arising at age 7 years followed by sequential mutational events in ETV6 and RUNX1 driving acute myeloid leukemia (AML) at age 9. Comprehensive genotype-phenotype analysis with 28 previously reported patients found the presence of MDS did not impact overall survival, but in silico variant pathogenicity prediction scores for SAMD9 distinguished patients with poor prognosis. Overall, our analysis shows progression of MDS to AML can be monitored by following mutation evolution in leukemia related genes in patients with MIRAGE syndrome, and specific SAMD9 mutations likely influence disease severity and overall survival.
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http://dx.doi.org/10.1016/j.cancergen.2020.06.002DOI Listing
July 2020

Partially CD3-Depleted Unrelated and Haploidentical Donor Peripheral Stem Cell Transplantation Has Favorable Graft-versus-Host Disease and Survival Rates in Pediatric Hematologic Malignancy.

Biol Blood Marrow Transplant 2020 03 22;26(3):493-501. Epub 2019 Nov 22.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3/CD19 depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P= .05) and EFS (P= .05). Relapse was more common in children in second complete remission (P = .03). Partially CD3-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.022DOI Listing
March 2020

Hodgkin lymphoma patients have an increased incidence of idiopathic acquired aplastic anemia.

PLoS One 2019 5;14(4):e0215021. Epub 2019 Apr 5.

Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America.

Idiopathic acquired aplastic anemia (AA) is a rare lymphocyte-mediated bone marrow aplasia. No specific mechanisms or triggers of AA have been identified. We recently observed several patients who developed AA after Hodgkin lymphoma (HL). We hypothesized that the co-occurrence of HL and AA is not random and may be etiologically significant. To test this hypothesis, we determined the incidence of AA in HL patients at our institution. We identified four patients with co-occurring HL and AA, with the incidence of AA in HL patients >20-fold higher compared to the general population. We identified 12 additional patients with AA and HL through a systematic literature review. Of the 16 total patients,15 (93.8%) developed AA after or concurrent with a HL diagnosis. None of the patients had marrow involvement by HL. Five of 15 patients were in complete remission from HL at the time of AA diagnosis, and six had a concurrent presentation with no prior cytotoxic therapy, with diagnostic timeframe information unavailable for four patients. The median interval between HL diagnosis and AA onset was 16 months, ranging from concurrent to 14 years after a HL diagnosis. The median survival after AA diagnosis was 14 months (range: 1 month to 20 years). Our results show that patients with HL have a higher incidence of AA compared to the general population and suggest that HL-related immune dysregulation may be a risk factor for AA. Better recognition and management of AA in HL patients is needed to improve outcomes in this population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450628PMC
December 2019

Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study.

Haematologica 2019 10 4;104(10):1974-1983. Epub 2019 Apr 4.

Boston Children's Hospital and Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×10L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; =0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.
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http://dx.doi.org/10.3324/haematol.2018.206540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886407PMC
October 2019

Development of hemolytic paroxysmal nocturnal hemoglobinuria without graft loss following hematopoietic stem cell transplantation for acquired aplastic anemia.

Pediatr Transplant 2019 06 22;23(4):e13393. Epub 2019 Mar 22.

Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

PNH is the most common clonal hematopoietic disorder arising in patients with aAA. PNH is caused by mutations in PIGA, a gene that encodes the catalytic subunit of an enzyme involved in the biosynthesis of GPI anchors, transmembrane glycolipids required for cell surface expression of many proteins. PNH clones likely arise as immune escape mechanisms in aAA by preventing CD1D-restricted T-cell recognition of GPI anchors and GPI-linked autoantigens. Though many patients with aAA treated with IST will develop subclinical PNH clones, only a subset will develop PNH disease, characterized by increased thrombosis, intravascular hemolysis, and potential for severe organ dysfunction. In contrast to IST, allogeneic HSCT for patients with aAA is thought to cure bone marrow aplasia and prevent hematopoietic clonal evolution to PNH. Herein, we present a phenomenon of host-derived PNH disease arising in a patient with aAA many years following MSD-BMT, highlighting the importance of monitoring for this clonal disease in aAA patients with stable mixed donor/recipient chimerism after HSCT. We also provide a literature review for similar occurrences of PNH arising after HSCT.
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http://dx.doi.org/10.1111/petr.13393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548609PMC
June 2019

Bone marrow niches of germline FANCC/FANCG deficient mice enable efficient and durable engraftment of hematopoietic stem cells after transplantation.

Haematologica 2019 07 24;104(7):e284-e287. Epub 2019 Jan 24.

Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia

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http://dx.doi.org/10.3324/haematol.2018.202143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601109PMC
July 2019

CD3/CD19 Depleted Matched and Mismatched Unrelated Donor Hematopoietic Stem Cell Transplant with Targeted T Cell Addback Is Associated with Excellent Outcomes in Pediatric Patients with Nonmalignant Hematologic Disorders.

Biol Blood Marrow Transplant 2019 03 9;25(3):549-555. Epub 2018 Oct 9.

Cellular Therapy and Transplant Section, Division of Oncology Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Unrelated donor hematopoietic stem cell transplantation (HSCT) is increasingly being used to cure nonmalignant hematologic diseases (NMHD) in patients who lack HLA matched related donors. Both graft rejection and graft-versus-host disease (GVHD) remain major barriers to safe and effective transplant for these patients requiring unrelated donors. Partial T cell depletion combined with peripheral stem cell transplantation (pTCD-PSCT) has the potential advantages of providing a high stem cell dose to facilitate rapid engraftment, maintaining cells that may facilitate engraftment, and decreasing GVHD risk compared with T cell-replete HSCT. Here, we report a single-institution, retrospective experience of unrelated donor pTCD-PSCT for pediatric patients with NMHD. From 2014 to 2017, 12 pediatric patients with transfusion-dependent NMHD underwent matched unrelated donor (MUD) or mismatched unrelated donor (MMUD) pTCD HSCT in our center using disease-specific conditioning. Donor PSCs underwent CD3 T cell and CD19 B cell depletion using CliniMACS, followed by a targeted addback of 1 × 10 CD3 T cells/kg to the graft before infusion. All 12 patients demonstrated rapid trilinear engraftment. At a median follow-up of 740days (range, 279 to 1466), all patients were alive with over 92% total peripheral blood donor chimerism and without transfusion dependence or recurrence of their underlying hematologic disease. Immune reconstitution was rapid and comparable with T cell-replete HSCT. No patients developed severe acute GVHD (grades III to IV) or chronic extensive GVHD, and all patients had discontinued systemic immune suppression. Viral reactivations were common, but no patient developed symptoms of life-threatening infectious disease. Our data indicate that MUD and MMUD pTCD-PSCTs are safe and effective approaches that enable rapid engraftment and immune reconstitution, prevent severe GVHD, and expand availability of HSCT to any patients with NMHD who have closely MUDs.
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http://dx.doi.org/10.1016/j.bbmt.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122955PMC
March 2019

Successful treatment of pulmonary mucormycosis in two pediatric hematopoietic stem cell transplant patients.

Pediatr Transplant 2018 11 16;22(7):e13270. Epub 2018 Jul 16.

Division of Oncology, Section of Cellular Therapy & Transplant, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Pulmonary mucormycosis diagnosed immediately after hematopoietic stem cell transplantation frequently portends a poor prognosis. However, here we describe two cases in children that were treated successfully to highlight the efficacy of a multidisciplinary approach. Despite diagnosis in the immediate post-transplant period and requirement for ongoing immunosuppression to prevent or treat GVHD, both are long-term survivors due to early surgical debridement with transfusion support and prompt initiation of targeted antifungal therapy. In the absence of evidence-based treatment guidelines, survival of pulmonary mucormycosis is achievable even in high-risk patients with a multidisciplinary team to guide management.
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http://dx.doi.org/10.1111/petr.13270DOI Listing
November 2018
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