ABSTRACT
Inborn errors of immunity (IEI) are often associated with inflammatory bowel disease (IBD). IEI can be corrected by allogeneic hematopoietic stem cell transplantation (HSCT); however, peritransplantation intestinal inflammation may increase the risk of gut graft-versus-host disease (GVHD). Vedolizumab inhibits the homing of lymphocytes to the intestine and may attenuate gut GVHD, yet its role in preventing GVHD in pediatric patients with IEI-associated IBD has not been studied. Here we describe a cohort of pediatric patients with IEI-associated IBD treated with vedolizumab before and during allogeneic HSCT. The study involved a retrospective chart review of pediatric patients with IEI-associated IBD treated with vedolizumab at 6 weeks, 4 weeks, and 1 week before undergoing HSCT. The conditioning regimen consisted of treosulfan, fludarabine, and cyclophosphamide with rabbit antithymocyte globulin, and GVHD prophylaxis included tacrolimus and steroids. Eleven patients (6 females) with a median age of 5 years (range, 0.4 to 14 years) with diverse IEI were included. IBD symptoms were characterized by abdominal pain, loose stools, and blood in stools. Four patients had developed a perianal fistula, and 1 patient had a rectal prolapse. One patient had both a gastrostomy tube and a jejunal tube in situ. Treatment of IBD before HSCT included steroids in 11 patients, anakinra in 2, infliximab in 4, sulfasalazine in 2, mesalazine in 2, and vedolizumab. IBD symptoms were considered controlled in the absence of abdominal pain, loose stools, or blood in stools. Graft sources for HSCT were unrelated donor cord in 5 patients (2 with a 5/8 HLA match, 2 with a 7/8 match, and 1 with a 6/8 match), peripheral blood stem cells in 5 patients (2 haploidentical, 1 with a 9/10 HLA match, and 2 with a 10/10 match), and bone marrow in 1 patient (10/10 matched sibling donor). The median number of vedolizumab infusions was 4 (range, 3 to 12) before HSCT and 1 (range, 1 to 3) after HSCT, and all were reported to be uneventful. All patients had engrafted. Acute GVHD occurred in 4 patients and was limited to grade I skin GVHD only. Chronic GVHD occurred in 1 patient and again was limited to the skin. There was no gut GVHD. Three patients experienced cytomegalovirus viremia, and 2 patients had Epstein-Barr virus viremia. At the time of this report, all patients were alive with no evidence of IBD at a median follow-up of 15 months (range, 3 to 39 months). Administration of vedolizumab pre- and post-HSCT in pediatric patients with IEI-associated IBD is well tolerated and associated with a low rate of gut GVHD. These findings provide a platform for the prospective study and use of vedolizumab for GVHD prophylaxis in pediatric patients with known intestinal inflammation as a pre-HSCT comorbidity.
Subject(s)
Antibodies, Monoclonal, Humanized , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Inflammatory Bowel Diseases , Transplantation, Homologous , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Hematopoietic Stem Cell Transplantation/adverse effects , Female , Child , Male , Adolescent , Child, Preschool , Inflammatory Bowel Diseases/drug therapy , Retrospective Studies , Graft vs Host Disease/prevention & control , Graft vs Host Disease/drug therapy , Infant , Immunomodulation , Transplantation Conditioning/methodsABSTRACT
After primary infection, Varicella Zoster (VZV) persists in sensory dorsal root ganglia and may be reactivated in periods of diminished T-cell immunity. Varicella Zoster reactivation post allogenic stem cell transplantation (HSCT) can be challenging to diagnose as it does not always present with characteristic skin lesions. We describe a pediatric patient who presented with isolated severe abdominal pain with no other symptoms. Cutaneous lesions appeared only 10 days later resulting in delayed diagnosis and treatment. He was successfully treated with intravenous acyclovir and recovered after a prolonged hospital stay with post-herpetic neuralgia. Abdominal pain in children post HSCT has a broad differential and VZV reactivation should be considered even in absence of cutaneous lesions. Early diagnosis and treatment are essential to reduce VZV-related morbidity and mortality. In this article we present a case report and review clinical presentation and outcome of similar cases in the literature.
Subject(s)
Chickenpox , Hematopoietic Stem Cell Transplantation , Herpes Zoster , Humans , Child , Herpes Zoster/diagnosis , Herpes Zoster/drug therapy , Herpes Zoster/etiology , Herpesvirus 3, Human/physiology , Virus Activation , Hematopoietic Stem Cell Transplantation/adverse effects , Abdominal Pain/complications , Stem Cell Transplantation/adverse effectsABSTRACT
OBJECTIVES: Pulmonary hemorrhage (PH) is a serious complication posthematopoietic stem cell transplant (HSCT). In view of limited available pediatric data, we performed a retrospective study to describe epidemiology, management, and outcomes of PH post-HSCT in children in our national center. DESIGN: Retrospective study. SETTING: Academic children's hospital (2000-2015). SUBJECTS: Children (< 18 yr) with PH and requiring PICU care post-HSCT. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The historical prevalence of PH in our center was 2.7% (31/1,148). Twenty patients had a concomitant infection, 15 had bacterial infection, 8 had viral infection, and 3 patients had a fungal infection. With a median follow-up time of 60 months, 7 of 31 patients were alive. Early PH (< 40 d post-HSCT) was associated with improved survival (6/15 vs 1/16, p = 0.035). Patients who received high-dose pulsed corticosteroid had improved survival when compared with those who did not (7/22 vs 0/9, p = 0.0012); this also applied to the subgroup of patients with a concomitant infection (5/15 vs 0, p = 0.001). None of the patients who survived had measurable respiratory sequelae. CONCLUSIONS: PH is a rare but serious complication after HSCT. Corticosteroids were associated with improved survival even in patients with a concomitant infection.
Subject(s)
Hematopoietic Stem Cell Transplantation , Child , Humans , Retrospective Studies , Risk Factors , Hematopoietic Stem Cell Transplantation/adverse effects , Stem Cell TransplantationABSTRACT
Hematopoietic cell transplantation (HCT) is the only readily available cure for many life-threatening pediatric nonmalignant diseases (NMD), but most patients lack a matched related donor and are at higher risk for graft-versus-host disease (GVHD). Use of abatacept (Aba) to target donor T-cell activation has been safe and effective in preventing GVHD after unrelated donor (URD) HCT for malignant diseases (Aba2 trial). Our primary objective was to evaluate the tolerability of Aba added to standard GVHD prophylaxis (cyclosporine and mycophenolate mofetil) in pediatric patients with NMD undergoing URD HCT. In this single-arm, single-center phase 1 trial, 10 patients receiving reduced intensity or nonmyeloablative conditioning underwent URD HCT. Immune reconstitution was assessed longitudinally via flow cytometry and compared to pediatric patients on Aba2. Nine patients successfully engrafted, with 1 primary graft rejection in the setting of inadequate cell dose; secondary graft rejection occurred in 1 patient with concurrent cytomegalovirus viremia. Two deaths occurred, both unrelated to Aba. One patient developed probable posttransplant lymphoproliferative disease, responsive to rituximab and immune suppression withdrawal. No patients developed severe acute or chronic GVHD, and 8 patients were off systemic immunosuppression at 1 year. Immune reconstitution did not appear to be impacted by Aba, and preservation of naïve relative to effector memory CD4+ T cells was seen akin to Aba2. Thus, 4 doses of Aba were deemed tolerable in pediatric patients with NMD following URD HCT, with encouraging preliminary efficacy and supportive immune correlatives in this NMD cohort.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Pancytopenia , Humans , Child , Abatacept/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Graft vs Host Disease/pathology , Pancytopenia/etiology , Unrelated Donors , Bone Marrow Failure Disorders/etiologyABSTRACT
BACKGROUND: There is insufficient guidance in using posttransplant cyclophosphamide in patients with organ dysfunctions. Abatacept (Aba), a T cell costimulation blockade, has recently been shown to prevent severe acute graft-versus-host disease (GVHD). OBSERVATION: We report adding Aba as GVHD prophylaxis in 4 pediatrics patients who received haplo-hematopoietic cell transplantation. Two patients had grade 2 acute GVHD and 2 had mild chronic GVHD. All 4 patients are alive with full donor chimerism, and 3 are off immunosuppressants. CONCLUSION: An Aba-based regimen can result in reliable engraftment and acceptable GVHD when concerns of organ dysfunction prevents the use of posttransplant cyclophosphamide in haplo-hematopoietic cell transplantation.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Abatacept/therapeutic use , Child , Cyclophosphamide/therapeutic use , Graft vs Host Disease/drug therapy , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunosuppressive Agents/therapeutic use , Transplantation ConditioningABSTRACT
The introduction of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has made haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) a common approach in adults, but pediatric experience is limited. Based on the encouraging adult data and with the aim of decreasing the risk of graft failure, our center is increasingly using peripheral blood stem cells (PBSCs) from haplo donors with PTCy. Here we compare outcomes of bone marrow (BM) transplantation with traditional donor choices, including matched sibling donors (MSDs) and 10/10 HLA matched unrelated donors (MUDs), with those of haplo PBSC grafts in pediatric patients with hematologic malignancies. In this retrospective single-center study, the primary endpoint was the comparison of GVHD-free relapse-free survival (GRFS; defined as absence of acute GVHD [aGVHD] grade III-IV, relapse, death, or chronic GVHD [cGVHD] requiring systemic therapy) for the 3 cohorts. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), nonrelapse mortality (NRM), and incidence of aGVHD and cGVHD). A total of 104 consecutive patients underwent first allogeneic (allo)-HSCT for a hematologic malignancy or myelodysplastic syndrome between January 2014 and December 2020 using a haplo family donor (PBSCs; n = 26), an MSD (BM; n = 31), or an MUD (BM; n = 47). Patient demographic and transplantation characteristics were not significantly different across the cohorts, apart from remission status, with the haplo cohort having more patients in third or later complete remission before HSCT (P < .01). The median duration of follow-up for the entire cohort was 573 days. The cumulative incidence of aGVHD (grade II-IV or grade III-IV) was not significantly different among the cohorts; however, the cumulative incidence of cGVHD at 18 months was highest in the MUD cohort (31.7%, versus 10.0% in the MSD cohort and 9.2% in the haplo cohort; P = .02). There were no differences in the 18-month cumulative incidence of relapse or NRM. OS and RFS at 18 months were 80.7% (95% confidence interval [CI], 61.7% to 100%) and 73.8% (95% CI, 55.5% to 98.1%) for the haplo cohort, 83.4% (95% CI, 72.8% to 95.5%) and 70.3% (95% CI, 57.9% to 85.3%) for the MUD cohort, and 80.9% (95% CI, 66.9% to 97.7%) and 66.5% (95% CI, 50.5% to 87.5%) for the MSD cohort, with no statistically significant differences among the cohorts. GRFS at 18 months was 61% (95% CI, 43.3% to 85.9%) for the haplo cohort, 44.6% (95% CI, 31.8% to 62.5%) for the MUD cohort, and 62.1% (95% CI, 45.7% to 84.3%) for the MSD cohort (P = .26). Haploidentical PBSC HSCT with PTCy had comparable outcomes to MSD and MUD BM HSCT and less cGVHD compared with MUD BM HSCT in children. The logistical advantages and lower resource burden of haplo HSCT with PBSCs make it a feasible alternative to MUD HSCT in children with hematologic malignancies. Given that this is a retrospective comparison of transplantation platforms rather than donor types, further prospective studies are warranted. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Subject(s)
Graft vs Host Disease , Hematologic Neoplasms , Adult , Allografts , Bone Marrow , Child , Cyclophosphamide/therapeutic use , Graft vs Host Disease/epidemiology , Hematologic Neoplasms/therapy , Humans , Neoplasm Recurrence, Local/complications , Retrospective Studies , Siblings , United States , Unrelated DonorsABSTRACT
BACKGROUND AIMS: Umbilical cord blood (UCB) infusion is being investigated as a treatment for a range of neurological conditions, primarily because of its potent immunomodulatory effects mediated via paracrine signaling. Although initial research mainly utilized autologous UCB, allogeneic samples from a sibling or unrelated donor have now become more common. With the use of allogeneic UCB, questions have arisen surrounding the necessity for human leukocyte antigen (HLA) matching, preparative regimens and immunosuppressant drugs. To investigate the safety of allogeneic UCB for the treatment of neurological conditions and the impact of HLA mismatching and immunosuppresion, the authors conducted a systematic review of the safety of allogeneic UCB infusion for neurological conditions. METHODS: A systematic review of published and gray literature was conducted to investigate the safety of allogeneic UCB infusions for neurological conditions. RESULTS: Authors identified 10 studies using allogeneic UCB to treat autism spectrum disorder, cerebral palsy, stroke, traumatic brain injury and various other conditions. A total of 361 participants (with at least 442 UCB infusions) received a range of HLA-matched/untyped allogeneic units and cell doses, with the majority not administered post-infusion immunosuppression. There were no reported serious adverse events definitely or probably related to the allogeneic UCB infusion, nor later potential complications such as graft-versus-host disease or teratoma formation. CONCLUSIONS: Although variability between studies is high, the available data do not identify safety concerns with allogeneic UCB infusion for the treatment of neurological conditions, even with variable HLA matching or no immunosuppression.
Subject(s)
Autism Spectrum Disorder , Cord Blood Stem Cell Transplantation , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Pharmaceutical Preparations , Cord Blood Stem Cell Transplantation/adverse effects , Fetal Blood , Graft vs Host Disease/therapy , HumansABSTRACT
BACKGROUND: The Collection of hematopoietic stem cells (HSC) and immune effector cells (IEC) has unique challenges in children. To maintain adequate blood flow, central venous catheters (CVCs) remain the standard of care in many centers, but are associated with procedural risks and increased resource utilization. The goal of this study was to determine feasibility and safety of peripheral venous catheter (PVC) cell collection in older children. METHODS: Patients and donors requiring venous access with weight >25 kg, age >8 years were screened for PVC collection via 18G PVCs. Those with poor venous access (on history/exam/pre-screening ultrasound) or unable to maintain suitable procedural position were excluded. Comparison was made to CVC collections in a matched patient cohort. RESULTS: Thirty-eight individuals were screened and met age/weight criteria for PVC collection. Five did not have PVC collection attempted due to poor access (n = 4) or behavioral concerns (n = 1). Thirty-three had PVC collection attempt (HSC = 22; IEC = 11) with median age 15.3 year (range 9.7-18.0) and weight 58.5 kg (range 27.9-115.4). Thirty-two of 33 (97%) patients were collected successfully by PVC without adverse events. Comparing PVC to matched CVC collection cohort (n = 18), there was no significant difference in flow rate (48.2 mL/h vs 53.9 mL/h, p = 0.12), collection time (266 min vs 262 min, p = 0.85) or collection efficiency (IEC/CD3 60.9% vs 60.8% p = 0.99; HSC/CD34 53.6% vs 41.3% p = 0.05). CONCLUSION: PVC collection of HSC and IEC is feasible and safe in older children with comparable collection efficiency to CVC collections. Ultrasound screening may reduce failure rates. PVC collections can reduce the risk of CVC insertions and associated healthcare costs.
Subject(s)
Catheterization, Central Venous , Central Venous Catheters , Adolescent , Aged , Child , Humans , Antigens, CD34 , Catheterization, Central Venous/adverse effects , Central Venous Catheters/adverse effects , Hematopoietic Stem Cells , UltrasonographyABSTRACT
BACKGROUND: EPP is characterized by photosensitivity and by liver disease. When LT is performed in EPP, recurrence often occurs in the allograft due to ongoing protoporphyrin production in bone marrow. Therefore, curative treatment requires allogeneic HSCT after LT. Long-term immunosuppression could be spared by using the same donor for both transplants. METHODS: A 2-year-old girl with EPP in liver failure underwent liver transplant from her father. Transfusion and apheresis therapy were used to lower protoporphyrin levels before and after liver transplant. Ten weeks after liver transplant, she underwent HSCT, using the same donor. Conditioning was with treosulfan, fludarabine, cyclophosphamide, and ATG. GVHD prophylaxis was with abatacept, methotrexate, MMF, and tacrolimus. We followed the patient's erythrocyte protoporphyrin and liver and skin health for 2 years after transplant. RESULTS: After hematopoietic stem cell engraftment, a decline in protoporphyrin levels was observed, with clinical resolution of photosensitivity. Liver biopsies showed no evidence of EPP. Mild ACR occurred and responded to steroid pulse. Two years post-HSCT, the patient has been weaned off all immunosuppression and remains GVHD and liver rejection free. CONCLUSIONS: Sequential liver and HSCT from the same haploidentical donor are feasible in EPP. This strategy can allow for discontinuation of immune suppression.
Subject(s)
Hematopoietic Stem Cell Transplantation , Liver Transplantation , Porphyria, Erythropoietic/surgery , Transplantation, Haploidentical , Biopsy , Female , Humans , Infant , Living Donors , Male , Transplantation ConditioningABSTRACT
Pediatric acute myeloid leukemia (AML) is a heterogeneous disease that requires a multifaceted treatment approach. Although outcomes for low-risk AML have improved significantly over recent decades, high-risk AML continues to be associated with an adverse prognosis. Recent advances in molecular diagnostics, risk stratification, and supportive care have contributed to improvements in outcomes in pediatric AML. Targeted approaches, for example, the use of tyrosine kinase inhibitors to treat FLT3-ITD AML, offer promise and are currently undergoing clinical investigation in pediatric patients. New approaches to hematopoietic stem cell transplantation, including the use of haploidentical donors, are significantly expanding donor options for patients with high-risk AML. This review provides an overview of recent advances in the treatment of pediatric AML that are likely to have clinical impact and reshape the standard of care.
Subject(s)
Leukemia, Myeloid, Acute , Child , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation , Prognosis , Retrospective Studies , Transplantation, Homologous , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.
Subject(s)
Lymphohistiocytosis, Hemophagocytic/diagnosis , Phenotype , Adolescent , Adult , Age of Onset , Alleles , Biomarkers , Biopsy , Child , Child, Preschool , Disease Progression , Female , Genetic Predisposition to Disease , Genotype , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Infant , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/metabolism , Magnetic Resonance Imaging , Male , Mutation , Neuroimaging , Symptom Assessment , Young AdultABSTRACT
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH), a rare hyperinflammatory immuneregulatory disorder, is a challenge in hematopoietic stem cell transplantation (HSCT) because of the high rate of mixed chimerism, relapse, and graft failure (GF) unless intensive myeloablative regimens are used. However, historically conventional myeloablative regimens (conv MA) are associated with high toxicity and mortality. PROCEDURE: We retrospectively compared transplant outcomes between three preparative regimens of varying intensities: Conv MA (n = 15), reduced-intensity conditioning (RIC, n = 12), and a treosulfan-based reduced-toxicity conditioning (RTC, n = 9). RESULTS: Patients in the RIC cohort had a higher incidence of mixed donor chimerism and five patients (42%) developed secondary GF (P = .002) compared to the other two regimens. There was a higher incidence of veno-occlusive disease and intensive care unit (ICU) admissions in the Conv MA cohort. With the RTC regimen, there was a similar 2-year overall survival (89, 73, and 83%; P = .87), but improved compound EFS (lack of relapse, GF, second transplant or additional donor cell infusions, or death; 89, 73, and 42%, P = .041) in RTC, Conv MA, and RIC regimen, respectively. CONCLUSIONS: The intensity of the preparative regimen has a significant impact on outcome of HSCT for HLH. The newly described treosulfan-based RTC provides for a stable graft with a reasonable toxicity profile.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Lymphohistiocytosis, Hemophagocytic/therapy , Transplantation Conditioning/methods , Adolescent , Antineoplastic Agents, Alkylating/adverse effects , Antineoplastic Agents, Alkylating/therapeutic use , Busulfan/adverse effects , Busulfan/analogs & derivatives , Busulfan/therapeutic use , Child , Child, Preschool , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Infant , Male , Retrospective Studies , Survival Analysis , Transplantation Conditioning/adverse effects , Transplantation, Homologous/adverse effects , Transplantation, Homologous/methods , Treatment OutcomeABSTRACT
EBV-associated PTLD following allogeneic HSCT is a serious complication associated with significant mortality. In this retrospective study, we evaluated whether lymphocyte subset numbers and CD8:CD20 ratio at time of EBV viremia in children undergoing allogeneic HSCT could predict development of PTLD. Absolute lymphocyte count, lymphocyte subsets, and CD8:CD20 ratio at the time of EBV viremia were analyzed. Patients who were treated preemptively with rituximab for high blood EBV viral load were excluded. Out of 266 patients transplanted during the study period, 26 patients were included in the analysis. Patients were divided into two cohorts; cohort 1 included patients with EBV-associated PTLD (n = 5; four with proven, one with probable PTLD). Cohort 2 included patients with EBV viremia without PTLD (n = 21). Lymphocyte recovery was slower in the PTLD group. CD8:CD20 ratio was significantly lower in the PTLD group (median 0.15) compared to the non-PTLD group (median 2.4, P = .012). Using the ROC curve and 1 as the cutoff value, CD8:CD20 ratios were analyzed. In the PTLD group, 4/5 patients (80%) had a ratio <1 whereas in the non-PTLD group, all 21 patients had a ratio >1. Sensitivity and specificity were 80% and 100%, respectively. Negative and PPVs were 95% and 100%, respectively. Profoundly low T-cell count and CD8:CD20 ratio may be used to predict development of PTLD in the context of EBV viremia in children post-allogeneic HSCT. Further studies are needed to validate this finding.
Subject(s)
Antigens, CD20/immunology , CD8-Positive T-Lymphocytes/immunology , Epstein-Barr Virus Infections/blood , Hematopoietic Stem Cell Transplantation , Lymphoproliferative Disorders/blood , Lymphoproliferative Disorders/virology , Postoperative Complications/blood , Postoperative Complications/virology , Viremia/blood , Viremia/virology , Adolescent , Allografts , Child , Child, Preschool , Epstein-Barr Virus Infections/immunology , Humans , Lymphocyte Count , Lymphocyte Subsets , Lymphoproliferative Disorders/immunology , Postoperative Complications/immunology , Predictive Value of Tests , Retrospective Studies , Sensitivity and Specificity , T-Lymphocytes/immunology , Viremia/immunologyABSTRACT
BACKGROUND: Peripheral hematopoietic stem cell (HSC) collections are needed for autologous hematopoietic stem cell transplantation (HSCT). Since 2015, our institution has utilized a secondary chamber mononuclear cell (MNC) protocol on the Spectra Optia apheresis system. Recently, a new continuous mononuclear collection protocol (CMNC) was developed for the same device. As there is limited data available regarding the use of the CMNC protocol in children, we compared collection efficiency (CE2), side effects, and clinical feasibility between the two protocols in patients <18 years old. STUDY DESIGN AND METHODS: We prospectively collected clinical, laboratory, and technical collection data from HSC collection procedures performed with the Spectra Optia apheresis system utilizing the CMNC protocol. Data were compared to retrospectively collected data utilizing the MNC protocol. Data collection included donor demographics, precollection peripheral CD34+ cell counts, total CD34+ cells collected, collection efficiency, side effects, and collection product characteristics. RESULTS: A total of 96 HSC collection procedures were performed on 79 pediatric patients utilizing either the MNC (61 patients) or CMNC (18 patients) protocol. The collection efficiencies were comparable between MNC and CMNC cohorts (52.9% vs 54.9%, P = 0.711). Platelet loss was significantly lower in the CMNC cohort (P = 0.002), especially in children weighing <15 kg. Product volumes were higher with CMNC. No significant collection-related side effects were noted with either protocol. CONCLUSIONS: MNC and CMNC protocols have comparable collection efficiencies and are both feasible and safe for the use in children. Centers may choose between the methods depending on clinical needs.
Subject(s)
Leukapheresis/methods , Adolescent , Antigens, CD34/blood , Child , Data Collection/methods , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cell Transplantation/methods , Humans , Leukapheresis/instrumentation , Leukocytes, Mononuclear , Pediatrics , Transplantation, AutologousABSTRACT
The original version of this Article omitted a declaration from the Competing Interests statement, which should have included the following: 'A patent has been applied for by Emory University with F.E.L, I.S. and D.C. N. as named inventors. The patent application number is PCT/US2016/036650'. This has now been corrected in both the PDF and HTML versions of the Article.
ABSTRACT
Human antibody-secreting cells (ASC) in peripheral blood are found after vaccination or infection but rapidly apoptose unless they migrate to the bone marrow (BM). Yet, elements of the BM microenvironment required to sustain long-lived plasma cells (LLPC) remain elusive. Here, we identify BM factors that maintain human ASC > 50 days in vitro. The critical components of the cell-free in vitro BM mimic consist of products from primary BM mesenchymal stromal cells (MSC), a proliferation-inducing ligand (APRIL), and hypoxic conditions. Comparative analysis of protein-protein interactions between BM-MSC proteomics with differential RNA transcriptomics of blood ASC and BM LLPC identify two major survival factors, fibronectin and YWHAZ. The MSC secretome proteins and hypoxic conditions play a role in LLPC survival utilizing mechanisms that downregulate mTORC1 signaling and upregulate hypoxia signatures. In summary, we identify elements of the BM survival niche critical for maturation of blood ASC to BM LLPC.
Subject(s)
Bone Marrow/metabolism , Cell Survival/physiology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , 14-3-3 Proteins/metabolism , Adult , Antibody-Producing Cells/cytology , Antibody-Producing Cells/metabolism , Cell Survival/genetics , Cells, Cultured , Female , Fibronectins/metabolism , Humans , Male , Middle Aged , Protein Binding , Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism , Young AdultABSTRACT
BACKGROUND: Graft-versus-host disease (GVHD) remains a major cause of mortality and morbidity in allogeneic hematopoietic stem cell transplantation (HSCT). In adults, early blood stream infection (BSI) and acute GVHD (AGVHD) have been reported to be related. The impact of BSI on risk for AGVHD, however, has not been assessed in pediatric patients. PROCEDURE: We conducted a retrospective analysis to test the hypothesis that early BSI (before day +30) predisposes allogeneic pediatric transplant patients to severe AGVHD. We analyzed 293 allogeneic HSCT performed at Children's Healthcare of Atlanta between 2005 and 2014 that met eligibility criteria. RESULTS: The cumulative incidence of acute grade III-IV GVHD at 100 days after HSCT was 17.1%. In multivariate analysis, risk for acute grade III-IV GVHD was associated with HLA-mismatched donor (hazard ratio [HR] = 4.870, P < 0.001), and BSI between day 0 and +30 prior to AGVHD (HR = 3.010, P = 0.001). CONCLUSIONS: These results indicate that early BSI appears to be a risk factor for acute grade III-IV GVHD. Further research is needed to determine if the link is causal.
Subject(s)
Graft vs Host Disease/epidemiology , Hematologic Diseases/therapy , Hematopoietic Stem Cell Transplantation , Infections/epidemiology , Acute Disease , Adolescent , Adult , Allografts , Child , Child, Preschool , Female , Follow-Up Studies , Graft vs Host Disease/microbiology , Hematologic Diseases/epidemiology , Humans , Infant , Infant, Newborn , Infections/microbiology , Male , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND: During major ABO-mismatched bone marrow transplant (BMT), the infusion of incompatible red blood cells (RBCs) that are present in the bone marrow graft can cause adverse events from hemolysis. RBC depletion of the bone marrow graft can decrease this risk, but the optimal method to prevent hemolysis is unclear. PROCEDURE: We conducted a retrospective cohort study of patients who underwent major ABO-mismatched BMT at a pediatric center and had RBC depletion with either hydroxyethyl starch (HES) sedimentation or Ficoll density gradient separation. Postinfusion hemoglobinuria and creatinine values were compared. RESULTS: Between 2002 and 2016, 37 patients received HES-treated and 16 patients received Ficoll-treated major ABO-mismatched bone marrow grafts. The median residual volume of RBCs was significantly greater with HES-treated grafts (HES 21.0 ml vs. Ficoll 1.4 ml, P < 0.0001). Patients who received HES-treated grafts had a higher prevalence of postinfusion hemoglobinuria (HES 57% vs. Ficoll 6%, P = 0.0009), but renal impairment was rare. Considering only HES-treated grafts, the volume of RBCs was not associated with either postinfusion hemoglobinuria or a creatinine increase. CONCLUSIONS: Ficoll density gradient separation achieves smaller RBC volumes and less postinfusion hemoglobinuria than HES sedimentation, but both can prevent significant hemolysis. Further studies are needed to determine the residual incompatible RBC volume threshold in major ABO-mismatched BMT.
Subject(s)
Blood Group Incompatibility/complications , Blood Group Incompatibility/prevention & control , Bone Marrow Transplantation/methods , Cell Separation/methods , Hemolysis , ABO Blood-Group System , Child , Cohort Studies , Erythrocytes , Female , Humans , Male , Retrospective StudiesABSTRACT
Blood stream infections (BSI) are a major source of morbidity and mortality both in allogeneic blood and marrow transplant (BMT) recipients. Various risk factors for BSI in BMT have been identified. The impact of race and cytomegalovirus (CMV) viremia, a common complication after engraftment, however, has not been rigorously assessed. This is important because both CMV infection and ganciclovir, the mainstay of pre-emptive therapy, have myelosuppressive and immunosuppressive effects. We conducted a retrospective analysis to test the hypothesis that race and CMV viremia predispose allogeneic BMT patients to postengraftment BSI. We analyzed 278 allogeneic BMT performed at Children's Healthcare of Atlanta between January 1, 2005 and December 31, 2014 that met eligibility criteria. We performed a multivariate analysis to estimate the effect of CMV viremia on risk for BSI in the postengraftment period (days +30 to 100). Risk for BSI was associated with CMV viremia (hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.51 to 7.36; P = .003); grade III and IV acute graft-versus-host disease (HR, 3.28; 95% CI, 1.55 to 6.92; P = .002), and African American race (HR, 2.22; 95% CI, 1.09 to 4.51; P = .027). The results of our study highlight the importance of a novel risk factor for postengraftment BSI, not previously considered-African American race.
Subject(s)
Bacteremia/ethnology , Black or African American , Bone Marrow Transplantation , Hematopoietic Stem Cell Transplantation , Viremia/ethnology , Adolescent , Allografts , Bacteremia/etiology , Bone Marrow Transplantation/adverse effects , Child , Child, Preschool , Cytomegalovirus Infections/complications , Disease Susceptibility , Female , Genetic Diseases, Inborn/therapy , Hematologic Diseases/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunocompromised Host , Immunosuppressive Agents/adverse effects , Infant , Infant, Newborn , Male , Neutropenia/complications , Risk Factors , Viremia/etiology , Young AdultABSTRACT
PURPOSE: This study evaluated factors associated with increased risk of pulmonary toxicity (PT) from any cause in pediatric patients after myeloablative conditioning, using total body irradiation (TBI), followed by allogeneic hematopoietic stem cell transplantation (HSCT). METHODS AND MATERIALS: The records of 129 consecutive pediatric patients (range: 1-21 years of age) who underwent TBI-based myeloablative conditioning for hematologic malignancies at our institution between January 2003 and May 2014 were reviewed. Although total TBI doses ranged from 10.5 to 14 Gy, lung doses were limited to 10 Gy with partial transmission blocks. TBI dose rates ranged from 5.6 cGy/min to 20.9 cGy/min. PT was classified using clinical symptoms, radiographic evidence, and ventilatory defects on pulmonary function tests. Noninfectious (idiopathic) pneumonia syndrome (IPS) was characterized by patients exhibiting PT while demonstrating no signs of infection throughout the follow-up period. RESULTS: PT from any cause developed in 70.5% of patients and was significantly associated with increased transplantation-related mortality (TRM) (P=.03) and decreased overall survival (OS) (P=.02). IPS developed in 23.3% of patients but was not associated with increased TRM (P=.6) or decreased OS (P=.5). Acute graft-versus-host disease (GVHD) significantly affected PT (P=.001) but did not significantly influence the development of IPS (P=.4). Infection was a leading cause of PT (75.8%). TBI dose rate significantly affected development of overall PT (P=.02) and was the sole factor to significantly influence the incidence of IPS (P=.002). TBI total dose, dose per fraction, disease type, transplantation chemotherapy, age of patient, sex, and donor type did not significantly impact overall PT or IPS. CONCLUSIONS: A high incidence of PT was noted in this large series of homogeneously treated pediatric patients undergoing TBI for allogeneic HSCT. TBI dose rates affected overall PT and strongly influenced IPS. TBI dose rate is a contributing factor influencing pulmonary toxicity and rates less than 15 cGy/min should be considered to decrease the risk of IPS.