The relationship between regulatory T cells (Tregs) and acute graft-versus-host disease (GVHD) in clinical allogeneic bone marrow transplantation (BMT) recipients is not well established. We conducted a prospective analysis of peripheral blood Tregs as determined by the frequency of CD4+CD25hiFOXP3+ lymphocytes in 215 BMT patients. Autologous BMT patients (N=90) and allogeneic BMT patients without GVHD (N=65) had similar Treg frequencies, whereas allogeneic patients with GVHD (N=60) had Treg frequencies that were 40% less than those without GVHD. Treg frequencies decreased linearly with increasing grades of GVHD at onset and correlated with eventual maximum grade of GVHD (p<0.001). In addition, frequency of Tregs at onset of GVHD predicted the response to GVHD treatment (p=0.003). Patients with Treg frequencies less than the median had higher non-relapse mortality than patients with Tregs greater than the median, but experienced equivalent relapse mortality, resulting in an inferior survival at two years (38% vs. 63%, p=0.03). Treg frequency may therefore have important prognostic value as a biomarker of acute GVHD.
BackgroundAcute colonic pseudo-obstruction (ACPO) refers to dilatation of the colon and decreased bowel motility without evidence of mechanical obstruction. Neostigmine, an acetylcholinesterase inhibitor, has been used in patients in whom supportive therapy failed to resolve ACPO. Here, we report the results of administering neostigmine to treat ACPO in children with hematologic malignancies.MethodsBetween September 2005 and December 2009, 10 patients (8 male and 2 female) were diagnosed with ACPO at the Department of Pediatrics, Catholic University of Korea. Diagnosis of ACPO was based on typical clinical features as well as colonic dilatation found on abdominal CT imaging. Neostigmine was administered subcutaneously at a dosage of 0.01 mg/kg/dose (maximum 0.5 mg) twice daily for a maximum of 5 total doses. ACPO was determined to be responsive to neostigmine if the patient showed both stool passage and improvement of clinical symptoms.ResultsThe study group included 8 acute lymphoblastic leukemia patients, 1 patient with malignant lymphoma, and 1 patient with juvenile myelomonocytic leukemia. The median age at ACPO diagnosis was 8.5 years (range, 3-14). Overall, 8 patients (80%) showed therapeutic response to neostigmine at a median of 29 hours after the initial administration (range, 1-70). Two patients (20%) showed side effects of grade 2 or above, but none complained of cardiovascular symptoms that required treatment.ConclusionIn this study, ACPO was diagnosed most often in late-childhood ALL patients. Subcutaneous neostigmine can be used to effectively treat ACPO diagnosed in children with hematologic malignancies without major cardiovascular complications.
BackgroundAutoimmune cytopenia (AIC) is a rare complication of allogeneic hematopoietic cell transplantation (HCT). In this study, we reviewed the diagnosis, treatment and response to therapy for pediatric patients with post-HCT AIC at our institution.MethodsOf the 292 allogeneic HCTs performed from January, 2011 to December, 2015 at the Department of Pediatrics, The Catholic University of Korea, seven were complicated by post-HCT AIC, resulting in an incidence of 2.4%.ResultsAll seven patients with post-HCT AIC had received unrelated donor transplant. Six of seven patients had a major donor-recipient blood type mismatch. The subtypes of AIC were as follows: immune thrombocytopenia (ITP) 2, autoimmune hemolytic anemia (AIHA) 2, Evans syndrome 3. Median time from HCT to AIC diagnosis was 3.6 months. All but one patient responded to first line therapy of steroid±intravenous immunoglobulin (IVIG), but none achieved complete response (CR) with this treatment. After a median duration of treatment of 15.3 months, two patients with ITP achieved CR and five had partial response (PR) of AIC. Five patients were treated with rituximab, resulting in the following response: 2 CR, 2 PR, 1 no response (NR). Median time to response to rituximab was 26 days from first infusion. All patients are alive without event.ConclusionPost-HCT AIC is a rare complication that may not resolve despite prolonged therapy. Rapid initiation of second line agents including but not limited to B cell depleting treatment should be considered for those that fail to achieve CR with first line therapy.
In this single-institution study of Korean pediatric ALL patients, risk group based intensification with omission of cranial irradiation resulted in EFS comparable to previous studies, excellent survival of low- and standard-risk patients, and a low rate of CNS relapse.
PurposeLymphocyte subset recovery is an important factor that determines the success of hematopoietic stem cell transplantation (HSCT). Temporal differences in the recovery of lymphocyte subsets and the factors influencing this recovery are important variables that affect a patient's post-transplant immune reconstitution, and therefore require investigation.MethodsThe time taken to achieve lymphocyte subset recovery and the factors influencing this recovery were investigated in 59 children who had undergone HSCT at the Department of Pediatrics, The Catholic University of Korea Seoul St. Mary's Hospital, and who had an uneventful follow-up period of at least 1 year. Analyses were carried out at 3 and 12 months post-transplant. An additional study was performed 1 month post-transplant to evaluate natural killer (NK) cell recovery. The impact of pre- and post-transplant variables, including diagnosis of Epstein-Barr virus (EBV) DNAemia posttransplant, on lymphocyte recovery was evaluated.ResultsThe lymphocyte subsets recovered in the following order: NK cells, cytotoxic T cells, B cells, and helper T cells. At 1 month post-transplant, acute graft-versus-host disease was found to contribute significantly to the delay of CD16+/56+ cell recovery. Younger patients showed delayed recovery of both CD3+/CD8+ and CD19+ cells. EBV DNAemia had a deleterious impact on the recovery of both CD3+ and CD3+/CD4+ lymphocytes at 1 year post-transplant.ConclusionIn our pediatric allogeneic HSCT cohort, helper T cells were the last subset to recover. Younger age and EBV DNAemia had a negative impact on the post-transplant recovery of T cells and B cells.
Background: Acute myeloid leukemia with the t(8;21)(q22;q22) rearrangement (RUNX1-RUNX1T1 (+) AML) is known to have a favorable prognosis. Our study aimed to determine the most important prognostic variables among an aggregate of clinical, genetic, and treatment response-based factors in pediatric RUNX1-RUNX1T1 (+) AML. Materials and Methods: We analyzed the characteristics and outcome of 40 patients who were diagnosed with and treated for RUNX1-RUNX1T1 (+) AML from April 2008 to December 2016 at our institution. Results: A<−2.2 log fusion transcript decrement after remission induction, myeloid sarcoma type extramedullary involvement (EMI) at diagnosis, higher initial white blood cell count, and presence of KIT mutation predicted lower event-free survival. Both lower fusion transcript decrement after remission induction and the presence of EMI at diagnosis proved to be significant adverse factors in the multivariate study. The 5-year event-free survival was 70.0±7.2% (28/40); 8 of the 12 relapsed patients survive disease-free, resulting in 5-year overall survival of 89.5±5.0% (36/40). Conclusions: Kinetics of response to remission induction chemotherapy, measured in terms of the PCR value for the fusion transcript, and the presence of myeloid sarcoma type EMI at diagnosis may predict the risk of relapse in pediatric RUNX1-RUNX1T1 (+) AML.
514 JMM and XQ contributed equally to this work. Regulatory T cells (Treg) play an important role in the maintenance of tolerance after bone marrow transplantation (BMT) in experimental models. However, the relationship between Treg and acute graft-versus-host disease (GVHD) in allogeneic BMT recipients is not well established. We conducted a prospective analysis of Treg frequency in 215 BMT patients (125 allogeneic, 90 autologous) at the University of Michigan. Fresh peripheral blood samples were acquired prior to therapy within 24 hours of GVHD onset and at equivalent time points in patients without GVHD. Treg frequency was measured in triplicate by three color cytometry analysis to determine the frequency of CD4+CD25hiFOXP3+ cells within total lymphocytes. There were no significant differences between patients with and without GVHD for median age, nonmalignant disease, conditioning intensity, and median day of sample acquisition. Recipients of grafts from donors who were not family members or who were not HLA-matched were overrepresented in the GVHD group. Autologous BMT patients (N=90) and allogeneic BMT patients without GVHD (N=65) had the same mean Treg frequency (1.09% ± 0.10 vs. 1.09% ± 0.11, p = 0.54), showing that the use of calcineurin inhibitors did not affect Treg frequency. Patients with GVHD (N=60) had 40% fewer Treg (0.66% ± 0.07, p < 0.001) than those without GVHD. Frequencies of Tregs decreased in a linear fashion with each increasing grade of GVHD at onset, and were significantly reduced in patients with ≥ grade II compared to patients without GVHD (p < 0.001) (Figure 1). The calculated Receiver Operating Characteristic (ROC) curve for Treg frequency as an independent biomarker of GVHD was 0.69 (95%CI, 0.55-0.83). Treg frequency also correlated with the eventual maximum overall grade of GVHD (p < 0.001), suggesting a prognostic value for this measurement. Therefore, we evaluated whether Treg frequency would correlate with non relapse mortality (NRM) in the 60 patients with GVHD. Patients with low Treg frequency (<0.5%, N=30) had a significantly greater NRM (41% vs. 8%, p = 0.03) than patients with high Treg frequency (≥0.5%, N=30), which resulted in an inferior survival at two years (38% vs. 63%, p = 0.03) (Table 1). Acute GVHD accounted for the majority of NRM in the low Treg frequency group. Relapse mortality was similar between groups (p = 0.9) (Table 1). This difference in survival remained significant after adjusting for other important prognostic factors such as age, degree of HLA-match, and conditioning intensity (p = 0.05). In this set of sixty patients, frequency of CD4+CD25hiFOXP3+ Tregs at onset of GVHD correlates with GVHD severity, eventual maximum grade and NRM. Treg frequency thus has important diagnostic and prognostic value as biomarker for acute GVHD. Disclosures: No relevant conflicts of interest to declare.
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