The presence of increasing host chimerism or persistent mixed chimerism (MC) after hematopoietic stem cell transplantation for leukemia in children is a predictor of relapse. To reduce the risk of relapse, we prospectively studied post-transplantation chimerism-based immunotherapy (IT) using fast withdrawal of immunosuppression (FWI) and donor lymphocyte infusions (DLI) in children with early post-transplantation MC. Forty-three children with hematologic malignancies at 2 institutions were enrolled prospectively in this study from 2009 until 2012 and were followed for a mean of 42 (SD, 10) months. Twelve patients (28%) were assigned to the observation arm based on the presence of graft-versus-host disease (GVHD) or full donor chimerism (FDC), and 5 (12%) sustained early events and could not undergo intervention. Twenty-six (60%) patients with MC were assigned to IT with FWI, which started at a median of 49 days (range, 35 to 85 days) after transplantation. Fourteen patients proceeded to DLI after FWI. Toxicities of treatment included GVHD, which developed in 19% of patients undergoing intervention, with 1 of 26 (4%) dying from GVHD and 1 (4%) still requiring therapy for chronic GVHD 21 months after DLI. Patients with MC undergoing IT had similar 2-year event-free survival (EFS) (73%; 95% confidence interval (CI), 55% to 91%) compared with patients who achieved FDC spontaneously (83%; 95% CI, 62% to 100%); however, because 50% of all relapses in the IT occurred later than 2 years after transplantation, the EFS declined to 55% (95% CI, 34% to 76%) at 42 (SD, 11) months. There were no late relapses in the observation group. EFS in the entire cohort was 58% (95% CI, 42% to 73%) at 42 (SD, 11) months after transplantation. Evidence of disease before transplantation remained a significant predictor of relapse, whereas development of chronic GVHD was protective against relapse.
Delayed immune reconstitution after allogeneic transplant for pediatric acute leukemia has been implicated by some studies as a risk for leukemic relapse. However, results regarding the specific laboratory parameters of interest have been conflicting. We initiated a retrospective review of 97 pediatric patients who underwent allogeneic stem cell transplantation for ALL, AML or JMML between the years of 2000 and 2010. We collected available clinical outcomes data which included lymphocyte subset (CD3, CD4, CD8, CD19, CD16/56) recovery at 90 and 180 days, proliferative response of CD3 T cells to phytohemagglutinin (PHA) at 90 and 180 days, and donor CD3 chimerism at 30 days post-transplant. Median cutoffs associated with immune reconstitution that were used for data analysis included a CD4 count >200, CD8 count >200, and PHA >30% of lower limit of normal control. Full donor CD3 chimerism was defined as no evidence of host DNA down to a sensitivity of 1%. Data for immunophenotype was available for 71 patients; CD3 chimerism was available for 50 patients, and PHA responses were available for 47 patients. No significant difference in CD4 or CD8 T cell recovery was detected between relapse and non-relapse patients. However, a higher rate of relapse was observed in patients with a PHA response <30% within the first 180 days (4/7, 5-year RFS 42.8%), compared to those with PHA >30% (5/40, 5-year RFS 84.8%, P = .02). In the subset of patients for whom both PHA and chimerism data were available, a higher rate of relapse was observed in patients with either mixed CD3 chimerism or poor PHA response (8/27), compared to those who recovered both full donor CD3 chimerism and CD3 PHA response >30% (0/7, P = .1). Historically, tailoring of immunotherapy post-transplant has focused on the treatment of graft-versus-host disease. With the availability of clinical tools to better predict leukemic relapse post-transplant, further intervention (such as withdrawal of immunosuppression and/or DLI) may be implemented safely and effectively for those who require it. This preliminary data indicates that PHA response is a clinically accessible indicator of immune reconstitution that may be an important variable to consider when predicting a patient's risk for relapse. Further study is needed to determine the degree to which PHA response might affect specific groups of patients.
Background: Our group and others (Greinix BBMT 2015) have shown that higher proportions of recent thymic emigrants (RTEs: CD4+CD45RA+CD31+) at d100 are a prognostic biomarker for chronic GvHD in adults. We sought to understand whether RTEs, as well as regulatory T cells (CD4+CD25+CD127Lo) that co-express naïve and recently emigrated markers (CD45RA+CD31+; Treg RTEs) were prognostic at d100 for pediatric cGvHD. Methods: Allo-HCT patients (<18yrs) with malignant and non-malignant diagnoses were enrolled before HCT and prospectively followed for cGvHD until 1-year post-HCT. Blood was analyzed by 8-color flow cytometry at d100 (+/- 14d) for prognostic cellular cGvHD biomarkers. Mean values are reported. Biomarkers were considered clinically significant if means were >1.5× or <0.7× the control and P < .05. Two hundred and twelve patients were enrolled before June 30, 2016: 144 were evaluable with 1-year follow up and 68 excluded for relapse, non-engraftment or early death. Of the evaluable patients, 37 (25.7%) developed NIH criteria cGvHD, 34 (23.6%) had late aGvHD but no cGvHD, and 73 (50.7%) had no cGvHD. The no cGvHD group included patients both with and without a past history aGvHD, as we found previous aGvHD had no impact on d100 RTE and Treg RTE percentages in the absence of cGvHD. Late aGvHD was evaluated as a separate group independent of the cGvHD group. Results: RTEs as a % of CD4 T cells were significantly lower at d100 in patients with cGvHD compared to no cGvHD, and were prognostic for the later development of cGvHD (Table 1). Similar relationships existed for Treg RTEs, being significantly lower in cGvHD compared to no cGvHD. To determine whether RTEs and Treg RTEs were prognostic for any form of GvHD after d100, a combined group of cGvHD and late aGvHD was created and compared to the no cGvHD group. Both RTEs and Treg RTEs were significantly lower at d100 compared to the no cGvHD group and were prognostic for the development of any form of GvHD after d100.Table 1Cell PopulationNo cGvHDcGvHD onlyP-value*(AUC)Late aGvHD onlyP-value*(AUC)cGvHD + Late aGVHDP-value*(AUC)RTEs (% of CD4 T cells)13.5%7.8%.007 (.64)9.4%.08 (NS)8.5%.009 (.62)Treg RTEs (% of Tregs)13.2%6.4%.002 (.67)9.1%.06 (NS)7.6%.004 (.62)AUC, Area under curve on receiver operator curve.*Compared to the no cGvHD group. Open table in a new tab AUC, Area under curve on receiver operator curve. *Compared to the no cGvHD group. Conclusions: In this multi-institution study, both RTEs and Treg RTEs at d100 were prognostic biomarkers for pediatric cGvHD, irrespective of a previous history of aGvHD before d100. Interestingly, both T cell populations were lower compared to the no cGvHD group, a finding that is opposite to what our group and others have observed in adults with cGvHD. In a combined analysis of both late aGvHD and cGvHD, lower RTEs and Treg RTEs were also prognostic for GvHD after d100. These data suggest that thymic function may play a larger role in the later development of GvHD post-HCT for children compared to adults.
Abstract Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.
Hypogonadism has been observed in both the HIV-infected population and injection drug users (IDUs). Considering these populations in conjunction is essential because IDUs and HIV often occur in the same individual. Additionally, although the etiology of hypogonadism may be different in each population, its treatment with respect to the underlying condition is similar. The philosophy of both AIDS and IDU treatment has changed drastically in recent years, due to several factors. Survival rates of HIV patients have been steadily increasing, forcing a closer examination of the long-term effects of AIDS-related symptoms, and the quality of life issues associated therewith. In comparison, IDU is now viewed as a chronic addiction like that for alcoholism, which must be treated, rather than an untreatable personal problem. Therefore, it is logical that the endocrine and metabolic changes associated with both HIV and IDU should be examined to help alleviate these symptoms in a continuing effort to treat the underlying condition.
Neuroblastoma can originate from any site in the sympathetic nervous system, presenting as a mass in the abdomen, mediastinum, neck, or pelvis. Prompt administration of chemotherapy appears to be effective for treating intraspinal neuroblastoma, and it may avoid some of the long-term sequelae associated with either radiation or surgical resection and laminectomy. Neuroblastomas may be diploid or hyperdiploid, and chromosomal content by measurement of DNA index has established that near-diploid DNA content is less favorable and associated with other adverse prognostic markers. Therapy for high-risk neuroblastoma is currently divided into three phases: intensive induction treatment, marrow ablative therapy, and management of minimal residual disease (MRD). Very high-dose myeloablative therapy may be used to try to overcome residual and potentially resistant tumor and is followed by autologous hematopoietic cell transplantation (HCT). Tandem transplantation uses repetitive high-dose therapies followed by HCT to provide further increases in dose intensity.
