An unprespecified interim analysis of results from a phase 1–2 study of gene therapy for sickle cell disease shows resolution of severe vaso-occlusive events in 25 patients who could be evaluated. In ...the 24 months before enrollment, these patients had a median of 3.5 severe vaso-occlusive events per year.
Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease ...progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12), or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered at www.clinicaltrials.gov as #NCT00745420.
•Children with sickle cell disease engrafted unrelated donor marrow after reduced intensity conditioning.•A high incidence of GVHD and associated mortality compromised safety of the trial.
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.
•Using central review in a multi-institution study, 28.2% of submitted cGVHD cases in children were reclassified using the NIH-CC.•The NIH-CC are feasible and reliable for children, but further refinement of criteria, specifically for pediatric cGVHD, is needed.
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Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study ...(ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1− and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.
•Profiling of immune cell populations and plasma markers at day 100 post-HSCT demonstrates biological differences between cGVHD and L-aGVHD.•Immune profiling differences between patients meeting NIH diagnostic criteria and those with distinctive features only were similar.
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Cell biology researchers, cellular engineers, and clinicians are teaming together to create powerful drugs. The use of cell-derived products as biologics is rapidly advancing. These human cell-based ...products have great potential for treating serious conditions but may have unidentified risks. Manipulations, expansions, and gene modifications increase the risks of unexpected outcomes. Implementation of the 21st Century Cures Act is opening avenues for accelerated approvals of these drugs for use in clinical trials and licensure. Although overwhelming, collaboration between regulators, industry, and research and medical communities enables the field to safely meet the needs of critically ill patients.
Adenovirus (ADV) infections are associated with significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The virus is endemic in the general pediatric population and ...frequently causes severe disease in immunocompromised patients, especially children. We report our experience with cidofovir (CDV) for treatment of ADV infection in 57 HSCT patients, median age 8 years (range 0.5-26).
Peripheral blood was prospectively screened weekly on all patients for ADV by quantitative real-time PCR for the first 100 days post-HSCT or longer if clinically indicated. Cultures for viral pathogens were performed from other involved sites. Upon detection of ADV by PCR, culture or tissue histopathology, CDV was given intravenously at 5 mg/kg weekly for 2 consecutive weeks, then every 2 weeks until 3 consecutive ADV-negative samples were documented from all previously invoved sites.
The clinical manifestations of ADV infection were: diarrhea (53%), fever (21%), hemorrhagic cystitis (12%), and pneumonitis (11%). Eight patients (14%) presented with disseminated disease. CDV treatment resulted in complete resolution of clinical symptoms in 56 (98%) patients in whom the virus became undetectable by all methods. One patient died due to ADV pneumonitis. No cases of dose-limiting nephrotoxicity were observed. CONCLUSIONS. Cidofovir appeared safe and effective for the treatment of ADV infection in this predominantly pediatric HSCT population. Vigilant surveillance and early treatment with CDV can prevent the poor outcomes associated with ADV disease. A larger prospective study is needed to further determine the role of CDV in the treatment of ADV after HSCT.
Abstract
Background
The healthcare costs of patients who receive hematopoietic stem cell transplantation (HSCT) are substantial. At the same time, the increasing use of pediatric HSCT leaves more ...caregivers of pediatric HSCT recipients at risk for financial burden—an understudied area of research.
Methods
Financial burden experienced by caregivers of recipients who received autologous or allogeneic transplants was assessed using an explanatory mixed‐methods design including a one‐time survey and semi‐structured interviews. Financial burden was assessed through an adapted COmprehensive Score for financial Toxicity (COST) as well as questions about the types of out‐of‐pocket costs and cost‐coping behaviors. Chi‐squared or Fisher's exact tests were used to assess differences in costs incurred and coping behaviors by financial toxicity and financial toxicity by demographic factors. Interviews were audio recorded, transcribed, and analyzed using directed content analysis.
Results
Of 99 survey participants, 64% experienced high financial toxicity (COST 22). Caregivers with high financial toxicity were more likely to report costs related to transportation and diet. High financial toxicity was associated with nearly all cost‐coping behaviors (e.g., borrowed money). High financial toxicity was also associated with increased use of hospital financial support and transportation assistance. Qualitative analysis resulted in four categories that were integrated with quantitative findings: (1) care‐related out‐of‐pocket costs incurred, (2) cost‐coping behaviors, (3) financial support resources used, and (4) multilevel recommendations for reducing financial burden.
Conclusions
Considering the substantial, long‐term financial burden among pediatric HSCT patients and their caregivers, this population would benefit from adapted and tailored financial burden interventions.
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