In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor ...γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1.
We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc).
All patients received bone marrow-derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients.
This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.).
An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect ...causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 59% of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.
•PK deficiency manifests a broad spectrum in anemia severity that moderately improves after splenectomy.•Close attention to monitoring for iron overload, gallstones, and other complications is recommended in all patients with PK deficiency.
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Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of ...this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Chicago’s Ann & Robert H. Lurie Children’s Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 ± 5% and 29 ± 5%, respectively. Findings were validated in the independent SEER cohort, with 10-year OS rates of 52 ± 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten-year OS for patients treated with a GTR was 61 ± 7% and PFS was 36 ± 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease.
Survival analysis following oncological treatments require specific analysis techniques to account for data considerations, such as failure to observe the time of event, patient withdrawal, loss to ...follow-up, and differential follow up. These techniques can include Kaplan-Meier and Cox proportional hazard analyses. However, studies do not always report overall survival (OS), disease-free survival (DFS), or cancer recurrence using hazard ratios, making the synthesis of such oncologic outcomes difficult. We propose a hierarchical utilization of methods to extract or estimate the hazard ratio to standardize time-to-event outcomes so that study inclusion into meta-analyses can be maximized. We also provide proof-of concept results from a statistical analysis that compares OS, DFS, and cancer recurrence for robotic surgery to open and non-robotic minimally invasive surgery. In our example, use of the proposed methodology would allow for the increase in data inclusion from 108 hazard ratios reported to 240 hazard ratios reported or estimated, resulting in an increase of 122%. While there are publications summarizing the motivation for these analyses, and comprehensive papers describing strategies to obtain estimates from published time-dependent analyses, we are not aware of a manuscript that describes a prospective framework for an analysis of this scale focusing on the inclusion of a maximum number of publications reporting on long-term oncologic outcomes incorporating various presentations of statistical data.
Background Voriconazole, an antifungal agent, is associated with various cutaneous reactions, including phototoxicity, accelerated photoaging, and skin cancer. Incidence and risk factors for these ...reactions in children have not been well described. Objective We sought to determine the incidence of and factors associated with phototoxic reactions and nonmelanoma skin cancer in pediatric patients treated with voriconazole. Methods This was a retrospective analysis of 430 pediatric patients treated with voriconazole between 2003 and 2013 at Boston Children's Hospital. Results Incidence of phototoxicity was 20% in all children treated with voriconazole and 47% in children treated for 6 months or longer. Factors associated with phototoxicity included white race, cystic fibrosis, cumulative treatment time, and cumulative dose. Four patients (1%) had nonmelanoma skin cancer; all experienced a phototoxic reaction during voriconazole treatment. Of those with phototoxicity, 5% were discontinued on voriconazole, 6% were referred to dermatology, and 26% received counseling about sun protection from their primary physician. Limitations Our study is limited by its retrospective design and potential referral bias associated with a tertiary-care center. Conclusions Voriconazole-associated phototoxicity is relatively common in children and may lead to nonmelanoma skin cancer. However, those with phototoxic reactions are often continued on therapy, rarely referred to dermatology, and infrequently counseled on sun protection.
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Background: PKD is the most common enzyme defect of the glycolytic pathway causing hereditary non-spherocytic chronic hemolytic anemia. PKD is transmitted as an autosomal recessive trait, caused by ...both homozygous and compound heterozygote mutations in the PKLR gene, and is characterized by molecular heterogeneity with > 200 different mutations reported.
Aim: To describe the PKLR genotypes in the PKD NHS with an in depth characterization of 20 newly reported mutations.
Methods: Participants (pts) were enrolled in the PKD NHS, a prospective international study open at 23 sites in North America and Europe. Pts with prior PKLR gene sequencing were not resequenced. DNA from all other pts was extracted and the PKLR gene analyzed by Sanger sequencing at 1 of 2 central labs. All new missense mutations affected highly conserved residues in multiple domains of the PKLR gene, were not detected in 1000 genomes and LOVD database, and were considered pathogenic by NCBI and/or UniProtKB and by Polyphen analysis.
Results: Genotype information was available on 140 enrolled pts. Of these, 66 (47%) were related to other subjects enrolled in the study. Molecular characterization confirmed the wide heterogeneity of PKD with 65 different mutations identified, including: 42 missense, 20 disruptive mutations (7 splicing, 6 frameshift, 3 stop codons, and 4 large deletions), 2 inframe insertion/deletions, and 1 promoter variant. Sixty-six pts were homozygous, of whom 55 were of Amish origin carrying the p.R479H mutation. Of the 55, 46 had been transfusion dependent prior to splenectomy and 9 had only received transfusions for acute stressors; 93% had been splenectomized, and all were transfusion independent post-splenectomy.
Thirty-nine cases had 2 different missense mutations; 18 had one missense and one disruptive mutation, and 16 had 2 disruptive mutations; 1 patient with 17% residual PK activity displayed 3 different mutations (R510W, E241X and V276WXfs45). Besides R479H, the most common mutations were: R510W (16% of the mutated alleles), R486W (12%), and G241X (9%). Frequencies of R510W and R486W were less than those reported in Europe (41% and 30%, respectively). Twenty mutations, all affecting the PK structural domains, have not been previously described: 14 missense, 3 splicing (c.966(-9) a>g; c.1116(+2) t>c; c.375(+1) g>a), 1 frameshift (R40R fsX7), 1 inframe insertion of 2 amino acids, and 1 large deletion spanning intron 2 to intron 3 (Table).
The 3 new splice site mutations were predicted to affect normal splicing when analyzed by HSF3.0, using both HSF and MaxEnt algorithms; in particular, homozygous c.966(-9) a>g was detected in a patient with moderate anemia, reticulocytosis, and mental retardation of unclear etiology. The two new missense mutations detected at a homozygous level (A137V and N156G) were associated with moderate or severe anemia and need for regular transfusions. The latter is located in the Aβ3 catalytic domain/K binding site and probably affects the catalytic efficiency of the enzyme. All the remaining new variants were detected in compound heterozygosity making it difficult to predict their effect on clinical phenotype. Intra-family clinical variability was observed; no correlation was found among the kinds of mutations and the residual PK activity.
Conclusion: The molecular features of the largest international cohort of PKD pts are described, including a report of 20 new mutations, thus confirming the wide heterogeneity of the molecular genotype in PKD.
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Morton:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees. Eber:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yaish:Agios: Membership on an entity's Board of Directors or advisory committees. Nottage:Janssen Pharmaceuticals: Employment. Kuo:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Grace:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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