To gain insight into how primary immunodeficiencies (PIDs) affect children's health status and quality of life.
The French Reference Center for PIDs conducted a prospective multicenter cohort that ...enrolled participants who met all criteria: patients included in the French Reference Center for PIDs registry, children younger than18 years, and living in France. Participants were asked to complete both a health questionnaire and a health-related quality of life (HR-QoL) questionnaire. A severity score was assigned to each health condition: grade 1 (mild) to grade 4 (life-threatening). HR-QoL in children was compared with age- and sex-matched French norms.
Among 1047 eligible children, 656 were included in the study, and 117 had undergone hematopoietic stem cell transplantation; 40% experienced at least one grade 4 condition, and 83% experienced at least one grade 3 or 4 condition. Compared with the French norms, children with PID scored significantly lower for most HR-QoL domains. Low HR-QoL scores were associated strongly with burden of poor conditions.
Our results quantify the magnitude of conditions in children with PID and demonstrate that the deleterious health effects borne by patients already are evident in childhood. These results emphasize the need to closely monitor this vulnerable population and establish multidisciplinary healthcare teams from childhood.
ClinicalTrials.gov: NCT02868333 and EudraCT 2012-A0033-35.
Background
Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical ...characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT.
Methods
Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3).
Results
Median observation time was 8 (range, 1‐93) months. Progression‐free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT‐SHH, n = 2; ATRT‐MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT‐MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT‐MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT‐MYC) died of intracerebral hemorrhage prior to response evaluation.
Conclusions
Long‐term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.
Abstract
PURPOSE
To assess the 3-year EFS rate of children younger than 5 years of age with high-risk medulloblastoma (MB) treated according to the prospective multicenter trial HR MB-5.
PATIENTS AND ...METHODS
After surgery, all children received 2 cycles of Etoposide- Carboplatine. If partial (PR) or complete response (CR) was achieved after induction chemotherapy, children received 2 courses of thiotepa (600mg/m²) with stem cell rescue. For patients in CR after high-dose chemotherapy, they received one course of Cyclophosphamide – Busilvex with stem cell rescue (Phase I part). The others patients (not in PR after induction or in CR after thiotepa) were treated with 2 cycles of Temozolomide-Irinotecan followed by age-adapted craniospinal irradiation and maintenance treatment.
RESULTS
28 children (2 to 4 years; median: 3.0 years) were enrolled. Group 3 MB were most common (57%). The response rate to Etoposide-Carboplatine was 60.7%. Among 20 patients treated with Thiotepa, 13 children were in CR and received Cyclophosphamide – Busilvex without radiotherapy. Out of them, 9 patients (45%) are alive in CR without craniospinal irradiation (median follow-up 5 years). Among 15 patients treated with radiotherapy, 8 patients are alive (median follow-up 3.8 years). The study was prematurely stopped for an excess of events. The median follow-up was 4 years (range 1.5 - 6.1). The 3-year EFS and OS were 42.3% 25.9 - 60.6 and 71.3% 52.7 - 84.7, respectively.
CONCLUSIONS
This risk-adapted strategy did not improve EFS in young children with high-risk MB. However, the study shows that good responders to chemotherapy can be cured without recourse to irradiation.
In terms of overall survival (OS), limited data are available for the very long-term outcomes of children treated for optic pathway glioma (OPG) with up-front chemotherapy. Therefore, we undertook ...this study with the aim of clarifying long-term OS and causes of death in these patients.
We initiated and analyzed a historical cohort study of 180 children with OPG treated in France with BB-SFOP chemotherapy between 1990 and 2004. The survival distributions were estimated using Kaplan-Meier method. The effect of potential risk factors on the risk of death was described using Cox regression analysis.
The OS was 95% 95% CI: 90.6-97.3 5 years after diagnosis and significantly decreased over time without ever stabilizing: 91.6% at 10 years 95% CI: 86.5-94.8, 80.7% at 15 years 95% CI: 72.7-86.8 and 75.5% 95% CI: 65.6-83 at 18 years. Tumor progression was the most common cause of death (65%). Age and intracranial hypertension at diagnosis were significantly associated with a worse prognosis. Risk of death was increased by 3.195% CI: 1.5-6.2 (p=0.002) for patients less than 1 year old at diagnosis and by 5.295% CI: 1.5-17.6 (p=0.007) for patients with initial intracranial hypertension. Boys without diencephalic syndrome had a better prognosis (HR: 0.3 95% CI: 0.1-0.8, p=0.007).
This study shows that i) in children with OPG, OS is not as favorable as previously described and ii) patients can be classified into 2 groups depending on risk factors (age, intracranial hypertension, sex and diencephalic syndrome) with an OS rate of 50.4% at 18 years 95% CI: 31.4-66.6 in children with the worst prognosis. These findings could justify, depending on the initial risk, a different therapeutic approach to this tumor with more aggressive treatment (especially chemotherapy) in patients with high risk factors.
Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of ...post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.
The most frequent germline mutations responsible for non syndromic congenital sideroblastic anemia are identified in ALAS2 and SLC25A38 genes. Iron overload is a key issue and optimal chelation ...therapy should be used to limit its adverse effects on the development of children. Our multicentre retrospective descriptive study compared the strategies for diagnosis and management of congenital sideroblastic anemia during the follow-up of six patients with an ALAS2 mutation and seven patients with an SLC25A38 mutation. We described in depth the clinical, biological and radiological phenotype of these patients at diagnosis and during follow-up and highlighted our results with a review of available evidence and data on the management strategies for congenital sideroblastic anemia. This report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications. The use of an international registry would certainly help defining recommendations for the management of these rare disorders to improve patient outcome.
Context: Shwachman Diamond disease (SDS) is caused by an SBDS mutation, is typically associated with neutropenia and exocrine pancreas deficiency. Pancytopenia, myelodysplastic syndrome (MDS) or ...acute myeloid leukemia (AML), are life-threatening complications of SDS. To date, the sole risk factors identified for SDS are early symptoms (before age of 3 months) and mild chronic anemia or thrombocytopenia(1).
Methods: To determine which mutations underlie clonal development and leukemic changes in SDS, we screened a series of patients with congenital neutropenias at various time points of follow-up. We used a consensus NGS panel of 41 genes involved in the development of myeloid malignancies (Haloplex® Agilent) (2, 3). Patients with SBDS mutations included in the French Severe Congenital Neutropenia registry or followed in the Leuwen University were screened when bone marrow samples were available as well as other subtypes of congenital neutropenia.
Results: Among the 139 SDS patients, bone marrow samples of 23 patients were available for screening at various time points. We found isolated somatic TP53 mutations in 10 cases. In addition one patient had concomitant FLT3 TKD and TP53 mutations, and another patient had the recurrent IDH1 p.Arg132Cys variant. Strikingly, no TP53 mutations were observed when the screening was extended to 70 non-SDS neutropenia patients. None of the 11 SDS patients without any detectable mutations (with a threshold of detection of 0.5%) had any severe hematological expression nor presented any major hematological complications at time of sampling. By contrast, among the 12 SDS patients with somatic mutations, AML or MDS were observed in 3 cases, 1 with the IDH1 mutation (Variant allelic frequency (VAF): 42%), 1 with the recurrent TP53 p.Gly245Ser mutation (VAF:53%), 1 with two TP53 mutations (VAFs : 19% and 37%). Severe cytopenias without MDS or AML were found in 2 other cases, one with an isolated TP53 mutation at 24%, and one with both TP53 and FLT3 mutations around 45%. In the 7 remaining patients, allele frequencies of TP53 variants were found below 2% in four cases, and at 3%, 14%, and 37% in the 3 other patients. By sequential analysis in one patient we found a p.Val272Met variant (1.1% at 9 years) which was no more observed but was replaced by the recurrent p.Arg175His mutation (4% at 12 years and 14% at 15 years). Figure 1 depicts the allele frequencies of the variants with time among the 23 patients. The three patients with MDS / AML died despite hematopoietic stem cell transplantation (HSCT) in two of them. In contrast, the two patients with severe cytopenias and TP53 mutations who were transplanted are doing well three years after HSCT, and no TP53 mutation was detected one year after transplant.
Conclusion: TP53 mutations are associated with hematological complications and specifically acquired in SDS when compared to other congenital neutropenias. This is in line with the frequency of complex karyotype MDS/AML in SDS(1). Routine evaluation of TP53 load in SDS patients may offer a powerful tool to screen SDS who may be susceptible to have severe hematological complications in a preemptive transplantation strategy setting.
References: 1. J. Donadieu et al., Haematologica 97, 1312 (2012). 2. P. Hirsch et al., Nat. Commun. 7, 12475 (2016). 3. E. Papaemmanuil et al., N. Engl. J Med. 374, 2209 (2016).
Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier and « Le Fond de dotation Contre la Leucémie“. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot (ASSQF) for their support.
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No relevant conflicts of interest to declare.
Background
Congenital rhabdoid tumors are rare and highly aggressive malignancies. In general, patients are considered to be incurable and are often treated using an exclusive, primarily palliative ...approach.
Methods
A prospective and retrospective collection of 42 patients from the European Rhabdoid Registry (EU‐RHAB), France and Moscow (2006–2016) diagnosed within the first 28 days of life was evaluated. Genetic and clinical reference evaluation included SMARCB1 and/or SMARCA4 (fluorescence‐in‐situ‐hybridization, multiplex ligation‐dependent probe amplification, and sequencing) mutation analysis and immunohistochemistry. Forty‐eight percent (20/42) of patients were treated according to the EU‐RHAB therapy, 7% (3/42) according to the pilot approach Rhabdoid 2007, 33% (14/42) with individual schedules, and 12% (5/42) received no chemotherapy at all.
Results
Forty point five percent (17/42) of patients presented with extracranial rhabdoid tumors, 33.5% (14/42) with rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumor), and the remainder 26% (11/42) demonstrated synchronous tumors. Metastases at diagnosis were present in 52% (22/42) of patients. A germline mutation was detected in 66% (25/38) and was associated with a poor prognosis (4.2 ± 4.1% vs. 48 ± 16.4%, P < 0.00005). A gross total resection (GTR) was realized in 17%. A GTR (42.9 ± 18.7% vs. 4.9 ± 4.3%, P = 0.04), therapy according to a standardized approach (20.9 ± 8.7% vs. 7.1 ± 6.9 %, P = 0.0018), and a complete remission (CR) (23.6 ± 9.8% vs. 1.3 ± 3.6%, P = 0.04) were significant prognostic factors.
Conclusions
The management of patients with congenital rhabdoid tumors requires a major multidisciplinary effort. In many instances, cure is not possible and a palliative approach is warranted. Our data indicate a positive impact of standardized therapeutic approaches on survival, making a tailored approach toward affected patients and their families mandatory.
Abstract
A retrospective European survey was conducted to collect data sets on treatment and outcome of children with intramedullary spinal cord AT/RT. Twelve patients (male, n=4; median age 32 ...range, 0.7–97 months) were identified. Lumbar (n=9) and thoracic segments (n=9) were most commonly involved, followed by sacral (n=3) and cervical segments (n=2). In 8 patients more than one spinal cord region was affected. Half of the patients presented with metastatic disease. Primary tumor resection was partial in 6 and gross total in 2 patients. In 4 patients tumors were biopsied only. Central pathology review was performed in 10 patients. Systemic postoperative chemotherapy was administered to all patients. Three patients only received intrathecal therapy and five were irradiated (craniospinal, n=3; local, n=2). Median observation time of the entire cohort was 6 (range, 1–71) months. Three patients, treated according to the EU-RHAB guidelines are alive in complete remission 58, 60, and 71 months after diagnosis. One patient died of intracerebral haemorrhage prior to response evaluation. Five patients progressed early and died within 1–3 months following diagnosis. Three patients died after 7–22 months due to disease progression after having achieved a partial remission (n=1) or disease stabilization (n=2). Event-free and overall survival rates at 1 and (2 years) were 38.9 ± 14.7% (29.2 ± 13.9%) and 41.7 ± 14.2% (25 ± 12.5%), respectively. Spinal cord AT/RT carry a rather grave prognosis. Long-term survival in selected patients is achievable using aggressive multimodality treatment.
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