The study of cell free DNA (cfDNA) enables sequential analysis of tumor cell-specific genetic alterations in neuroblastoma patients.
Eighteen patients with relapsing neuroblastoma having received ...Lorlatinib, a 3rd generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for 9 patients, and sequentially for 5 patients (blood/bone marrow plasma) by performing WGS library construction followed by ALK-targeted ddPCR of the hotspot mutations (F1174L, R1275Q, I1170N) (variant allele fraction (VAF) detection limit 0.1%) and WES to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES.
Overall response rate to Lorlatinib was 33% (CI 13-59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification (MNA). ALK VAFs correlated with the overall clinical disease status, with a VAF<0.1% in clinical remission, versus higher VAFs (>30%) at progression. Importantly, sequential ALK ddPCR detected relapse earlier than clinical imaging. cfDNA WES revealed new SNVs, not seen in the primary tumor, in all instances of disease progression after Lorlatinib treatment, indicating clonal evolution, including alterations in genes linked to tumor aggressivity (TP53) or novel targets (EGFR). Gene pathway analysis revealed an enrichment for genes targeting cell differentiation in emerging clones, and cell adhesion in persistent clones. Evidence of clonal hematopoiesis could be observed in follow-up samples.
We demonstrate the clinical utility of combining ALK cfDNA ddPCR for disease monitoring and cfDNA WES for the study of clonal evolution and resistance mechanisms in neuroblastoma patients receiving ALK targeted therapy.
Ovarian function impairment and infertility are among the most frequent late effects after hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate ovarian function, ...occurrence of premature ovarian insufficiency (POI), and spontaneous pregnancy in a large cohort of adult survivor women who had undergone HSCT for leukemia before puberty. We conducted a retrospective observational study in women from the national cohort L.E.A., the long-term French follow-up program after childhood leukemia. The median follow-up duration was 18 years (14.2-23.3) after HSCT. Among 178 women, 106 (60%) needed pubertal induction with hormone substitution treatment, whereas 72 (40%) had spontaneous menarche. After spontaneous menarche, 33 (46%) developed POI, mostly within 5 years of HSCT. Older age at time of HSCT and cryopreservation of ovarian tissue appeared as significant risk factors for POI. More than 65% of patients who underwent HSCT before the age of 4.8 years had spontaneous menarche, and almost 50% didn't have POI at last evaluation, whereas more than 85% with HSCT after the age of 10.9 years didn't have spontaneous menarche and needed induction of puberty with hormone replacement therapy. Twenty-two women (12%) had at least one spontaneous pregnancy, with 17 live-births, 14 miscarriages, 4 legal abortions, and 2 therapeutic abortions. These results add supplementary data to better counsel patients and their families on the chances of ovarian residual function and pregnancy after HSCT, as well as on the potential interest of fertility preservation.
Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use programs. However, no clinical ...data of these prescriptions is systematically collected.
To measure the feasibility of the collection of clinical safety and efficacy data of compassionate and off-label innovative anticancer therapies, with adequate pharmacovigilance declaration to inform further use and development of these medicines.
This cohort study included patients treated at French pediatric oncology centers from March 2020 to June 2022. Eligible patients were aged 25 years or younger with pediatric malignant neoplasms (solid tumors, brain tumors, or hematological malignant neoplasms) or related conditions who received compassionate use or off-label innovative anticancer therapies. Follow up was conducted through August 10, 2022.
All patients treated in a French Society of Pediatric Oncology (SFCE) center.
Collection of adverse drug reactions and anticancer activity attributable to the treatment.
A total of 366 patients were included, with a median age of 11.1 years (range, 0.2-24.6 years); 203 of 351 patients (58%) in the final analysis were male. Fifty-five different drugs were prescribed, half of patients (179 of 351 51%) were prescribed these drugs within a compassionate use program, mainly as single agents (74%) and based on a molecular alteration (65%). Main therapies were MEK/BRAF inhibitors followed by multi-targeted tyrosine kinase inhibitors. In 34% of patients at least a grade 2 clinical and/or grade 3 laboratory adverse drug reaction was reported, leading to delayed therapy and permanent discontinuation of the innovative therapy in 13% and 5% of patients, respectively. Objective responses were reported in 57 of 230 patients (25%) with solid tumors, brain tumors, and lymphomas. Early identification of exceptional responses supported the development of specific clinical trials for this population.
This cohort study of the SACHA-France (Secured Access to Innovative Medicines for Children with Cancer) suggested the feasibility of prospective multicenter clinical safety and activity data collection for compassionate and off-label new anticancer medicines. This study allowed adequate pharmacovigilance reporting and early identification of exceptional responses allowing further pediatric drug development within clinical trials; based on this experience, this study will be enlarged to the international level.
Purpose
The long-term impact of treatment in infants with acute leukemia (AL) is poorly understood and of concern.
Patients and methods
We analyzed the incidence, in the L.E.A. cohort, of and risk ...factors for late sequelae in the survivors of infant AL diagnosed before the age of one year, according to group: type of AL, transplantation, sex, and age ≤ or > 6 months. Of 113 survivors, 55 had had lymphoblastic AL and 58 myeloblastic AL. The median follow-up was 11.7 years 1.9-34.7. Sixty-three were treated with chemotherapy only (and four with central nervous system irradiation) and 50 received transplantation (with a chemotherapy-based regimen except for three).
Results
The most frequently observed sequelae included problems of height, body mass index, and gonadal or thyroid function (Figure 1). We found a mean of 1.3 +/-0.1 sequelae per patient. In multivariate analysis, treatment after the age of six months significantly decreased the incidence of major growth failure (OR 0.38, p = 0.04) and low weight (OR 0.3, p = 0.02) (Figure 2). Transplants performed in first remission did not affect the occurrence of late effects (p = 0.2) (Figure 3). Parent-reported child quality of life (QoL) scores were similar among groups and to the normative population. Adults had diminished QoL as measured by psychosocial subscales relative to French norms but with no difference between groups.
Conclusion
Altogether, these results highlight the need for comprehensive follow-up with hormone replacement therapy and psychological intervention. Our results in a large cohort with very limited use of irradiation, did not show an increased risk of late sequelae relative to older children. We conclude, that transplantation should be considered when warranted, as there is no increased risk of late effects.
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No relevant conflicts of interest to declare.
INTRODUCTION
Acute leukemia (AL) accounts for one third of childhood cancers. Cardiovascular conditions are serious long-term complications of childhood AL. However, few studies have investigated the ...risk of metabolic syndrome (MetS), a known predictor of cardiovascular disease, in patients treated without hematopoietic stem cell transplantation (HSCT). We describe the overall and age-specific prevalence, and risk factors for MetS and its components in the L.E.A. French cohort of childhood AL survivors treated without HSCT.
METHODS
L.E.A. is a long-term follow-up program involving all childhood AL survivors treated in the French participating centers since 1980 (clinicaltrials.gov identifier: NCT 01756599). MetS was defined according to the National Cholesterol Education Program - Adult Treatment Panel III (NCEP-ATPIII) criteria revised in 2005.
RESULTS
The study included 650 adult patients. The mean age at evaluation was 24.2 years and the mean follow-up after leukemia diagnosis was 16.0 years. Central nervous system (CNS) irradiation was performed in 18.0% of patients (n=117). The prevalence of MetS was 6.9% (95% CI 5.1-9.2). The age-specific cumulative prevalence at 20, 25, 30 and 35 years of age was 1.3%, 6.1%, 10.8% and 22.4%, respectively, as shown in the Figure. The prevalence of decreased HDL-cholesterol, increased triglycerides, increased fasting glucose, increased blood pressure and increased abdominal circumference was 26.8%, 11.7%, 5.8%, 36.7% and 16.7%, respectively.
The risk factors significantly associated with metabolic syndrome in the multivariate analysis were male gender, older age at last evaluation and higher body mass index at diagnosis, as shown in the Table. Cumulative steroid dose was not a significant risk factor.
CNS-irradiated and non-irradiated patients exhibited different patterns of metabolic abnormalities, with more frequent abdominal obesity in irradiated patients and more frequent hypertension in non-irradiated patients.
DISCUSSION
Our study aimed to precisely describe the overall and age-specific prevalence, and risk factors of MetS in a large cohort of childhood AL survivors treated without HSCT. Notably, the subgroup treated with chemotherapy alone is one of the largest ever published, which is of particular interest as current protocols include very limited CNS irradiation indications.
The prevalence of MetS was approximately two-fold higher than that observed in the adult French general population under 40 years of age. Moreover, the prevalence of MetS was found to increase markedly with age.
An increased BMI at diagnosis was a risk factor for MetS. Children with an elevated BMI at diagnosis may have a genetic predisposition to metabolic disturbances or a socio-familial environment that renders them more vulnerable to metabolic complications.
CNS irradiation was not found to be a risk factor for MetS. In the literature however, brain irradiation has been frequently reported as a risk factor for MetS. This variation with our study can probably be explained in part by the observation that our irradiated patients displayed a lower risk of elevated blood pressure along with a greater risk of increased abdominal circumference. The irradiated patients may therefore have a different metabolic risk profile compared with the non-irradiated patients, thereby suggesting varying mechanisms of pathogenesis.
The results of our study confirm the need for early and prolonged follow-up of adult survivors of childhood AL even when treated without HSCT and without CNS irradiation. This prerequisite could enable both early detection of metabolic abnormalities and implementation of appropriate therapeutic procedures to reduce the morbidity and mortality associated with cardiovascular complications in such patients.
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No relevant conflicts of interest to declare.
To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had ...undergone allogeneic hematopoietic stem cell transplantation (a-HSCT).
We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units.
From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with “emergent” fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10−4) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents.
The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children.
Les nausées et vomissements chimio-induits sont des effets indésirables fréquents et redoutés des traitements anticancéreux. L’impact majeur des nausées et vomissements chimio-induits sur l’état ...général du patient et sur sa qualité de vie nécessite une prophylaxie adaptée au niveau émétisant de sa chimiothérapie et au profil du patient. L’objectif du présent travail est de proposer une mise à jour des recommandations de prise en charge des nausées et vomissements chimio-induits en oncohématologie pédiatrique grâce à une adaptation des recommandations de bonne pratique clinique du Pediatric Oncology Group of Ontario (POGO) pour une utilisation en France. L’adaptation des recommandations de bonne pratique clinique est une méthode reconnue permettant d’ajuster des recommandations de bonne pratique clinique déjà existantes au contexte local. Un groupe de travail pluridisciplinaire francophone a été constitué afin de se concerter sur chacune des recommandations du POGO concernant les nausées et vomissements chimio-induits en phases aiguë et retardée, non-maîtrisés, réfractaires et anticipés ainsi que sur le niveau de preuve qui les appuient. Il a été demandé aux membres du groupe s’ils souhaitaient adopter, modifier ou rejeter chacune des recommandations du POGO en vue d’en proposer une version française. La validation d’une recommandation nécessitait un minimum de 80 % des votes en sa faveur. Les arbres décisionnels et tableaux créés par le groupe de travail recensent toutes les recommandations et permettent d’avoir une meilleure vue d’ensemble pour une prise de décision adaptée au profil du patient. Dès lors que ces recommandations seront diffusées et implémentées dans les établissements de soins prenant en charge les enfants atteints de cancer en France, une évaluation de l’adhésion aux recommandations et du contrôle des nausées et vomissements chimio-induits devrait être entreprise.
Chemotherapy-induced nausea and vomiting (CINV) are frequent and dreaded side effects in cancer treatments. CINV has a major impact on patient's condition and quality of life. Prophylaxis is tailored to patient's profile and the emetogenic level of their chemotherapy. The aim of this study is to update the recommendations for CINV prevention and management in pediatric onco-hematology for use in France, by adapting the guidelines of the Pediatric Oncology Group of Ontario (POGO). Clinical practice guideline adaptation is a recognized method for tailoring existing clinical practice guidelines to local context. A multidisciplinary French-speaking panel was formed to discuss about POGO guideline recommendations for the acute and delayed phases, breakthrough, refractory and anticipatory CINV and the evidence supporting them. Panel members were asked whether they wanted to adopt, modify or reject each of the POGO guideline recommendations. Panel members translated each recommendation and adapted recommendations for an implementation in France. Their acceptance required agreement at least 80 % of panel members. Algorithms and tables were created, listing all the recommendations and providing a better overview for decision-making process adapted to the patient's profile. These recommendations should be reviewed for implementation at French institutions caring for pediatric cancer patients and once implemented, the rates of adherence to recommendations and CINV control should be reported.
Although survival from childhood cancer has increased, little is known on the long-term impact of treatment late effects on occupational attainment or work ability.
A total of 3512 five-year ...survivors treated before the age of 19 years in 10 French cancer centres between 1948 and 2000 were identified. Educational level, employment status and occupational class of survivors were assessed by a self-reported questionnaire. These outcome measures were compared with sex-age rates recorded in the French population, using indirect standardisation. Paternal occupational class was also considered to control for the role of survivors' socioeconomic background on their achievement. Multivariable analyses were conducted to explore clinical characteristics associated with the outcomes.
A total of 2406 survivors responded to the questionnaire and survivors aged below 25 years were included in the current analysis. Compared with national statistics adjusted on age and sex, male survivors were more likely to be college graduates (39.2% vs 30.9% expected; P<0.001). This higher achievement was not observed either for leukaemia or central nervous system (CNS) tumour survivors. Health-related unemployment was higher for survivors of CNS tumour (28.1% vs 4.3%; P<0.001) but not for survivors of other diagnoses. Survivors of non-CNS childhood cancer had a similar or a higher occupational class than expected.
Survivors treated for CNS tumour or leukaemia, especially when treatment included cranial irradiation, might need support throughout their lifespan.
Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit ...of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI.
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