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Noninfectious manifestations-allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies-are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis.To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events.Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them.This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

Sirolimus is widely used in transplantation, where its therapeutic drug monitoring (TDM) is well established. Evidence of a crucial role for sirolimus in the PI3K/AkT/mTor pathway has stimulated interest in its involvement in neoplasia, either as monotherapy or in combination with other antineoplastic agents. However, in cancer, there is no consensus on sirolimus TDM. In the RAPIRI phase I trial, the combination sirolimus + irinotecan was evaluated as a new treatment for refractory pediatric cancers. Blood sampling at first sirolimus intake (D1) and at steady state (D8), followed by LC/MS2 analysis, was used to develop a population pharmacokinetic model (Monolix® software). A mono-compartmental model with first-order absorption and elimination best fit the data. The only covariate retained for the final model was “body surface area” (D1 and D8). The model also demonstrated that 1.5 mg/m2 would be the recommended sirolimus dose for further studies and that steady-state TDM is necessary to adjust the dosing regimen in atypical profiles (36.4% of the population). No correlation was found between sirolimus trough concentrations and efficacy and/or observed toxicities. The study reveals the relevance of sirolimus TDM in pediatric oncology as it is needed in organ transplantation.

Simple Summary More and more relapsing or refractory pediatric cancers are described to present hypoxic features linked to a worse outcome. Therefore, the aim of our phase I study RAPIRI was the targeting of the central node mTor/HIF-1α with rapamycin plus irinotecan and determine the appropriated dose of this combination. As expected, the tolerance was optimal across all dose levels and no maximum tolerated dose of both drugs was reached. The pharmacokinetics (PK) helped us to refine the doses to use in the future phase II trial and the importance of PK follow-up in such combination. We also confirmed in almost half of the interpretable patients for tumor response a non-progressive disease. All those observations additionally to the ancillary’s studies provide strong evidence to propose a next trial focusing on brain tumors and sarcomas and using biweekly 125 mg/m2 irinotecan dose with a PK follow-up and a rapamycin dose of 1.5 mg/m2/day, reaching a blood concentration above 10 µg/L. Abstract Hypoxic environment is a prognostic factor linked in pediatric cancers to a worse outcome, favoring tumor progression and resistance to treatments. The activation of mechanistic Target Of Rapamycin (mTor)/hypoxia inducible factor (HIF)-1α pathway can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a phase I trial associating both drugs in pediatric refractory/relapsing solid tumors. Patients were enrolled according to a 3 + 3 escalation design with ten levels, aiming to determine the MTD (maximum tolerated dose) of rapamycin plus irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day), associating biweekly intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics, efficacy analyses, and pharmacodynamics were evaluated. Forty-two patients, aged from 2 to 18 years, were included. No MTD was reached. Adverse events were mild to moderate. Only rapamycin doses of 1.5 mg/m2/day reached over time clinically active plasma concentrations. Tumor responses and prolonged stable disease were associated with a mean irinotecan area under the curve of more than 400 min.mg/L. Fourteen out of 31 (45.1%) patients had a non-progressive disease at 8 weeks. Most of them were sarcomas and brain tumors. For the phase II trial, we can then propose biweekly 125 mg/m2 irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m2/day, reaching a blood concentration above 10 µg/L.

Background: Castleman disease (CD) is a very rare non-malignant lymphoproliferation of undetermined origin. CD diagnosis is difficult and often delayed because of insidious onset, low awareness and clinical heterogeneity. Two major disease phenotypes can be distinguished: unicentric CD (UCD) and multicentric CD (MCD). Diagnosis confirmation is based on histopathological findings on an involved lymph node. Objectives: We attempted to survey all cases of paediatric CD identified in France so far, in order to set up a national registry aimed to improve CD early recognition, treatment and follow-up, within the context of a new reference centre (http://www.castleman.fr). Methods: In 2016, we e-mailed a questionnaire to members of the French paediatric immunohaematology society, the French paediatric rheumatology society and the French Reference Centre for Castleman Disease to retrospectively collect cases of paediatric CD (first symptoms before age 18 years). Anatomopathological confirmation was mandatory. Results: We identified 23 patients (12 girls and 11 boys) diagnosed with UCD (n=17) and MCD (n=6) between 1994 and 2018 in 14 centres. The average age at first symptoms was 11.5 years for UCD and 8.3 years for MCD. The mean diagnosis delay was 8.2 months for UCD and 5.2 years for MCD. In UCD, the initial symptoms were: isolated lymph nodes (n = 10) or lymph node associated with other symptoms (n = 7), fever was present in 3 patients. Patients with MCD presented with fever (n=5), abdominal lymph nodes (n=5), failure to thrive (n=3), hepatomegaly and/or splenomegaly (n=3), arthralgia (n=2), abdominal pain (n=2), fatigue (n=2), facial oedema (n=1), isolated lymphadenopathy (n=1), trunk rash (n=1), vascular hepatopathy with oesophageal varicose veins (n=1), diarrhea (n=1) or cholestasis (n=1). One patient had a Duchenne muscular dystrophy. No patients had HIV or HHV8 infection. In MCD cases, one patient with recurrent fevers, had a heterozygous mutation in MEFV gene and another had a homozygous mutation in TNFRSF1A gene (P75L). A UCD patient experienced fever episodes and pericarditis two years after surgery. Genetic tests revealed one heterozygous mutation in IL10RA gene (V406L) and one in IL36RN gene (S113L). Nevertheless, our patient did not have any psoriasis or inflammatory bowel disease. Treatment of UCD was mainly surgical resection, steroids, and radiotherapy. Treatments of MCD were tocilizumab, rituximab, anakinra, steroids, chemotherapy and splenectomy. Overall survival after an average of 6 years of follow-up, was 100% for both unicentric and multicentric forms. Conclusion: Paediatric CD seems still underdiagnosed with a significant diagnosis delay specially for the MCD but new international criteria will help in future. In UCD, surgery is the main treatment. New drugs are used specially for the MCD, but more studies need to be conduct in children. The global survey is better in children than adults. Disclosure of Interests: Charlotte Borocco: None declared, Claire Ballot-Schmit: None declared, Oanez Ackermann: None declared, Nathalie Aladjidi: None declared, Jeremie Delaleu: None declared, Vannina Giacobbi-Milet: None declared, Sarah Jannier: None declared, Eric Jeziorski: None declared, Yves Perel: None declared, Francois Maurier: None declared, Christophe Piguet: None declared, Eric Oksenhendler: None declared, Isabelle Kone-Paut Grant/research support from: SOBI has supported drug product (anakinra) for the presented study, Consultant for: SOBI, Novartis, Pfizer, Abbvie, UCB, CHUGAI, ROCHE, Caroline Galeotti: None declared

We report a family in which 3 of 5 children as well as the mother, had a gain-of-function (GOF) mutation in the signal transducer and activator of transcription (STAT1) associated with early-onset rosacea and demodicidosis. The proband case (Fig. 1) was a 13-year-old boy of non-consanguineous parents, known for a hypothyroidism, failure to thrive and chronic mucocutaneous candidiasis (CMC) since he was 5-6 years old. On examination, he had medio-facial erythema with telangiectasia, as well as sometimes pruritic papulopustular lesions of the face and neck. This article is protected by copyright. All rights reserved.

Background: Hypoxic environment is a pejorative prognostic factor in pediatric solid tumors (ST). It is favoring neoangiogenesis, tumor progression and resistance to treatments through the activation of mTor and HIF-1α pathways. Those hypoxic markers can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a dose-escalation phase I trial combining both drugs to inhibit tumor hypoxic mechanisms present in several pediatric refractory/relapsing ST. Procedure: Patients were enrolled in this 3+3 escalation trial with ten dose levels. The primary endpoint was to determine the maximum tolerated dose (MTD) of rapamycin when combined with irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day) and associated biweekly with intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics (PK), efficacy analyses and pharmacodynamics (UGT1A1 status, cytokines/chemokines assessment, MRI markers and proteins' expression) were evaluated. Results: 42 patients were treated and had mild to moderate reversible toxicities. No MTD was present up to the tenth level. The PK were highly variable. Nevertheless, the usually targeted concentrations of rapamycin over time were reached at 1.5 mg/m2/day dose. When looking to the 2 partial responses (PR) and 19 stable diseases (SD) in 31 assessable patients, the mean irinotecan AUC was 363 min.mg/L and the mean D8 rapamycin AUC was 9.3 min.mg/L. No significant relationship was observed between dose escalation and response, but progressive tumors' subgroup (PD) had slightly lower mean irinotecan AUC (321 min.mg/L) and D8 rapamycin AUC (6.5 min.mg/L). The two main tumor groups were brain tumors (BTs) and sarcomas. A high proportion of those patients experienced tumor responses (3/4 ependymomas, 2/3 medulloblastomas, 1 rhabdoid tumor, 2/3 high-grade gliomas and 5/6 osteosarcomas). In all 17 assessable patients for immunohistochemistry, the two targeted proteins, mTor and HIF-1α, were expressed, but the resistance to this double strategy was significantly linked to the HIF-2α protein hyperexpression. In the BTs, lower ADC values in MRI were also a prerequisite for tumor responsiveness. Cytokine analyses, distinguished specific proinflammatory and angiogenic signatures during first course of treatment: PR patients had an increase of TNF, associated to a stable PIGF and a decrease of VEGF-C; the SD subgroup had a significant increase of VEGF-D and a stable or increase of sFLT1 and PD group had a constant increase of IL8 and VEGF-D. Conclusion: Despite no MTD, we can propose a next phase II trial with rapamycin dose of 1.5 mg/m2/day associated with 125 mg/m2 irinotecan in STs not expressing HIF-2α protein. A precise PK follow-up will be used to reach an irinotecan AUC up to 360 min.mg/L and a D8 rapamycin blood concentration of 10 µg/L. The cytokine evaluation will help us to predict during first cycle the potential tumor response. Citation Format: Sarah Jannier, Veronique Kemmel, Consuelo Sebastia, Agathe Chammas, Amelia-Naomi Sabo, Erwan Pencreach, Françoise Farace, Benoit Lhermitte, Birgit Geoerger, Isabelle Aerts, Didier Frappaz, Pierre Leblond, Nicolas Andre, Yves Perel, Nadège Corradini, Anne Isabelle Bertozzi, Florence Vincent, Natacha Entz-Werle. Phase I study with rapamycin combined with irinotecan, the SFCE RAPIRI I trial, a new way to target tumor hypoxia in pediatric refractory cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT136.

10540 Background: NTRK ( Neurotrophic receptor tyrosine kinase) fusion transcript was initially described in infantile fibrosarcoma (IFS) and is now known to be present in many other rare types of tumor with a lower incidence. The main objective of the study is to describe the presentation and outcome of unselected tumors with NTRK fusion transcript (NTRK-FTT) to better consider the role of TRK inhibitors (TRKi) in such entities. Methods: We selected patients (pts) from the Institut Curie biobank (adults and children) with NTRK-FTT and which were assessed by RT-qPCR then RNA sequencing in a prospective or retrospective process, between 2001 and 2019. Results: We identified 62 NTRK-FTT among 2119 screened tumors (2.2 cases/year with RT-qPCR and 6.9 cases/year with RNA seq after 2016), NTRK3 (44 cases) (including 41 NTRK3-ETV6), NTRK2 (9) or NTRK1 (9). Most of pts had under 2 years (y) (74%) and only 7 pts were adults. We report preliminary analysis of clinical observation for the first 27 pts. Median age was 0.4 y [0-60.2]. Pathologic diagnosis was IFS (12 cases), various CNS tumors (4), atypical teratoid rhabdoid tumor (1), myofibroblastic inflammatory tumor (2), benign tumors (3), cellular congenital mesoblastic nephroma (2), lipofibromatosis like neural tumor, myxoïd liposarcoma, unclassifiable sarcoma (1 each). Two pts had metastatic tumors. Among all, 22 had surgery (1 mutilating), 15 chemotherapy, 4 radiotherapy, and 5 received TRKi, as second line treatment (2 pts) or ≥ third line (3 pts). After a median follow-up of 50 months [range, 1-155], 20/27 pts remained in complete remission, 3 had stable residue, and 4 had progressive disease (associated to 1 disease-related and 1 toxic deaths). Five-year OS is 88% [95%CI, 73.5-100] and 5y-EFS 59.5% [95%CI, 41.7-84.9]. Conclusions: This descriptive study showed that NTRK-FTT is rare (2.9%), encompasses a variety of different histotypes (n = 14). Systematic RNA sequencing allowed to depict 3.5 times more NTRK-FTT than targeted RT-qPCR. Overall outcome is favorable despite frequent tumor events. According to tumor type and the uncertainties regarding the long-term side effects of TRKi, the benefit/risk ratio must be carefully evaluated before using these drugs in first line.

BACKGROUND Evaluation of long-term tolerance to antiretroviral exposure during pregnancy is required. An increased risk of cancer has been suggested in children exposed in utero to didanosine. METHODS Updated evaluation of cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in the French perinatal study of children born to HIV+ mothers, by cross-checking with the National Cancer Registry. Associations between cancer risk and exposure to NRTIs were evaluated by univariate survival analysis and Cox proportional hazard models. Standardized incidence ratios (SIR) were used for comparison with the general population. RESULTS A total of 21 cancers were identified in 15 163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero, between 1990 and 2014. Five children were exposed to zidovudine monotherapy, and 16 to various combinations, seven including didanosine. Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In a multivariate analysis, didanosine exposure was significantly associated with higher risk [hazard ratio = 3.0 (0.9-9.8)]. The risk was specifically linked with first-trimester exposure [hazard ratio = 5.5 (2.1-14.4)]. Overall, the total number of cases was not significantly different from that expected for the general population [SIR = 0.8 (0.47-1.24)], but was twice that expected after didanosine exposure [SIR = 2.5 (1.01-5.19)]. CONCLUSION There are strong arguments to suggest that didanosine displays transplacental oncogenicity. Although not extrapolable to other NRTIs, they stress the need for comprehensive evaluation of the transplacental genotoxicity of this antiretroviral class.