Search

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 ×10The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children.

This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or 2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non–dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71. Key Points: • The recommended phase 2 dose of InO for pediatric patients with ALL was established at 1.8 mg/m2 per course. • Of the patients with multiple R/R ALL, 85% reached CR after 1 course of single-agent InO at the RP2D, 100% of whom had MRD negativity.

PURPOSE Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MATERIALS AND METHODS MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10−4), and high (≥ 5 × 10−4). RESULTS EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively ( P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively ( P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively ( P < .0001), while for myeloid-style–treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). CONCLUSION This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.

Background The outcome of infants with KMT2A-germline ALL is much better than of infants with KMT2A-rearranged ALL, but still worse than of non-infant ALL patients. Here, we describe the outcome and prognostic factors for infants with KMT2A-germline ALL treated on Interfant-06 protocol. Methods 167 infants with KMT2A-germline ALL were enrolled in Interfant-06. Univariate analysis on prognostic factors (age, WBC at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI) (n=163). Bone marrow minimal residual disease (MRD) was measured in 73 patients, by real-time quantitative PCR of immunoglobulin genes and/or T-cell receptor genes, at various time points (EOI, n= 68, end of consolidation (EOC) n= 56, and before OCTADAD (n=57)). MRD results were classified as negative, intermediate (< 5*10 -4), and high (≥5*10 -4). Genetic data on NUTM1 rearrangements and MRD were available in 53 patients. Results The 6-year event free survival [SE] and overall survival [ SE] was 73.9% (3,6) and 87.2% (2.7). 28 of 31 (90%) relapses occurred early, within 2 years of diagnosis. Treatment related mortality was 3.6%. Age 6 months of age (p=0.04). Of the MRD timepoints, MRD at end of induction (EOI) was most prognostic for outcome. At EOI, 76.5% (n=52/68) of patients were either MRD negative (41.2%, n=28) or intermediate MRD (35.3%, n=24). 23.5% (n=16) had high EOI MRD, which was associated with significantly lower 6-year DFS (SE), compared to patients with intermediate or negative EOI MRD (61.4% (12.4), 76.4% (11.3) and 87.9% (6.6), respectively; p=0.02, Figure 1a). At EOC, 55.4% (n=31/56) of patients were MRD negative. Outcome by MRD levels at EOC was not significantly different (p=0.24); the 6-year DFS (SE) of negative and intermediate EOC MRD patients was 89.0% (6.0) and 72.7 % (10.6), respectively, while only one of the 5 patients with high EOC MRD relapsed in BM and CNS (Figure 1b). MRD data for both EOI and EOC were available for 55 patients. Of these patients, 18 were MRD negative at EOI and EOC, with a 6-year DFS 93.3% (SE, 6.4). Five patients had negative EOI MRD, but showed intermediate EOC MRD levels; none of these patients relapsed. There were 12 of 55 patients who were MRD positive at EOI and became MRD negative at EOC. These patients had a 6-year DFS of 82.5 % (SE, 11.3). Patients with detectable disease at both timepoints had a 6-year DFS of 68.3% (SE,10.8) (n=20, Figure 1c). At the end of MARMA (TP5), 77.2% (n=44/57) of patients were MRD negative. MRD at TP5 was significantly related to DFS (Figure 1d); the 6-year DFS was 89.6% (SE, 5.0) for MRD negative patients, compared to 65.6% (SE, 14.0) for patients with intermediate MRD levels (p= 0.039). In the current study, NUTM1 status was known in 53 patients with MRD data. Of them, 13 harbored a NUTM1-rearrangement. Seven out of 11 (63.6%) were aged< 6 months and 6 out of 42 (14.3%) were older. None of them relapsed, despite positive EOI MRD detected in 8 cases. Conclusion We conclude that young age at diagnosis and low EOI MRD are favorable prognostic factors in infants with KMT2A-germline ALL. However, the prognostic value of MRD is not as strong as in infants with KMT2A-rearranged ALL or older children with ALL. This can partly be explained by the differences in genetic makeup of infants with KMT2A-germline ALL, thus supporting the hypothesis that in the future a combined MRD- and genetic-based stratification of KMT2A-g infants might be considered Figure 1 Figure 1. Disclosures Biondi: Colmmune: Honoraria; Bluebird: Other: Advisory Board; Novartis: Honoraria; Incyte: Consultancy, Other: Advisory Board; Amgen: Honoraria. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Schrappe: Novartis: Honoraria, Other: research support; SigmaTau: Other: research support; Amgen: Other: research support; Servier: Honoraria; Novartis: Honoraria; JazzPharma: Honoraria; JazzPharma: Honoraria, Other: research support; SHIRE: Other: research support; Servier: Honoraria, Other: research support.

The objective was to evaluate health care providers' (HCP) adherence to and efficacy of varicella post-exposure prophylaxis (PEP) recommendations. It was an observational, prospective, multicenter study set in Ile-de-France, France.All children under 18 with a cancer diagnosis, currently or within 3months of receiving cancer treatment, regardless of varicella zoster virus (VZV) serostatus or previous personal history of varicella, were eligible. Study participants with significant exposure were reviewed prospectively for PEP indications. Main outcome measures were the percentage of exposure situations for which HCP were guideline-compliant, the proportion of available VZV serostatuses and the incidence of breakthrough varicella after different PEP approaches.A total of 51 patients from 15 centers were enrolled after 52 exposure episodes. Median age at exposure was 5 years (range, 1-15). Exposure within the household led to 38% of episodes. Prophylactic treatment consisted in specific anti-VZV immunoglobulins (V-ZIG) (n=19) or in oral aciclovir (n=15). No prophylactic treatment was given for 18 patients (in compliance, n=16). In compliance with guidelines, 17 patients received V-ZIG, 11 did not develop varicella (65%, [95% CI, 39-90%]); 15 received aciclovir, 13 did not develop varicella (87%, [95% CI, 67-100%]). Breakthrough varicella occurred in 11 patients, with simple clinical course in all cases; in 8/47 (17%) episodes when PEP was guideline-compliant versus 3/5 (60%) when not.Recommendations have been respected and are efficient. PEP needs to be standardized and a study carried out to define the optimal approach. Anti-VZV immunization of seronegative family members should be encouraged.

Background: In developed countries, cancer remains the leading cause of pediatric death from illness after the neonatal period. Objective: To describe the end-of-life care characteristics of children and adolescents with solid tumors (ST) or hematologic malignancies (HM) who died from tumor progression in the Île-de-France area. Methods: This is a regional, multicentric, retrospective review of medical files of all children and adolescents with cancer who died over a 1-year period. Extensive data from the last 3 months of life were collected. Results: A total of 99 eligible patients died at a median age of 9.8 years (range, 0.3–24 years). The most frequent terminal symptoms were pain (n = 86), fatigue (n = 84), dyspnea (n = 49), and anorexia (n = 41). Median number of medications per patient was 8 (range, 3–18). Patients required administration of opioids (n = 91), oxygen (n = 36), and/or sedation (n = 61). Decision for palliative care was present in all medical records and do-not-resuscitate orders in 90/99 cases. Symptom prevalence was comparable between children and adolescents with ST and HM. A wish regarding the place of death had been expressed for 64 patients and could be respected in 42 cases. Death occurred in hospital for 75 patients. Conclusions: This study represents a large and informative cohort illustrating current pediatric palliative care approaches in pediatric oncology. End-of-life remains an active period of care requiring coordination of multiple care teams.

Depuis l’émergence de l’infection à SARS-CoV-2, de très nombreuses recommandations ont été émises. Cependant la nature de la maladie et la spécificité du traitement des leucémies aiguës lymphoblastiques de l’enfant et de l’adolescent ont conduit le Comité Leucémies de la Société Française de lutte contre les Cancers et leucémies de l’Enfant et de l’adolescent (SFCE) à proposer des recommandations propres. Voici la deuxième version de ces recommandations prenant en compte l’évolution des connaissances sur l’infection COVID19.

Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence ofMRD was measured in 249 infants by DNA-based polymerase chain reaction of rearrangedEOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9%

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (

Introduction: Data regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) has initiated a study to better describe the presentation and evolution of COVID-19 in patients followed in French pediatric oncology and hematology wards. Methods: All patients diagnosed with COVID-19 (polymerase chain reaction [PCR] positive for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], or positive IgM serology, or chest computed tomography scan and clinical signs typical of COVID-19) and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Results: Data was available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Conclusion: Children and young adults infected with SARS-CoV-2 and treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored. (NCT04433871)

WOS: 000469839300005 PubMed ID: 30765470 TCF3-HLF-positive leukemia represents a rare subtypeof childhood acute lymphoblastic leukemia (ALL), characterized by a high rate of treatment failure despite treatment intensification and allogeneic stem cell transplantation (SCT). Given the high and homogeneous expressionof CD19 on blast cells of this leukemia subtype, thesepatients may benefit from CD19-directed immunotherapy. Here, we report the experience on nineTCF3-HLF-positive ALL patients, most of whom weretreated early in first consolidation with blinatumomab asa bridge to SCT between 2015 and 2018. Treatment withblinatumomab was generally well tolerated; reversibleneurotoxicity was observed in two patients. All ninepatients achieved molecular remission after blinatumomab treatment; seven underwent SCT and for onepatient SCT is planned. Median follow up after start ofblinatumomab treatment was 342 days, and four patientsremain in molecular remission after a follow up of 1317,1292, 1245, and 342 days, respectively. Three patientsdied because of infectious complications not directlyrelated to blinatumomab, because they occurred eitherafter SCT or after emergence of a CD19-negativeleukemia clone. In the light of these encouraging observations, CD19-directed immunotherapy should be considered early after induction chemotherapy inTCF3-HLF-positive ALL children and patients’ outcomemonitored systematically by study groups.

ObjectiveTo analyse parents’ and children’s understanding of consent information and assess their decision-making process in paediatric oncology.DesignProspective observational study.SettingsEleven French paediatric oncology units.PatientsParents and children who have been asked to give consent for participation in an early phase trial.InterventionsThirty-seven children and 119 parents were questioned using an audio-recorded semistructured interview.Main outcome measuresThe participants’ understanding of nine elements of the informed consent was assessed by comparing their answers with the informed consent leaflet. Their decision-making process was also evaluated.ResultsMost parents and children had an excellent understanding regarding their participation in a clinical trial (respectively 88.2% and 48.6%), the right to withdraw (76.5% and 43.2%) and the prospects of collective benefits (74.8% and 48.6%). By contrast, less than half of the parents and few of the children correctly understood the alternatives (respectively 47.5% and 27%), the risks related to participation (44.5% and 10.8%), the prospects of individual benefits (33.6% and 10.8%) and the purpose of the clinical trial (12.6% and 2.7%). Twenty-six (70.3%) children participated in the decision-making process. Most parents and children felt they had no choice but to participate in the trial to have access to a new anticancer treatment.ConclusionsWhat might appear to be a poor understanding of the research protocol may actually correspond to the families’ interpretation of the situation as a coping mechanism. All children (except infants) should get age-tailored information in order for them to have a meaningful involvement in research.

Background: Infant acute lymphoblastic leukemia (ALL) is a rare disease with dismal outcome. While outcomes for older children have improved, with event-free survival (EFS) currently above 85%, newly diagnosed infants ( Methods: We conducted a prospective, single-arm, international, multicenter, phase 2 study. Newly diagnosed patients 0.05% before OCTADAD and all HR patients in complete remission were eligible for HSCT. (Serious) Adverse Events ((S)AEs) were collected from the start of blinatumomab until the next treatment block. Outcome data were compared to historical controls. Results: Twenty-eight patients were enrolled. Baseline characteristics are shown in Table 1. The median follow-up was 11 months (range 1.5-33 months). All patients received the full course of blinatumomab without treatment interruptions. Seven SAEs were reported during blinatumomab (3 fever, grade 1 and 4 infections, grade 3-4). None of the patients experienced neurological (S)AEs. In total, 70 AEs were reported, the most frequent grade >3 adverse events were febrile neutropenia (n= 2), anemia (n=5), and elevated GGT (n=2). MRD negative complete response occurred in 54% (n=15/28) at TP blina1, as well as at TP blina2 (after 2 and 4 weeks of blinatumomab, Table 2), which tended to be higher compared to the end of consolidation in Interfant06 (40%, p=0.16). There were 89% (25/28) of patients who were MRD negative or not quantifiable ( Conclusion: This is the first trial to use blinatumomab in infants with newly diagnosed KMT2A-r ALL. Blinatumomab added to the Interfant06 backbone was very well tolerated, and has promising efficacy in terms of a high rate of complete MRD response and short term EFS. Longer follow-up is awaited, but the low relapse rate after blinatumomab is remarkable, given that in historical controls relapses occur frequently and early, during therapy. Given these findings, blinatumomab will be implemented for all infants with newly diagnosed KMT2A-r ALL in the next Interfant21 protocol. Figure 1 Figure 1. Disclosures Nysom: Y-mAbs: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: teaching; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: teaching. Biondi: Amgen: Honoraria; Incyte: Consultancy, Other: Advisory Board; Bluebird: Other: Advisory Board; Novartis: Honoraria; Colmmune: Honoraria. OffLabel Disclosure: Investigational use of blinatumomab

To study the management of acute appendicitis in neutropenic patients, we retrospectively reviewed cases of acute appendicitis in neutropenic children treated for cancer. The patients' demographics, medical records, and outcomes were tracked. We compared nonoperative treatment versus emergency or delayed surgery. The cases of 30 patients with a mean age of 8.8 years in 12 French departments of Pediatric Hematology/Oncology between 1995 and 2013 were studied. Most patients (90%) were treated for hematological malignancies. Seven of the 30 children were successfully treated with exclusive medical treatment. Early surgery was performed in 6 patients, and the remaining 17 underwent combined management with a first-line antibiotic treatment and delayed appendectomy. Treatments were successful in all cases with transitory complications in only 3 patients. No death linked to infection was reported. Surgery was well tolerated even in the neutropenic period. Appendix perforation was a major risk factor of prolonged hospitalization. Histologic as well as bacteriologic and mycologic/parasitologic analyses were required in case of surgery. Analysis of diagnostic assessments showed the major importance of imaging (ultrasonography and tomography) on diagnosis confirmation. We could not come to a conclusion in the few numbers of reviewed cases because of a significant difference in management strategies, but we can conclude that early surgery after adequate supportive care is an acceptable modality of treatment and must be chosen in the face of life-threatening conditions.

Introduction: The open-label, expanded access study (RIALTO) demonstrated that blinatumomab is efficacious with a manageable safety profile in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates cytotoxic T cells to kill target B cells. Here, findings from the final analysis of RIALTO are presented (NCT02187354). Methods: Enrolled in the study were children >28 days and Results: As of the data cutoff date (January 10, 2020) for the final analysis, demographics and baseline characteristics of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 61% had For best treatment response within the first 2 cycles, results are comparable to that of the primary analysis. Among 110 patients, overall CR rate was 62.7% (n= 69). Of 98 patients with ≥5% blasts at baseline, 59% (n=58) achieved CR; of them, 79% (n=46) achieved an MRD response and 62% (n=39) proceeded to HSCT. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response Among the 12 patients with Of 110 patients treated with blinatumomab, median OS (95% CI) was 14.6 (11-24.5) months with median follow-up time of 18.2 months, which increased by 1.5 months compared with that reported in the primary analysis, with 29.9% of patients still surviving at month 24. Median RFS (95% CI) remains unchanged at 8.5 months (4.7-14.0), with a median follow-up time of 11.5 months in patients who achieved CR; 38% of patients relapsed and 9% died. RFS was more favorable for patients who received HSCT post blinatumomab (70%) than for those who did not (30%) at month 12, respectively, which is consistent with the results from primary analysis. Among patients who had HSCT prior to blinatumomab (n= 45), median OS (95%) was 16.6 (7.1-NE) months vs 14.6 (10.9-24.5) months in patients without HSCT prior to blinatumomab (n= 65). Compared with the primary analysis, 5 additional patients received HSCT after achieving CR in the final analysis. Median OS among patients in CR after HSCT by MRD responders vs MRD non-responders was NE at 15-month analysis (Figure). Safety results in the final analysis were consistent with those reported in the primary analysis. Of 110 patients, 99% experienced TEAEs, with 65% being grade ≥3 (see Table 3 for details). TRAEs were reported in 74% of patients; 26% were grade ≥3 and 19% were deemed serious. Details on grade ≥3 TRAEs are shown in Table 3. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusions: Overall, the safety and efficacy results from the final analysis are consistent with those reported in the primary analysis as no new safety signals were observed. These findings strengthen the observation that blinatumomab demonstrates durable efficacy and is a suitable treatment option in children with R/R BCP-ALL. Table 1. Disclosures Locatelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceeutical: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Current Employment, Other: Personal Fees ; 20190300609: Patents & Royalties: Licensed patient . Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. Bader:Medac: Patents & Royalties, Research Funding; Amgen: Consultancy, Speakers Bureau; Neovii: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding. Schlegel:bluebird bio: Honoraria. Bourquin:Servier: Other: Travel Support. Handgretinger:Amgen: Honoraria. Brethon:Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Rössig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Viswagnachar:IQVIA: Current Employment.

International audience; Since the emergence of the SARS-CoV-2 infection many recommendations have been made. However the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19.

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

If acute leukemia is the most frequent cancer in childhood (33%), it remains a very rare diagnosis in infants less than one year old, e.g. less than 5% of cases. At this age, the frequency of acute lymphoblastic leukemia (ALL) (almost all of B-lineage) is quite similar to the one of myeloblastic forms (AML). Infant leukemia frequently presents with high hyperleucocytosis, major tumoral burden and numerous extra-hematological features, especially in central nervous system and skin. Whatever the lineage, the leukemic cell is often very immature cytologically and immunologically. Rearrangements of the Mixed Lineage Leukemia (MLL) gene, located on band 11q23, are the hallmark of these immature leukemias and confer a particular resistance to conventional approaches, corticosteroids and chemotherapy. The immaturity of infants less than 1-year-old is associated to a decrease of the tolerable dose-intensity of some drugs (anthracyclines, alkylating agents) or asks questions about some procedures like radiotherapy or high dose conditioning regimen, responsible of inacceptable acute and late toxicities. The high level of severe infectious diseases and other high-grade side effects limits also the capacity to cure these infants. The survival of infants less than 1-year-old with AML is only 50% but similar to older children. On the other hand, survival of those with ALL is the same, then quite limited comparing the 80% survival in children over one year. Allogeneic stem cell transplantations are indicated in high-risk subgroups of infant ALL (age below 6 months, high hyperleucocytosis >300.10(9)/L, MLL-rearrangement, initial poor prednisone response). However, morbidity and mortality remain very important and these approaches cannot be extended to all cases. During the neonatal period, the dismal prognosis linked to the high number of primary failures or very early relapses and uncertainties about the late toxicities question physicians about ethics. It is an emergency to propose different strategies (targeted therapies) to these infants with acute leukemia as conventional trials failed to improve outcome.

PURPOSE Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A ( MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value. MATERIALS AND METHODS Three risk groups were defined: low risk (LR): KMT2A germline; high risk (HR): KMT2A-rearranged and older than 6 months with WBC count 300 × 109/L or more or a poor prednisone response; and medium risk (MR): all other KMT2A-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE). RESULTS A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% [SE 4.0; n = 169] v IB 36.8% [SE, 3.9; n = 161]; log-rank P = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response. CONCLUSION Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.

BACKGROUND: Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and complete remission without platelet recovery (CR+CRp) rate. Further multi-drug combinations need to be investigated. We used the VANDA regimen as a template, cytarabine being replaced by clofarabine. PATIENTS AND METHODS: A phase I study combining escalating doses of clofarabine (25% increments from 20 to 40 mg/m(2) /d) with fixed doses of mitoxantrone, etoposide, asparaginase, and dexamethasone was undertaken in children presenting with very early or second or post-transplant ALL relapse. RESULTS: Twenty patients were enrolled, 19 were evaluable. Four patients had previously been allografted. Dose-limiting toxicity (DLT) appeared at dose level 3 (32 mg/m(2) ), one out of six patients experienced a liver DLT. At dose level 4 (40 mg/m(2) ), four DLT occurred (two fungal infection and two liver DLT). The maximum tolerated dose (MTD) of clofarabine was thus determined to be 32 mg/m(2) . There was no toxic death. Eleven (57.9%) patients achieved a CR. Six patients proceeded to allogeneic stem cell transplantation. CONCLUSION: Clofarabine MTD was 32 mg/m(2) /d in this combination which appeared feasible and effective in this population. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc

Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 (N/F) mutations and RAS/PTEN (R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD

Introduction: Although survival rates in children and adolescents with acute lymphoblastic leukemia (ALL) have improved significantly, relapsed or refractory (R/R) ALL remains a leading cause of cancer-related deaths in pediatric patients. Blinatumomab is a bispecific T-cell engager (BiTE®) immuno-oncology therapy that activates endogenous cytotoxic T cells to kill target B cells. We report the primary analysis results of RIALTO, an expanded access study, where pediatric patients with R/R ALL were treated with blinatumomab (NCT02187354). Methods: Enrolled in the study were children and adolescents >28 days and Results: Of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 60% were 7-17 years of age, 61% had Of 98 patients with ≥5% blasts at baseline, 58 (59%) achieved CR ( Among 98 patients with ≥5% blasts at baseline, median OS was 13.1 months (95% CI, 9.8-21.3), with median follow-up time of 17.4 months. For patients reaching CR after the first 2 cycles, the median RFS was 8.5 months (95% CI, 3.4-NE), with a median follow-up time of 11.2 months; 38% of patients relapsed and 9% died. Of 110 patients treated with blinatumomab, 99% experienced TEAEs, with 65% being grade ≥3, including neurologic events (6%), cytokine release syndrome (CRS, 2%), cytopenias (38%), elevated liver enzymes (13%), infections (18%), and neutropenia (14%). TRAEs were reported in 74% of patients; 36% were grade ≥3 and 26% were deemed serious. Grade ≥3 TRAEs included neurologic events (5%), CRS (2%), cytopenias (9%), elevated liver enzyme (4%), infections (5%), and neutropenia (6%). Due to TRAEs, 22% of patients interrupted treatment and 5% discontinued treatment. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusion: Overall, the safety profile of blinatumomab in this expanded access study in pediatric patients with R/R ALL was tolerable and consistent with that in other blinatumomab clinical trials. Patients, including those with persistent MRD and genetic disorders at baseline, achieved high rates of CR and MRD responses with low rates of relapse and disease progression. These findings support blinatumomab as a suitable treatment option for pediatric patients with R/R ALL. Disclosures Locatelli: BluebirdBio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Employment, Other: holds stock, Patents & Royalties: & other intellectual property. Bader:Amgen (Brasil), Novartis: Consultancy, Speakers Bureau; Medac: Patents & Royalties, Research Funding; Riemser, Neovii: Research Funding; Celgene: Consultancy. Bourquin:Servier: Other: Travel support. Rossig:BMS, Pfizer, Roche: Other: speaker honoraria; Amgen, Celgene,EUSA Pharma, Genetech, Novartis, Roche: Other: advisory board.

Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody linked to calicheamicin, approved for relapsed/refractory (R/R) CD22+ B-cell precursor adult acute lymphoblastic leukemia (BCP-ALL) at starting dose of 1.8 mg/m2/course. A phase I study in pediatric patients (pts) is being performed and sponsored by Erasmus MC in collaboration with Pfizer, registered in the Dutch Trial Registry (NTR57360). Study design: Children aged 1-18 years with R/R CD22+ BCP-ALL (ALL) were included after IRB approval and informed consent was obtained. Key inclusion criteria consisted of M2/M3 marrow and adequate liver and kidney function. The study aimed to determine the recommended phase 2 dose (RP2D) of single agent InO; secondary objectives included safety, response and pharmacokinetics (PK). Dose escalation followed the Rolling-6 design, with dose-limiting toxicity (DLT) evaluation during course 1 and defined as delay in hematological (hem) recovery after D42 in responding pts and grade (gr) ≥3 non-hem toxicities >48 hours (or >7 days for liver tests). DL1 was 1.4 mg/m2 (0.6-0.4-0.4 mg/m2). Overall response rate (ORR) was defined as CR, CRp (ANC >0.5x10.9/l but PLT ≤50x10.9/l) and CRi (ANC ≤0.5x10.9/l and/or PLT ≤50,000/µL). Central minimal residual disease (MRD) analysis by flow cytometry and RQ-PCR was considered negative if In the first cohort, 2 patients at DL2 experienced a DLT per protocol definition, however these toxicities were considered non-dose limiting; both pts achieved CR. An IRB-approved amendment allowed repeating the DL1 and DL2 DLT assessment in a 2nd cohort. Survival analysis used the Kaplan-Meier method. Results are based on a database snapshot on June 22, 2019. Results: 25 pts were enrolled (Jan 2017-Apr 2019), median age 11 years (range 1.7-16.9); 3 (12%) were refractory, 15 (60%) ≥2nd relapsed ALL and 7 (28%) 1st relapse post-HSCT (median 2 prior treatment regimens, range 2-7). Eleven (44%) pts were previously transplanted; median baseline WBC 3.5 x109/L (range 0.2-8.6). In total, 46 courses of InO were administered (median 2/pt, range, 1-4). 23 of 25 treated pts were DLT-evaluable. In the first cohort, 1/6 and 2/5 pts at DL1 and DL2 experienced a DLT per protocol definition (transaminases elevation and no hem. recovery), but considered non-dose limiting. After the IRB-approved amendment, in the 2nd cohort, 0/6 and 1/6 pts in DL1 and DL2 had a DLT (no hem recovery). All 25 pts had at least 1 adverse event (AE) in Course 1 [24 gr 3-4]: 20 pts experienced ≥1 gr 3-4 hem AE, 15 pts a gr 3-4 non-hem AE (13 treatment-related, mainly febrile neutropenia/infections and lab abnormalities). Gr 3-4 transaminases elevation related to InO was seen in 3 pts (12%) and bilirubin in 2 (8%) in Course 1. 2 cases of VODs (gr 3-4) were reported after InO, both after follow-up chemotherapy (including HD-MTX) for R/R disease. None of these pts received any HSCT. After Course 1, 75% of pts responded at DL1 and 85% at DL2; ORR 80% (CR n=15, CRp n=1, CRi n=4). MRD was available in 19/20 responding pts: 15 (79%) reached MRD-negative CR as best response (6/9 at DL1 and 9/10 at DL2). Consolidation treatment with HSCT (n=6) or CAR-T cells (n=2) was given a median time of 61 days (range 23-125) after the last InO dose. None of these pts had been previously transplanted. The median follow-up for responding pts was 13.3 months (mos), median duration of response 8 mos (range 1.1-14.0). EFS was 66.7% (95% CI 47.9-93.0) and 33.4% (95% CI: 16.5 − 67.4), while the OS 63.3% (95% CI: 45.8−87.6) and 38.7% (95% CI: 21.3 - 70.4) at 6 and 12 mos, respectively. During follow-up, at relapse 13 pts had material available and sufficient ALL cells for reliable CD22 analysis: 2/13 showed CD22-negativity. After multiple doses, observed Ino medium maximum concentrations in DL1 (n=9) and DL2 (n=5) were 217 and 246 ng.hr/mL, comparable to the simulated adult concentration 234 ng.hr/mL at 1.8 mg/m2 dose. Conclusions: InO was well tolerated and showed remarkable activity in these heavily pretreated pts. The RP2D was established at 1.8 mg/m2/course (0.8-0.5-0.5 mg/m2), confirming the dose used in adults. Two cases of VOD were recorded after follow-up chemotherapy. The ORR was 80%; 79% of responding pts had MRD-negative CR, with 40% of pts being alive after 1 year of follow-up. A phase II single agent study in R/R pediatric ALL is ongoing and a Phase 1 of InO in combination with chemotherapy will start soon. Disclosures Díaz de Heredia: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rossig:Amgen, Celgene,EUSA Pharma, Genetech, Novartis, Roche: Other: advisory board; BMS, Pfizer, Roche: Other: speaker honoraria. van der Velden:Amgen: Honoraria, Research Funding; Jansen: Research Funding; BD Biosciences: Research Funding. van der Sluis:medac: Consultancy; jazz farmaceuticals: Consultancy. Chen:Pfizer Inc.: Employment. Sleight:Pfizer: Employment, Equity Ownership. Nysom:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Teaching and lectures. Øra:Bayer: Membership on an entity's Board of Directors or advisory committees. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zwaan:Novartis: Consultancy; Janssen: Consultancy; Jazz pharmaceuticals: Other: Travel support; Daiichi Sankyo: Consultancy; Servier: Consultancy; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Roche: Consultancy; Incyte: Consultancy.

Purpose: Hypomethylating agents are approved in adults with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS). By contrast, data in pediatric hematologic malignancies are scarce. Herein, we report the off-label administration of Azacitidine (Aza) in a cohort of children, adolescents and young adults (AYA). Methods: Patients from Robert-Debré, Saint-Louis and Armand-Trousseau University Hospitals (Assistance Publique-Hôpitaux de Paris), 25 year-old or younger at initiation of treatment and who received Aza between 2009 and 2019 were included. Data on indication, efficacy and toxicity of the treatment were retrospectively collected. Results: As 3 patients (pts) were treated twice with Aza at different stages of their disease, 35 treatments in 32 patients were analyzed. Median age at diagnosis was 11.7 y (range 0.1-22.4). Diagnosis were: 16 Acute Myeloid Leukemias (AML), 6 Juvenile Myelomonocytic Leukemias (JMML), 7 Myelodysplastic Syndromes (MDS), 2 Mixed Phenotype Acute Leukemias (MPAL) and 1 Interdigitating Dendritic Cells Sarcoma. Aza was administrated after a median of 2 lines of treatment (range 0-6) and front line in 5 out of 32 pts (16%; MDS = 4, JMML = 1). Concomitant therapy was administrated in 15/35 treatments (43%) (Sorafenib = 6, Gemtuzumab Ozogamicin = 2, donor lymphocyte infusions = 2, other = 5). Fourteen out of 35 treatments (40%) were delivered in patients with a history of hematopoietic stem cell transplantation (HSCT). Aza was administrated either intravenously (n = 11) or subcutaneously (n = 24) at a dose of 75mg/m² for 7 (20/35, 57%) or 5 (6/35, 17%) consecutive days every 28 days, i.e. same daily dose as in adults; at reduced doses (≤ 50mg/m²) in 3/35 patients; at a dosing scheme varying from one cycle to another in 6/35 patients. Patients received a median of 3 cycles of Aza per treatment (range 1-31). A total of 137 cycles was delivered. Aza was well tolerated with only 5/137 cycles delayed due to hematological (n = 3) or non-hematological (n = 2) toxicity. Aza was discontinued due to toxicity in 2/137 cycles (1 rectal bleeding, 1 severe sepsis). Anemia was noted in 68/130 cycles (52%), thrombocytopenia in 68/128 cycles (53%), neutropenia in 84/127 cycles (66%) and febrile neutropenia in 25/131 cycles (19%). Two grade 5 side effects were observed: 1 patient died from cerebral hemorrhage in a context of anti-platelet poly-immunization, another from septic shock in a context of neutropenia. Most common non-hematological side effects included: nausea, vomiting, diarrhea, subcutaneous injections lesions (local inflammation or hematoma) and infections. Responses to Aza are detailed in the attached table. Best responses to Aza included: 2 complete remissions (CR) both after 3 cycles, 3 CR with incomplete hematologic recovery (CRi) after a median of 2 cycles (range 1-2), 2 partial remissions (PR) after 2 and 3 cycles, 6 stable diseases (SD) during a median of 2 cycles (range 2-12) and 2 hematologic improvements. Overall response rate (sum of CR, CRi, PRs), was 19% (6/32) (3 non evaluable responses). Three out of the 6 patients treated with Aza combined with Sorafenib (AML = 4, MPAL = 2) obtained a response (CR: 2, CRi: 1). The association led to HSCT for 2 of them; the third patient had a CR maintained almost 3 years without HSCT, before relapsing on therapy. One patient with MDS had a SD for 12 months after palliative treatment with Aza. Overall, Aza treatment allowed to proceed to HSCT in 8 out of 32 patients (25%), 7 out of 8 proceeding to a first HSCT [CR: 1 patient, CRi: 3 patients, PR: 2 patients, SD: 1 patient, progressive disease: 1 patient]. These 8 pts included: 4 pts with AML, alive in CR after a median follow-up of 29.5 months (2 of them received concomitant targeted therapy); 2 pts with JMML (1 alive in CR after a follow-up of 25 months); 2 pts with MDS (both died, 7 and 30 months after Aza initiation). Finally, 24 out of 32 patients died and overall survival at 5 years was 23% (IC95% [11;48]) with no difference according to diagnosis. Conclusion: In a cohort of pediatric and AYA patients with heavily pretreated myeloid malignancies, Aza was well tolerated, and allowed to bridge 25% of patients to HSCT. Further prospective studies are needed to explore combination of Aza with targeted therapy in pediatric patients. Disclosures Boissel: NOVARTIS: Consultancy.

INTRODUCTION Infant acute lymphoblastic leukemia is a high-risk subtype characterized by a very high incidence of KMT2A (MLL) gene rearrangements. In 1999, a large international consortium (Interfant) commenced; the first Interfant-99 protocol (Pieters et al, Lancet 2007) was used as baseline for the current Interfant-06 study, which run in 18 groups worldwide. AIMS To determine:In a randomised study whether two AML-type courses ADE (araC, daunorubicin, etoposide) and MAE (mitoxantrone, araC, etoposide) after induction improved outcome compared to the consolidation IB course in KMT2A-rearranged cases (MR and HR risk group). With a target of 320 randomised cases, the study had 80% power to detect a DFS difference of 16% at 3 years (41% DFS in the control arm, α=0.05).The prognostic relevance of clinical and biological parameters.The outcome of Interfant-06 versus Interfant-99.The role of SCT in HR patients and in MR patients with MRD ≥ 10e-4 at the start of OCTADAD. As Interfant-99 showed outcome differences between the West-European/North-American groups who started Interfant (original countries) versus other countries that joined later, analyses were also performed separately in these groups. RISK GROUPS AND TREATMENT Three risk groups were defined: low risk (LR) - KMT2A germline; high risk (HR) - KMT2A rearrangement plus age < 6 months plus white blood cell count (WBC) >300 x 10e9/L or a poor prednisone response; medium risk (MR) - comprised all other KMT2A-rearranged cases. Treatment consisted of induction (prednisone prephase, dexamethasone, VCR, asparaginase, DNR), consolidation phase, either IB (araC, 6-MP, cyclofosfamide) or ADE/MAE in the experimental arm, MARMA (HD-araC, HD-MTX, 6-MP, asparaginase), OCTADAD (VCR, dexamethasone, asparaginase, DNR, 6-TG, araC, cyclofosfamide) and maintenance (6-MP, MTX) with intrathecal therapy in all courses. All HR patients were allocated to receive allogeneic stem cell transplantation (SCT). After June 2009, SCT was also undertaken in MR cases with MRD ≥ 10 e-4 at start of OCTADAD as the Interfant-99 update showed a very poor outcome for these patients. RESULTS 651 infants were included (167 LR, 320 MR, 164 HR). In the original countries, 6-yr EFS (SE) and survival rates were 49.4 (2.5) and 62.1 (2.4) respectively, which were each 6% (not significantly) higher than in Interfant-99 study. In the other countries, the 6-yr EFS and survival rates were 39.0 (3.6) and 49.7 (3.7). The outcome of patients treated in the original countries was significantly better than in other countries due to lower rates of toxic death and resistant disease. The 6-year EFS and survival of all 651 cases were 46.1 (2.1) and 58.2 (2.0) respectively. 330/407 eligible cases (81%) were randomised. The 6-yr cumulative incidence (CI) of relapse with ADE/MAE was 47.5 (4.0) which was not significantly (p = 0.11) lower than the 54.9 (4.1) with IB. The 6-yr CI of death in remission was 10.2 (2.4) with ADE/MAE versus 8.3 (2.2) with IB (p = 0.51). This resulted in no significant differences in 6-yr DFS rates of 39.3 (4.0) and 36.8 (3.9) respectively (the 3-yr DFS were 45.3 [3.9] versus 38.6 [3.9]). The 6-yr EFS rate of 164 HR patients was 20.9 (3.4) with the intention to use SCT in all HR patients; 76 of them received SCT as many HR patients had very early events. Out of 23 MR patients with MRD ≥ 10e-4 before OCTADAD, 16 received SCT; 4/23 are in CCR. In total, 14.4% of MR/HR patients receiving SCT died of transplant-related mortality. T(4;11) and t(11;19) translocated cases had a significantly lower EFS than other KMT2A-rearranged cases (p = 0.005). Multivariate analyses identified KMT2A rearrangement, age < 6 months, WBC ≥ 300 x 10e9/L, and poor prednisone response but not CD10, type of MLL translocation and sex as significant predictors of adverse DFS. CONCLUSIONS The Interfant-06 study is by far the largest study performed in infant ALL. The 6-yr survival in West-European/North-American countries is 62%, which is 12% higher than in other participating countries. Two postinduction AML-type chemotherapy courses versus course IB did not lead to a significant better DFS. 6-yr survival rates are 6% higher than on Interfant-99, which is not a statistically significant improvement. Pilot studies by COG and Interfant are currently exploring the feasibility of adding azacytidine and blinatumomab to the Interfant backbone, which may lead to a worldwide randomised trial with these drugs in infant ALL. Disclosures Locatelli: Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vora:Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board; Amgen: Other: Advisory board; Novartis: Other: Advisory board.

Introduction: Inotuzumab ozogamicin (INO) is an anti-CD22-drug conjugate therapeutic agent, in which a cytotoxic agent, calicheamicin, is conjugated to a humanized IgG4 anti-CD22 mAb (de Vries et al., Leukemia, 2012). As CD22 expression is confined to the B-cell lineage and is largely expressed in mature and immature B-cell malignancies, INO represents an attractive drug to treat B-cell acute lymphoid leukemia (ALL). INO has been evaluated in clinical trials and its efficacy has been reported in adult and elderly patients (pts) with ALL (Kantarjian et al., NEJM, 2016; Lancet Oncol 2018 and Cancer 2018). Since half of the total number of cases of ALL occurs in children and teenagers and it is the most frequently diagnosed malignancy in children, with the vast majority arising from B-cell lineage (85%), INO is also a drug of interest for the 15% of pediatric pts who are not cured by current treatments. We here report French pediatric pts with refractory or relapsed (r/r) B-cell ALL who were treated by INO through a compassionate use access program. Methods: French pediatric hematology centers provided retrospective clinical follow-up on pts' ≤ 18 years old affected by r/r B-cell ALL who received at least one dose of INO, provided by Pfizer through a compassionate use program following authorization by the French regulatory agency (ANSM) between 2015 and 2017. All pts were treated according to the adult phase 3 clinical trial dose of 1.8 mg/m2 during the first course divided as followed: 0.8 mg/m2 of body surface at day 1 and 0.5 mg/m2 at day 8 and 15. A second course could be repeated at the same dosage if the response was not complete after the first course. Then the consolidation courses of treatment could be continued at the dose of 1.5 mg/m2 divided as 0.5 mg/m2 of body surface at day 1, 8 and 15, up to 3 total cycles. Results: Eleven pts aged from 3 to 18 years old received INO; and were: 2 between 1 and 10 years old, 4 between 10 and 15 and 5 between 15 and 18. They received from 1 to 3 cycles of INO. They were heavily pretreated, as 6 of them received INO while refractory to the treatment of a first relapse, and 5 of them in treatment of second relapse or more. Prior to INO therapy, 4/11 pts had undergone allogenic hematopoietic stem cell transplantation (HSCT) and 7/11 pts had received anti-CD19 therapy with either Blinatumomab (6/7) or CAR-T cells (1/7). Pre-INO treatment medullary status was M3 (>25% blasts) for 8/11 pts, M2 (5-25%) for 2 pts and M1 ( Eight pts were in complete remission (CR) after one cycle (M2/M3 marrow prior to INO: 7, M1: 1), including 2 pts with an undetectable MRD (< 10-5). These 2 pts received a second cycle of INO and were brought to HSCT; both of them are alive (20 months (m)+, 27 m+). The 6 remaining pts in CR but MRD+ subsequently died: 1) 5 received a second cycle of INO without documentation of MRD negativity. All of them relapsed whatever the following treatment (time to disease progression ranged from 1 week to 17 months). 2) 1 pt was brought to HSCT but died of cardiac failure 3 months after the procedure. As observed in adults, hepatic and hematologic adverse events were observed. All pts developed hematologic toxicities, 10/11 pts with grade 3/4 anemia, neutropenia or thrombocytopenia. Febrile neutropenia of grade 3/4 occurred for 5 pts. Cholestasis with grade 3/4 elevations of GGT or transaminases was noted in 4/11 pts. Sinusoidal obstruction syndrome (SOS) occurred in 1 pt who had previously undergone HSCT, during his first course of INO. Two pts who subsequently underwent HSCT developed SOS during transplant. All of these 3 pts recovered normal hepatic function. None of them died from INO direct toxicities. Conclusion: Toxicities developed by these young patients were very similar to the ones reported in adults with hepatic and infectious toxicities. The incidence of SOS seems significant in patients that underwent HSCT either before or after INO treatment. INO showed promising results in pediatric compassionate use program in our French cohort, similarly to the one reported by Bhojwani D et al. (ASCO abstract, 2017). Its safety and efficacy in r/r B-cell ALL are to be further investigated in pediatric populations within prospective clinical trials currently underway in EU and US. Disclosures Baruchel: Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Amgen: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel, accommodations or expenses; Celgene: Consultancy; Servier: Consultancy; Shire: Research Funding.

Introduction Despite a high cure rate for pediatric ALL, the prognosis for pts who suffer from r/r disease remains poor. Pediatric pts with r/r ALL face multiple lines of therapy, acute and long-term treatment toxicities, and have limited survival. New agents that are able to provide durable disease control and long-term survival with limited toxicity are needed. Blinatumomab (blin) is a bispecific T-cell engaging (BiTE®) antibody construct that redirects CD3+ cytotoxic T cells to lyse CD19+ B cells. We evaluated the safety and efficacy of blin in pediatric pts with B-cell precursor r/r ALL enrolled in an expanded access study initiated in 2014 (NCT02187354). Methods Eligible pts with r/r CD19+ ALL (≥ 2 relapses, relapse after allogeneic hematopoietic stem cell transplant [HSCT], or refractory to prior treatment) were > 28 days to < 18 years of age and had ≥ 5% blasts or < 5% blasts but with a minimal residual disease (MRD) level ≥ 10-3. Prior treatment with blin was allowed if the pt was not blin-refractory or intolerant (study re-enrollment was not allowed). Blin was dosed by continuous infusion (4 weeks on/2 weeks off) for up to 5 cycles: 15 µg/m2/d for pts with ≤ 25% blasts; 5 µg/m2/d on days 1−7 of cycle 1, 15 µg/m2/d thereafter for pts with > 25% blasts. Subsequent therapy, including HSCT, was off protocol and per investigator preference. The primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included morphologic complete response (CR; < 5% blasts) and MRD response (< 10-4 leukemic blasts by PCR or flow cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and HSCT rate after blin treatment. Results Of 98 treated pts (median age, 8.5 [range 0.4-17.0] years), 93% were enrolled in Europe, 54% had > 25% blasts at baseline, 41% had ≥ 50% blasts, and 48% had a cytogenetic abnormality. Prior treatments included HSCT (44%), radiotherapy (15%), and blin (4%); 56% of pts had ≥ 2 relapses, 41% had relapsed after HSCT, 14% were primary refractory and 20% were refractory to reinduction therapy. At data cutoff (March 9, 2018), 37 pts were on study. The median number of completed treatment cycles was 2 (range 1-5), with 4 pts completing 5 cycles of blin. Overall, 99% of pts experienced a TEAE, with a rate of 64% for grade ≥ 3. TRAEs were reported in 77% of pts (26% for grade ≥ 3); 21% were deemed serious. The most frequent TEAEs (any grade) included pyrexia (83%), vomiting (27%), headache (24%), and anemia (19%). Among TEAE categories of interest, rates of any grade/grade ≥ 3 were 67%/9% for infusion reactions, 44%/16% for infections, 43%/5% for neurologic events, 40%/31% for cytopenias, 18%/12% for elevated liver enzymes, 16%/2% for cytokine release syndrome, 8%/0% for decreased immunoglobulins, 4%/2% for tumor lysis syndrome, and 1%/0% for capillary leak syndrome. Dose interruption due to a TRAE was required by 19% of pts, and 4% discontinued blin due to a TRAE. There were 9 fatal AEs, all unrelated to blin. In the first 2 cycles of treatment, 60% of all 98 pts achieved CR, 40% achieved CR with full recovery of peripheral blood counts (PBC), and 48% achieved MRD response. Of 2 pts with t(17;19), both achieved CR with full PBC recovery and MRD response; of 4 pts with Down syndrome, 3 achieved CR (2 full PBC recovery) and MRD response; of 4 pts who had received prior blin treatment, 3 achieved CR (3 full PBC recovery) with blin retreatment and 2 achieved MRD response. Among 59 pts who achieved CR within 2 cycles, 27 (46%) proceeded to HSCT; 19 relapsed and 5 died after a median follow-up 5.3 (range, 0.3-13.2) months for a median RFS of 8.5 (95% CI, 2.9-NE) months from the time of CR. Among all 98 pts, median follow-up was 12.2 (range, 0.5-14.1) months; there were 38 deaths (32 disease related), and median OS was 13.0 (95% CI, 9.3-NE) months. Conclusions The safety profile of single-agent blin in this expanded access study was generally consistent with profiles reported in prior controlled trials of blin in pediatric and adult pts with r/r ALL. Blin was active in this pediatric r/r ALL population. Blin induced MRD response in almost half of the pts, including pts with t(17;19) or prior blin treatment. Pts with a lower leukemia burden (< 50% blasts) had a better probability of response to blin vs pts with a higher burden. These data further support blin as a treatment option for pediatric pts with r/r ALL. Table. Table. Disclosures Locatelli: Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zugmaier:Amgen Inc.: Consultancy, Employment, Patents & Royalties: 20170327581, 9688760, 20170122947, 9486475, 20160208001, 9192665, 20150071928, 8840888, 20140227272, 20140228316, 20130323247, 20130287774, 20130287778, 20110262440, 20100112603, 7700299, 20070037228. Bader:Riemser: Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Medac: Patents & Royalties, Research Funding; Novartis: Consultancy, Speakers Bureau. Bourquin:Amgen: Other: Travel Support. Handgretinger:Miltenyi Biotec: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding. Rossig:Genetech: Consultancy; Roche: Consultancy, Honoraria; MorphoSys: Honoraria; Celgene: Consultancy; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Honoraria; EUSA Pharm: Consultancy.

Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome–positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL–mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).

In core binding factors (CBF) acute myeloid leukemia (AML), the disruption of CBFalpha/beta genes impairs normal hematopoietic differentiation and is supposed to cooperate with additional mutations promoting proliferation. The incidence and the prognosis of receptor tyrosine kinase (RTK) c-Kit and FLT3 mutations and Ras mutations were evaluated in 103 pediatric and adult patients with CBF-AML. c-Kit mutations were present in 17% patients. c-Kit exon 8 mutations were more frequent in inv(16) than in t(8;21) subset (20 versus 6%). Only one patient had FLT3-ITD but FLT3-D835 was as frequent as reported in AML population (7%). Ras mutations were significantly more frequent in inv(16) than in t(8;21) subset (36 versus 8%, P=0.001). RTK mutations were associated with a higher white blood cell count (WBC) (36 versus 21 G/L, P=0.05). FLT3 mutations were significantly associated with a shorter EFS and survival (P

10530 Background:Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown antileukemia activity and tolerability in pts with r/r ALL. We further evaluated safety and efficacy of blin in the first 40 pediatric pts with r/r ALL enrolled in an expanded access study (NCT02187354). Methods: Eligible pts (28 d to < 18 yrs) had ≥ 5% blasts and r/r ALL (refractory, ≥ 2 relapses or relapse after transplant [HCT]). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (≥ 5 to < 25% blasts: 15 µg/m2/d; ≥ 25% blasts: 5 µg/m2/d on d1−7 in cycle 1, then 15 µg/m2/d). The primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs); key efficacy endpoints were complete response (CR) and minimal residual disease (MRD, by PCR or flow cytometry) in the first 2 cycles, relapse-free survival, overall survival and HCT rate. Results: Of the first40 treated pts (median age, 9 [range, 1−17] yrs), 24 (60%) had ≥ 2 relapses, 20 (50%) relapsed after HCT and 5 (13%) were primary refractory; 18 (45%) had ≥ 50% blasts and 21 (53%) had prior HCT. Safety and key efficacy outcomes are shown in the table, including 63% CR in the first 2 cycles. There were 8 relapses and 20 deaths after treatment. Regardless of causality, the most frequent TEAEs were pyrexia (78%), cytokine release syndrome (CRS; 23%) vomiting (23%) and anemia (20%); all 9 CRS events were grade (gr) 1 or 2 and 1 tumor lysis syndrome was gr 3. 10 (25%) pts interrupted treatment and 2 (5%) discontinued due to TRAEs; 13 (33%) pts had gr ≥ 3 TRAEs, including 2 of 3 neurologic events (depressed level of consciousness and headache; both gr 3); 2 fatal AEs were considered unrelated to blin. Conclusions:Here single-agent blin showed antileukemia activity in pediatric pts with high-risk r/r ALL including t(17;19) and AEs consistent with those previously reported for r/r ALL. Clinical trial information: NCT02187354. [Table: see text]