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Summary Background Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Methods We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1–2·3 × 106 cells per kg and adults received UCART19 doses of 6 × 106 cells, 6–8 × 107 cells, or 1·8–2·4 × 108 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952. Findings Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3–4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%. Interpretation These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable. Funding Servier.

BACKGROUND Neuroblastoma is the most common malignant cause of spinal compression in the pediatric population. More than 30% of patients who are impaired prior to treatment remain impaired after the completion of therapy. Those who do not improve after decompressive laminectomy may go on to develop severe delayed spinal deformities. METHODS. To decrease the long term sequelae of routine neurosurgical intervention for all intraspinal extensions of neuroblastoma, the French NBL 90 Study was formulated to use chemotherapy as a first-line treatment for all nonmetastatic neuroblastomas with intraspinal extension. Neurosurgical decompression and excision was recommended only for patients demonstrating rapid neurologic deterioration. RESULTS. The overall survival of the 42 patients registered was 97%. Initial neurologic impairment was present in 27 patients (64%), including 11 with paraplegia. Thirty-two patients received chemotherapy as first-line treatment. Complete regression of the intraspinal component was observed in 13 patients and partial regression of greater than 50% of the initial volume in 5 patients. Of 19 evaluable patients presenting with a neurologic deficit and treated with primary chemotherapy, recovery was complete in 11 and partial in 3. Four patients failed to recover from long-standing pretreatment paraplegia. Only one patient worsened during therapy, and recovered completely after emergent neurosurgical intervention. Seven patients underwent initial neurosurgical procedures; six had a neurologic deficit and five recovered completely, including all three who presented with acute onset of paraplegia. Three patients had extraspinal surgery as exclusive treatment. Six patients (15%) suffered severe neurologic sequelae. Only one of the patients who underwent surgery required spinal stabilization for progressive deformity, but follow-up is limited. CONCLUSIONS. By treating patients with dumbbell neuroblastoma initially with chemotherapy, the authors were able to reduce the size of the intraspinal mass in 58% of patients, improve partial neurologic deficits in 92%, and avoid neurosurgical decompression in 60%. Neurologic deficits also improved in 83% of patients requiring emergent neurosurgical intervention. Cancer 1996;78:311-9.

International audience; l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®) .

A case of fatal Epstein-Barr virus infection in a previously healthy girl who was first found to have severe infectious mononucleosis with spontaneous recovery is reported. Because an abnormal immune response to the virus persisted, the disease relapsed, manifesting in cutaneous and pulmonary lesions associated with hemophagocytic syndrome responsible for death. Pathologic findings were characterized by polymorphous atypical lymphoid infiltrate, prominent necrosis, and histiocytic hyperplasia. Lymphoid cells displayed CD8 phenotype and clonal T-cell receptor gene rearrangement. Viral genome was detected in lesions by Southern blot and located in nuclei of lymphoid cells by in situ hybridization. Pathologic findings suggested fatal infectious mononucleosis; however, phenotype and genotype favored a malignant diagnosis. Clonality was demonstrated to have arisen during primary infection. Virologic examination indicated that Epstein-Barr virus was a causative agent. Such a process belongs to the recently recognized spectrum of Epstein-Barr virus-related T-cell lymphoproliferative disorders that might overlap fatal infectious mononucleosis in patients who are especially vulnerable to the virus.

From June 1989 through to November 1998, 121 children with newly diagnosed T-cell lymphoblastic lymphoma (T-LBL) were included in the EORTC 58881 trial conducted by the Children's Leukaemia Group. The therapy regimen was based on a Berlin-Frankfurt-Munster protocol, for a total duration of 24 months. Cranial irradiation, prophylactic cranial and local, was omitted, even for patients with central nervous involvement at diagnosis. In total, 119 patients were evaluable. The median follow-up was 6.7 years. The overall event-free survival (EFS) rate at 6 years was 77.5% (standard error (SE)=4%). Median time of relapse was 1 year after complete remission (range 0.2-5.9 years). Only two (1.8%) patients had an isolated central nervous system relapse. For patients with complete response (n=16) to the 7-day prephase, the EFS rate at 6 years was 100% versus 14% (P

The two main complications of severe chronic neutropenia are fatal sepsis and myelodysplasia/acute leukemia (MDS/AL). Granulocyte colony-stimulating factor (G-CSF) therapy has significantly reduced the frequency and severity of infections, but its possible influence on the risk of malignancy is not known.The French Severe Chronic Neutropenia (SCN) Registry has prospectively collected data since 1994 on 231 patients with various forms of SCN, namely severe congenital neutropenia (n=101), cyclic neutropenia (n=60), glycogen storage disease type Ib (GSDIb) (n=15) and Shwachman-Diamond syndrome (SDS)(n=55). The median overall follow-up is 11.1 years. Parameters of exposure to G-CSF therapy, such as the time averaged dose, follow up after first use of G-CSF, and the cumulative dose, have been recorded.Eight septic deaths occurred, of which 6 among patients with severe congenital neutropenia and 2 in patients with cyclic neutropenia; none of these 8 patients was receiving G-CSF therapy. No septic deaths occurred during G-CSF therapy. Thirteen cases of MDS/AL were recorded. The cumulative incidence of MDS/AL was 2.7% (SD 1.3%) at 10 years and 8.1% (SD 2.7%) at 20 years.Risk factors for MDS/AL were the diagnostic category, the severity of neutropenia, younger age at diagnosis, and strong exposure to G-CSF. MDS/AL only occurred in patients with severe congenital neutropenia and SDS. Owing to their particular susceptibility to infections, patients with severe congenital neutropenia had the strongest exposure to G-CSF; the risk of leukemia increased with the degree of G-CSF exposure in this subgroup.

Purpose To assess the results and morbidity of treatment of children with localized pelvic neuroblastoma (NB). Patients and Methods All consecutive cases of localized pelvic NB registered in the French multicenter prospective studies NBL90 and NBL94 between 1990 and 1999 were reviewed. Resectability was decided on the basis of clinical and radiologic evaluation. In unresectable tumors, primary chemotherapy (combinations of carboplatin-etoposide and vincristine-cyclophosphamide-doxorubicine) was administered before surgery. Results Forty-seven children (with 26 resectable tumors and 21 unresectable) were included in this study. At the end of treatment, 31 children were in complete remission (66%). Long-term neurologic sequelae were observed in seven patients (15%), directly attributable to surgery in three cases. After a median follow-up of 48 months (range, 13 to 129 months), 44 patients are alive. Six children experienced local relapse; four of these children achieved subsequent remission. The projected overall survival and event-free survival (EFS) rates at 5 years are, respectively, 93% ± 4% and 84% ± 5%. Survival of children treated with preoperative chemotherapy are similar to those treated by primary surgery (80% and 88% respectively). The extent of surgical resection seemed to have no influence on the outcome (EFS rates 76% and 89% in case of gross residue and complete resection or microscopic residue, respectively). Conclusion Our data confirm the excellent survival of localized pelvic NBs. Considering the efficacy of preoperative chemotherapy, patients with pelvic NB should be carefully screened for primary surgery. The risk of neurologic impairment during radical excision should be balanced with the good survival of children with minimal residual disease.

Purpose: The presence of metastasis is a major prognostic factor in Ewing tumor (ET). The relapse pattern of patients with localized tumors has long indicated that cases with disseminated ET cells escape detection at diagnosis. ET cells are characterized by specific gene fusions that can be detected with high sensitivity and specificity by reverse transcriptase polymerase chain reaction (RT-PCR). Patients and Methods: RT-PCR targeting EWS-FLI-1 or EWS-ERG transcripts was used to search for occult tumor cells in peripheral blood (PB) and bone marrow (BM) at diagnosis in 172 patients with ET, and the prognostic significance of this parameter was assessed. Results: As we suggested previously in a smaller series of patients, RT-PCR positivity of the BM was correlated with a high risk of adverse outcome in the overall study population (P = .007). More interestingly, among patients with otherwise localized tumors, BM micrometastasis also predicted significantly poorer disease-free survival rates (P = .043). The presence of circulating tumor cells (CTC) was more frequently observed in patients with large tumors (P = .006). CTC were associated with a poor outcome among patients with clinically localized disease (P = .045). Patients with clinically localized disease and peripheral occult tumor cells as evidenced by BM and/or PB RT-PCR positivity had axial or proximal tumors and experienced relapses at a systemic rather than at a local level. Conclusion: Patients with localized ET and BM micrometastasis or CTC are comparable to patients with metastases in terms of the localization of the primary tumor, outcome, and relapse pattern.

Auteur(s) : Helene AUBERT-WASTIAUX1 helene.aubert.wastiaux@gmail.com, Sebastien BARBAROT1, Francoise MECHINAUD2, Celine BOSSARD1, Jean-Francois STALDER3 1 Clinique dermatologique, CHU Hotel-Dieu, 1, place Alexis-Ricordeau, 44000 Nantes, France 2 Hematologie pediatrique, CHU Hotel-Dieu, 1, place Alexis-Ricordeau, 44000 Nantes, France 3 Anatomo-pathologie, CHU Hotel-Dieu, 1, place Alexis-Ricordeau, 44000 Nantes, France A 4-year-old boy was referred in 2006 with a 2-month history of erythematous, [...]