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We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with the CD19-directed CAR T cells ARI-0001 in two centers (adult and pediatric), including patients treated in the CART19-BE-01 trial and the consecutive compassionate use program. iEMD was detected by PET-CT in 78% (14/18), and/or by cerebrospinal fluid analysis in 28% (5/18). Patients received cyclophosphamide and fludarabine followed by 1 x 10(6) ARI-0001 cells/kg, initially as a single dose (first patient) and later split into three fractions (10%, 30%, and 60%). Cytokine release syndrome (CRS) occurred in 50% (9/18) of patients, with no cases of grade >= 3 CRS, and 1 case (6%) of grade 1 neurotoxicity. Tocilizumab was used in 6% of patients (1/18). Procedure-related mortality was 0% at 2 years. Objective responses were seen in 94% (95% confidence interval [CI]: 73%-99%) of patients, with complete responses (CR) seen in 78% (95% CI: 52%-94%) of them. Progression-free and overall survival were 49% (95% CI: 30%-79%) and 61% (95% CI: 40%-92%) at 2 years. In conclusion, the use of ARI-0001 cells in patients with R/R ALL and iEMD was associated with a safety and efficacy profile that is comparable with what is observed in patients with marrow involvement and in line with other CART19 products.

Children with acute leukaemia (AL) are a high-risk population for infections and life-threatening conditions requiring paediatric intensive care unit (PICU) admission, presenting an increased mortality rate. A few literature exists about PICU outcomes in this kind of patients, especially with haematopoietic stem cell transplant (HSCT) background. We investigated the clinical and epidemiological characteristics of these patients as well as their outcomes. A retrospective, single-centre analytical/observational study was conducted from January 2011 to December 2018 in the PICU of a tertiary care hospital. AL patients from 28 days to 18 years old admitted to the PICU were included, excluding those with histories of HSCT or CAR T-cell therapy. We collected epidemiological and clinical characteristics, laboratory and microbiology results and outcomes. Forty-three patients with AL required urgent admission (35 lymphoblastic and 8 myeloblastic) for 63 different episodes. The main reasons were sepsis (21, 33.3%), hyperleukocytosis (12, 19%), respiratory failure (11, 17.5%) and seizures (8, 12.7%). Nineteen (30.2%) required inotropic support, and fifteen (23.8%) required mechanical ventilation. Three patients died at the hospital (3/43, 6.9%). Sixty-day mortality was 9.3%, and 1-year mortality was 13.9%. There was no differences regarding the type of AL and 60-day mortality (log-rank 2.652, p = 0.103). Conclusion: In our study, the main cause of admission for AL patients was infection, which was associated to more severity and longer hospital admission.

Asparaginase (ASP) is an essential component for the acute lymphoblastic leukemia (ALL) treatment, but toxicities, such as allergy, frequently limit its use. Although the potentially lower PEG-ASP formulation immunogenicity, few studies with conflicting results have compared the allergy incidence between Escherichia coli-ASP and PEG-ASP in the same protocol. We aimed at comparing the allergy incidence in children receiving native E. coli-ASP versus PEG-ASP within the same clinical protocol (Spanish Society of Pediatric Hematology and Oncology ALL-SEHOP-PETHEMA 2013). One hundred and twenty-six children (1-19 years) diagnosed with ALL from 2013 to 2020 were included. Patients in group 1 received a sequential scheme of native E. coli-ASP 10,000 IU/m2 intramuscularly (IM) followed by PEG-ASP 1000 IU/m2 IM. Patients in group 2 received PEG-ASP 1000 IU/m2 IM upfront. Clinical allergy incidence was compared between both groups. Serum ASP activity (SAA) was measured in a subgroup of patients, and silent inactivation was recorded. The cumulative incidence of clinical allergy was significantly higher in group 1 (native followed by PEG-ASP) than in group 2 (PEG-ASP upfront), 24.7% versus 4.1% (p = 0.0085). Adequate ASP activity was achieved with PEG-ASP 1000 IU/m2 dose in most patients (median SAA 412.5 and 453.0 IU/L at days 7 and 14). The incidence of silent inactivation in PEG-ASP upfront patients was very low. PEG-ASP-used upfront was associated with a lower incidence of clinical allergy than that observed in the sequential use of native E. coli-ASP followed by PEG-ASP. PEG-ASP at 1000 IU/m2 was effective in achieving enough ASP activity in most patients.

We evaluated the administration of ARI-0001 cells (chimeric antigen receptor T cells targeting CD19) in adult and pediatric patients with relapsed/refractory CD19+ malignancies. Patients received cyclophosphamide and fludarabine followed by ARI-0001 cells at a dose of 0.4–5 × 106 ARI-0001 cells/kg, initially as a single dose and later split into 3 fractions (10%, 30%, and 60%) with full administration depending on the absence of cytokine release syndrome (CRS). 58 patients were included, of which 47 received therapy: 38 with acute lymphoblastic leukemia (ALL), 8 with non-Hodgkin’s lymphoma, and 1 with chronic lymphocytic leukemia. In patients with ALL, grade ≥3 CRS was observed in 13.2% (26.7% before versus 4.3% after the amendment), grade ≥3 neurotoxicity was observed in 2.6%, and the procedure-related mortality was 7.9% at day +100, with no procedure-related deaths after the amendment. The measurable residual disease-negative complete response rate was 71.1% at day +100. Progression-free survival was 47% (95% IC 27%–67%) at 1 year: 51.3% before versus 39.5% after the amendment. Overall survival was 68.6% (95% IC 49.2%–88%) at 1 year. In conclusion, the administration of ARI-0001 cells provided safety and efficacy results that are comparable with other academic or commercially available products. This trial was registered as ClinicalTrials.gov: NCT03144583 .

Children with acute leukaemia (AL) are a high-risk population for infections and life-threatening conditions requiring paediatric intensive care unit (PICU) admission, presenting an increased mortality rate. A few literature exists about PICU outcomes in this kind of patients, especially with haematopoietic stem cell transplant (HSCT) background. We investigated the clinical and epidemiological characteristics of these patients as well as their outcomes. A retrospective, single-centre analytical/observational study was conducted from January 2011 to December 2018 in the PICU of a tertiary care hospital. AL patients from 28 days to 18 years old admitted to the PICU were included, excluding those with histories of HSCT or CAR T-cell therapy. We collected epidemiological and clinical characteristics, laboratory and microbiology results and outcomes. Forty-three patients with AL required urgent admission (35 lymphoblastic and 8 myeloblastic) for 63 different episodes. The main reasons were sepsis (21, 33.3%), hyperleukocytosis (12, 19%), respiratory failure (11, 17.5%) and seizures (8, 12.7%). Nineteen (30.2%) required inotropic support, and fifteen (23.8%) required mechanical ventilation. Three patients died at the hospital (3/43, 6.9%). Sixty-day mortality was 9.3%, and 1-year mortality was 13.9%. There was no differences regarding the type of AL and 60-day mortality (log-rank 2.652, p = 0.103).Conclusion: In our study, the main cause of admission for AL patients was infection, which was associated to more severity and longer hospital admission. What is Known: • Acute leukaemia is the most common childhood cancer. Admission to a paediatric intensive care unit is required in 30% of children with acute leukaemia. • Regarding the outcomes of children with acute leukaemia that require admission to the intensive care unit data are scarce. What is New: • Mortality in acute leukaemia patients admitted to the paediatric intensive care unit is lower than that of patients with a history of stem cell therapy but higher than that of patients with solid tumours. • The main reason for admission was sepsis, which is related in literature to more severity and long length of stay.

CD19-CAR T-cell therapy (CART19) causes B-cell aplasia (BCA) and dysgammaglobulinemia but there is a lack of information about the degree of its secondary immunodeficiency. We conducted a prospective study in children and young adults with acute lymphoblastic leukaemia treated with CART19, analysing the kinetics of BCA and dysgammaglobulinemia during therapy, as well as the B-cell reconstitution in those with CART19 loss. Thirty-four patients were included (14 female) with a median age at CART19 infusion of 8.7 years (2.9–24.9). Median follow-up after infusion was 7.1 months (0.5–42). BCA was observed 7 days after infusion (3–8), with persistence at 24 months in 60% of patients. All patients developed a progressive decrease in IgM and IgA: 71% had undetectable IgM levels at 71 days (41–99) and 13% undetectable IgA levels at 185 days (11–308). Three of 12 patients had protective levels of IgA in saliva. In two of three patients who lost CART19, persistent B-cell dysfunction was observed. No severe infections occurred. In conclusion, BCA occurs soon after CART19 infusion, with a progressive decrease in IgM and IgA, and with less impairment of IgA, suggesting the possibility of an immune reservoir. A persistent B-cell dysfunction might persist after CART19 loss in this population.

We evaluated the administration of ARI-0001 cells (chimeric antigen receptor T cells targeting CD19) in adult and pediatric patients with relapsed/refractory CD19(+) malignancies. Patients received cyclophosphamide and fludarabine followed by ARI-0001 cells at a dose of 0.4–5 × 10(6) ARI-0001 cells/kg, initially as a single dose and later split into 3 fractions (10%, 30%, and 60%) with full administration depending on the absence of cytokine release syndrome (CRS). 58 patients were included, of which 47 received therapy: 38 with acute lymphoblastic leukemia (ALL), 8 with non-Hodgkin’s lymphoma, and 1 with chronic lymphocytic leukemia. In patients with ALL, grade ≥3 CRS was observed in 13.2% (26.7% before versus 4.3% after the amendment), grade ≥3 neurotoxicity was observed in 2.6%, and the procedure-related mortality was 7.9% at day +100, with no procedure-related deaths after the amendment. The measurable residual disease-negative complete response rate was 71.1% at day +100. Progression-free survival was 47% (95% IC 27%–67%) at 1 year: 51.3% before versus 39.5% after the amendment. Overall survival was 68.6% (95% IC 49.2%–88%) at 1 year. In conclusion, the administration of ARI-0001 cells provided safety and efficacy results that are comparable with other academic or commercially available products. This trial was registered as ClinicalTrials.gov: NCT03144583.

Background Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood. Although intensive chemotherapy has improved survival in those patients, important side effects, including hyperbilirubinemia, are frequent. Gilbert syndrome (GS) is a frequent condition that causes a reduction in glucuronidation and intermittent hyperbilirubinemia episodes. This could provoke a greater exposure to some cytotoxic agents used in ALL, increasing the risk of toxicity. On the other hand, unexplained hyperbilirubinemia could lead to unnecessary modifications or even treatment withdrawals, which could increase the risk of relapse, but data regarding this in ALL pediatric population are scarce. Methods Retrospective study to analyze toxicity, outcome and treatment modifications related to GS in children diagnosed with ALL. Results A total of 23 of 159 patients were diagnosed with GS. They had statistically higher hyperbilirubinemias during all treatment phases (P