Search

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849 ), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.

Background: Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe. Methods: This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list. Findings: The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included two new medicines (everolimus and vinorelbine) following applications we made as a result of this project. Interpretation: Medicines that were defined as essential within this project should be available for the treatment of childhood and adolescent cancer continuously and across Europe. This list can be used to support and guide stakeholders and policy makers in negotiations on a national and European level regarding shortages, accessibility, and affordability of these medicines. Funding: None.

Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) patients suffer risk of chemotherapy-associated toxicities and poor outcomes. We evaluated tisagenlecleucel in 16 patients with DS-ALL in two phase 2 trials (ELIANA [NCT02435849], ENSIGN [NCT02228096]) and a phase 3b, managed access protocol (B2001X [NCT03123939]). Patients were 5-22 years old, had a median of two prior lines of therapy (range, 1-4), and four (25%) had prior stem cell transplants. Fourteen of 16 patients (88%) achieved complete remission (CR) or CR with incomplete blood count recovery (CRi); 12 of 14 (86%) with CR/CRi were minimal residual disease-negative. With a median follow-up of 13.2 months (range, 0.5-49.3 months), six patients (43%) relapsed after CR (three, CD19-negative; three, unknown) between 80-721 days post-infusion. Ongoing remissions in nine patients ranged from 6-48 months. Any-grade and grade 3/4 AEs occurred in 16 and 14 patients, respectively; 44% experienced grade 3/4 cytokine release syndrome and 13% experienced grade 3/4 neurological events. Grade 3/4 prolonged cytopenias occurred in 44% of patients. No grade 3/4 infections were observed. Tisagenlecleucel expansion and long-term persistence were consistent with previous reports. Comparable to ALL patients without DS, tisagenlecleucel produced high remission rates, manageable side-effects, and promising long-term outcomes in pediatric/young adult patients with DS-ALL.Children with Down syndrome have a 20 times higher risk of developing a type of blood cancer called Down syndrome-associated acute lymphoblastic leukemia (ALL). Children who develop Down syndrome-associated ALL typically receive chemotherapy to treat their cancer; however, they can experience severe toxicity or other consequences from these therapies, especially stem cell transplant, and have a poor prognosis if their disease returns after treatment. These children need an effective but less toxic treatment option. Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that specially modifies the patient’s own T-cells to recognize and attack the cancer cells. Tisagenlecleucel is approved for use in children and young adults with ALL whose disease reappears after two or more treatments or whose disease doesn’t respond to treatment. Here we present data from 16 patients across three clinical studies showing that tisagenlecleucel is well-tolerated and an effective treatment option for children and young adults with Down syndrome-associated ALL, and was similar to what is observed in patients without Down syndrome. Taken together, patients with Down syndrome-associated ALL have unique medical needs, and tisagenlecleucel may help them live longer, avoid stem cell transplantation, and the toxicity from chemotherapy.

Iron overload (IOL) is a frequently reported complication following hematopoietic stem cell transplantation (HSCT) that has been investigated extensively in the field of hemoglobinopathies but has not been thoroughly characterized after HSCT in pediatric malignancies. Our aim was to assess prevalence, severity, risk factors, and management of IOL, as defined using biochemical (serum ferritin) and radiologic tools (T2*-weighted magnetic resonance imaging [MRI]), in a cohort of pediatric patients who underwent HSCT for either malignant or benign diseases. This monocentric, retrospective, observational study included all the 163 patients alive and in continuous remission at 24 months post-HSCT out of the 219 consecutive children and adolescents who underwent HSCT at our institution between 2012 and 2018, were included in the study. IOL was classified into 4 categories: absent, mild, moderate, and severe. Among the 163 patients, 73% had some degree of IOL (mild in 37%, moderate in 29%, and severe in 7%). Moderate/severe IOL was more frequent among patients diagnosed with a malignant disease versus those with a benign disease (43% versus 19%; P =.0065). Trend lines for serum ferritin showed a “bell-shaped” distribution, with the highest levels recorded during the first 6 months post-HSCT, followed by a spontaneous reduction. Both pre-HSCT (1659 ng/mL versus 617 ng/mL; P

Background: Chimeric antigen receptor (CAR)-T cells represent a potentially curative strategy for patients with relapsed or refractory (R/R) B-cell malignancies. To elucidate a possible host immune activation following CAR-T-cell infusion, we investigated the effects of tisagenlecleucel administration on the patients’ immune populations in 25 patients with R/R diffuse large B-cell lymphoma (DLBCL) and B-lineage acute lymphoblastic leukemia (B-ALL). Methods: The modulation of CAR-T cells over time, the numeric changes, as well as the cytokine production capability of different lymphocyte populations and circulating cytokine levels, were analyzed. Results: Our results confirmed the ability of tisagenlecleucel to control the disease, with an overall response observed in 84.6% of DLBCL and in 91.7% of B-ALL patients at 1-month post-infusion, and showed that most patients who subsequently relapsed could undergo further treatment. Interestingly, we could document a significant increase in CD3+, CD4+, CD8+, and NK cells over time, as well as a decrease in Treg cells, and an increased IFNγ and TNFα production by T lymphocytes. Conclusions: Taken together, our results indicate that in patients with DLBCL and B-ALL, the administration of tisagenlecleucel is capable of inducing a marked and prolonged in vivo modulation/reshaping of the host immune system, both in children and adults.

Hematopoietic stem cell transplantation (HSCT) is often the only curative treatment option for patients suffering from various types of malignant diseases and some non-cancerous conditions. Nevertheless, it is associated with a high risk of complications leading to transplant-related mortality and long-term morbidity. An increasing number of therapeutic and prevention strategies have been developed over the last few years to tackle the complications arising in patients receiving an HSCT. These strategies have been mainly carried out in adults and some are now being translated into children. In this manuscript, we review the recent advancements in the development and implementation of treatment options for post-HSCT non-infectious complications in pediatric patients with leukemia and other non-malignant conditions, with a special attention on the new agents available within clinical trials. We focused on the following conditions: graft failure, prevention of relapse and early interventions after detection of minimal residual disease positivity following HSCT in acute lymphoblastic and myeloid leukemia, chronic graft versus host disease, non-infectious pulmonary complications, and complications of endothelial origin.

BackgroundImmunocompromised patients are at increased risk of SARS-CoV-2 infections. Patients undergoing chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory B-cell malignancies are uniquely immunosuppressed due to CAR T-mediated B-cell aplasia (BCA). While SARS-CoV-2 mortality rates of 33%–40% are reported in adult CAR T-cell recipients, outcomes in pediatric and young adult CAR T-cell recipients are limited.MethodsWe created an international retrospective registry of CAR T recipients aged 0–30 years infected with SARS-CoV-2 within 2 months prior to or any time after CAR T infusion. SARS-CoV-2-associated illness was graded as asymptomatic, mild, moderate, or severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C). To assess for risk factors associated with significant SARS-CoV-2 infections (infections requiring hospital admission for respiratory distress or supplemental oxygen), univariate and multivariable regression analyses were performed.ResultsNine centers contributed 78 infections in 75 patients. Of 70 SARS-CoV-2 infections occurring after CAR T infusion, 13 (18.6%) were classified as asymptomatic, 37 (52.9%) mild, 11 (15.7%) moderate, and 6 (8.6%) severe COVID-19. Three (4.3%) were classified as MIS-C. BCA was not significantly associated with infection severity. Prior to the emergence of the Omicron variant, of 47 infections, 19 (40.4%) resulted in hospital admission and 7 (14.9%) required intensive care, while after the emergence of the Omicron variant, of 23 infections, only 1 (4.3%) required admission and the remaining 22 (95.7%) had asymptomatic or mild COVID-19. Death occurred in 3 of 70 (4.3%); each death involved coinfection or life-threatening condition. In a multivariable model, factors associated with significant SARS-CoV-2 infection included having two or more comorbidities (OR 7.73, CI 1.05 to 74.8, p=0.048) and age ≥18 years (OR 9.51, CI 1.90 to 82.2, p=0.014). In the eight patients infected with SARS-CoV-2 before CAR T, half of these patients had their CAR T infusion delayed by 15–30 days.ConclusionsIn a large international cohort of pediatric and young adult CAR-T recipients, SARS-CoV-2 infections resulted in frequent hospital and intensive care unit admissions and were associated with mortality in 4.3%. Patients with two or more comorbidities or aged ≥18 years were more likely to experience significant illness. Suspected Omicron infections were associated with milder disease.

Background: Cytokine release syndrome (CRS) is a major complication after chimeric-antigen receptor T-cell treatment, characterized by an uncontrolled systemic inflammatory reaction. We investigated the potential role of diclofenac in the management of CRS in five pediatric patients treated for relapsed/refractory B-lineage acute lymphoblastic leukemia. Methods In case of persistent fever with fever-free intervals shorter than 3 hours, diclofenac continuous infusion was initiated, at the starting dose of 0.5 mg/Kg/day, the lowest effective pediatric dose in our experience, possibly escalated up to 1 mg/Kg/day, as per institutional guidelines. Results: CRS occurred at a median of 20 hours (range 8–27) after tisagenlecleucel infusion. Diclofenac was started at a median of 20 hours (range 13–33) after fever onset. A mean of 3.07 febrile peaks without diclofenac and 0.95 with diclofenac were reported ( p = 0.02). Clinical benefit was achieved by hampering the progression of tachypnea and tachycardia. Despite fever control, CRS progressed in four of the five patients, and hypotension requiring vasopressors and fluid retention, as well as hypoxia, occurred. Vasopressors were followed by 1–2 doses of tocilizumab (one in patient 2 and two in patients 3, 4, and 5), plus steroids in patients 4 and 5. Conclusion: Based on a limited number of patients, diclofenac leads to better fever control, which translates into symptom relief and improvement of tachycardia, but could not prevent the progression of CRS.

Thrombocytopenia results from a variety of conditions, including radiation, chemotherapy, autoimmune disease, bone marrow disorders, pathologic conditions associated with surgical procedures, hematopoietic stem cell transplant (HSCT), and hematologic disorders associated with severe aplastic anemia. Immune thrombocytopenia (ITP) is caused by immune reactions that accelerate destruction and reduce production of platelets. Thrombopoietin (TPO) is a critical component of platelet production pathways, and TPO receptor agonists (TPO-RAs) are important for the management of ITP by increasing platelet production and reducing the need for other treatments. Romiplostim is a TPO-RA approved for use in patients with ITP in the United States, European Union, Australia, and several countries in Africa and Asia, as well as for use in patients with refractory aplastic anemia in Japan and Korea. Romiplostim binds to and activates the TPO receptor on megakaryocyte precursors, thus promoting cell proliferation and viability, resulting in increased platelet production. Through this mechanism, romiplostim reduces the need for other treatments and decreases bleeding events in patients with thrombocytopenia. In addition to its efficacy in ITP, studies have shown that romiplostim is effective in improving platelet counts in various settings, thereby highlighting the versatility of romiplostim. The efficacy of romiplostim in such disorders is currently under investigation. Here, we review the structure, mechanism, pharmacokinetics, and pharmacodynamics of romiplostim. We also summarize the clinical evidence supporting its use in ITP and other disorders that involve thrombocytopenia, including chemotherapy-induced thrombocytopenia, aplastic anemia, acute radiation syndrome, perisurgical thrombocytopenia, post-HSCT thrombocytopenia, and liver disease.

Thyroid late effects are among the most frequent sequelae reported after pediatric hematopoietic stem cell transplantation (HSCT). Although the detrimental effects of radiotherapy on the developing thyroid gland have been extensively assessed, the role of chemotherapy-only conditioning regimens remains controversial. We aimed to describe the occurrence, monitoring, and management of thyroid function disorders (ie, Graves disease, Hashimoto thyroiditis, and nonautoimmune hypothyroidism), nodules, and volumetric changes over a 20-year observation period in a single pediatric transplantation unit. In addition, we assessed the impact of different conditioning regimens on thyroid health. The study population for this retrospective observational analysis comprised 244 pediatric patients who underwent HSCT for malignant or nonmalignant diseases between 1999 and 2018 and for whom at least 4 thyroid function tests and 1 or more thyroid ultrasound(s) assessed sequentially after HSCT were available. The 15-year cumulative incidence of either autoimmune or nonautoimmune thyroid dysfunctions (34%, SE 5.3%) did not differ statistically between total body irradiation (TBI)-based and chemotherapy-based regimens (P = .23). Indeed, the cumulative incidence after busulfan (Bu)-based conditioning was overall superimposable to that recorded after TBI (10-year cumulative incidence, 22.2% versus 25.9%, respectively). Nevertheless, the cumulative incidence of nonautoimmune hypothyroidism was statistically higher after Bu-based conditioning (12.4%, SE 3.7%) than after other chemotherapy-only-based conditioning regimens (3.1%, SE 3.1%; P = .02, 5-year cumulative incidence), treosulfan (Treo) included. The overall cumulative incidence of nodules was low for the first 5 years after HSCT (1.9%, SE .9%) but subsequently increased steeply over time, with a 15-year cumulative incidence as high as 52.1% (SE 7.5%). TBI-conditioned patients had a higher 15-year cumulative incidence of nodules (66.8%, SE 9.1%) compared with patients receiving chemotherapy-only regimens (33.6%, SE 9.5%; P = .02), whereas age >10 years at transplantation showed a protective effect (hazard ratio, .42, 95% confidence interval, .2 to .88). Finally, a systematic sonographic follow-up highlighted a progressive statistically significant reduction in thyroid anteroposterior diameter among patients conditioned with TBI (P = .005), but not in those who received chemotherapy-only regimens. TBI and younger age at HSCT have a statistically significant detrimental effect on the occurrence of thyroid nodules, both benign and malignant. TBI and Bu expose patients to a higher cumulative incidence of thyroid dysfunction compared with other chemotherapy-only regimens, Treo included. Accordingly, Bu can be considered the most thyrotoxic agent among those administered as a part of a chemotherapy-only conditioning regimen. Finally, patients conditioned with TBI, but not those with other regimens, show a progressive decrease in thyroid volume over time, as assessed by sequential ultrasound examinations.

BACKGROUND: Chimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability. METHODS: We report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells. RESULTS: The cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3(+) lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD(–)). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion. CONCLUSION: SB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities. TRIAL REGISTRATION: ClinicalTrials.gov NCT03389035. FUNDING: This study was supported by grants from the Fondazione AIRC per la Ricerca sul Cancro (AIRC); Cancer Research UK (CRUK); the Fundación Científica de la Asociación Española Contra el Cáncer (FC AECC); Ministero Della Salute; Fondazione Regionale per la Ricerca Biomedica (FRRB).

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory multisystemic disease. Familial hemophagocytic lymphohistiocytosis (FHL) represents a group of rare autosomal recess...

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

During cancer treatments in childhood hematological malignancies, reduced exercise tolerance is one of the main hardships. Precision-based training programs help children, adolescents, and young adults and their families to resume regular physical activity, exercise, and sports once they return to their communities after the intensive phases spent in hospital. This study was aimed at verifying whether an intermittent recovery test, the Yo-Yo AD, could provide a simple and valid way to evaluate an individual’s capacity to perform repeated intense exercise and to follow up on the impact of tailored exercise in children, adolescents, and young adults with hematological malignancies. The Yo-Yo AD involved the repetition of several shuttles to muscle exhaustion, at pre-established speeds (walking and slow running). The heart rate (HR) and oxygen saturation (SaO2) were monitored during the test. The total distance and the walking/running ability, measured as the slope of the HR vs. distance correlation, were investigated before (T0) and after 11 weeks (T1) of precision exercise intervention. The Yo-Yo AD was also performed by healthy children (CTRL). Ninety-seven patients (10.58 ± 4.5 years, 46% female) were enrolled. The Yo-Yo AD showed the positive impact of the exercise intervention by increasing the distance covered by the individuals (T0 = 946.6 ± 438.2 vs. T1 = 1352.3 ± 600.6 m, p < 0.001) with a more efficient walking/running ability (T0 = 2.17 ± 0.84 vs. T1 = 1.73 ± 0.89 slope, p < 0.0164). CTRLs performed better (1754.0 ± 444.0 m, p = 0.010). They were equally skillful (1.71 ± 0.27 slope) when compared to the patients after they received the precision-based intervention. No adverse events occurred during the Yo-Yo AD and it proved to be an accurate way of correctly depicting the changes in performance in childhood hematological malignancies.

Osteonecrosis (ON) is a well-known sequela of paediatric acute lymphoblastic leukaemia (ALL) treatment. Incidence differs substantially among studies and the clinical significance of radiological findings is not fully established. We analysed 256 consecutive patients with ALL treated in our Institution between October 2010 and December 2016. Within the cohort, 41 developed ON, with a mean 5-year cumulative incidence of 18.5 (standard error, SE, 5.7)% overall. The mean (SE) 5-year cumulative incidence of ON was 12.7 (2.1)% after censoring upon stem cell transplantation (SCT) and/or relapse. Patients aged >= 10 years and patients allocated to the high-risk stratum had a 10-fold and fivefold higher risk of ON respectively. The risk of ON was more than double in relapsed patients, whereas no significant impact of gender, immunophenotype and SCT was demonstrated. Multiple lesions (median four joints involved per patient) were detected by magnetic resonance imaging in all but one patient, with the knee being the most affected joint. Lesions affecting convex joint surfaces experienced the worst evolution, whereas most lesions on diaphyses and concave surfaces remained radiologically stable or disappeared during follow-up. ON has a high prevalence in paediatric ALL, presenting with multiple lesions. Lesions involving convex surfaces were at higher risk of radiological deterioration.