ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies.

Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21(10%) with Hodgkin lymphoma and eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% CI 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (p=.76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI 19.5-32.4). Germline ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n=110) were classified as having absent (n=81) or residual (n=29) ATM kinase activity. Four-year EFS was 39.4% (95% CI 29-53.3) vs 78.7% (95% CI 63.7-97.2), (p<.001), and TRM rates were 37.6% (95% CI 26.4-48.7) vs 4.0% (95% CI 0-11.8), (p=.017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR=0.362, 95% CI 0.16-0.82; p=.009) and increased TRM (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

Primary osteosarcoma of the ribs: A report from the Cooperative Osteosarcoma Study Group.

PURPOSE: Primary rib osteosarcoma has not been investigated extensively, and clinical characteristics and optimal therapeutic strategies have not been defined. The authors used the database of the Cooperative Osteosarcoma Study Group (COSS) to analyze this tumor-site in depth. METHODS: The COSS database was searched for treatment-naive, high-grade osteosarcomas of the rib. Affected patients were analyzed for demographic and tumor-related factors, treatments, and outcomes. RESULTS: A total of 44 patients (23 males, 21 females; median age, 23 years [range, 6-59]) were identified. Primary metastases were detected in six of 44 (14%) patients. Surgery was performed in 40 of 44 (91%) patients and rendered 35 of 44 (80%) patients macroscopically disease-free. Chemotherapy was known to have been administered in 43 of 44 (98%) patients and radiotherapy in seven of 42 (17%) (no data for two patients). A good response to chemotherapy was only noted in five (33%) of those 15 evaluable patients who had received any preoperative chemotherapy. After a median follow-up of 2.49 (0.22-40.35) years for all patients and 6.61 (0.25-40.35) years for 26 survivors (21 of these in first complete remission), 5-year actuarial overall and event-free survival were 53.0% (8.5%) and 42.2% (8.1%), respectively. Incomplete tumor surgery was the most notable negative prognostic factor. Osteoblastic histology and a poor response to chemotherapy may have contributed. CONCLUSION: This large series provides evidence that patients with costal primaries are older than the average osteosarcoma patient, but appear to share the similar tumor biology and-if treated according to standard protocols-prognostic factors with tumors of other sites. Early, preoperative diagnosis and permanent, definitive local control remain major challenges and should contribute to improved outcomes.

Effect of two additional doses of intrathecal methotrexate during induction therapy on serious infectious toxicity in pediatric patients with acute lymphoblastic leukemia.

Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status. In the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (4.4%) patients treated with five doses (P<0.001; Odds Ratio 2.86 [95% Confidence Interval 1.99-4.13]). In a multivariate regression model, treatment with additional IT MTX proved to be the strongest risk factor for life-threatening infections (Odds Ratio 2.85 [1.96-4.14]). Fatal infections occurred in 16 (0.3%) and 38 (1.6%) patients treated with three or five IT MTX doses, respectively (P<0.001). As the relevance of additional intrathecal MTX in induction for relapse prevention in CNS2 patients is unclear, doses of intrathecal therapy have been reduced for these patients. (Clinicaltrials.gov identifiers: NCT01117441 and NCT00613457).

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series.

No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22+ blasts was 72% (range 40-100%, n = 9). The median dose in the first course was 1.74 mg/m2 (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27-80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.

Predicting fever in neutropenia with safety-relevant events in children undergoing chemotherapy for cancer: The prospective multicenter SPOG 2015 FN Definition Study.

BACKGROUND: Fever in neutropenia (FN) remains a frequent complication in pediatric patients undergoing chemotherapy for cancer. Preventive strategies, like primary antibiotic prophylaxis, need to be evidence-based. PROCEDURE: Data on pediatric patients with any malignancy from the prospective multicenter SPOG 2015 FN Definition Study (NCT02324231) were analyzed. A score predicting the risk to develop FN with safety-relevant events (SRE; bacteremia, severe sepsis, intensive care unit admission, death) was developed using multivariate mixed Poisson regression. Its predictive performance was assessed by internal cross-validation and compared with the performance of published rules. RESULTS: In 238 patients, 318 FN episodes were recorded, including 53 (17%) with bacteremia and 68 (21%) with SRE. The risk-prediction score used three variables: chemotherapy intensity, defined according to the expected duration of severe neutropenia, time since diagnosis, and type of malignancy. Its cross-validated performance, assessed by the time needed to cover (TNC) one event, exceeded the performance of published rules. A clinically useful score threshold of ≥11 resulted in 2.3% time at risk and 4.1 months TNC. Using external information on efficacy and timing of intermittent antibiotic prophylaxis, 4.3 months of prophylaxis were needed to prevent one FN with bacteremia, and 5.2 months to prevent one FN with SRE, using a threshold of ≥11. CONCLUSIONS: This score, based on three routinely accessible characteristics, accurately identifies pediatric patients at risk to develop FN with SRE during chemotherapy. The score can help to design clinical decision rules on targeted primary antibiotic prophylaxis and corresponding efficacy studies.

Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols.

ABL-class fusions other than BCR-ABL1 characterize around 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5×10-4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: clinicaltrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).

Four Additional Doses of PEG-L-Asparaginase During the Consolidation Phase in the AIEOP-BFM ALL 2009 Protocol Do Not Improve Outcome and Increase Toxicity in High-Risk ALL: Results of a Randomized Study.

PURPOSE: The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS: A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS: By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P < .001). CONCLUSION: Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.

Different fever definitions and the rate of fever and neutropenia diagnosed in children with cancer: a retrospective two-center cohort study.

BACKGROUND: The definition of fever, and thus fever and neutropenia (FN), varies between different pediatric oncology centers. Higher temperature limit should reduce FN rates, but may increase rates of FN with complications by delaying therapy. This study determined if different fever definitions are associated with different FN rates. PROCEDURE: Two pediatric oncology centers had used three fever definitions in 2004-2011: ear temperature ≥38.5 °C persisting ≥2 hours (low definition); axillary temperature ≥38.5 °C ≥ 2 hours or ≥39.0 °C once (middle); and ear temperature ≥39.0 °C once (high). Clinical information was retrospectively extracted from charts. FN rates were compared using mixed Poisson regression. RESULTS: In 521 pediatric patients with cancer, 783 FN were recorded during 6,009 months cumulative chemotherapy exposure time (501 years; rate, 0.13/month [95% CI, 0.12-0.14]), 124 of them with bacteremia (16%; 0.021/month [0.017-0.025]). In univariate analysis, the high versus low fever definition was associated with a lower FN rate (0.10/month [0.08-0.11] vs. 0.15/month [0.13-0.16]; rate ratio, 0.66 [0.45-0.97]; P = 0.036), the middle definition was intermediate (0.13/month [0.11-0.15]). This difference was not confirmed in multivariate analysis (rate ratio, 0.94 [0.67-1.33]; P = 0.74). The high versus low definition was not associated with an increased rate of FN with bacteremia (multivariate rate ratio, 1.39 [0.53-3.62]; P = 0.50). CONCLUSION: A higher fever definition was not associated with a lower FN rate, nor with an increased rate of FN with bacteremia. These may be false negative findings due to methodological limitations. These questions, with their potential impact on health-related quality of life, and on costs, need to be assessed in prospective studies.

Pediatric-Inspired Regimens in the Treatment of Acute Lymphoblastic Leukemia in Adolescents and Young Adults: A Systematic Review.

Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) have significantly worse outcomes than their younger counterparts. Current treatment guidelines rely mostly on non-randomized retrospective studies. We performed a systematic review of studies published within the last 15 years comparing pediatric-inspired regimens (PIR) versus adult-type regimens or performing an age-stratified analysis of outcomes in the AYA population. Due to the heterogeneity of data, a meta-analysis was not possible. However, the gathered data show a trend toward improvement in outcomes and an acceptable toxicity profile in patients treated with PIRs compared to conventional adult-type regimens. There is still room for further improvement, as older patients within the AYA population tend to perform poorly with PIR or conventional adult-type chemotherapy. Further randomized studies are needed to develop an optimal treatment strategy for AYA with ALL.

Outcome prediction in pediatric fever in neutropenia: Development of clinical decision rules and external validation of published rules based on data from the prospective multicenter SPOG 2015 FN definition study.

BACKGROUND: Fever in neutropenia (FN) remains a serious complication of childhood cancer therapy. Clinical decision rules (CDRs) are recommended to help distinguish between children at high and low risk of severe infection. The aim of this analysis was to develop new CDRs for three different outcomes and to externally validate published CDRs. PROCEDURE: Children undergoing chemotherapy for cancer were observed in a prospective multicenter study. CDRs predicting low from high risk infection regarding three outcomes (bacteremia, serious medical complications (SMC), safety relevant events (SRE)) were developed from multivariable regression models. Their predictive performance was assessed by internal cross-validation. Published CDRs suitable for validation were identified by literature search. Parameters of predictive performance were compared to assess reproducibility. RESULTS: In 158 patients recruited between April 2016 and August 2018, 360 FN episodes were recorded, including 56 (16%) with bacteremia, 30 (8%) with SMC and 72 (20%) with SRE. The CDRs for bacteremia and SRE used four characteristics (type of malignancy, severely reduced general condition, leucocyte count <0.3 G/L, bone marrow involvement), the CDR for SMC two characteristics (severely reduced general condition and platelet count <50 G/L). Eleven published CDRs were analyzed. Six CDRs showed reproducibility, but only one in both sensitivity and specificity. CONCLUSIONS: This analysis developed CDRs predicting bacteremia, SMC or SRE at presentation with FN. In addition, it identified six published CDRs that show some reproducibility. Validation of CDRs is fundamental to find the best balance between sensitivity and specificity, and will help to further improve management of FN.

Invasive fungal diseases impact on outcome of childhood ALL - an analysis of the international trial AIEOP-BFM ALL 2009.

In children with acute lymphoblastic leukemia (ALL), risk groups for invasive fungal disease (IFD) with need for antifungal prophylaxis are not well characterized, and with the advent of new antifungal compounds, current data on outcome are scarce. Prospectively captured serious adverse event reports of children enrolled in the international, multi-center clinical trial AIEOP-BFM ALL2009 were screened for proven/probable IFD, defined according to the updated EORTC/MSG consensus definitions. In a total of 6136 children (median age 5.2 years), 224 proven/probable IFDs (65 yeast and 159 mold) were reported. By logistic regression, the risk for proven/probable IFDs was significantly increased in children ≥12 years and those with a blast count ≥10% in the bone marrow on day 15 (P < 0.0001 each). Proven/probable IFDs had a 6-week and 12-week mortality of 10.7% and 11.2%, respectively. In the multivariate analysis, the hazard ratio for event-free and overall survival was significantly increased for proven/probable IFD, age ≥12 years, and insufficient response to therapy (P < 0.001, each). Our data define older children with ALL and those with insufficient treatment-response at high risk for IFD. As we show that IFD is an independent risk factor for event-free and overall survival, these patients may benefit from targeted antifungal prophylaxis.

Outcome for Children and Young Adults With T-Cell ALL and Induction Failure in Contemporary Trials.

PURPOSE: Historically, patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission at the end of induction (EOI) have had poor long-term survival. The goal of this study was to examine the efficacy of contemporary therapy, including allogeneic hematopoietic stem cell transplantation (HSCT) in first remission (CR1). METHODS: Induction failure (IF) was defined as the persistence of at least 5% bone marrow (BM) lymphoblasts and/or extramedullary disease after 4-6 weeks of induction chemotherapy. Disease features and clinical outcomes were reported in 325 of 6,167 (5%) patients age 21 years and younger treated in 14 cooperative study groups between 2000 and 2018. RESULTS: With a median follow-up period of 6.4 years (range, 0.3-17.9 years), the 10-year overall survival (OS) was 54.7% (SE = 2.9), which is significantly higher than the 27.6% (SE = 2.9) observed in the historical cohort from 1985 to 2000. There was no significant impact of sex, age, white blood cell count, central nervous system disease status, T-cell maturity, or BM disease burden at EOI on OS. Postinduction complete remission (CR) was achieved in 93% of patients with 10-year OS of 59.6% (SE = 3.1%) and disease-free survival (DFS) of 56.3% (SE = 3.1%). Among the patients who achieved CR, 72% underwent HSCT and their 10-year DFS (with a 190-day landmark) was significantly better than nontransplanted patients (63.8% [SE = 3.6] v 45.5% [SE = 7.1]; P = .005), with OS of 66.2% (SE = 3.6) versus 50.8% (SE = 6.8); P = .10, respectively. CONCLUSION: Outcomes for patients age 21 years and younger with T-ALL and IF have improved in the contemporary treatment era with a DFS benefit among those undergoing HSCT in CR1. However, outcomes still lag considerably behind those who achieve remission at EOI, warranting investigation of new treatment approaches.

Serious medical complications in children with cancer and fever in chemotherapy-induced neutropenia: results of the prospective multicenter SPOG 2003 FN study.

BACKGROUND: Fever and chemotherapy-induced neutropenia (FN) is the most frequent potentially lethal complication of therapy in children with cancer. This study aimed to describe serious medical complications (SMC) in children with FN regarding incidence, clinical spectrum, and associated characteristics. PROCEDURE: Pediatric patients presenting with FN induced by non-myeloablative chemotherapy were observed in a prospective multicenter study. SMC was defined as potentially life-threatening complication (PLTC), transfer to the pediatric intensive care unit (PICU), or death. RESULTS: A total of 443 FN episodes were reported from 8 centers. Of these, 411 episodes were reported from 4 centers recruiting consecutively and without bias regarding the risk of complications. They were used for calculation of proportions. An SMC was reported in 23 episodes [5.6%; 95% confidence interval (CI): 3.7-8.1], usually defined by more than one criterion. These were PLTC in 13 episodes, PICU in 22, and death in 3 (mortality, 0.7%; 95% CI: 0.2-2.1). Both a delayed onset of SMC (14 of 23 episodes, 61%) and a biphasic clinical course (11 of 23, 48%) were frequently observed. In a multivariate logistic regression analysis, 4 characteristics were significantly and independently associated with the risk of SMC: diagnosis of acute myeloid leukemia, interval since chemotherapy ≤7 days, severely reduced general condition, and hemoglobin ≥9.0 g/dl at presentation. CONCLUSIONS: In children with FN, SMC were rare, and mortality was very low. Those with SMC often had a delayed onset and biphasic clinical course with secondary deterioration.

First-day step-down to oral outpatient treatment versus continued standard treatment in children with cancer and low-risk fever in neutropenia. A randomized controlled trial within the multicenter SPOG 2003 FN study.

BACKGROUND: The standard treatment of fever in chemotherapy-induced neutropenia (FN) includes emergency hospitalization and empirical intravenous antimicrobial therapy. This study determined if first-day step-down to oral outpatient treatment is not inferior to continued standard regarding safety and efficacy in children with low-risk FN. PROCEDURE: In a randomized controlled non-blinded multicenter study, pediatric patients with FN after non-myeloablative chemotherapy were reassessed after 8-22 hours of inpatient intravenous antimicrobial therapy. Low-risk patients were randomized to first-day step-down to experimental (outpatient, oral amoxicillin plus ciprofloxacin) versus continued standard treatment. Exact non-inferiority tests were used for safety (no serious medical complication; non-inferiority margin of difference, 3.5%) and efficacy (resolution of infection without recurrence, no modification of antimicrobial therapy, no adverse event; 10%). RESULTS: In 93 (26%) of 355 potentially eligible FN episodes low-risk criteria were fulfilled, and 62 were randomized, 28 to experimental (1 lost to follow-up) and 34 to standard treatment. In intention-to-treat analyses, non-inferiority was not proven for safety [27 of 27 (100%) vs. 33 of 34 (97%; 1 death) episodes; 95% upper confidence border, 6.7%; P = 0.11], but non-inferiority was proven for efficacy [23 of 27 (85%) vs. 26 of 34 (76%) episodes; 95% upper confidence border, 9.4%; P = 0.045]. Per-protocol analyses confirmed these results. CONCLUSIONS: In children with low-risk FN, the efficacy of first-day step-down to oral antimicrobial therapy with amoxicillin and ciprofloxacin in an outpatient setting was non-inferior to continued hospitalization and intravenous antimicrobial therapy. The safety of this procedure, however, was not assessable with sufficient power.

Time to antibiotics is unrelated to outcome in pediatric patients with fever in neutropenia presenting without severe disease during chemotherapy for cancer.

Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. We analyzed the association between time from recognition of fever to start of antibiotics (TTA) and SRE (death, admission to intensive care unit, severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation with FN. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. TTA (median, 120 min; interquartile range, 49-180 min) was not associated with SRE, with a trend for less SREs in episodes with longer TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. In conclusion, TTA was unrelated to poor clinical outcome in pediatric patients with FN presenting without severe disease. We saw strong evidence for triage bias which could only be partially adjusted.

CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study.

Relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may occur in the central nervous system (CNS). Most clinical trials of CAR T-cell therapy excluded patients with active CNS leukemia, partially for concerns of neurotoxicity. Here, we report an international study of fifty-five children and adolescents who received CAR T-cell therapy for relapsed BCP-ALL with CNS involvement at the time of referral. All patients received bridging therapy, 16 still having active CNS disease at the time of lymphodepletion. Twelve patients received CD28-based CAR T-cells, 9 being subsequently treated with allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Forty-three patients received 4-1BB-based CAR T-cells. Cytokine-release syndrome (CRS) and neurotoxicity occurred in 65% and 38% of patients, respectively, more frequently following treatment with CD28-based CARs. Fifty-one of 54 evaluable patients (94%) achieved complete response following this therapy. Relapse occurred in 22 patients: 19/43 following 4-1BB-based CARs (12 CNS relapses), and 3/12 after CD28-based CARs with subsequent HSCT (no CNS relapse). Patients treated with tisagenlecleucel for an isolated CNS relapse had a high incidence of a subsequent CNS relapse (6 of 8). CAR T-cells were found to be effective in this cohort, though the risk of CNS relapse was not completely mitigated by this approach.

Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study.

BACKGROUND: Children aged younger than 3 years were excluded from the ELIANA phase 2 trial of tisagenlecleucel in children with acute lymphoblastic leukaemia. The feasibility, safety, and activity of tisagenlecleucel have not been defined in this group, the majority of whom have high-risk (KMT2A-rearranged) infant acute lymphoblastic leukaemia and historically poor outcomes despite intensification of chemotherapy, and for whom novel therapies are urgently needed. We aimed to provide real-world outcome analysis of the feasibility, activity, and safety of tisagenlecleucel in younger children and infants with acute lymphoblastic leukaemia. METHODS: We did an international, multicentre, retrospective cohort study at 15 hospitals across ten countries in Europe. Eligible patients were children aged younger than 3 years at screening between Sept 1, 2018, and Sept 1, 2021, who were screened for tisagenlecleucel therapy for relapsed or refractory B-cell precursor acute lymphoblastic leukaemia according to licensed indications. Patients received a single intravenous infusion of tisagenlecleucel. We tracked chimeric antigen receptor T-cell therapy outcomes using a standardised data reporting form. Overall survival, event-free survival, stringent event-free survival, B-cell aplasia, and toxicity were assessed in all patients who received a tisagenlecleucel infusion. FINDINGS: 38 eligible patients were screened, of whom 35 (92%) received a tisagenlecleucel infusion. 29 (76%) of 38 patients had KMT2A-rearranged acute lymphoblastic leukaemia, and 25 (66%) had relapsed after previous allogeneic haematopoietic stem-cell transplantation (HSCT). Patients had previously received a median of 2 lines (IQR 2-3) of (non-HSCT) therapy. Seven (18%) of 38 patients had received inotuzumab and 14 (37%) had received blinatumomab. After a median of 14 months (IQR 9-21) of follow-up, overall survival at 12 months after tisagenlecleucel infusion was 84% (64-93; five patients had died), event-free survival was 69% (47-83; nine events), and stringent event-free survival was 41% (23-58; 18 events). The probability of ongoing B-cell aplasia was 70% (95% CI 46-84; seven events) at 12 months. Adverse events included cytokine release syndrome, which occurred at any grade in 21 (60%) of 35 patients and at grade 3 or worse in five (14%), and neurotoxicity at any grade in nine (26%), none of which were severe. Measurable residual disease-negative complete response with or without haematological recovery occurred in 24 (86%) of 28 patients who had measurable disease. INTERPRETATION: These data suggest that tisagenlecleucel has antitumour activity and has an acceptable safety profile for young children and infants with B-cell precursor acute lymphoblastic leukaemia. FUNDING: None.

Lineage-restricted sympathoadrenal progenitors confer neuroblastoma origin and its tumorigenicity.

Neuroblastoma (NB) is the most common cancer in infants and it accounts for six percent of all pediatric malignancies. There are several hypotheses proposed on the origins of NB. While there is little genetic evidence to support this, the prevailing model is that NB originates from neural crest stem cells (NCSCs). Utilizing in vivo mouse models, we demonstrate that targeting MYCN oncogene to NCSCs causes perinatal lethality. During sympathoadrenal (SA) lineage development, SOX transcriptional factors drive the transition from NCSCs to lineage-specific progenitors, characterized by the sequential activation of Sox9/Sox10/Sox4/Sox11 genes. We find the NCSCs factor SOX10 is not expressed in neuroblasts, but rather restricted to the Schwannian stroma and is associated with a good prognosis. On the other hand, SOX9 expression in NB cells was associated with several key biological processes including migration, invasion and differentiation. Moreover, manipulating SOX9 gene predominantly affects lineage-restricted SA progenitors. Our findings highlight a unique molecular SOX signature associated with NB that is highly reminiscent of SA progenitor transcriptional program during embryonic development, providing novel insights into NB pathobiology. In summary, we provide multiple lines of evidence suggesting that multipotent NCSCs do not contribute to NB initiation and maintenance.