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PURPOSE We aimed to study prognostic factors and efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first remission of patients with noninfant childhood acute lymphoblastic leukemia (ALL) with 11q23/ KMT2A rearrangements treated with chemotherapy regimens between 1995 and 2010. PATIENTS AND METHODS Data were retrospectively retrieved from 629 patients with 11q23/ KMT2A-rearranged ALL from 17 members of the Ponte-di-Legno Childhood ALL Working Group. Clinical and biologic characteristics, early response assessed by minimal residual disease at the end of induction (EOI) therapy, and allo-HSCT were analyzed for their impact on outcomes. RESULTS A specific 11q23/ KMT2A translocation partner gene was identified in 84.3% of patients, with the most frequent translocations being t(4;11)(q21;q23) (n = 273; 51.5%), t(11;19)(q23;p13.3) (n = 106; 20.0%), t(9;11)(p21_22;q23) (n = 76; 14.3%), t(6;11)(q27;q23) (n = 20; 3.8%), and t(10;11)(p12;q23) (n = 14; 2.6%); 41 patients (7.7%) had less frequently identified translocation partner genes. Patient characteristics and early response varied among subgroups, indicating large biologic heterogeneity and diversity in therapy sensitivity among 11q23/ KMT2A-rearranged ALL. The EOI remission rate was 93.2%, and the 5-year event-free survival (EFS) for the entire cohort was 69.1% ± 1.9%, with a range from 41.7% ± 17.3% for patients with t(9;11)-positive T-ALL (n = 9) and 64.8% ± 3.0% for patients with t(4;11)-positive B-ALL (n = 266) to 91.2% ± 4.9% for patients with t(11;19)-positive T-ALL (n = 34). Low EOI minimal residual disease was associated with favorable EFS, and induction failure was particularly predictive of nonresponse to further therapy and relapse and poor EFS. In addition, EFS was not improved by allo-HSCT compared with chemotherapy only in patients with both t(4;11)-positive B-ALL (n = 64 v 51; P = .10) and 11q23/ KMT2A-rearranged T-ALL (n = 16 v 10; P = .69). CONCLUSION Compared with historical data, prognosis of patients with noninfant 11q23/ KMT2A-rearranged ALL has improved, but allo-HSCT failed to affect outcome. Targeted therapies are needed to reduce relapse and treatment-related mortality rates.

Supplementary Data from Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukemia

We assessed minimal residual disease (MRD) detection and B-cell aplasia after tisagenlecleucel therapy for acute lymphoblastic leukemia (ALL) to define biomarkers predictive of relapse (N = 143). Next-generation sequencing (NGS) MRD detection >0 in bone marrow (BM) was highly associated with relapse. B-cell recovery [signifying loss of functional chimeric antigen receptor (CAR) T cells] within the first year of treatment was associated with a hazard ratio (HR) for relapse of 4.5 [95% confidence interval (CI), 2.03–9.97; P < 0.001]. Multivariate analysis at day 28 showed independent associations of BMNGS-MRD >0 (HR = 4.87; 95% CI, 2.18–10.8; P < 0.001) and B-cell recovery (HR = 3.33; 95% CI, 1.44–7.69; P = 0.005) with relapse. By 3 months, the BMNGS-MRD HR increased to 12 (95% CI, 2.87–50; P < 0.001), whereas B-cell recovery was not independently predictive (HR = 1.27; 95% CI, 0.33–4.79; P = 0.7). Relapses occurring with persistence of B-cell aplasia were largely CD19− (23/25: 88%). Detectable BMNGS-MRD reliably predicts risk with sufficient time to consider approaches to relapse prevention such as hematopoietic cell transplantation (HCT) or second CAR-T cell infusion.Significance:Detectable disease by BMNGS-MRD with or without B-cell aplasia is highly predictive of relapse after tisagenlecleucel therapy for ALL. Clonotypic rearrangements used to follow NGS-MRD did not change after loss of CD19 or lineage switch. High-risk patients identified by these biomarkers may benefit from HCT or investigational cell therapies.See related commentary by Ghorashian and Bartram, p. 2.This article is highlighted in the In This Issue feature, p. 1

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.

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Survival for patients following relapse remains poor, and achieving complete remission (CR) after relapse is the first critical step to cure. Carfilzomib is a proteasome inhibitor with an acceptable safety profile and clinical activity in adults with multiple myeloma but has not been assessed in children. The primary objective of this phase 1b study was to assess the safety and tolerability of carfilzomib combined with vincristine, dexamethasone, asparaginase, and daunorubicin (VXLD) in children with relapsed and/or refractory ALL.Patients aged 1-21 years (n = 24) received 4-week induction therapy with carfilzomib at dose levels of 27 mg/mFollowing dose escalation of carfilzomib, the recommended phase 2 carfilzomib dose was identified as 56 mg/mThese data support the use of carfilzomib in pediatric patients with relapsed and/or refractory ALL.

Background. Osteonecrosis (ON) is a long-known complication of acute leukemia (AL) management affecting 1 to 10% of young patients, leading to long-term morbidity. Widespread access to Magnetic Resonance Imagery (MRI) over the past ten years has allowed earlier detection and more accurate assessment. This study investigated clinical and radiological features of ON, among the large French cohort L.E.A (Leucémie Enfant Adolescent) Procedure. Patients with ON were retrospectively enrolled and risk factors for the onset, the multifocal involvement and severe damage were analyzed. Quality of life (QoL) was also evaluated. A sub-study described radiological features. Results. 129/4973 patients developed ON (2.5%) and were preferentially aged over 10 years at time of AL diagnosis (OR 22.46, p

International audience; Purpose: In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences.Method: 891 patients, from the SFGM-TC registry, aged between 1 and 25 years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts.Results: Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5 year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA.Conclusion: AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population.Keywords: Acute lymphoblastic leukemia; Adolescents and young adults; Graft versus host disease; Hematopoietic stem cell transplantation.

The 3-year results are presented for ZUMA-4, a phase 1/2 multicenter study evaluating the safety and efficacy of KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pediatric/adolescent patients with relapsed/refractory (R/R) Bcell acute lymphoblastic leukemia (B-ALL). Phase 1 explored two dose levels and formulations. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Of 31 enrolled patients, KTE-X19 was administered to 24 (median age 13.5 years, range 3-20; median follow-up 36.1 months). No DLTs were observed. All treated patients had grade ≥3 adverse events, commonly hypotension (50%) and anemia (42%). Grade 3 cytokine release syndrome rates were 33%, 75%, 27%, and 22% in the all-treated, 2×106, 1×106 (68 mL formulation), and 1×106 (40 mL formulation) CAR T cells/kg groups; 21%, 25%, 27%, and 11% of patients experienced grade ≥3 neurologic events, respectively. Overall complete remission (CR) rates (including CR with incomplete hematologic recovery) were 67%, 75%, 64%, and 67% in the all-treated, 2×106, 1×106 (68 mL), and 1×106 (40 mL) CAR T cells/kg groups, respectively. Overall minimal residual disease (MRD)-negativity rates were 100% among responders; 88% of responders underwent subsequent allogeneic stem-cell transplant (alloSCT). In the 1×106 (40 mL) group (recommended phase 2 dose), median duration of remission censored at alloSCT and median overall survival were not reached. Pediatric/adolescent patients with R/R B-ALL achieved high MRD-negative remission rates with manageable safety profile after a single dose of KTE-X19. Phase 2 is ongoing at the 1×106 CAR T cells/kg (40 mL) dose.

Prior to regulatory approval of blinatumomab in pediatric patients with relapsed/refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (R/R Ph- BCP-ALL), blinatumomab was made available via an expanded access program (EAP).This retrospective observational study included patients receiving blinatumomab in the EAP between January 1, 2014 and June 30, 2017 who were followed until death, entry into a clinical trial, end of follow-up, or end of the study period (December 31, 2017), whichever occurred first.Among 113 children enrolled, 72 were diagnosed with R/R Ph- BCP-ALL and 41 were minimal residual disease positive (MRD+, either Ph- or Ph+). In the R/R group, 38 (53%) patients achieved hematological response within two cycles. Of these, 19 (50%) proceeded to hematopoietic stem cell transplantation (HSCT) without bridging myelosuppressive therapy. Of 36 patients in the R/R group evaluable for MRD, 30 (83%) had an MRD response. In the R/R group, median relapse-free survival was 5.4 months and median overall survival (OS) was 8.2 months. Of 36 patients in the MRD+ group who were evaluable for MRD after two cycles, 27 (75%) had an MRD response. Overall, 24 (59%) of the MRD+ patients proceeded to HSCT without other bridging therapy. Median disease-free survival was 13.6 months; median OS was not reached.In this real-world pediatric cohort, blinatumomab was effective within two cycles. Over half of patients with R/R Ph- BCP-ALL achieved hematological response and most achieved MRD response in the MRD+ group, confirming the efficacy of blinatumomab in pediatric trials.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus–driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm– and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

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.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first-or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplanta-tion and be definitive therapy versus those in whom it provides a more effective bridge to hae-matopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully huma-nised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prior-itisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary medi-astinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this pop-ulation. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials.CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell ther-apies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success.The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies.Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regu-latory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially impor-tant as these are very expensive therapies.The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

10001 Background: Approximately 15-20% of pediatric pts with ALL or LL will be refractory to/relapse after frontline treatment; relapsed disease is associated with poor outcomes. In a phase 2 study, 2 of 7 (28.6%) pts with T-cell ALL in first relapse achieved a complete response (CR) using the vincristine, prednisone, PEG-asparaginase, and doxorubicin (VPLD) reinduction backbone. DARA, a human IgGκ monoclonal antibody targeting CD38 approved for treating multiple myeloma, has shown preclinical efficacy in ALL models. We report the initial results of DARA plus VPLD in pediatric and young adult pts with relapsed/refractory T-cell ALL or LL enrolled in the phase 2, open-label DELPHINUS study. Methods: Eligible pts were aged 1-30 y, had T-cell ALL or LL in first relapse or refractory to 1 prior induction/consolidation regimen, and had a performance status ≥70. DARA (16 mg/kg IV QW) was given with VPLD in Cycle 1 and with methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine in Cycle 2. Pts received age/risk-adjusted intrathecal therapy. Response was measured at the end of each cycle by local bone marrow morphology. The primary endpoint for ALL pts was CR rate in pediatric pts at the end of Cycle 1. Pts achieving CR after Cycles 1 or 2 could proceed to allogeneic HSCT off study. Overall response rate (ORR) was defined as CR or CR with incomplete hematological recovery (CRi) at any time before start of subsequent therapy or HSCT. Minimal residual disease (MRD) negativity (< 0.01%) at any time before disease progression, start of subsequent therapy, or HSCT was centrally reviewed by flow cytometry. Results: Twenty-four pediatric (age 1-17 y) and 5 young adult (age 18-30 y) ALL pts and 10 LL pts (age 1-30 y) received ≥1 DARA dose. Median (range) age was 10.0 (2-25) y (ALL) and 14.5 (5-22) y (LL); median (range) time from initial diagnosis to first study treatment was 2.0 (0.1-6.1) y (ALL) and 0.8 (0.5-6.0) y (LL). Pediatric ALL pts received a median (range) of 2 (1-3) treatment cycles; young adult ALL pts and LL pts each received 2 (1-2). Among pediatric ALL pts, 10 (41.7%) pts (90% CI, 24.6-60.3) achieved CR at the end of Cycle 1. ORR was 83.3% (CR, 13 [54.2%] pts; CRi, 7 [29.2%] pts) in pediatric and 60.0% (all CR) in young adult ALL pts and 40.0% (all CR) in LL pts. Ten (41.7%) pediatric ALL pts achieved MRD negativity. All pediatric ALL pts had a grade 3/4 TEAE. No pediatric ALL pt discontinued DARA primarily due to AEs and 1 (4.2%) died due to TEAEs (brain edema and hepatic failure) attributed to study treatment but unrelated to DARA. Conclusions: The addition of DARA to VPLD in pediatric and young adult pts with relapsed/refractory T-cell ALL or LL showed initial activity, generating improved response rates compared to those achieved with backbone therapy alone, with a manageable safety profile. Clinical trial information: NCT03384654.

BACKGROUND: There is a variability of the results in the published prognostic sickle cell disease (SCD) studies. The aim of this article is to assess and demonstrate how the methods used for analysis of laboratory parameters impact the prognostic study results in children with sickle cell disease. METHODS: Firstly, a systematic review of published studies was conducted to identify the methods used in statistical analyses on laboratory parameters. Secondly, four different identified analysis were successively applied on laboratory data collected prospectively in our cohort of newborns with SCD in order to evaluate the association between laboratory parameters and cerebral vasculopathy, depending on the analysis strategy. RESULTS: Thirty-one studies were included in the systematic review in which hemoglobin and reticulocyte counts were the most frequently collected parameters. Through this review, we noted four different statistical strategies. In almost one half of the cohort studies, laboratory parameter was collected only one time per patient. When several values were available, only one statistical analysis considered the time variation. When we applied these four different statistical strategies to our cohort of SCD children, we highlighted that the conclusion on prognostic value of parameters (either as protective or as risk factor) depends on the analysis strategies applied. CONCLUSION: The laboratory parameter prognostic value depends on the analysis strategy chosen for its analysis. It raises fundamental questions about methodological approaches that concern clinician researchers. Identifying prognostic factors is currently essential for better understanding of SCD. Taking into account longitudinal data and standardization of analyses in prognostic cohort studies should allow drawing valuable and reproducible conclusions.

Salvage options for children with relapsed ALL remain sub-optimal, particularly for T-cell ALL, with disease refractoriness and further relapse remaining the leading cause of death. Achieving complete remission (CR) after relapse is the first critical step to cure. Combining the proteasome inhibitor (PI) bortezomib with chemotherapy showed promising CR rates in previous studies in pediatric ALL (Messinger 2012, Horton 2019, Bertaina 2017). We report a multicenter phase 1 pediatric trial for relapsed ALL (NCT02303821) investigating the second generation PI carfilzomib plus VXLD (vincristine, dexamethasone, PEG-asparaginase, daunorubicin) induction therapy. Carfilzomib plus UKALLR3 (dexamethasone, mitoxantrone, methotrexate, PEG-asparaginase, vincristine) was also evaluated but considered not tolerable (Burke 2019). Patients (pts) received 4 weeks of VXLD plus carfilzomib administered intravenously on days 1, 2, 8, 9, 15, and 16. Pts were recruited in cohorts of 3 dose-limiting-toxicity (DLT) evaluable pts, with carfilzomib dose escalation based on a Bayesian logistic regression model. Pts achieving ≥ stable disease post-induction, could receive a cycle of modified BFM consolidation therapy (mercaptopurine, cyclophosphamide, cytarabine, pegaspargase, vincristine) plus carfilzomib at the same dose level and schedule given during induction. Pts Of 16 DLT-evaluable pts, 2 DLTs were observed in the VXLD cohort among 8 DLT-evaluable pts at the 56 mg/m 2 dose level (pulmonary hemorrhage on day 1 [n=1] and G4 thrombocytopenia past day 45 of induction [n=1]). G3-4 hematological AEs occurred in 54% of pts. Non-hematological >G3 treatment emergent adverse events (TEAEs) of note are listed in Table 2. Serious TEAEs (SAEs) were reported in 58% of pts with the most common being bacteremia, acute pancreatitis, and posterior reversible encephalopathy syndrome (PRES; all n=2, 8%); both cases of PRES were considered carfilzomib related and occurred in pts given a prior allogeneic stem cell transplant. Three fatal TEAEs occurred within 30 days of the last dose, all in the 56 mg/m 2 cohort (multiorganism sepsis, pneumonia-unspecified, and leukemia). Both pts who died due to toxicity had refractory relapse 9 and 6 months after a stem cell transplant, respectively. The RP2D was identified as 56mg/m 2. PK assays demonstrated no significant age-related differences in area under the curve across age groups or between children and adults (Table 3). Pharmacodynamic assays indicated complete suppression of proteasome activity in peripheral blood at dose levels >27 mg/m 2. Among all pts (n=24), 21% (n=5) achieved CR; 29% (n=7) CRi or CRp; 8% (n=2) partial response (PR); 17% (n=4) stable disease (SD); 8% (n=2) progressive disease; 8% (n=2) were not evaluable (NE); 8% (n=2) died without response assessment. CR/CRp/CRi by dose are listed in Table 2. All pts with CRi or better recovered full or partial hematological function by day 45 without evidence of leukemia progression. Twelve pts proceeded to consolidation, including 2 NE, 1 with PR, and 1 with SD at the end of induction. Ten pts (83%) who received consolidation were in remission on day 29 post-consolidation (CR, n=5; CRi/CRp, n=5), 1 was NE, and 1 remained in SD. Carfilzomib in combination with VXLD chemotherapy was found to be tolerable with promising efficacy in pediatric pts with highly advanced ALL. The RP2D of carfilzomib in this combination chemotherapy regimen was identified as 56 mg/m 2. Further efficacy and additional safety data are currently being investigated in phase 2 of this trial. Figure 1 Figure 1. Disclosures Ziegler: Amgen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Bautista: Bayer: Consultancy; Amgen: Consultancy; Roche/Genentech: Consultancy, Honoraria; Eusa Pharma: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees. Gore: Sanofi Paris: Current equity holder in publicly-traded company; Anchiano: Current equity holder in publicly-traded company; Blueprint Medicines: Current equity holder in publicly-traded company; Roche/Genentech: Consultancy, Honoraria; Mirati: Current equity holder in publicly-traded company; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Clovis: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. 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. O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Obreja: Amgen: Current Employment, Current equity holder in publicly-traded company. Morris: Amgen: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Carfilzomib is approved in the United States for the treatment of adult patients with relapsed or refractory multiple myeloma. It has not been approved for use in pediatric patients with ALL.

Background: Detection of MRD is an important predictor of patient outcome following treatment of B-ALL; importantly, MRD is emerging as a useful tool to detect early relapse, which may fulfill a key previously unmet clinical need. Objective: To evaluate the potential of MRD to predict morphologic relapse in pediatric and AYA patients with B-ALL. Methods: Bone marrow (BM) and peripheral blood (PB) specimens at screening (pre-tisagenlecleucel infusion), post-infusion, and relapse from two B-ALL clinical trials (ELIANA [NCT02435849] and ENSIGN [NCT02228096]) were tested using immunoglobulin next-generation sequencing (IgNGS) and flow cytometry (FC). We assessed concordance between two MRD assays to determine which method could support early relapse detection and whether using PB with IgNGS was comparable with BM testing with FC. Results: IgNGS was performed in 300 samples from 88 patients. 237 samples from 83 patients also had FC MRD results available. Baseline samples, which had high disease burden, showed 100% MRD concordance between both assays. However, post-treatment, where the leukemic burden was dramatically reduced, IgNGS detected a greater number of MRD-positive samples vs FC at each sensitivity level tested (10-4, 10-5, and 10-6). At the highest sensitivity level of 10-6, IgNGS was able to detect 18% more MRD-positive post-treatment samples. IgNGS was able to detect MRD positivity 1-4 months ahead of clinical relapse in a small number of relapsed patients, whether relapse was CD19+ or CD19-. MRD burden in BM was higher than in PB using both FC and IgNGS. In patients with matching data available, IgNGS was able to detect more MRD-positive PB samples than FC MRD-positive BM samples. Patients who were MRD negative by both IgNGS and FC at the end of first month post-infusion had better progression-free survival (PFS) and overall survival (OS) compared with those with detectable MRD. Tumor clonality at baseline and clonal evolution following tisagenlecleucel treatment will be presented. Conclusion: MRD detection using IgNGS in PB may be used as a surrogate for FC assessment of MRD in BM. Patients who were MRD negative by IgNGS 1 month after infusion had improved PFS and OS vs those with detectable MRD; ongoing studies will provide further information on the applicability of IgNGS MRD detection and its association with long-term outcome in tisagenlecleucel-treated pediatric and AYA relapsed/refractory B-ALL patients. Citation Format: Michael A. Pulsipher, Xia Han, Máire Quigley, Gabor Kari, Susana Rives, Theodore W. Laetsch, Gary D. Myers, Hidefumi Hiramatsu, Gregory A. Yanik, Muna Qayed, Timothy Driscoll, Michael W. Boyer, Heather Stefanski, Jochen Buchner, Andre Baruchel, Peter Bader, Lan Yi, Creton Kalfoglou, Harlan Robins, Erik Yusko, Gullu Gorgun, Eric Bleickardt, Stephane Wong, Stephan A. Grupp. Potential utility of minimal residual disease (MRD) to identify relapse in pediatric and young adult (AYA) B-cell acute lymphoblastic leukemia (B-ALL) patients treated with tisagenlecleucel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT077.

Minimal residual disease (MRD) assessment provides a powerful prognostic factor for therapeutic stratification in acute lymphoblastic leukemia (ALL). Multiparameter flow cytometry (MFC) has the potential for a rapid and sensitive identification of high risk patients. Our group has previously published that MRD levels analyzed by clone specific Ig/TcR-QPCR and MFC were concordant at a sensitivity of 10(-4) . Here we report the MFC methodological aspects from this multi-center experience.MRD was assessed by MFC in 1030 follow-up samples from 265 pediatric and adult patients with de novo ALL treated in the FRALLE, EORTC, or GRALL clinical trials. MRD assessment as applied by the eight participating MFC laboratories is described in detail regarding cell preparation, leukemia-associated immunophenotype (LAIP) markers and data analysis. Samples were obtained from bone marrow (BM) and peripheral blood (PB). Immunostaining was performed after erythrocyte lysis or Ficoll enrichment.This study confirms the applicability of MFC-based MRD assessment in 97% of patients with ALL at the 10(-4) cut-off. MRD values after Ficoll enrichment and erythrocyte lysis were found comparable. Higher MRD values were obtained in BM than in PB, especially for B-lineage ALL.Measurement of MRD by MFC at the 10(-4) cut-off is applicable within a few hours for almost all patients and using a comparable analytical strategy allows for multicenter collaborative studies. The method can be introduced in a strategy aimed at defining the risk of failure of patients with childhood or adult ALL.

Describe the epidemiology, clinical profiles and outcomes associated with head and neck (HN) involvement in children/adolescents with B-cell non-Hodgkin lymphoma (B-NHL).Analysis of children/adolescents with HN B-NHL prospectively enrolled in the SFOP LMB-89 trial (July 1989-June 1996).One hundred and twelve of 561 patients (20%) had HN involvement. The mean age of the patients was 8.4 years. Murphy staging differed between the HN patients and the others (P0.0001): 9% versus 5% of the patients presented with stage I disease, 36% versus 11% presented with stage II disease, 12% versus 59% presented with stage III disease, 17% versus 10% with stage IV disease and 27% versus 16% with B-AL. Twenty-nine HN patients (26%) had CNS involvement at diagnosis versus 8.5% in the group without HN involvement (P0.0001). Patients were treated according to the LMB89 protocol: 3 HN patients were allocated to group A, 70 to group B and 39 to group C. Ninety-seven percent of HN patients achieved CR and event-free and overall survival at 4 years was 95.5% (5 deaths in patients with CNS disease). On multivariate analysis, EFS was significantly better in HN patients than in non-HN patients (P = 0.021), but not OS (P = 0.11).The HN site is the second most common location for B-NHL at diagnosis and is more frequently associated with disseminated disease and CNS involvement than other sites. However, outcomes are no worse for these patients than for the rest of the population.

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(®) .