RESUMO
We previously reported a better outcome in adult and pediatric T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 mutations without alterations of K-N-RAS and PTEN genes. Availability of high-throughput next-generation sequencing strategies (NGS) led us to refine the outcome prediction in T-ALL. Targeted whole-exome sequencing of 72 T-ALL related oncogenes was performed in 198 adult T-ALLs in first remission (CR1) from the GRAALL-2003/2005 protocols (ClinicalTrial.gov, NCT00222027, NCT00327678) and 242 pediatric T-ALLs from the FRALLE2000T. This approach enabled the identification of the first NGS-based classifier in T-ALL categorizing low-risk patients as those with N/F, PHF6, or EP300 mutations, excluding N-K-RAS, PI3K pathway (PTEN, PIK3CA, and PIK3R1), TP53, DNMT3A, IDH1/2, and IKZF1 alterations, with a 5-year cumulative incidence of relapse (CIR) estimated at 21%. Conversely, the remaining patients were classified as high-risk, exhibiting a 5-year CIR estimated at 47%. We externally validated this stratification in the pediatric cohort. NGS-based classifier was highly prognostic, independently of minimal residual disease (MRD) and white blood cells counts (WBC), in both adult and pediatric cohorts. Integration of the NGS-based classifier into a comprehensive risk stratification model, including WBC count at diagnosis and MRD at the end of induction, enabled the identification of an adverse risk subgroup (25%) with a 5-year CIR estimated at 51%, and a favorable risk group (32%) with a 5-year CIR estimated at 12%. NGS-based stratification combined with WBC and MRD sharpens the prognostic classification in T-ALL and identifies a new subgroup of patients who may benefit from innovative therapeutic approaches.
RESUMO
Given the poor outcome of refractory and relapsing T-ALL, identifying prognostic markers is still challenging. Using SNP-array analysis, we provide a comprehensive analysis of genomic imbalances in a cohort of 317 newly-diagnosed T-ALL patients including 135 children and 182 adults with respect to clinical and biological features and outcomes. SNP-array results identified at least one somatic genomic imbalance in virtually all T-ALL patients (~96%). Del(9)(p21) (~70%) and UPD(9)p21)/CDKN2A/B (~28%) were the most frequent genomic imbalances. Unexpectedly del(13q14)/RB1/DLEU1 (~14%) was the second more frequent CNV followed by del(6)(q15)/CASP8AP2 (~11%), del(1)(p33)/SIL-TAL1 (~11%), del(12)(p13)ETV6/CDKN1B (~9%), del(18)(p11)/PTPN2 (~9%), del(1)(p36)/RPL22 (~9%), and del(17)(q11)/NF1/SUZ12 (~8%). SNP-array also revealed distinct profiles of genomic imbalances according to age, immunophenotype, and oncogenetic subgroups. In particular, adult T-ALL patients demonstrated a significantly higher incidence of del(1)(p36)/RPL22, and del(13)(q14)/RB1/DLEU1, and lower incidence of del(9)(p21) and UPD(9p21)/CDKN2A/B. We determined a threshold of 15 genomic imbalances to stratify patients into high- and low-risk groups of relapse. Survival analysis also revealed the poor outcome, despite the low number of affected cases, conferred by the presence of chromothripsis (n=6, ~2%), del(16)(p13)/CREBBP (n=15, ~5%) as well as the newly identified recurrent gain at 6q27 involving MLLT4 (n=10, ~3%). Genomic complexity, del(16)(p13)/CREBBP and gain at 6q27 involving MLLT4 maintained their significance in multivariate analysis for survival outcome. Our study thus demonstrated that whole genome analysis of imbalances provides new insights to refine risk stratification in T-ALL.
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The acquisition of genetic abnormalities engendering oncogene dysregulation underpins cancer development. Certain proto-oncogenes possess several dysregulation mechanisms, yet how each mechanism impacts clinical outcome is unclear. Using T-cell acute lymphoblastic leukemia (T-ALL) as an example, we show that patients harboring 5'super-enhancer (5'SE) mutations of the TAL1 oncogene identifies a specific patient subgroup with poor prognosis irrespective of the level of oncogene dysregulation. Remarkably, the MYB dependent oncogenic 5'SE can be targeted using Mebendazole to induce MYB protein degradation and T-ALL cell death. Of note Mebendazole treatment demonstrated efficacy in vivo in T-ALL preclinical models. Our work provides proof of concept that within a specific oncogene driven cancer, the mechanism of oncogene dysregulation rather than the oncogene itself can identify clinically distinct patient subgroups and pave the way for future super-enhancer targeting therapy.
Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteína 1 de Leucemia Linfocítica Aguda de Células T/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , MebendazolRESUMO
The reintegration of excised signal joints resulting from human V(D)J recombination was described as a potent source of genomic instability in human lymphoid cancers. However, such molecular events have not been recurrently reported in clinical patient lymphoma/leukemia samples. Using a specifically designed NGS-capture pipeline, we here demonstrated the reintegration of T-cell receptor excision circles (TRECs) in 20/1533 (1.3%) patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). Remarkably, the reintegration of TREC recurrently targeted the tumor suppressor gene, ZFP36L2, in 17/20 samples. Thus, our data identified a new and hardly detectable mechanism of gene deregulation in lymphoid cancers providing new insights in human oncogenesis.
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Carcinogênese , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Instabilidade Genômica , Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Fatores de TranscriçãoRESUMO
T-cell acute lymphoblastic leukemia (T-ALL) is a group of aggressive hematological cancers with dismal outcomes that are in need of new therapeutic options. Polycomb repressor complex 2 (PRC2) loss-of-function alterations were reported in pediatric T-ALL, yet their clinical relevance and functional consequences remain elusive. Here, we extensively analyzed PRC2 alterations in a large series of 218 adult T-ALL patients. We found that PRC2 genetic lesions are frequent events in T-ALL and are not restricted to early thymic precursor ALL. PRC2 loss of function associates with activating mutations of the IL7R/JAK/STAT pathway. PRC2-altered T-ALL patients respond poorly to prednisone and have low bone marrow blast clearance and persistent minimal residual disease. Furthermore, we identified that PRC2 loss of function profoundly reshapes the genetic and epigenetic landscapes, leading to the reactivation of stem cell programs that cooperate with bromodomain and extraterminal (BET) proteins to sustain T-ALL. This study identifies BET proteins as key mediators of the PRC2 loss of function-induced remodeling. Our data have uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.
Assuntos
Regulação Leucêmica da Expressão Gênica , Mutação com Perda de Função , Complexo Repressor Polycomb 2/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Animais , Antineoplásicos Hormonais/uso terapêutico , Linhagem Celular Tumoral , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Mutação com Perda de Função/efeitos dos fármacos , Masculino , Camundongos SCID , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Prednisona/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Células Tumorais Cultivadas , Adulto JovemRESUMO
In a patient with severe microcephaly, congenital bone marrow failure, growth retardation, and renal hypoplasia, we identified a likely pathogenic variant in NUF2 that impairs the cell's ability to properly complete mitosis. Interestingly, these clinical features as well as the observed cellular alterations are highly reminiscent of what is reported in Fanconi Anaemia supporting a unifying causal role of the variant in the disease. This case provides the first evidence that a kinetochore defect, previously associated with microcephaly, can be responsible for an inherited bone marrow failure syndrome, highlighting the unique pathological link between neurogenesis and haematopoiesis.
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Anemia de Fanconi , Microcefalia , Humanos , Proteínas de Ciclo Celular , Síndrome Congênita de Insuficiência da Medula Óssea , Microcefalia/genéticaRESUMO
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that accounts for â¼20% of ALL cases. Intensive chemotherapy regimens result in cure rates >85% in children and <50% in adults, warranting a search of novel therapeutic strategies. Although immune-based therapies have tremendously improved the treatment of B-ALL and other B-cell malignancies, they are not yet available for T-ALL. We report here that humanized, non-Fcγ receptor (FcγR)-binding monoclonal antibodies (mAbs) to CD3 have antileukemic properties in xenograft (PDX) models of CD3+ T-ALL, resulting in prolonged host survival. We also report that these antibodies cooperate with chemotherapy to enhance antileukemic effects and host survival. Because these antibodies show only minor, manageable adverse effects in humans, they offer a new therapeutic option for the treatment of T-ALL. Our results also show that the antileukemic properties of anti-CD3 mAbs are largely independent of FcγR-mediated pathways in T-ALL PDXs.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Complexo CD3/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Antineoplásicos Imunológicos/imunologia , Complexo CD3/antagonistas & inibidores , Terapia Combinada , Dexametasona/administração & dosagem , Relação Dose-Resposta Imunológica , Feminino , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Organismos Livres de Patógenos Específicos , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Primary mediastinal large B-cell lymphoma (PMLBL) is a rare entity predominantly affecting adolescents and young adults. Recently, an international phase II trial in pediatric patients using dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) failed to reproduce excellent survival reported in some adult studies. The optimal therapy regimen needs to be determined in this disease. The French prospective LMB2001 trial included all patients ≤18 years with mature B-cell lymphoma treated in French centers. For patients with PMLBL, treatment included four to eight courses of Lymphomes Malins B (LMB)-based chemotherapy without radiotherapy. From 2008, rituximab was added before each chemotherapy course. From 09/2001 to 03/2012, 42 patients with PMLBL were registered. The median age was 15 years (range, 8-18). Twenty-one patients were treated with chemotherapy plus rituximab. The median follow-up was 7.1 years (interquartile range, 5.8-11.1). Five-year event-free and overall survival were 88.1% (95% confidence interval (CI): 75.0-94.8) and 95.2% (95% CI: 84.0-98.7) for the whole population. The 5-year EFS was 81.0% (95% CI: 60.0-92.3) and 95.2% (95% CI: 77.3-99.2) (hazard ratio =0.24; 95% CI: 0.03- 2.2) and 5-year overall survival was 90.5% (95% CI: 71.1-97.3) and 100% for patients treated without and with rituximab, respectively. Only one of 21 patients treated with rituximab and LMB-based chemotherapy had local early treatment failure but achieved prolonged complete remission with second-line chemotherapy and radiotherapy. Intensive LMBbased chemotherapy with rituximab achieved excellent survival in children/adolescents with PMLBL. Further international prospective studies are required to confirm these results in this population.
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Linfoma Difuso de Grandes Células B , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Ciclofosfamida , Doxorrubicina/efeitos adversos , Etoposídeo , Humanos , Linfoma Difuso de Grandes Células B/patologia , Prednisona/uso terapêutico , Estudos Prospectivos , Rituximab , Vincristina/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Hepatitis-associated aplastic anemia (AA) is a rare syndrome combining acute hepatitis of variable severity and AA. Hepatitis may be severe enough to require urgent liver transplantation (LT). Herein, we describe clinical presentation and management of a cohort of pediatric patients diagnosed with AA after undergoing LT for nonviral hepatitis. METHODS: To describe this rare clinical situation, we performed a national survey and identified nine children treated for AA following LT during the last 10 years in France. RESULTS: All patients were treated first for hepatic failure with urgent LT. AA was diagnosed with a median delay of 34 days [21-200] from the diagnosis of hepatitis. Seven children were treated with antithymocyte globulin/cyclosporine, one with CSA alone and one received bone marrow transplantation. At the last visit (median follow-up: 4 years), outcomes were excellent: all patients were alive and in hematological remission (complete remission: 7; partial remission: 2). Immunosuppressive therapy was pursued in all patients due to the liver transplant. No unusual toxicities were reported. CONCLUSION: AA after LT is considered a therapeutic challenge. Nevertheless, hematological outcome is good using a standard immunosuppressive approach.
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Anemia Aplástica , Hepatite , Terapia de Imunossupressão/efeitos adversos , Transplante de Fígado , Adolescente , Anemia Aplástica/epidemiologia , Anemia Aplástica/cirurgia , Criança , Pré-Escolar , Feminino , Seguimentos , França/epidemiologia , Hepatite/epidemiologia , Hepatite/etiologia , Hepatite/terapia , Humanos , MasculinoAssuntos
Antígenos CD19 , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Antígenos CD19/imunologia , Masculino , Feminino , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos QuiméricosAssuntos
Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Prognóstico , Adulto JovemRESUMO
In children, nasopharyngeal carcinoma (NPC) is a very rare tumor, mostly Epstein-Barr Virus related and quite always diagnosed at a locally advanced stage. With current protocols associating induction cisplatin-based chemotherapy and concomitant chemoradiotherapy, prognosis is excellent with overall survival higher than 85%. However, long-term toxicities are frequent. Improvement in radiation therapy modalities like intensity-modulated radiation therapy and new strategies with radiation dose adaptation to chemotherapy response have been introduced to reduce acute and long-term toxicities. Actually, 2 main questions remain: is it possible to pursue a therapeutic deescalation in children with low-risk NPC or very good response to induction chemotherapy in order to reduce the risk of late effects? Could an immunologic maintenance treatment improve prognosis of children with high-risk NPC? International collaborative groups and prospective trials including biological studies are necessary to answer these questions to improve childhood NPC treatment and knowledge.
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Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Criança , Humanos , Oncologia/métodos , Oncologia/tendênciasRESUMO
Nodular Lymphocyte predominant Hodgkin lymphoma (NLPHL) are rare lymphomas in pediatric patients comprising less than 10 % of all Hodgkin lymphoma (HL). They are for the most part diagnosed at stage I or II and indolent with lymphadenopathy often preceding the diagnosis by many months/years. Survival is excellent. Historically, patients were treated according to classical HL protocols. Due to high toxicity and excellent prognosis, management of NLPHL shifted to de-escalation protocol with good results. No treatment beyond surgical resection was proposed for localized unique nodal disease completely resected. The closed European protocol (EuroNet PHL LP1) evaluated the efficacy of low intensity chemotherapy protocol based on CVP courses (cyclophosphamide vinblastine prednisone) for stage IA/IIA not fully resected. Final results are not yet available. Advanced stage NLPHL are rare and there is no clinical trial and no consensus treatment in children. The SFCE lymphoma committee recently established recommendations for staging and treatment of limited and advanced NLPHL in children based on current practices and published results. The goal was to allow homogeneous practice on a national scale. If incomplete resection for patients with stage I/IIA combination of low intensity chemotherapy (CVP) and rituximab is recommended. For intermediary and advanced stage intensification with AVD (adriamycine vinblastine dacarbazine) or CHOP courses (cyclophosphamide doxorubicine vincristine prednisone) combined with rituximab are advocated. In children, there is no indication for first-line local treatment with radiotherapy.
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Doença de Hodgkin , Linfoma Folicular , Humanos , Criança , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Vimblastina/uso terapêutico , Rituximab/uso terapêutico , Prednisona/uso terapêutico , Ciclofosfamida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfócitos/patologiaRESUMO
BACKGROUND: Congenital abnormalities of the kidney and the urinary tract (CAKUT) are among the most frequent causes of antenatal consultation. In this retrospective study we evaluated the outcome of children for whom antenatal consultation was performed between 2006 and 2011 in one single pediatric nephrology center, with a particular focus on the outcome of children whose parents declined a therapeutic abortion. CASE-DIAGNOSIS/TREATMENT: Thirty-four cases of isolated CAKUT were found. Of these, 19 terminations of pregnancies (TOP) were proposed, and ten TOP were refused for these patients. Among the ten infants whose parents refused an abortion, five died in the first month of life. Their median creatinine level at 3 days of life was 56 (range 25-316) µmol/L. For the five surviving patients, the median age at the time of analysis was 29 months, at which time all had a normal serum creatinine with a variable degree of proteinuria.Oligohydramnios was found in three of the patients who died. However, two of the five surviving patients also had oligohydramnios. CONCLUSION: In ten patients for whom TOP was proposed for severe CAKUT and refused, five had normal serum creatinine at a median age of 29 months. No one predictive factor seems to have sufficient specificity to motivate a therapeutic abortion proposal, suggesting the need of long-term follow-up studies.
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Rim/anormalidades , Diagnóstico Pré-Natal , Sistema Urinário/anormalidades , Aborto Induzido , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Oligo-Hidrâmnio/etiologia , Gravidez , Estudos RetrospectivosRESUMO
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.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Antígenos CD19 , Antígenos CD28 , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Estudos Retrospectivos , Linfócitos TRESUMO
T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients.
Assuntos
Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prognóstico , Linfócitos T/patologiaRESUMO
The marketing authorization of tisagenlecleucel, a 2nd generation of CD19-directed CAR T-cells, containing the 4-1 BB co-stimulatory domain, in 2017 in USA and in 2018 in EU, has revolutionized the therapeutic strategy in advanced B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents and young adults (AYAs) with relapsed or refractory disease. This innovative treatment, based on a "living drug", has shown very impressive short-term responses. However, safety profile and complex logistics require high expertise centers and tight collaborations between addressing and treating centers. Current research is exploring the possibility to move to first line ALL with high-risk features and/or first high-risk relapse. More efficient CAR T-cells products, are still lacking to counteract the escape mechanisms already described. Moreover, to define the bridge-to-CAR time for each patient remains a challenge to obtain optimal disease burden allowing expansion and persistence of CAR T-cells. Also difficult is to identify patients who will benefit from further therapy after infusion, such as allogeneic HSCT or may be immuno-modulatory treatment. Finally, CAR T-cells directed against T-ALL are only in their beginning but require more complex engineering process to avoid T- cell immune-deficiency or fratricide.