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1.
N Engl J Med ; 389(10): 899-910, 2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37314354

RESUMO

BACKGROUND: Cytidine deamination that is guided by clustered regularly interspaced short palindromic repeats (CRISPR) can mediate a highly precise conversion of one nucleotide into another - specifically, cytosine to thymine - without generating breaks in DNA. Thus, genes can be base-edited and rendered inactive without inducing translocations and other chromosomal aberrations. The use of this technique in patients with relapsed childhood T-cell leukemia is being investigated. METHODS: We used base editing to generate universal, off-the-shelf chimeric antigen receptor (CAR) T cells. Healthy volunteer donor T cells were transduced with the use of a lentivirus to express a CAR with specificity for CD7 (CAR7), a protein that is expressed in T-cell acute lymphoblastic leukemia (ALL). We then used base editing to inactivate three genes encoding CD52 and CD7 receptors and the ß chain of the αß T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease, respectively. We investigated the safety of these edited cells in three children with relapsed leukemia. RESULTS: The first patient, a 13-year-old girl who had relapsed T-cell ALL after allogeneic stem-cell transplantation, had molecular remission within 28 days after infusion of a single dose of base-edited CAR7 (BE-CAR7). She then received a reduced-intensity (nonmyeloablative) allogeneic stem-cell transplant from her original donor, with successful immunologic reconstitution and ongoing leukemic remission. BE-CAR7 cells from the same bank showed potent activity in two other patients, and although fatal fungal complications developed in one patient, the other patient underwent allogeneic stem-cell transplantation while in remission. Serious adverse events included cytokine release syndrome, multilineage cytopenia, and opportunistic infections. CONCLUSIONS: The interim results of this phase 1 study support further investigation of base-edited T cells for patients with relapsed leukemia and indicate the anticipated risks of immunotherapy-related complications. (Funded by the Medical Research Council and others; ISRCTN number, ISRCTN15323014.).


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Criança , Feminino , Humanos , Antígenos CD19 , Antígenos CD7 , Antígeno CD52 , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/genética , Recidiva , Transplante de Células-Tronco , Linfócitos T
2.
Blood ; 2024 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-38905593

RESUMO

Infant acute lymphoblastic leukemia (ALL) is an aggressive malignancy that has historically been associated with a very poor prognosis. Despite large co-operative international trials and incremental increases in intensity of therapy, there has been no significant improvement in outcome over the last 3 decades. Using representative cases, we highlight the key differences between KMT2A-rearranged and KMT2A-germline infant ALL, and how advances in molecular diagnostics are unpicking KMT2A-germline genetics and guiding treatment reduction. We focus on KM2TA-rearranged infant B-cell ALL where the last few years have seen the emergence of novel therapies which both are more effective and less toxic than conventional chemotherapy. Of these, there is promising early data on the efficacy and tolerability of the bi-specific T-cell engager monoclonal antibody, blinatumomab, as well as the use of autologous and allogeneic chimeric antigen receptor T-cell therapy. We discuss how we can improve risk stratification and incorporate these new agents to replace the most toxic elements of currently deployed intensive chemotherapy schedules with their associated unacceptable toxicity.

3.
Blood ; 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39158071

RESUMO

Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) have poor outcomes compared with newly diagnosed, treatment-naïve patients. The phase 2, open-label DELPHINUS study evaluated daratumumab (16 mg/kg intravenously) plus backbone chemotherapy in children with relapsed/refractory B-cell ALL (n=7) after ≥2 relapses and children and young adults with T-cell ALL (children, n=24; young adults, n=5) or LL (n=10) after first relapse. The primary endpoint was complete response (CR) in the B-cell ALL (end of Cycle 2) and T-cell ALL (end of Cycle 1) cohorts, after which patients could proceed off study to allogeneic hematopoietic stem cell transplant (HSCT). Seven patients with advanced B-cell ALL received daratumumab with no CRs achieved; this cohort was closed due to futility. For the childhood T-cell ALL, young adult T-cell ALL, and T-cell LL cohorts, the CR (end of Cycle 1) rates were 41.7%, 60.0%, and 30.0%, respectively; overall response rates (any time point) were 83.3% (CR+CR with incomplete count recovery [CRi]), 80.0% (CR+CRi), and 50.0% (CR+partial response); minimal residual disease-negativity (<0.01%) rates were 45.8%, 20.0%, and 50.0%; observed 24-month event-free survival rates were 36.1%, 20.0%, and 20.0%; observed 24-month overall survival rates were 41.3%, 25.0%, and 20.0%; and allogeneic HSCT rates were 75.0%, 60.0%, and 30.0%. No new safety concerns with daratumumab were observed. In conclusion, daratumumab was safely combined with backbone chemotherapy in children and young adults with T-cell ALL/LL and contributed to successful bridging to HSCT. This trial was registered at www.ClinicalTrials.gov as NCT03384654.

4.
Blood ; 143(2): 118-123, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-37647647

RESUMO

ABSTRACT: CD19-negative relapse is a leading cause of treatment failure after chimeric antigen receptor (CAR) T-cell therapy for acute lymphoblastic leukemia. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral cotransduction with vectors encoding our previously described fast-off rate CD19 CAR (AUTO1) combined with a novel CD22 CAR capable of effective signaling at low antigen density. Twelve patients with advanced B-cell acute lymphoblastic leukemia were treated (CARPALL [Immunotherapy with CD19/22 CAR Redirected T Cells for High Risk/Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia] study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Of 12 patients, 10 (83%) achieved a measurable residual disease (MRD)-negative complete remission at 2 months after infusion. Of 10 responding patients, 5 had emergence of MRD (n = 2) or relapse (n = 3) with CD19- and CD22-expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months, there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95% confidence interval [CI], 41%-91%) at 6 and 12 months. The 6- and 12-month event-free survival rates were 75% (95% CI, 41%-91%) and 60% (95% CI, 23%-84%), respectively. These data suggest dual targeting with cotransduction may prevent antigen-negative relapse after CAR T-cell therapy.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Humanos , Criança , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/genética , Recidiva , Antígenos CD19 , Linfócitos T , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico
5.
Blood ; 141(7): 743-755, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36332176

RESUMO

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.


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma não Hodgkin , Linfoma , Segunda Neoplasia Primária , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Linfoma/complicações , Linfoma não Hodgkin/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações
6.
Blood ; 139(12): 1785-1793, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-34192312

RESUMO

Comparison of treatment strategies in de novo pediatric acute lymphoblastic leukemia (ALL) requires standardized measures of efficacy. Key parameters that define disease-related events, including complete remission (CR), treatment failure (TF; not achieving CR), and relapse (loss of CR) require an updated consensus incorporating modern diagnostics. We collected the definitions of CR, TF, and relapse from recent and current pediatric clinical trials for the treatment of ALL, including the key components of response evaluation (timing, anatomic sites, detection methods, and thresholds) and found significant heterogeneity, most notably in the definition of TF. Representatives of the major international ALL clinical trial groups convened to establish consensus definitions. CR should be defined at a time point no earlier than at the end of induction and should include the reduction of blasts below a specific threshold in bone marrow and extramedullary sites, incorporating minimal residual disease (MRD) techniques for marrow evaluations. TF should be defined as failure to achieve CR by a prespecified time point in therapy. Relapse can only be defined in patients who have achieved CR and must include a specific threshold of leukemic cells in the bone marrow confirmed by MRD, the detection of central nervous system leukemia, or documentation of extramedullary disease. Definitions of TF and relapse should harmonize with eligibility criteria for clinical trials in relapsed/refractory ALL. These consensus definitions will enhance the ability to compare outcomes across pediatric ALL trials and facilitate development of future international collaborative trials.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Consenso , Humanos , Neoplasia Residual/diagnóstico , Ponte , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Indução de Remissão , Falha de Tratamento
7.
Pediatr Blood Cancer ; 70(3): e30159, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36565277

RESUMO

BACKGROUND: National advisory panels (NAPs) have been established for the care of children and young people (CYP) with cancer in the United Kingdom since 2011, with an increase in panel number in recent years. Their practice has not previously been reviewed; therefore, we sought to evaluate the role, practice and impact of six selected NAPs offering expertise in ependymoma, histiocytosis, leukaemia, neuroblastoma, renal tumours and sarcoma. PROCEDURE: This service evaluation used mixed methodology, including review of NAP documentation, semi-structured interviews with the NAP chairs and an analysis of the cases referred for discussion. RESULTS: Total 1110 referrals were analysed. Results demonstrated the significant scope and amount of work undertaken by the NAPs, largely testament to the commitment of the panel members. Specific roles fulfilled have been highlighted, and NAP recommendations have been shown to influence clinical decision-making and be implemented in the majority of cases. Despite widespread good practice, areas to address have been identified; these include clarity regarding NAP membership, consistency in recommendations, the consideration of holistic information to promote personalised management and the exploration of wider multidisciplinary team roles. CONCLUSIONS: In the context of increasing demand and the escalating number of NAPs, it is timely to consider how service improvement can be facilitated. Best practice guidelines have been formulated as a product of this study, to promote a sustainable and effective model for NAPs. Review and benchmarking national panel performance against these guidelines will drive high standards of care going forward and they should be embedded as standard practice.


Assuntos
Leucemia , Neuroblastoma , Sarcoma , Criança , Humanos , Adolescente , Reino Unido
8.
Br J Haematol ; 196(3): 753-763, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34676543

RESUMO

While next-generation sequencing technologies provide excellent strategies to screen for newly defined genetic abnormalities of prognostic or therapeutic significance in patients with B-other-acute lymphoblastic leukaemia (ALL), they are not widely available. We used a dual screening approach, incorporating fluorescence in situ hybridisation (FISH) and Multiplex Ligation-dependent Probe Amplification (MLPA), to establish the frequency and long-term outcome of a representative cohort of specific subgroups of B-other-ALL recruited to the childhood ALL trial, UKALL2003. We focussed on abnormalities of known prognostic significance, including ABL-class fusions and ERG deletions, as a surrogate marker for DUX4-rearranged ALL. ABL-class fusions accounted for ~4% of B-other-ALL and were associated with high levels of minimal residual disease (MRD; 14/23 with MRD >5%) and a high relapse rate (55·7%) following treatment without tyrosine kinase inhibitor (TKI), confirming the importance of prospective screening with a view to incorporating TKI into therapy. Patients with deletions of ERG (~10% of B-other-ALL) had a 10-year event-free-survival of 97·2%, validating previous reports of their excellent outcome. Rearrangements of ZNF384, MEF2D and NUTM1 were observed at low frequencies. Here, we estimate that approximately one third of B-other-ALL patients can be reliably classified into one of the known genetic subgroups using our dual screening method. This approach is rapid, accurate and readily incorporated into routine testing.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Hibridização in Situ Fluorescente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Gerenciamento Clínico , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Lactente , Cariotipagem , Masculino , Reação em Cadeia da Polimerase Multiplex , Proteínas de Fusão Oncogênica , Reino Unido , Adulto Jovem
9.
Br J Haematol ; 198(1): 142-150, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35348200

RESUMO

In successive UK clinical trials (UKALL 2003, UKALL 2011) for paediatric acute lymphoblastic leukaemia (ALL), polyethylene glycol-conjugated E. coli L-asparaginase (PEG-EcASNase) 1000 iu/m2 was administered intramuscularly with risk-stratified treatment. In induction, patients received two PEG-EcASNase doses, 14 days apart. Post-induction, non-high-risk patients (Regimens A, B) received 1-2 doses in delayed intensification (DI) while high-risk Regimen C patients received 6-10 PEG-EcASNase doses, including two in DI. Trial substudies monitored asparaginase (ASNase) activity, ASNase-related toxicity and ASNase-associated antibodies (total, 1112 patients). Median (interquartile range) trough plasma ASNase activity (14 ± 2 days post dose) following first and second induction doses and first DI dose was respectively 217 iu/l (144-307 iu/l), 265 iu/l (165-401 iu/l) and 292 iu/l (194-386 iu/l); 15% (138/910) samples showed subthreshold ASNase activity (<100 iu/l) at any trough time point. Older age was associated with lower (regression coefficient -9.5; p < 0.0001) and DI time point with higher ASNase activity (regression coefficient 29.9; p < 0.0001). Clinical hypersensitivity was observed in 3.8% (UKALL 2003) and 6% (UKALL 2011) of patients, and in 90% or more in Regimen C. A 7% (10/149) silent inactivation rate was observed in UKALL 2003. PEG-EcASNase schedule in UKALL paediatric trials is associated with low toxicity but wide interpatient variability. Therapeutic drug monitoring potentially permits optimisation through individualised asparaginase dosing.


Assuntos
Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anticorpos/uso terapêutico , Antineoplásicos/uso terapêutico , Asparaginase , Criança , Monitoramento de Medicamentos , Escherichia coli , Humanos , Polietilenoglicóis , Leucemia-Linfoma Linfoblástico de Células Precursoras/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
10.
Blood ; 135(17): 1438-1446, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32315382

RESUMO

Risk stratification is essential for the delivery of optimal treatment in childhood acute lymphoblastic leukemia. However, current risk stratification algorithms dichotomize variables and apply risk factors independently, which may incorrectly assume identical associations across biologically heterogeneous subsets and reduce statistical power. Accordingly, we developed and validated a prognostic index (PIUKALL) that integrates multiple risk factors and uses continuous data. We created discovery (n = 2405) and validation (n = 2313) cohorts using data from 4 recent trials (UKALL2003, COALL-03, DCOG-ALL10, and NOPHO-ALL2008). Using the discovery cohort, multivariate Cox regression modeling defined a minimal model including white cell count at diagnosis, pretreatment cytogenetics, and end-of-induction minimal residual disease. Using this model, we defined PIUKALL as a continuous variable that assigns personalized risk scores. PIUKALL correlated with risk of relapse and was validated in an independent cohort. Using PIUKALL to risk stratify patients improved the concordance index for all end points compared with traditional algorithms. We used PIUKALL to define 4 clinically relevant risk groups that had differential relapse rates at 5 years and were similar between the 2 cohorts (discovery: low, 3% [95% confidence interval (CI), 2%-4%]; standard, 8% [95% CI, 6%-10%]; intermediate, 17% [95% CI, 14%-21%]; and high, 48% [95% CI, 36%-60%; validation: low, 4% [95% CI, 3%-6%]; standard, 9% [95% CI, 6%-12%]; intermediate, 17% [95% CI, 14%-21%]; and high, 35% [95% CI, 24%-48%]). Analysis of the area under the curve confirmed the PIUKALL groups were significantly better at predicting outcome than algorithms employed in each trial. PIUKALL provides an accurate method for predicting outcome and more flexible method for defining risk groups in future studies.


Assuntos
Biomarcadores Tumorais/análise , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Seleção de Pacientes , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
11.
Genes Chromosomes Cancer ; 60(9): 604-615, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33938069

RESUMO

Low hypodiploidy (30-39 chromosomes) is one of the most prevalent genetic subtypes among adults with ALL and is associated with a very poor outcome. Low hypodiploid clones can often undergo a chromosomal doubling generating a near-triploid clone (60-78 chromosomes). When cytogenetic techniques detect a near triploid clone, a diagnostic challenge may ensue in differentiating presumed duplicated low hypodiploidy from good risk high hyperdiploid ALL (51-67 chromosomes). We used single-nucleotide polymorphism (SNP) arrays to analyze low hypodiploid/near triploid (HoTr) (n = 48) and high hyperdiploid (HeH) (n = 40) cases. In addition to standard analysis, we derived log2 ratios for entire chromosomes enabling us to analyze the cohort using machine-learning techniques. Low hypodiploid and near triploid cases clustered together and separately from high hyperdiploid samples. Using these approaches, we also identified three cases with 50-60 chromosomes, originally called as HeH, which were, in fact, HoTr and two cases incorrectly called as HoTr. TP53 mutation analysis supported the new classification of all cases tested. Next, we constructed a classification and regression tree model for predicting ploidy status with chromosomes 1, 7, and 14 being the key discriminators. The classifier correctly identified 47/50 (94%) HoTr cases. We validated the classifier using an independent cohort of 44 cases where it correctly called 7/7 (100%) low hypodiploid cases. The results of this study suggest that HoTr is more frequent among older adults with ALL than previously estimated and that SNP array analysis should accompany cytogenetics where possible. The classifier can assist where SNP array patterns are challenging to interpret.


Assuntos
Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Diploide , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Triploidia , Proteína Supressora de Tumor p53/genética
12.
Br J Haematol ; 194(3): 613-616, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34212378

RESUMO

T-ALL is rare in infancy with only 10 (1.5%) of 651 patients of that subtype in the Interfant-06 infant ALL trial. We report 3 cases of t(6;7) (TCR/MYB) infant T-cell Acute Lymphoblastic Leukaemia who appear to have a distinct clinical presentation with CNS disease and refractory disease or late relapse.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas c-myb/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Humanos , Lactente , Translocação Genética
13.
J Pediatr Hematol Oncol ; 43(3): e380-e384, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32218099

RESUMO

Although outcomes for children with B-cell non-Hodgkin lymphoma are excellent, between 20% and 40% demonstrate residual radiologic abnormalities at disease assessment during consolidation therapy, the significance of which remains uncertain. The authors report the outcomes for all children treated for B-cell non-Hodgkin lymphoma at our center over an 11-year period. Twenty-four of 64 (38%) children had residual radiologic abnormalities at disease remission assessment. Seven (29%) underwent histologic biopsies that were normal. No children with residual radiologic abnormalities experienced disease relapse or death, suggesting that imaging at this time point creates clinical uncertainty without indicating residual disease or predicting relapse.


Assuntos
Linfoma de Células B/diagnóstico por imagem , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Humanos , Lactente , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Imageamento por Ressonância Magnética , Masculino , Neoplasia Residual/diagnóstico por imagem , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/patologia , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Ultrassonografia
14.
Br J Haematol ; 191(4): 562-567, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33190256

RESUMO

Sixty years ago, there was no expectation of cure for children with acute lymphoblastic leukaemia (ALL) and treatment was essentially palliative. In the year 2020, >90% of children and >70% of young adults can expect to be cured with first-line therapy and 20-50% of relapses can be salvaged depending on age and timing of relapse. The focus of treatment is gradually shifting from intensive therapy to the use of new agents to optimise efficacy, while minimising acute and long-term toxicity. The UKALL trials have made important contributions to the refinement of treatment stratification and scheduling, which have delivered the excellent outcomes to date without new agents. This year UKALL, with other groups across Europe, will begin a new collaborative group working from a unified ALL protocol (ALLTogether) that will incorporate new agents including immune-based approaches.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Humanos , Avaliação de Resultados em Cuidados de Saúde , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Reino Unido/epidemiologia
15.
Br J Haematol ; 191(5): 844-851, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32926422

RESUMO

Patients with an ABL-class fusion have a high risk of relapse on standard chemotherapy but are sensitive to tyrosine kinase inhibitors (TKI). In UKALL2011, we screened patients with post-induction MRD ≥1% and positive patients (12%) received adjuvant TKI. As the intervention started during UKALL2011, not all eligible patients were screened prospectively. Retrospective screening of eligible patients allowed the outcome of equivalent ABL-class patients who did and did not receive a TKI in first remission to be compared. ABL-class patients who received a TKI in first remission had a reduced risk of relapse/refractory disease: 0% vs. 63% at four years (P = 0·009).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-abl/genética
16.
Br J Haematol ; 185(1): 89-92, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30637732

RESUMO

Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses.


Assuntos
Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Adulto , Idoso , Pesquisa Biomédica , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Adulto Jovem
17.
Br J Haematol ; 181(4): 515-522, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29687881

RESUMO

Outcomes for teenage and young adult (TYA) patients with acute lymphoblastic leukaemia (ALL) who relapse on contemporary risk-adapted paediatric protocols are largely unknown and there is no consensus on optimal salvage strategies. We assessed the treatment and outcome of TYA patients (aged 16-24 years) recruited to the UKALL2003 trial, who relapsed following attainment of complete morphological remission. Forty-two of 223 patients (18·8%) relapsed, the majority (n = 26, 62%) on treatment. Thirty-eight (90%) patients received salvage treatment, with 22 (58%) achieving second remission (CR2) and 21 patients receiving an allogeneic haematopoietic cell transplant (alloHSCT). Post-relapse outcomes were poor with a 5-year overall survival (OS) of 23% (95% confidence interval; 11-37%). Outcomes for patients relapsing on active treatment were inferior to those relapsing after completing treatment (5-year OS 9% vs. 52%, log-rank P = 0·001). No patient with B cell ALL relapsing on treatment was alive at the end of the study period. TYA patients with ALL who relapse on the UK paediatric protocol, UKALL2003, are largely unsalvageable with conventional approaches aimed at achieving CR2 followed by alloHSCT. Future efforts should be aimed at identifying those patients who are destined to relapse and exploring novel treatment approaches for this high-risk group and for those who do relapse.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Neoplasia Residual , Recidiva , Terapia de Salvação , Taxa de Sobrevida , Reino Unido/epidemiologia , Adulto Jovem
18.
Blood ; 127(18): 2214-8, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-26872634

RESUMO

The EBF1-PDGFRB gene fusion accounts for <1% of B-cell precursor acute lymphoblastic leukemia (ALL) cases and occurs within the Philadelphia-like ALL subtype. We report 15 EBF1-PDGFRB-positive patients from childhood ALL treatment trials (ALL 97/99, UKALL 2003, UKALL 2011) in the United Kingdom. The fusion arose from interstitial deletion of 5q33 (n = 11), balanced rearrangement (n = 2), or complex rearrangement (n = 2). There was a predominance of females (n = 11), median age of 12 years, and median white blood cell count of 48.8 × 10(9)/L. Among 12 patients who achieved complete remission on earlier trials (ALL 97/99 and UKALL 2003), 10 were positive for minimal residual disease (MRD) at the end of induction, and 7 relapsed 18 to 59 months after diagnosis. The majority (9 of 12) remained alive 6 to 9 years after diagnosis. There are reports of EBF1-PDGFRB-positive patients who are refractory to conventional chemotherapy who achieve complete response when treated with the tyrosine kinase inhibitor imatinib. These findings have prompted screening for EBF1-PDGFRB in patients entered onto the current UKALL 2011 trial for whom induction therapy failed, who did not achieve remission by day 29, or who remained MRD positive (>0.5%) at week 14. Two UKALL 2011 patients, positive for EBF1-PDGFRB, received imatinib; 1 died 6 months after a matched unrelated bone marrow transplant as a result of undefined encephalopathy, and the other remained in remission 10 months after diagnosis.


Assuntos
Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Transativadores/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Criança , Pré-Escolar , Cromossomos Humanos Par 5/genética , Terapia Combinada , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Hibridização in Situ Fluorescente , Lactente , Masculino , Neoplasia Residual , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Indução de Remissão , Deleção de Sequência , Translocação Genética , Resultado do Tratamento , Adulto Jovem
20.
Genes Chromosomes Cancer ; 56(5): 363-372, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28033648

RESUMO

Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We aimed to determine the clinical and genetic landscape of those with IGH-CRLF2 or P2RY8-CRLF2 (CRLF2-r) using multiple genomic approaches. Clinical and demographic features of CRLF2-r patients were characteristic of B-ALL. Patients with IGH-CRLF2 were older (14 y vs. 4 y, P < .001), while the incidence of CRLF2-r among Down syndrome patients was high (50/161, 31%). CRLF2-r co-occurred with primary chromosomal rearrangements but the majority (111/161, 69%) had B-other ALL. Copy number alteration (CNA) profiles were similar to B-other ALL, although CRLF2-r patients harbored higher frequencies of IKZF1 (60/138, 43% vs. 77/1351, 24%) and BTG1 deletions (20/138, 15% vs. 3/1351, 1%). There were significant differences in CNA profiles between IGH-CRLF2 and P2RY8-CRLF2 patients: IKZF1 (25/35, 71% vs. 36/108, 33%, P < .001), BTG1 (11/35, 31% vs. 10/108, 9%, P =.004), and ADD3 deletions (9/19, 47% vs. 5/38, 13%, P =.008). A novel gene fusion, USP9X-DDX3X, was discovered in 10/54 (19%) of patients. Pathway analysis of the mutational profile revealed novel involvement for focal adhesion. Although the functional relevance of many of these abnormalities are unknown, they likely activate additional pathways, which may represent novel therapeutic targets.


Assuntos
Biomarcadores Tumorais/genética , Rearranjo Gênico , Genoma Humano , Mutação/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Citocinas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Adulto Jovem
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