Acute lymphoblastic leukemia (ALL)

  • Ribera Group_04_2018
ICO - German Trias i Pujol

Josep Carreras Leukaemia Research Institute
Edifici IMPPC
Can Ruti Campus
Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona, Spain

 

Directions

Summary

Our research is focused on Acute lymphoblastic Leukemia (ALL) disease, including B-cell precursor and T-precursor ALL. We want to resolve questions that require a full range of research from from basic to clinical. We aim to provide the physician with new tools, by using basic research data that will have an impact on healthcare, in order to improve survival rates in patients with this type of leukaemia.

Research

Acute Lymphoblastic Leukemia is still a non-curable neoplasia mainly in adult patients. The survival rates for ALL are much lower in adults than in children. The reasons for this survival difference lie largely in the higher frequency of poor prognosis subtypes of ALL in adults and a poorer tolerance of the treatment as age increases. Except for selected subgroups (i.e., Ph+ ALL), the current therapeutic protocols for ALL do not take into account the differences in the molecular background of the disease, and few new alternative therapies are only available in refractory or resistant ALL. Therefore, if we want to improve the survival of patients with ALL we first need to obtain detailed and relevant molecular information to enable doctors to accurately define the risk and decide on the treatment. Secondly, we need to have specific therapeutic alternatives available to apply to these new oncogenetic ALL subgroups.

Main Research Lines:

The current research of the group at the IJC Institute can be divided in two main areas:

1: Clinical research: Design and analysis of the results of the Spanish treatment protocols on adult ALL in the setting of the Spanish PETHEMA group (Programa Español de Tratamientos en Hematología).

2. Biologic and translational research

The ALL Group is currently evaluating the frequency and prognostic significance of new genetic markers in B- and T- lineage ALL. The results of this study, which are in line with the results found by other ALL working groups, will be applied in the new therapeutic protocols in ALL of the PETHEMA group.

In addition, we want to assess the anti-leukemic effect of the available drugs that specifically target candidate genes in an in vivo model. We also want to check if copy number alterations (CNAs) identified in other blood neoplasias such as; Acute Myeloblastic Leukaemia (AML), Non-Hodgkin Lymphoma (NHL) and Chronic Myeloid Leukaemia (CLL), or in solid cancers such as Melanoma and Breast Cancer, could also have an impact on ALL. We expect that the results obtained, will be used to re-classify ALL patients into different oncogenetic subgroups according to the predicted treatment response and the specific target therapy to be applied.

The identification of clonal heterogeneity in ALL at the time of diagnosis has introduced a high order of complexity to the disease. It is this clonal heterogeneity that is responsible for patient’s relapses, in which treatment has failed. Future projects in the group will be focused on the characterization of leukemic cells resistant to treatment using a genetic and functional approach.

Collaborations

People

Selected publications

Ribera J, Zamora L, Morgades M, Mallo M, Solanes N, Batlle M, Vives S, Granada I, Juncà J, Malinverni R, Genescà E, Guàrdia R, Mercadal S, Escoda L, Martinez-Lopez J, Tormo M, Esteve J, Pratcorona M, Martinez-Losada C, Solé F, Feliu E, Ribera JM

Copy number profiling of adult relapsed B-cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms.

Genes Chromosomes Cancer Nov 2017, 56 (11) 810-820. Epub 26 Ago 2017
The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays. A trend to acquire homozygous CDKN2A/B deletions and a significant increase in the number of copy number alterations (CNA) was observed from diagnosis to first relapse. Evolution from an ancestral clone was the main pattern of clonal evolution. Relapse samples were extremely heterogeneous regarding CNA frequencies. However, CDKN2A/B, PAX5, ETV6, ATM, IKZF1, VPREB1, and TP53 deletions and duplications of 1q, 8q, 17q, 21, X/Y PAR1, and Xp were frequently detected at relapse. Duplications of genes involved in cell proliferation, drug resistance and stem cell homeostasis regulation, as well as deletions of KDM6A and STAG2 genes emerged as specific alterations at relapse. Genomics of relapsed adult B-cell precursor ALL is highly heterogeneous, although some recurrent lesions involved in essential pathways deregulation were frequently observed. Selective and simultaneous targeting of these deregulated pathways may improve the results of current salvage therapies.
Més informació
Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia.

N. Engl. J. Med. 2 Mar 2017, 376 (9) 836-847.
Background Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects. Methods In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival. Results Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. Conclusions Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).
Més informació
Ribera J, Morgades M, Zamora L, Montesinos P, Gómez-Seguí I, Pratcorona M, Sarrà J, Guàrdia R, Nomdedeu J, Tormo M, Martínez-Lopez J, Hernández-Rivas JM, González-Campos J, Barba P, Escoda L, Genescà E, Solé F, Millá F, Feliu E, Ribera JM

Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols.

Cancer 1 Nov 2015, 121 (21) 3809-17. Epub 20 Jul 2015
Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL).
Més informació
Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Brüggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM

Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study.

Lancet Oncol. Gen 2015, 16 (1) 57-66. Epub 16 Des 2014
Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia.
Més informació
Ribera JM, Oriol A, Morgades M, Montesinos P, Sarrà J, González-Campos J, Brunet S, Tormo M, Fernández-Abellán P, Guàrdia R, Bernal MT, Esteve J, Barba P, Moreno MJ, Bermúdez A, Cladera A, Escoda L, García-Boyero R, Del Potro E, Bergua J, Amigo ML, Grande C, Rabuñal MJ, Hernández-Rivas JM, Feliu E

Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial.

J. Clin. Oncol. 20 Mai 2014, 32 (15) 1595-604. Epub 21 Abr 2014
Minimal residual disease (MRD) is an important prognostic factor in adults with acute lymphoblastic leukemia (ALL) and may be used for treatment decisions. The Programa Español de Tratamientos en Hematología (PETHEMA) ALL-AR-03 trial (Treatment of High Risk Adult Acute Lymphoblastic Leukemia [LAL-AR/2003]) assigned adolescent and adult patients (age 15 to 60 years) with high-risk ALL (HR-ALL) without the Philadelphia (Ph) chromosome to chemotherapy or to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) according to early cytologic response (day 14) and flow-MRD level after consolidation.
Més informació
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Current projects

Comparison of next generation sequencing (NGS) and high sensitivity citometry to asses minimal residual disease (MRD) in childhood and adult acute lymphoblastic leukemia

Responsable:José María Ribera
Codi:PI14/01971
Financiadors:
Data d'inici:01/01/2015
Data de finalització:31/12/2017

Identification of copy number alterations as targets for available drugs involved in T-ALL leukemogenesis and prognosis

Responsable:Eulàlia Genesca
Codi:CELGENE T-ALL
Financiadors:
Data d'inici:01/01/2014
Data de finalització:31/12/2016

Exploring Mechanisms of Resistance in Adult and Pediatric T-Acute Lymphoblastic Leukemia;(A.Bigas,IMIM)&(J.M.Ribera-E.Genescà,IJC)

Responsable:José María Ribera
Codi:GC16173697BIGA
Financiadors:
Data d'inici:01/11/2016
Data de finalització:31/10/2021

HARMONY - Healthcare Alliance for Resourceful Medicines Offensive against Neoplasms in hematology

Responsable:José María Ribera
Codi:116026 HARMONY H2020 JTI-IMI2 2015-06
Financiadors:
Data d'inici:01/01/2017
Data de finalització:31/12/2021

AMGEN Clinical Research Support

Responsable:José María Ribera
Codi:Curs AMGEN ALL
Financiadors:
Data d'inici:01/01/2018
Data de finalització:31/12/2018

Apoyo científico / Docente Solicitud de ayuda a la investigacion en leucemia aguda linfoblastica

Responsable:José María Ribera
Codi:AMG169
Financiadors:
Data d'inici:01/01/2017
Data de finalització:31/12/2018

Estudi observacional prospectiu de tractament adaptat al risc de la LMA i les SMD a Catalunya

Responsable:José María Ribera
Codi:SLT002/16/00433
Financiadors:
Data d'inici:01/04/2017
Data de finalització:31/12/2019

Previous projects

Study of the frequency and prognostic significance of Copy Number Alterations and CpG island methylation status in adult B-precursor Acute Lymphoblastic Leukemia patients enrolled in risk-adapted protocols of the Spanish PETHEMA Group

Responsable:José María Ribera
Codi:RD12/0036/0829
Financiadors:
Data d'inici:01/01/2011
Data de finalització:30/06/2014

Grup de Recerca Emergent: Grup de Recerca d'estudi de les neoplàsies hematològiques del IJC-Campus Trias i Pujol

Responsable:Francesc Solé
Codi:2014SGR225
Financiadors:
Data d'inici:01/01/2015
Data de finalització:31/12/2017