T-cell Acute Lymphoblastic leukemia (T-ALL), B-cell precursor ALL (BCP-ALL)

  • Ribera Group_04_2018
ICO - Germans 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 onthe analysis of the genomic and epigenomic landscape of adult ALL patients to find out genetic alterations predicting patientsresponse to treatment and to identify new alternative (targeted) therapies to apply to thosefor these patients. In this way, we aim to design more personalized treatments to increase the probability of survivaland cure of ALL patients.  

Research

ALL is a hematological cancer consequence of an uncontrolled proliferation of both subtypes of immature lymphocytes (B and T cell precursors), which prevent a healthy hematopoiesis capable of sustaining vital functions. While ALL is a curable disease in the pediatric population (cure rate> 90%), only half of adult patients survive the disease. Since 2012, our group analyzes biologic samples from adult ALL patients in order to deepen our knowledge about the origin, development and response to the treatment of this disease. During this time, we have found that each ALL is unique genetically, a fact that explains, in part, why not all patients respond equally to the same treatment.

Given this heterogeneous genetic landscape, it is necessary to analyze samples from a large number of patients in order to find genetic alterations with prognostic significance. To this end, our research group actively participates with the Spanish cooperative group PETHEMA (Programa Español de Tratamientos en Hematología), which is the reference cooperative group in the treatment of ALL in Spain and in several countries from South America, such as Argentina, Colombia or Paraguay. This allows us to correlate the genetic information with the clinical data of each patient and thus identify which genetic markers carry a higher risk of disease relapse.

 

The current research of the group is divided in two main areas, according to the two main subtypes distinguish in of ALL: 

 

1. B cell Precursor Acute Lymphoblastic Leukemia (BCP ALL):

Jordi Ribera (jribera@carrerasresearch.org), postdoctoral researcher.

BCP ALL is the most prevalent ALL subtype accounting for 75%-85% of ALL cases. Although it is a genetically heterogeneous disease, different cytogenetic subtypes have been identified so far and, more importantly, their prognosis has been clearly established in many clinical trials. This has allowed clinicians to stratify patients according to their genetic profile to schedule intensive or less intensive treatments, and more recently, targeted therapies and/or immunotherapy. However, not all patients within the same cytogenetic subtype show the same degree of response when receiving the same treatment, suggesting that additional genetic alterations may modulate the intrinsic prognosis of each cytogenetic subtype. In this sense, we are interested in characterizing the genetic alterations leading to treatment resistance and disease recurrence. To achieve this objective, we work at both clinical and translational level.

 

1.1  Genetic analysis for risk stratification for ongoing clinical trials of the PETHEMA Group

Previous research of our group has identified different genetic alterations in adult BCP ALL conferring a very high-risk of relapse that have been used to design the new national treatment protocol of PETHEMA for adult ALL (PETHEMA LAL19). This is allowing a more personalized treatment for each patient depending on the genetics of each ALL. For instance, Ph-negative patients with concomitant deletions of IKZF1 (Ikaros) and CDKN2A/B (Figure 1) have 90% of relapse probability and are receiving stem cell transplantation, instead of maintenance chemotherapy. The analysis of the results of LAL19 trial will be crucial to assess if these specific therapeutic interventions have improved patients’ survival and quality of life. We are currently analyzing samples from patients of this protocol to detect poor prognosis markers to be incorporated in the subsequent PETHEMA protocol. This is a continuous process of improvement performed in each protocol aiming to elaborate a confident gene alteration catalogue applicable in subsequent protocols of the group.

Figure 1. BCP ALL with concomitant IKZF1 and CDKN2A/B gene deletions.

Figure 1. BCP ALL with concomitant IKZF1 and CDKN2A/B gene deletions.

  

1.2  Genomic analysis for new biomarker discovery

In addition to give support for ALL diagnosis, we also analyze samples with “OMIC techniques”, which give us information about the whole genome of each ALL. By this, we can get additional information relevant for patients’ clinical care. For example, we have previously observed that not all patients with IKZF1 deletion show poor prognosis. By using RNAseq (Figure 2) we have identified different transcriptional programs depending on the type of IKZF1 deletion, which may behind the different patients’ response and may be molecular targets for therapeutic intervention. This has prompted us to lead a European study for the HARMONY Alliance (Project reference: ALL2) to get more insights into which is the best treatment for each patient with IKZF1 loss (personalized medicine).

Figure 2. Downregulated and upregulated genes of one subtype of IKZF1 deletions compared to patients without IKZF1 loss.

Figure 2. Downregulated and upregulated genes of one subtype of IKZF1 deletions compared to patients without IKZF1 loss.

 

2. T-cell Acute Lymphoblastic Leukemia (T-ALL):

Eulàlia Genescà (egenesca@carrerasresearch.org), senior researcher. 

T-ALL is the less common and the most complex and heterogeneous at the genetic level ALL subtype with dismal prognosis. Traditionally, the therapeutic protocols for ALL do not consider the differences in the molecular background of the two main ALL subtypes, and few new alternative therapies are only available in refractory or resistant ALL, especially in T-ALL. In such scenario, we believe that to improve the survival of patients with T-ALL we need firstly to obtain detailed and relevant molecular information 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 T-ALL subgroups. Therefore, two main lines of research are established in this area:

2.1. Improvement of stratification of adult T-ALL patients in the context of PETHEMA trials: we are using OMICs techniques (SNPa; TDS; digital karyotype) (Figure 3) to dissect the mutational landscape of T-ALL patients included in the PETHEMA treatment protocols to refine their stratification and improve their survival. The results obtained until now, are currently been applied in the ALL-2019 (NCT04179929) treatment protocol and research currently been performed in the group will be applied in future PETHEMA trials.

Figure 3. Mutational spectrum of ≥3 CK

Figure 3. Mutational spectrum of ≥3 CK

2.2 Development of new therapeutic alternatives: focused on the study of the mechanisms of relapse and the identification of the cells responsible for clonal resistance to treatment, we want to identify new ways to treat T-ALL patients to overcome resistance, which is responsible of treatment failure in 60% of T-ALL cases. In addition, we are using the genomic information obtained at time of diagnosis to explore new chemotherapeutic schedules in combination or not with new target therapies to improve treatment of these patients. For that, our lab has developed a primary co-culture system to grow leukemias in vitro and a PDX mouse model to assess these new anti-leukemic therapies in vivo (Figure 4).

Figure 4. Engraftment of a primary in the bone marrow of an immunodeficient mouse.

Figure 4. Engraftment of primary in the bone marrow of an immunodeficient mouse. 

We are convinced that the new treatments for ALL patients can only be obtained through basic research. The valuable information about the genome and epigenome extracted from patient samples will allow detecting genetic lesions involving critical pathways for proliferation of ALL cells that could be targetable with new drugs. This research is changing the treatment paradigm of ALL and will contribute significantly to improve the patients’ survival.

Collaborations

  • Instituto Universitario de Investigación en Biología Molecular y Celular del Cáncer de Salamanca (IBMCC-CSIC/USAL) 
  • 76 hospitales pertenecientes al grupo cooperativo de PETHEMA 
  • Centro del Cáncer, Hospital Clínico Universitario (CIC-USAL), Salamanca 
  • Hospital 12 de Octubre Madrid 
  • Centro de Investigación médica Aplicada (CIMA), Navarra 
  • Hospital Politécnico y Universitario La Fe. Valencia 
  • InstituteforResearch in Biomedicine (IRB), Barcelona 
  • Hospital del Mar d’InvestigacionsMèdiques, Barcelona 
  • Grupo de Matemática aplicada de la universidad de Cádiz (UCA) 

People

Selected publications

Ribera JM, García-Calduch O, Ribera J, Montesinos P, Cano-Ferri I, Martínez P, Esteve J, Esteban D, García-Fortes M, Alonso N, González-Campos J, Bermúdez A, Torrent A, Genesca E, Mercadal S, Martínez-Lopez J, Garcia-Sanz R

Ponatinib, Chemotherapy, and Transplant in Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Blood Adv 8 Jun 2022, . Epub 8 Jun 2022
Promising results have been shown combining ponatinib and chemotherapy in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The PONALFIL trial combined ponatinib (30 mg/day) with standard induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplant (alloHSCT) in newly diagnosed Ph+ALL patients aged 18-60 years. Ponatinib was only given pre-emptively after alloHSCT. Primary endpoints were hematologic and molecular response before alloHSCT and event-free survival (EFS), including molecular relapse as event. Thirty patients (median age 49 [19-59] years) entered the trial. All showed hematologic response, and alloHSCT was performed in 26 patients (20 in complete molecular response and 6 in major molecular response). Only one patient died by graft-versus-host disease and 5 patients showed molecular relapse after alloHSCT. No tyrosine kinase inhibitor (TKI) was given after HSCT in 18/26 patients. Twenty-nine patients are alive (median follow-up 2.1 years, range 0.2-4.0), with 3-year EFS and overall survival (OS) of 70% (95% CI, 51%-89%) and 96% (89%-100%). Comparison of the PONALFIL and the ALLPh08 trials (same schedule using imatinib as TKI ) by propensity score showed significant improvement in OS for patients in PONALFIL (3-year OS 96% vs. 53%, p=0.002). The most frequent grade 3-4 adverse events were hematologic (42%), infections (17%) and hepatic (22%), with only one vascular occlusive event. The combination of chemotherapy with ponatinib followed by alloHSCT is well tolerated, with encouraging EFS in adults with newly diagnosed Ph+ALL. Cross-trial comparison suggests improvement versus imatinib. (Clinicaltrials.gov NCT02776605).
Más información
Ribera JM, Morgades M, Genescà E, Chapchap EC, Montesinos P, Acuña-Cruz E, Gil C, García-Cadenas I, Barba P, González-Campos J, Queipo de Llano MP, Torrent A, Ribera J, Granada I, Bernal T, Díaz-Beyá M, Amigo ML, Coll R, Tormo M, Vall-Llovera F, Gómez-Centurión I, Sánchez-Sánchez MJ, Soria B, Cladera A, Artola MT, Garcia-Guiñon A, Giménez-Conca A, Amador ML, Martínez-Sánchez P, Algarra JL, Vidal MJ, Alonso N, Maluquer C, Llorente L, García-Boyero R, Ciudad J, Feliu E, Orfao A

Outcomes and prognostic factors of adults with refractory or relapsed T-cell acute lymphoblastic leukemia included in measurable residual disease-oriented trials.

Hematol Oncol Oct 2021, 39 (4) 529-538. Epub 18 Ago 2021
Despite high complete remission (CR) rates with frontline therapy, relapses are frequent in adults with T-cell acute lymphoblastic leukemia (T-ALL) with limited salvage options. We analyzed the outcomes and prognostic factors for CR to salvage therapy and overall survival (OS) of patients with R/R T-ALL included in two prospective measurable residual disease-oriented trials. Seventy-five patients (70 relapsed, 5 refractory) were identified. Relapses occurred in bone marrow, isolated or combined in 50 patients, and in the central nervous system (CNS; isolated or combined) in 20. Second CR was attained in 30/75 patients (40%). Treatment with FLAG-Ida and isolated CNS relapse were independently associated with a higher CR rate after first salvage therapy. The median OS was 6.2 (95% confidence interval [CI], 3.9-8.6) months, with a 4-year OS probability of 18% (95% CI, 9%-27%). No differences in survival were observed according to the treatment with hematopoietic stem cell transplantation in patients in CR after first salvage therapy. Multivariable analysis showed a ≥12-month interval between first CR and relapse, CR after first salvage therapy and isolated CNS relapse as favorable prognostic factors for OS with hazard ratios (HR) (95% CI) of 1.931 (1.109-3.362), 2.958 (1.640-5.334), and 2.976 (1.157-7.655), respectively. This study confirms the poor outcomes of adults with R/R T-ALL among whom FLAG-Ida was the best of the rescue therapies evaluated. Late relapse, CR after first rescue therapy and isolated CNS relapse showed prognostic impact on survival. More effective rescue therapies are needed in adults with R/R T-ALL.
Más información
Ribera JM, Morgades M, Montesinos P, Tormo M, Martínez-Carballeira D, González-Campos J, Gil C, Barba P, García-Boyero R, Coll R, Pedreño M, Ribera J, Mercadal S, Vives S, Novo A, Genescà E, Hernández-Rivas JM, Bergua J, Amigo ML, Vall-Llovera F, Martínez-Sánchez P, Calbacho M, García-Cadenas I, Garcia-Guiñon A, Sánchez-Sánchez MJ, Cervera M, Feliu E, Orfao A

A pediatric regimen for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: Results of the ALLRE08 PETHEMA trial.

Cancer Med Abr 2020, 9 (7) 2317-2329. Epub 5 Feb 2020
Pediatric-based or -inspired trials have improved the prognosis of adolescents and young adults (AYA) with Philadelphia chromosome-negative (Ph-neg) acute lymphoblastic leukemia (ALL).
Más información
Ribera JM, Morgades M, Ciudad J, Montesinos P, Esteve J, Genescà E, Barba P, Ribera J, García-Cadenas I, Moreno MJ, Martínez-Carballeira D, Torrent A, Martínez-Sánchez P, Monsalvo S, Gil C, Tormo M, Artola MT, Cervera M, González-Campos J, Rodríguez C, Bermúdez A, Novo A, Soria B, Coll R, Amigo ML, López-Martínez A, Fernández-Martín R, Serrano J, Mercadal S, Cladera A, Giménez-Conca A, Peñarrubia MJ, Abella E, Vall-Llovera F, Hernández-Rivas JM, Garcia-Guiñon A, Bergua JM, de Rueda B, Sánchez-Sánchez MJ, Serrano A, Calbacho M, Alonso N, Méndez-Sánchez JÁ, García-Boyero R, Olivares M, Barrena S, Zamora L, Granada I, Lhermitte L, Feliu E, Orfao A

Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome-negative adult lymphoblastic leukemia.

Blood 8 Abr 2021, 137 (14) 1879-1894.
The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph- adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph- adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance. This trial was registered at www.clinicaltrials.gov as # NCT01540812.
Más información
Genescà E, Morgades M, Montesinos P, Barba P, Gil C, Guàrdia R, Moreno MJ, Martínez-Carballeira D, García-Cadenas I, Vives S, Ribera J, González-Campos J, González-Gil C, Zamora L, Ramírez JL, Díaz-Beya M, Mercadal S, Artola MT, Cladera A, Tormo M, Bermúdez A, Vall-Llovera F, Martínez P, Amigo ML, Monsalvo S, Novo A, Cervera M, García-Guiñon A, Juncà J, Ciudad J, Orfao A, Ribera JM

Unique clinico-biological, genetic and prognostic features of adult early T cell precursor acute lymphoblastic leukemia.

Haematologica 19 Sep 2019, . Epub 19 Sep 2019Más información
Genescà E, Lazarenkov A, Morgades M, Berbis G, Ruíz-Xivillé N, Gómez-Marzo P, Ribera J, Juncà J, González-Pérez A, Mercadal S, Guardia R, Artola MT, Moreno MJ, Martínez-López J, Zamora L, Barba P, Gil C, Tormo M, Cladera A, Novo A, Pratcorona M, Nomdedeu J, González-Campos J, Almeida M, Cervera J, Montesinos P, Batlle M, Vives S, Esteve J, Feliu E, Solé F, Orfao A, Ribera JM

Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia.

J Hematol Oncol 24 Jul 2018, 11 (1) 96. Epub 24 Jul 2018
Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (≤ 0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.
Más información
Gachet S, El-Chaar T, Avran D, Genesca E, Catez F, Quentin S, Delord M, Thérizols G, Briot D, Meunier G, Hernandez L, Pla M, Smits WK, Buijs-Gladdines JG, Van Loocke W, Menschaert G, André-Schmutz I, Taghon T, Van Vlierberghe P, Meijerink JP, Baruchel A, Dombret H, Clappier E, Diaz JJ, Gazin C, de Thé H, Sigaux F, Soulier J

Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation.

Cancer Discov Dic 2018, 8 (12) 1614-1631. Epub 28 Sep 2018
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14,
Más información
Gachet S, Genescà E, Passaro D, Irigoyen M, Alcalde H, Clémenson C, Poglio S, Pflumio F, Janin A, Lasgi C, Dodier S, Soyer M, Duménil G, Ghysdael J

Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemia.

Leukemia Dic 2013, 27 (12) 2289-300. Epub 21 May 2013
Despite their initial efficient response to induction chemotherapy, relapse remains frequent in patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive malignancy of immature T-cell progenitors. We previously reported sustained calcineurin (Cn) activation in human lymphoid malignancies, and showed that Cn inhibitors have antileukemic effects in mouse models of T-ALL. It was unclear, however, from these studies whether these effects resulted from Cn inhibition in leukemic cells themselves or were an indirect consequence of impaired Cn function in the supportive tumor microenvironment. We thus generated a Notch (intracellular Notch 1, ICN1)-induced T-ALL mouse model, in which conditional Cn genetic deletion is restricted to leukemic cells. Ex vivo, Cn deletion altered the adhesive interactions between leukemic cells and their supportive stroma, leukemic cell survival, proliferation, migration and clonogenic potential. In vivo, Cn activation was found to be critical for leukemia initiating/propagating cell activity as demonstrated by the failure of Cn-deficient leukemic cells to transplant the disease to syngeneic recipient mice. Importantly, combination of vincristine treatment with Cre-mediated Cn ablation cooperated to induce long-term remission of ICN1-induced T-ALL. These findings indicate that Cn is a promising target in T-ALL relapse prevention, and call for clinical trials incorporating Cn inhibitors during consolidation therapy.
Más información
Ribera J, Granada I, Morgades M, González T, Ciudad J, Such E, Calasanz MJ, Mercadal S, Coll R, González-Campos J, Tormo M, García-Cadenas I, Gil C, Cervera M, Barba P, Costa D, Ayala R, Bermúdez A, Orfao A, Ribera JM

Prognostic heterogeneity of adult B-cell precursor acute lymphoblastic leukaemia patients with t(1;19)(q23;p13)/TCF3-PBX1 treated with measurable residual disease-oriented protocols.

Br J Haematol Feb 2022, 196 (3) 670-675. Epub 21 Sep 2021
The prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBX1 showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation).
Más información
Ribera J, Zamora L, Morgades M, Vives S, Granada I, Montesinos P, Gómez-Seguí I, Mercadal S, Guàrdia R, Nomdedeu J, Pratcorona M, Tormo M, Martínez-Lopez J, Hernández-Rivas JM, Ciudad J, Orfao A, González-Campos J, Barba P, Escoda L, Esteve J, Genescà E, Solé F, Feliu E, Ribera JM

Molecular profiling refines minimal residual disease-based prognostic assessment in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia.

Genes Chromosomes Cancer Nov 2019, 58 (11) 815-819. Epub 7 Ago 2019
Minimal residual disease (MRD) assessment is an essential tool in contemporary acute lymphoblastic leukemia (ALL) protocols, being used for therapeutic decisions such as hematopoietic stem cell transplantation in high-risk patients. However, a significant proportion of adult ALL patients with negative MRD still relapse suggesting that other factors (ie, molecular alterations) must be considered in order to identify those patients with high risk of disease progression. We have identified partial IKZF1 gene deletions and CDKN2A/B deletions as markers of disease recurrence and poor survival in a series of uniformly treated adolescent and adult Philadelphia chromosome-negative B-cell progenitor ALL patients treated according to the Programa Español de Tratamientos en Hematología protocols. Importantly, CDKN2A/B deletions showed independent significance of MRD at the end of induction, which points out the need for treatment intensification in these patients despite being MRD-negative after induction therapy.
Más información
Ribera J, Granada I, Morgades M, Vives S, Genescà E, González C, Nomdedeu J, Escoda L, Montesinos P, Mercadal S, Coll R, González-Campos J, Abella E, Barba P, Bermúdez A, Gil C, Tormo M, Pedreño M, Martínez-Carballeira D, Hernández-Rivas JM, Orfao A, Martínez-López J, Esteve J, Bravo P, Garcia-Guiñon A, Debén G, Moraleda JM, Queizán JA, Ortín X, Moreno MJ, Feliu E, Solé F, Ribera JM

The poor prognosis of low hypodiploidy in adults with B-cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients.

Br. J. Haematol. 27 Mar 2019, . Epub 27 Mar 2019
The prognostic significance of low-hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)-oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5-year cumulative incidence of relapse (CIR) of low-hypodiploid B-cell precursor (BCP)-ALL was significantly higher than that of high-hypodiploids (52% vs. 12%, P = 0.013). Low-hypodiploid BCP-ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5-year CIR (17% vs. 66%, P = 0.090) than low-hypodiploids aged >35 years. Older adults and elderly low-hypodiploid BCP-ALL patients show dismal prognosis although achieving an end-induction good MRD response.
Más información
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.
Más información
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).
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Current projects

Identificación de factores genéticos y no genéticos para predecir recaidas y definir nuevas terapias en la leucemia linfoblástica aguda de células T del adulto (LLA-T)

Responsable:Eulàlia Genesca
Código:PI22/01880
Financiadores:
Fecha de inicio:01/01/2023
Fecha de finalización:01/01/2025

Development of innovative therapy strategies to overcome therapy resistance in the primary therapy of adult T-cell acute lymphatic leukemia (T-ALL).

Responsable:Eulàlia Genesca
Financiadores:
Fecha de inicio:01/01/2023
Fecha de finalización:02/01/2025

Genomic and phenotypic profiling of responsive and resistant patients to salvage induction chemotherapy or immunotherapy treated within the Pethema LAL19 trial for adult Ph-negative acute lymphoblastic leukemia.

Responsable:Jordi Ribera
Financiadores:
Fecha de inicio:01/01/2022
Fecha de finalización:01/01/2024

Use of Next Generation Sequencing (NGS) as a unique genomic technique to use to improve diagnosis, prognosis and treatment of T-cell Acute Lymphoblastic Leukemia patients.

Responsable:Eulàlia Genesca
Financiadores:
Fecha de inicio:01/01/2020
Fecha de finalización:01/01/2023

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
Código:GC16173697BIGA
Financiadores:
Fecha de inicio:01/11/2016
Fecha de finalización:31/10/2022

Previous 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
Código:PI14/01971
Financiadores:
Fecha de inicio:01/01/2015
Fecha de finalización:31/12/2017

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
Código:RD12/0036/0829
Financiadores:
Fecha de inicio:01/01/2011
Fecha de finalización:30/06/2014