Revistas
Autores:
Stoelzel, F. (Autor de correspondencia); Fordham, S. E.; Nandana, D.; et al.
Revista:
JCI INSIGHT
ISSN:
2379-3708
Año:
2023
Vol.:
8
N°:
2
Págs.:
e150368
Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5 '-azacitidine (5 '-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5 '-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5 '-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.
Revista:
ENFERMEDADES INFECCIOSAS Y MICROBIOLOGÍA CLÍNICA
ISSN:
2529-993X
Año:
2023
Vol.:
41
N°:
7
Págs.:
438 - 440
Revista:
BLOOD ADVANCES
ISSN:
2473-9529
Año:
2023
Vol.:
7
N°:
1
Págs.:
167 - 173
Clonal evolution in acute myeloid leukemia (AML) originates long before diagnosis and is a dynamic process that may affect survival. However, it remains uninvestigated during routine diagnostic workups. We hypothesized that the mutational status of bone marrow dysplastic cells and leukemic blasts, analyzed at the onset of AML using integrated multidimensional flow cytometry (MFC) immunophenotyping and fluorescence-activated cell sorting (FACS) with next-generation sequencing (NGS), could reconstruct leukemogenesis. Dysplastic cells were detected by MFC in 285 of 348 (82%) newly diagnosed patients with AML. Presence of dysplasia according to MFC and World Health Organization criteria had no prognostic value in older adults. NGS of dysplastic cells and blasts isolated at diagnosis identified 3 evolutionary patterns: stable (n= 12 of 21), branching (n= 4 of 21), and clonal evolution (n= 5 of 21). In patients achieving complete response (CR), integrated MFC and FACS with NGS showed persistent measurable residual disease (MRD) in phenotypically normal cell types, as well as the acquisition of genetic traits associated with treatment resistance. Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation, and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in 80% of patients with newly diagnosed AML, using techniques other than single-cell multiomics.
Autores:
Redondo Velao, S. (Autor de correspondencia); García Cadenas, I.; Ángeles Cuesta, M.; et al.
Revista:
ACTA HAEMATOLOGICA
ISSN:
0001-5792
Año:
2023
Vol.:
146
N°:
2
Págs.:
161 - 165
Acute diarrhea is a common and debilitating complication in recipients of an allogeneic hematopoietic stem cell transplantation (HCT). In this prospective, observational, and multi-center study we examined all episodes occurring in the first 6 months of 142 consecutive adult patients who underwent a reduced-intensity conditioning (RIC) HCT in 10 Spanish tertiary University Hospitals. Fifty-four patients (38%) developed a total of 75 acute diarrhea episodes. The median time from HCT to the first episode was 38 days (4-157). The main cause of enterocolitis was lower GI-aGVHD (38%), followed by infections (21%) and drug-related toxicity (8%). Causative infectious causes were identified in only 16/75 episodes (21%). C. difficile-related infection (CDI) was the most common infectious agent with an incidence and recurrence of 13% and 2%, respectively. With a median follow-up for survivors of 32 months, the NRM and the overall survival (OS) at 1 year, were 20% (95% C.I.: 14-28%) and 69% (95% C.I.: 61-77%), respectively. Development of enterocolitis was not associated with higher NRM (p = 0.37) or worse OS (p = 0.9). This real-life study confirms that the diagnosis and management of acute diarrhea in the early stages after HCT is challenging. Nosocomial infections, seem to be relatively uncommon, probably due to more rational use of antibiotics.
Revista:
FRONTIERS IN IMMUNOLOGY
ISSN:
1664-3224
Año:
2023
Vol.:
14
Págs.:
1270843
Despite the potential of CAR-T therapies for hematological malignancies, their efficacy in patients with relapse and refractory Acute Myeloid Leukemia has been limited. The aim of our study has been to develop and manufacture a CAR-T cell product that addresses some of the current limitations. We initially compared the phenotype of T cells from AML patients and healthy young and elderly controls. This analysis showed that T cells from AML patients displayed a predominantly effector phenotype, with increased expression of activation (CD69 and HLA-DR) and exhaustion markers (PD1 and LAG3), in contrast to the enriched memory phenotype observed in healthy donors. This differentiated and more exhausted phenotype was also observed, and corroborated by transcriptomic analyses, in CAR-T cells from AML patients engineered with an optimized CAR construct targeting CD33, resulting in a decreased in vivo antitumoral efficacy evaluated in xenograft AML models. To overcome some of these limitations we have combined CRISPR-based genome editing technologies with virus-free gene-transfer strategies using Sleeping Beauty transposons, to generate CAR-T cells depleted of HLA-I and TCR complexes (HLA-IKO/TCRKO CAR-T cells) for allogeneic approaches. Our optimized protocol allows one-step generation of edited CAR-T cells that show a similar phenotypic profile to non-edited CAR-T cells, with equivalent in vitro and in vivo antitumoral efficacy. Moreover, genomic analysis of edited CAR-T cells revealed a safe integration profile of the vector, with no preferences for specific genomic regions, with highly specific editing of the HLA-I and TCR, without significant off-target sites. Finally, the production of edited CAR-T cells at a larger scale allowed the generation and selection of enough HLA-IKO/TCRKO CAR-T cells that would be compatible with clinical applications. In summary, our results demonstrate that CAR-T cells from AML patients, although functional, present phenotypic and functional features that could compromise their antitumoral efficacy, compared to CAR-T cells from healthy donors. The combination of CRISPR technologies with transposon-based delivery strategies allows the generation of HLA-IKO/TCRKO CAR-T cells, compatible with allogeneic approaches, that would represent a promising option for AML treatment.
Revista:
BRITISH JOURNAL OF HAEMATOLOGY
ISSN:
0007-1048
Año:
2023
Vol.:
201
N°:
6
Págs.:
1239 - 1244
Revista:
FRONTIERS IN IMMUNOLOGY
ISSN:
1664-3224
Año:
2022
Vol.:
13
Págs.:
977358
Artificial intelligence (AI) can unveil novel personalized treatments based on drug screening and whole-exome sequencing experiments (WES). However, the concept of "black box" in AI limits the potential of this approach to be translated into the clinical practice. In contrast, explainable AI (XAI) focuses on making AI results understandable to humans. Here, we present a novel XAI method -called multi-dimensional module optimization (MOM)- that associates drug screening with genetic events, while guaranteeing that predictions are interpretable and robust. We applied MOM to an acute myeloid leukemia (AML) cohort of 319 ex-vivo tumor samples with 122 screened drugs and WES. MOM returned a therapeutic strategy based on the FLT3, CBF beta-MYH11, and NRAS status, which predicted AML patient response to Quizartinib, Trametinib, Selumetinib, and Crizotinib. We successfully validated the results in three different large-scale screening experiments. We believe that XAI will help healthcare providers and drug regulators better understand AI medical decisions.
Autores:
Valle-Arroyo, J.; Páez-Vega, A.; Fernández-Moreno, R.; et al.
Revista:
TRANSPLANTATION AND CELLULAR THERAPY
ISSN:
2666-6375
Año:
2022
Vol.:
28
N°:
10
Págs.:
703.e1 - 703.e8
Cytomegalovirus (CMV) reactivation is an important cause of complications after hematopoietic stem cell transplantation (HSCT). Discrepancies between serologic and cellular CMV-specific immune response have been reported. This study evaluated the impact of lack of CMV-specific CD8+ T cell response in seropositive donors (ie, discordant donors) on the reconstitution of CMV-specific cell-mediated immunity (CMI) after related HSCT in seropositive recipients. CMV-CMI was assessed in donors and recipients using the QuantiFERON-CMV assay (QF). CMV-CMI was prospectively assessed for 1 year in 81 CMV-seropositive HSCT recipients with a haploidentical or matched related donor. A Cox proportional hazard regression analysis was performed. Of the 67 CMV-seropositive donors, 54 (80.6%) were D+QFpos. The remaining 13 CMV-seropositive donors (19.4%) had a QFneg result and thus were classified as discordant donors (D+QFneg). We found that patients with D+QFneg had a significantly higher risk of impaired CMV-CMI reconstitution compared with patients with D+QFpos (log-rank test, P = .001) or D- donors (log-rank test, P = .023). In addition, the D+QFneg group had a higher incidence of single-episode reactivation compared with D+QFpos or D- donors (69.2% versus 44.4% and 28.6%, respectively) but a lower incidence of CMV recurrence compared with the D- group (7.7% versus 57.1%; P = .003). After adjusting for other relevant variables, immune discordance in donors was independently associated with impaired CMV-CMI reconstitution compared with D+QFpos donors (adjusted hazard ratio [HR], 0.18; 95% confidence interval [CI], .06 to .52; P = .001) and D- donors (adjusted HR, .17; 95% CI, .05 to .59; P = .005). Discordant donors were associated with undetectable CMV-CMI during the 12-month follow-up period using the QF assay. The inability of these patients to become QFpos persisted even after CMV reactivation. This might be related to the low frequency of CMV recurrence in this group. CMV-CMI assessment, in conjunction with CMV serostatus, can be of utility to better classify stem cell donors as well as the risk of impaired CMV-CMI reconstitution after HSCT.
Revista:
FRONTIERS IN ONCOLOGY
ISSN:
2234-943X
Año:
2022
Vol.:
12
Págs.:
1054458
Acute myeloid leukemia (AML) in the elderly remains a clinical challenge, with a five-year overall survival rate below 10%. The current ELN 2017 genetic risk classification considers cytogenetic and mutational characteristics to stratify fit AML patients into different prognostic groups. However, this classification is not validated for elderly patients treated with a non-intensive approach, and its performance may be suboptimal in this context. Indeed, the transcriptomic landscape of AML in the elderly has been less explored and it might help stratify this group of patients. In the current study, we analyzed the transcriptome of 224 AML patients > 65 years-old at diagnosis treated in the Spanish PETHEMA-FLUGAZA clinical trial in order to identify new prognostic biomarkers in this population. We identified a specific transcriptomic signature for high-risk patients with mutated TP53 or complex karyotype, revealing that low expression of B7H3 gene with high expression of BANP gene identifies a subset of high-risk AML patients surviving more than 12 months. This result was further validated in the BEAT AML cohort. This unique signature highlights the potential of transcriptomics to identify prognostic biomarkers in in elderly AML.
Revista:
BLOOD ADVANCES
ISSN:
2473-9529
Año:
2021
Vol.:
5
N°:
3
Págs.:
760 - 770
The value of measurable residual disease (MRD) in elderly patients with acute myeloid leukemia (AML) is inconsistent between those treated with intensive vs hypomethylating drugs, and unknown after semi-intensive therapy. We investigated the role of MRD in refining complete remission (CR) and treatment duration in the phase 3 FLUGAZA clinical trial, which randomized 283 elderly AML patients to induction and consolidation with fludarabine plus cytarabine (FLUGA) vs 5-azacitidine. After consolidation, patients continued treatment if MRD was ¿0.01% or stopped if MRD was <0.01%, as assessed by multidimensional flow cytometry (MFC). On multivariate analysis including genetic risk and treatment arm, MRD status in patients achieving CR (N = 72) was the only independent prognostic factor for relapse-free survival (RFS) (HR, 3.45;P= .002). Achieving undetectable MRD significantly improved RFS of patients with adverse genetics (HR, 0.32;P= .013). Longer overall survival was observed in patients with undetectable MRD after induction though not after consolidation. Although leukemic cells from most patients displayed phenotypic aberrancies vs their normal counterpart (N = 259 of 265), CD34 progenitors from cases with undetectable MRD by MFC carried extensive genetic abnormalities identified by whole-exome sequencing. Interestingly, the number of genetic alterations significantly increased from diagnosis to MRD stages in patients treated with FLUGA vs 5-azacitidine (2.2-fold vs 1.1-fold;P
Revista:
HAEMATOLOGICA
ISSN:
0390-6078
Año:
2018
Vol.:
103
N°:
7
Págs.:
E318 - E321
Revista:
DRUGS OF TODAY
ISSN:
1699-3993
Año:
2016
Vol.:
52
N°:
12
Págs.:
643-651
The CD20 marker continues to be exploited as a therapeutic target for non-Hodgkin¿s lymphoma. Obinutuzumab is part of a new generation of anti-CD20 monoclonal antibodies, which are synthesized using molecular engineering technology, resulting in novel target epitopes and unprecedented optimization of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Rituximab is the current gold standard for anti-CD20 therapy, yet despite outstanding results published over the past decade, many patients continue to relapse after anti-CD20 regimens. Obinutuzumab is slowly positioning itself in the treatment of CD20+ B-cell neoplasms. On the basis of favorable results from the phase III GADOLIN trial, obinutuzumab was recently approved by the U.S. Food and Drug Administration in combination with bendamustine followed by obinutuzumab maintenance, for the treatment of follicular lymphoma (FL) patients who relapsed or are refractory to a rituximab-containing regimen. Additional phase III trials are underway to test obinutuzumab as a first-line anti-CD20 agent in FL with good preliminary results (GALLIUM trial); thus, it is likely that obinutuzumab will soon achieve a first-line indication. It is plausible that obinutuzumab will replace rituximab as the gold standard for chemoimmunotherapy in FL, although some safety concerns still need to be resolved. This review will address the preclinical pharmacology and the main aspects of the clinical development of obinu
Nacionales y Regionales
Título:
Ensayo Clínico de fase I/II para el tratamiento de la enfermedad del injerto contra el huésped con una nueva generación de células estromales mesenquimales que expresan ectópicamente CXCR4 e IL10
Código de expediente:
ICI22/00067
Investigador principal:
Felipe Luis Prósper Cardoso
Financiador:
INSTITUTO DE SALUD CARLOS III
Convocatoria:
2022 AES Investigación Clínica Independiente
Fecha de inicio:
01/01/2023
Fecha fin:
31/12/2026
Importe concedido:
1.207.250,00€
Otros fondos:
-
Título:
Mecanismos y eficacia de terapias combinadas basadas en la activación funcional de PP2A en leucemia mieloide aguda. Papel de las subunidades reguladoras PP2A como dianas terapéuticas.
Código de expediente:
PI20/01558
Financiador:
INSTITUTO DE SALUD CARLOS III
Convocatoria:
2020 AES Proyectos de investigación
Fecha de inicio:
01/01/2021
Fecha fin:
31/12/2024
Importe concedido:
268.620,00€
Otros fondos:
Fondos FEDER