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Investigación de los aspectos de la ciéncia básica, epidemiologica, clínica y traslacional de la leucemia y otras enfermedades hematologicas malignas

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Motlló C, Ribera JM, Morgades M, Granada I, Montesinos P, Brunet S, Bergua J, Tormo M, García-Boyero R, Sarrà J, Del Potro E, Grande C, Barba P, Bernal T, Amigo ML, Grau J, Cervera J, Feliu E

Frequency and prognostic significance of t(v;11q23)/KMT2A rearrangements in adult patients with acute lymphoblastic leukemia treated with risk-adapted protocols.

Leuk. Lymphoma Ene 2017, 58 (1) 145-152. Epub 27 Abr 2016
The karyotype is an important predictor of outcome in acute lymphoblastic leukemia (ALL). Rearrangements of the 11q23 region involving the KMT2A gene confer an unfavorable prognosis. Forty-six adult ALL patients from the PETHEMA Group treated with risk-adapted protocols, with t(v;11q23) were selected for this study. Complete response (CR) was attained in 38 patients; 25 remained in CR after consolidation. Twelve (48%) received allogeneic hematopoietic stem cell transplantation (HSCT) and 13 delayed intensification and maintenance. The 5-year CR duration probability was 37% (95% CI, 19%-55%). A trend for a longer CR duration was observed in patients undergoing HSCT vs. those receiving chemotherapy. The 5-year overall survival (OS) probability was 20% (95% CI, 5%-35%). The OS was better, albeit not significant, in patients with a MRD level <0.1% after induction (39% [95% CI, 14%-64%] vs. 13% [95% CI, 0%-36%]). Specific treatment approaches are required to improve the outcome of patients with KMT2A-rearrangements.
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Sorigue M, Garcia O, Baptista MJ, Sancho JM, Tapia G, Mate JL, Feliu E, Navarro JT, Ribera JM

Similar prognosis of transformed and de novo diffuse large B-cell lymphomas in patients treated with immunochemotherapy.

Med Clin (Barc) 27 Dic 2016, . Epub 27 Dic 2016
The prognosis of diffuse large B-cell lymphomas (DLBCL) transformed from indolent lymphoma (TL) has been considered poorer than that of de novo DLBCL. However, it seems to have improved since the introduction of rituximab.
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Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R

Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR.

Leukemia 27 Dic 2016, . Epub 27 Dic 2016
The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 [25%]; Vd, n=113 [28%]) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 [75%]; Vd, n=291 [72%]). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.45-0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33-0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ⩾CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.Leukemia accepted article preview online, 27 December 2016. doi:10.1038/leu.2016.390.
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Raje NS, Moreau P, Terpos E, Benboubker L, Grząśko N, Holstein SA, Oriol A, Huang SY, Beksac M, Kuliczkowski K, Tai DF, Wooldridge JE, Conti I, Kaiser CJ, Nguyen TS, Cronier DM, Palumbo A

Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma.

Br. J. Haematol. 22 Dic 2016, . Epub 22 Dic 2016
In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m(2) on a 21-day cycle. No significant intergroup differences were observed among primary (median progression-free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)] = 1·13 [0·80-1·59], P = 0·480; tabalumab 300 mg vs. placebo HR [95% CI] = 1·03 [0·72-1·45], P = 0·884). The most commonly-reported treatment-emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n = 162) had significantly longer mPFS than those with high BAFF expression (n = 55), using the 75th percentile cut-off point (mPFS [95% CI] = 8·3 [7·0-9·3] months vs. 5·8 [3·7-6·6] months; HR [95% CI] = 1·59 [1·11-2·29], P = 0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.
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Jordà M, Díez-Villanueva A, Mallona I, Martín B, Lois S, Barrera V, Esteller M, Vavouri T, Peinado MA

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells.

Genome Res. 20 Dic 2016, . Epub 20 Dic 2016
Cancer cells exhibit multiple epigenetic changes with prominent local DNA hypermethylation and widespread hypomethylation affecting large chromosomal domains. Epigenome studies often disregard the study of repeat elements owing to technical complexity and their undefined role in genome regulation. We have developed NSUMA (Next-generation Sequencing of UnMethylated Alu), a cost-effective approach allowing the unambiguous interrogation of DNA methylation in more than 130,000 individual Alu elements, the most abundant retrotransposon in the human genome. DNA methylation profiles of Alu repeats have been analyzed in colon cancers and normal tissues using NSUMA and whole-genome bisulfite sequencing. Normal cells show a low proportion of unmethylated Alu (1%-4%) that may increase up to 10-fold in cancer cells. In normal cells, unmethylated Alu elements tend to locate in the vicinity of functionally rich regions and display epigenetic features consistent with a direct impact on genome regulation. In cancer cells, Alu repeats are more resistant to hypomethylation than other retroelements. Genome segmentation based on high/low rates of Alu hypomethylation allows the identification of genomic compartments with differential genetic, epigenetic, and transcriptomic features. Alu hypomethylated regions show low transcriptional activity, late DNA replication, and its extent is associated with higher chromosomal instability. Our analysis demonstrates that Alu retroelements contribute to define the epigenetic landscape of normal and cancer cells and provides a unique resource on the epigenetic dynamics of a principal, but largely unexplored, component of the primate genome.
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