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Research in to the basic, epidemiological, preventive, clinical and translational aspects of leukemia and other hematologic malignancies

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Recent publications

Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstöcker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D

Cytopenia levels for aiding establishment of the diagnosis of myelodysplastic syndromes.

Blood 17 Aug 2016, . Epub 17 Aug 2016More information
Sorigue M, Ribera JM, Motlló C, Sancho JM

New drugs for follicular lymphoma.

Leuk. Res. 10 Aug 2016, 49 38-46. Epub 10 Aug 2016
Despite the improvement in prognosis since the advent of rituximab, follicular lymphoma is still incurable and remains the cause of death of most afflicted patients. With the expanding knowledge of the pathogenesis of B-cell malignancies, in the last few years a plethora of new therapies acting through a variety of mechanisms have shown promising results. This review attempts to analyze the evidence available on these new drugs, which include new monoclonal antibodies and immunoconjugates, the anti-angiogenic and immunomodulatory agent lenalidomide, the proteasome inhibitor bortezomib, inhibitors of B-cell receptor pathway enzymes, such as ibrutinib, idelalisib, duvelisib and entospletinib, BCL2 inhibitors and checkpoint inhibitors. We conclude that despite the high expectations around the new therapeutic options for patients with refractory disease, these new drugs have side effects that require caution with their use, particularly in light of the still short follow up and the lack of both randomized trials and data on combination regimens.
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Sorigue M, Ribera JM, Sancho JM


Ann. Oncol. 8 Aug 2016, . Epub 8 Aug 2016More information
Paiva B, Puig N, Cedena MT, de Jong BG, Ruiz Y, Rapado I, Martinez-Lopez J, Cordon L, Alignani D, Delgado JA, van Zelm MC, Van Dongen JJ, Pascual M, Aguirre X, Prosper F, Martín-Subero JI, Vidriales MB, Gutierrez NC, Hernandez MT, Oriol A, Echeveste MA, Gonzalez Y, Johnson SK, Epstein J, Barlogie B, Morgan GJ, Orfao A, Blade J, Mateos MV, Lahuerta JJ, Miguel JF

Differentiation stage of myeloma plasma cells: biological and clinical significance.

Leukemia 1 Aug 2016, . Epub 1 Aug 2016
The notion that plasma cells (PCs) are terminally-differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly-diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully-differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+), and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR:1.7;P=0.005) and overall survival (HR:2.1;P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (e.g.:PAX5), and show distinct mutation profile vs. fully-differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harboring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.Leukemia accepted article preview online, 01 August 2016. doi:10.1038/leu.2016.211.
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Palomo L, Garcia O, Arnan M, Xicoy B, Fuster F, Cabezón M, Coll R, Ademà V, Grau J, Jiménez MJ, Pomares H, Marcé S, Mallo M, Millá F, Alonso E, Sureda A, Gallardo D, Feliu E, Ribera JM, Solé F, Zamora L

Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features.

Oncotarget 29 Jul 2016, . Epub 29 Jul 2016
Clonal cytogenetic abnormalities are found in 20-30% of patients with chronic myelomonocytic leukemia (CMML), while gene mutations are present in >90% of cases. Patients with low risk cytogenetic features account for 80% of CMML cases and often fall into the low risk categories of CMML prognostic scoring systems, but the outcome differs considerably among them. We performed targeted deep sequencing of 83 myeloid-related genes in 56 CMML patients with low risk cytogenetic features or uninformative conventional cytogenetics (CC) at diagnosis, with the aim to identify the genetic characteristics of patients with a more aggressive disease. Targeted sequencing was also performed in a subset of these patients at time of acute myeloid leukemia (AML) transformation. Overall, 98% of patients harbored at least one mutation. Mutations in cell signaling genes were acquired at time of AML progression. Mutations in ASXL1, EZH2 and NRAS correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS). Patients with SRSF2 mutations associated with poorer OS, while absence of TET2 mutations (TET2wt) was predictive of shorter PFS. A decrease in OS and PFS was observed as the number of adverse risk gene mutations (ASXL1, EZH2, NRAS and SRSF2) increased. On multivariate analyses, CMML-specific scoring system (CPSS) and presence of adverse risk gene mutations remained significant for OS, while CPSS and TET2wt were predictive of PFS. These results confirm that mutation analysis can add prognostic value to patients with CMML and low risk cytogenetic features or uninformative CC.
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