Montes-Moreno, S. (Santiago)
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- A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma(National Academy of Sciences, 2011-07-26) Fresquet, V. (Vicente); Beltran, E. (E.); Rieger, M. (Melissa); Lossos, I.S. (Izidore S.); Martinez-Climent, J.A. (José Ángel); Montes-Moreno, S. (Santiago); Gesk, S. (Stefan); Almada, L.L. (Luciana L.); Richter, J.A. (José Ángel); Raquel; Siebert, R. (Reiner); Sagardoy, A. (Ainara); Martinez-Useros, J. (Javier); Fernandez-Zapico, M.E. (Martín E.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Piris, M.A. (Miguel A.); Sesma, I. (Izaskun)The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G(1)-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.
- Lenalidomide in combination with R-ESHAP in patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 1b study from GELTAMO group(2016) López-Guillermo, A. (Armando); González-Barca, E. (Eva); Ocio, E.M. (Enrique M.); Montes-Moreno, S. (Santiago); Martin, A. (Alejandro); Caballero, D. (Dolores); Canales-Albendea, M. A. (Miguel Ángel); Redondo, A. M. (Alba M.); Salar, A. (Antonio); Dlohuy, I. (Iván)Diffuse large B-cell lymphoma (DLBCL) patients failing rituximab-containing therapy have a poor outcome with the current salvage regimens. We conducted a phase 1b trial to determine the maximum tolerated dose (MTD) of lenalidomide in combination with R-ESHAP (rituximab, etoposide, cisplatin, cytarabine, methylprednisolone) (LR-ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were collected as a secondary objective. Subjects received 3 cycles of lenalidomide at escalating doses (5, 10 or 15 mg) given on days 1–14 of every 21-day cycle, in combination with R-ESHAP. Responding patients received BEAM (carmustine, etoposide, cytarabine, melphalan) followed by autologous stem-cell transplantation. Lenalidomide 10 mg/d was identified as the MTD because, in the 15 mg cohort, one patient experienced dose-limiting toxicity (grade 3 angioedema) and two patients had mobilization failure. A total of 19 patients (3, 12 and 4 in the 5, 10 and 15 mg cohorts, respectively) were evaluable. All toxicities occurring during LR-ESHAP cycles resolved appropriately and no grade 4–5 non-haematological toxicities were observed. The complete remission and overall response rates were 47·4% and 78·9%, respectively. With a median follow-up of 24·6 (17·4–38·2) months, the 2-year progression-free survival and overall survival were 44% and 63%, respectively. In conclusion, the LR-ESHAP regimen is feasible and yields encouraging outcomes.
- A new prognostic model identifies patients aged 80 years and older with diffuse large B-cell lymphoma who may benefit from curative treatment: A multicenter, retrospective analysis by the Spanish GELTAMO group(2018) Hernández, J. A. (José A.); Salas, Q. (Queralt); Navarro, B. (Belén); González-Barca, E. (Eva); Peñarrubia, M.J. (María Jesús); Queizán, J. A. (José A.); Montes-Moreno, S. (Santiago); Viguria, M.C. (María C.); Vahi, M. (María); Martin, A. (Alejandro); Caballero, D. (Dolores); García, T. (Tomás); Cordoba, R. (Raul); Díez, R. (Rosana); Canales-Albendea, M. A. (Miguel Ángel); González-López, T. J. (Tomás J.); Rodriguez, M. (Maria); de la Cruz, F. (Fatima); Díez-Baeza, E. (Eva); Monzón, E. (Encarna); Sancho, J. M. (Juan Manuel); Moraleda, J. M. (José M.); Pardal, E. (Emilia)The means of optimally managing very elderly patients with diffuse large B-cell lymphoma (DLBCL) has not been established. We retrospectively analyzed 252 patients aged 80-100 years, diagnosed with DLBCL or grade 3B follicular lymphoma, treated in 19 hospitals from the GELTAMO group. Primary objective was to analyze the influence of the type of treatment and comorbidity scales on progression-free survival (PFS) and overall survival (OS). One hundred sixty-three patients (63%) were treated with chemotherapy that included anthracyclines and/or rituximab, whereas 15% received no chemotherapeutic treatment. With a median follow-up of 44 months, median PFS and OS were 9.5 and 12.5 months, respectively. In an analysis restricted to the 205 patients treated with any kind of chemotherapy, comorbidity scales did not influence the choice of treatment type significantly. Independent factors associated with better PFS and OS were: age < 86 years, cumulative illness rating scale (CIRS) score < 6, intermediate risk (1-2) R-IPI, and treatment with R-CHOP at full or reduced doses. We developed a prognostic model based on the multivariate analysis of the 108 patients treated with R-CHOP-like: median OS was 45 vs. 12 months (P = .001), respectively, for patients with 0-1 vs. 2-3 risk factors (age > 85 years, R-IPI 3-5 or CIRS > 5). In conclusion, treatment with R-CHOP-like is associated with good survival in a significant proportion of patients. We have developed a simple prognostic model that may aid the selection patients who could benefit from a curative treatment, although it needs to be validated in larger series.
- Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group(2018) Gayoso, J. (Jorge); López-Guillermo, A. (Armando); Castro, N. (Nerea); Suárez-Lledó, M. (María); Briones, J. (Javier); Bello, J. I. (José I.); Rodríguez, M.J. (María José); López, A. (Andrés); Ramirez, M.J. (María Javier); Rifon, J. J. (Jose J.); Montes-Moreno, S. (Santiago); López-Jiménez, J. (Javier); Martin, A. (Alejandro); Caballero, D. (Dolores); Colorado, M. (Mercedes); Valcarcel, D. (David); Palomera, L. (Luis); Terol, M.J. (María José); Canales-Albendea, M. A. (Miguel Ángel); Sanchez, A. (Andrés); del Campo, R. (Raquel); Redondo, A. M. (Alba M.); Jarque, I. (Isidro); Arranz, R. (Reyes); González-Rodriguez, A.P. (Ana Pilar)We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28–71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9–72) and 14 (4–53) days to achieve neutrophil and platelet counts of >0.5 × 109/l and >20 × 109/l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40–77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12–0.56]) and OS (RR, 0.40 [95% CI 0.17–0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.