11 results on '"Sonia, Gonzalez"'
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2. Belantamab Mafodotin in Combination with Vrd for the Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Patients: Results from the Phase II, Open Label, Multicenter, GEM-BELA-Vrd Trial
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Veronica Gonzalez-Calle, Paula Rodriguez Otero, Beatriz Rey-Bua, Javier De La Rubia, Felipe De Arriba, Valentin Cabañas, Esther González Garcia, Enrique M. Ocio, Cristina Encinas, Alexia Suarez Cabrera, Joan Bargay, Joaquin Martinez Lopez, Marta Sonia Gonzalez, Jose Angel Hernandez-Rivas, Laura Rosiñol, Miguel-Teodoro Hernández, Bruno Paiva, Maria Teresa Cedena Romero, Noemi Puig, Juan-José Lahuerta, Joan Bladé, Jesús San-Miguel, and Maria-Victoria Mateos
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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3. Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Post-Hoc Analysis of Sustained Undetectable Measurable Residual Disease (MRD)
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Maria-Victoria Mateos, Joaquín Martínez-López, Paula Rodríguez-Otero, Jesús San-Miguel, Veronica Gonzalez-Calle, Marta Sonia Gonzalez, Albert Oriol, Norma C. Gutierrez, Rafael Rios, Laura Rosinol Dachs, Miguel Angel Alvarez, Joan Bargay, Ana Pilar Gonzalez, Fernando Escalante, Adrian Alegre, Belén Iñigo, Javier de la Rubia, Ana Isabel Teruel, Felipe De Arriba, Luis Palomera, Miguel-Teodoro Hernández, Javier Lopez Jimenez, Marta Reinoso Segura, Aránzazu García Mateo, Enrique M. Ocio, Joan Bladé, Juan-José Lahuerta, María Teresa Cedena, Noemi Puig, and Bruno Paiva
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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4. Multiomics Profiling of Measurable Residual Disease (MRD) for Understanding the Biology of Ultra-Drug Resistance in Multiple Myeloma (MM)
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Camila Guerrero, Noemi Puig, Maria Teresa Cedena Romero, Ibai Goicoechea, Leire Burgos, Diego Alignani, Aitziber Lopez, Sarai Sarvide, María José Calasanz, Ramon Garcia-Sanz, Joaquin Martinez-Lopez, Laura Rosiñol, Esther González Garcia, Albert Oriol, Rafael Rios, Estrella Carrillo-Cruz, Marta Sonia Gonzalez Perez, Carmen Montes Gaisan, Felipe De Arriba, Jose Maria Arguiñano, Josep M Marti, Yolanda Gonzalez-Montes, Antonio Garcia-Guiñon, Juan-José Lahuerta, Joan Bladé Creixenti, Maria-Victoria Mateos, Jesús San-Miguel, and Bruno Paiva
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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5. A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable Measurable Residual Disease (MRD) in Transplant-Eligible Multiple Myeloma (MM)
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Camila Guerrero, Noemi Puig, María Teresa Cedena, Ibai Goicoechea, Cristina Pérez Ruiz, Juan José Garcés, Cirino Botta, Maria Jose Calasanz, Norma C. Gutierrez, Maria Luisa Martin-Ramos, Albert Oriol, Rafael Rios, Miguel Hernández, Rafael Martínez, Joan Bargay, Felipe De Arriba, Luis Palomera, Ana Pilar Gonzalez, Adrián Mosquera Orgueira, Marta Sonia Gonzalez, Joaquín Martínez-López, Juan Jose Lahuerta, Laura Rosinol, Joan Bladé Creixenti, Maria-Victoria Mateos, Jesus San-Miguel, and Bruno Paiva
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
INTRODUCTION: There is expectation of using biomarkers to personalize treatment in MM. Yet, a successful treatment selection cannot be confirmed before 5 or 10 years of progression-free survival (PFS). Treatment individualization based on the probability of an individual patient to achieve undetectable MRD with a singular regimen, could represent a new model towards personalized treatment with fast assessment of its success. This idea has not been investigated previously. AIM: Develop a machine learning model to predict undetectable MRD in newly-diagnosed transplant-eligible MM patients, treated with a standard of care. METHODS: This study included a total of 278 newly-diagnosed and transplant-eligible MM patients treated with proteasome inhibitors, immunomodulatory drugs and corticosteroids. The training (n=152) and internal validation cohort (n=60) consisted of 212 active MM patients enrolled in the GEM2012MENOS65 trial. The external validation cohort was defined by 66 high-risk smoldering MM patients enrolled in the GEM-CESAR trial, which treatment differed only by the substitution of bortezomib by carfilzomib during induction and consolidation. RESULTS: We started by investigating patients' MRD status after VRD induction, HDT/ASCT and VRD consolidation according to their ISS and R-ISS, LDH levels, and cytogenetic alterations. Surprisingly, neither the ISS nor the R-ISS predicted significantly different MRD outcomes. Indeed, high LDH levels and del(17p13) were the only parameters associated with lower rates of undetectable MRD. Because these two features are relatively infrequent at diagnosis, we next aimed to evaluate other disease features and develop integrative, weighted and more effective models based on machine learning algorithms. Of 37 clinical and biological parameters evaluated, 17 were associated with MRD outcomes. These were subsequently modeled using logistic regression for machine learning classification, where the sum of the weighted coefficients multiplied by its input variable, is transformed into a probability outcome that ranges from 0 to 1 using a logit sigmoid function. The most effective model resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (plasma cell [PC] clonality in bone marrow and CTCs in blood) and immune related (myeloid precursors, mature B cells, intermediate neutrophils, eosinophils, CD27 negCD38 pos T cells and CD56 brightCD27 neg NK cells) biomarkers. Of note, immune biomarkers displayed the highest coefficient weights and were determinant to predict patients' MRD status in this model. Data obtained for an individual patient can be substituted into our formula, which results in a numerical probability of achieving undetectable (>0.5) vs persistent (0.685 or Patients predicted to achieve undetectable MRD using standard and high-confidence values showed longer PFS and overall survival (OS) than those with probability of persistent MRD. In fact, patients with >0.687 probability of achieving undetectable MRD showed 86% PFS and 94% OS at five years, whereas those in whom persistent MRD was predicted ( CONCLUSION: We demonstrated that it is possible to predict patients' MRD status with significant accuracy, using an integrative, weighted model based on machine learning algorithms. Although immune biomarkers are not commonly used, the raw data from which these can be developed is generally obtained in diagnostic laboratories using flow cytometry to screen for PC clonality. Furthermore, we made the model available to facilitate its use in clinical practice at www.MRDpredictor.com. Disclosures Puig: Celgene, Janssen, Amgen, Takeda: Research Funding; Celgene: Speakers Bureau; Amgen, Celgene, Janssen, Takeda: Consultancy; Amgen, Celgene, Janssen, Takeda and The Binding Site: Honoraria. Cedena: Janssen, Celgene and Abbvie: Honoraria. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. De Arriba: Amgen: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS-Celgene: Consultancy, Honoraria, Speakers Bureau. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Lahuerta: Celgene: Other: Travel accomodations and expenses; Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Bladé Creixenti: Janssen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Mateos: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; GSK: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding.
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- 2021
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6. Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd
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Maria-Victoria Mateos, Joaquin Martinez Lopez, Paula Rodríguez-Otero, Veronica Gonzalez-Calle, Marta Sonia Gonzalez, Albert Oriol, Norma C. Gutierrez, Rafael Rios, Laura Rosinol, Miguel Angel Alvarez, Joan Bargay, Ana Pilar Gonzalez, Adrian Alegre, Fernando Escalante, Belén Iñigo, Javier de la Rubia, Ana Isabel Teruel, Felipe De Arriba, Luis Palomera, Miguel-Teodoro Hernández, Javier Lopez Jimenez, Aránzazu García Mateo, Marta Reinoso Segura, Enrique Ocio, Bruno Paiva, Noemi Puig, María Teresa Cedena, Joan Bladé, Juan Jose Lahuerta, and Jesús F. San-Miguel
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Introduction: SMM is an asymptomatic plasma cell disorder with heterogeneous clinical behavior. Both the Spanish Myeloma and ECOG Groups have demonstrated that patients (pts) at high risk of progression to active MM have prolonged time-to progression upon receiving early treatment with R-based regimens. Our next step was to perform a phase 2, single arm trial, focusing on the same population, but aiming at abrogating the risk of progression through the achievement of sustained minimal residual disease negativity (MRD-ve) at 3 and 5 years after HDT-ASCT. Patients and methods: Ninety SMM pts at high-risk of progression (>50% at 2 yrs), younger than 70 years and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo criteria) or ifonly one criterion was present, pts should have >95%of aberrant PCs within the total PCsBM compartment by immunophenotyping plus immunoparesis (Spanish criteria). Induction therapy consisted of six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m 2 twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone at dose of 40 mg weekly. Melphalan at dose of 200 mg/m 2 followed by ASCT was given as intensification therapy followed by two KRd consolidation cycles and maintenance with R at dose of 10 mg plus dexamethasone at dose of 20 mg weekly for up to 2 yrs. The primary end-point was to evaluate the MRD-ve rate by next generation flow (NGF) after ASCT and MRD-ve rate maintained at 3 and 5 years after ASCT. Results: Between June 2015 and June 2017, 90 high-risk SMM pts were recruited and 70 pts (78%) have completed the treatment protocol. The reasons for early discontinuations were: IC withdrawal (4 pts), adverse events (8 pts) or biological progression (BP), either biochemical or because of MRD conversion from negative to positive (1 pt during induction and 7 pts during maintenance). Thirty-one pts (34%) shared at least one of the biomarkers considered as myeloma defining events that currently reclassify SMM into active MM. In the intent-to-treat (ITT) pts' population, after induction, the ≥CR rate was 41% and increased to 65% after HDT-ASCT and 72% after consolidation. During maintenance therapy, 7 pts experienced biological progression (2 pts conversion from MRD-ve into +ve and 5 pts biochemical progression) and the ≥CR rate at the end of treatment was 63.3%. In the ITT population, MRD-ve rates at 10 -5 were observed in 40% of pts after induction, 63% after HDT-ASCT, 68% after consolidation and 52% after maintenance therapy. Among MRD-ve patients after maintenance therapy that had MRD assessed one year after, 67% showed sustained MRD-ve. After a median f/u of 55 months (range: 6.2-71), only three patients progressed to symptomatic disease and the three had at baseline anyone of the biomarkers defining myeloma-defining events. At 5 years, 94% of pts remain alive and progression-free and 95% of pts alive (Figure 1). Overall, twenty-six pts (29%) have experienced biological progression (19 of them were conversion of MRD-ve into +ve), 8 of them during treatment phase (1 during induction and 7 during maintenance) and 16 pts during the follow-up period. The only factors predicting biological progression was failure to achieve MRD-ve at the end of treatment and unsustained MRD-ve at 1 year after finalizing maintenance. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were reported in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three pts reported hypertension (G2 in two and G3 in one). In all but two of the pts, PBSC collection was successful with a median of 4.10 x 10 6/Kg CD34 cells collected. All pts engrafted but one patient developed late graft failure. During consolidation, 2 pts developed G3-4 neutropenia, 3 pts G3-4 infections and 1 pt skin rash. Seven pts had to discontinue maintenance therapy due to: G3-4 hematological toxicity (4 pts), SPM (2pts) and cardiac arrest (1pt). One additional patient withdrew the IC. Conclusions: These results suggest that early treatment with intention to abrogate risk of progression in transplant candidate high risk SMM patients is associated with a 94% PFS at 55 months and a sustained MRD negative rate at 1 year post treatment of 67%. Figure 1 Figure 1. Disclosures Mateos: Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Rodríguez-Otero: Celgene-BMS, Janssen, Amgen, Sanofi, GSK, Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria. Gonzalez-Calle: BMS, Janssen, Amgen: Honoraria. Oriol: Celgene: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. de la Rubia: Takeda: Consultancy; Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; GSK: Consultancy; Celgene, Takeda, Janssen, Sanofi: Honoraria; Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; Celgene: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Membership on an entity's Board of Directors or advisory committees. De Arriba: Amgen: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Ocio: MSD: Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy; Secura-Bio: Consultancy. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Puig: Celgene, Janssen, Amgen, Takeda: Research Funding; Celgene: Speakers Bureau; Amgen, Celgene, Janssen, Takeda: Consultancy; Amgen, Celgene, Janssen, Takeda and The Binding Site: Honoraria. Cedena: Janssen, Celgene and Abbvie: Honoraria. Lahuerta: Celgene: Other: Travel accomodations and expenses; Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board.
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- 2021
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7. Curativestategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd
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Maria-Victoria Mateos, Joaquin Martínez-López, Paula Rodriguez Otero, Enrique M. Ocio, Marta Sonia Gonzalez, Albert Oriol, Norma C. Gutierrez, Bruno Paiva, Rafael Rios, Laura Rosinol, Miguel Angel Alvarez, Maria Jose Calasanz, Joan Bargay, Ana Pilar Gonzalez, Adrián Alegre, Fernando Escalante, Rafael Martínez, Noemi Puig, Javier De La Rubia, Ana Isabel Teruel, María Teresa Cedena, Felipe De Arriba, Luis Palomera, Miguel T Hernández, Javier Lopez Jimenez, Jesús Martín, Esther Piensa, Aránzazu García Mateo, Veronica Gonzalez De La Calle, Joan Bladé, Juan Jose Lahuerta, and Jesus F San-Miguel
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Immunology ,Cell Biology ,Hematology ,Biochemistry ,health care economics and organizations - Abstract
Introduction:SMM is an asymptomatic and heterogeneous plasma cell disorder. The Spanish Myeloma Group demonstrated that patients at high risk of progression benefit from early treatment with Rd. In addition, our preliminary results of the curative approach (GEM-CESAR) showed encouraging results (Mateos ASH 2017). Aim: The primary end-point was to evaluate the Minimal Residual Disease negative (MRD-ve) rate by next generation flow (NGF) after induction and ASCT and the sustained MRD-ve rate at 3 and 5 yrs after ASCT as secondary end-points. Our aim was to increase the MRD -ve rate from 34% (reported in NDMM patients after VTD and ASCT) to 50%. As all patients have completed induction and ASCT, we report the results of the primary end point, efficacy and safety after induction and ASCT. Methods: In this phase II single arm trial, 90 SMM patients at high-risk of progression (>50% at 2 yrs), younger than 70 yrs and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo criteria) or ifonly one criterion was present, patients must have a proportionof aberrant PCs within the total PCsBM compartment by immunophenotypingof 95% plus immunoparesis (Spanish criteria). Asymptomatic MM patients with any of the three biomarkers recently included into the definition of active MM were allowed to be included. Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2followed by ASCT was given as intensification therapy and three months later, patients received two KRd consolidation cycles followed by maintenance with R at dose of 10 mg on days 1-21 plus dex at dose of 20 mg weekly for up to 2 yrs Results: Between June 2015 and June 2017, the 90 SMM patients at high risk of progression were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM. The primary end point of the trial was met, since 55% of the patients who completed induction and ASCT achieved MRD -ve by NGF (sensitivity 3 x 10-6). Upon analyzing the results after induction, 88 patients completed the 6 induction cycles and were evaluable for response (two patients early discontinued): the ORR was 98% including 41% of ≥CR (32% sCR and 9% CR) and 41% of VGPR rate. Two patients were mobilization failures and one patient rejected ASCT. Two additional patients experienced biological progression before ASCT and went off the study. Eighty-three patients, therefore, proceeded to HDT-ASCT and were evaluable at day +100: the ORR was 100% including ≥CR in 63% of the patients (51% sCR and 12% CR) and VGPR rate in 23%. The MRD-ve rate increased from 31% after induction to 55% with the ASCT. No differences in outcome have been observed according neither to the definition of high risk (Mayo or Spanish model) nor ultra high risk SMM. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were the most frequent non-hematological AE observed in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three patients reported hypertension (G2 in two and G3 in one). Thirteen patients required lenalidomide dose reduction whilst carfilzomib was not reduced in any patient. In four patients, dexamethasone was reduced. In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All patients engrafted. Consolidation and maintenance phases are ongoing. After a median follow-up of 17 months (5-36), 94% of patients remain alive and free of progression and 97% of them alive. Three patients experienced biological progression and discontinued the study: one of them was refractory to the rescue therapies and died and the other two are receiving rescue therapies. One additional patient died early during induction due to a massive ischemic stroke unrelated to the treatment. Conclusions: Although longer follow-up is required, this "curative strategy for high risk SMM" continues being encouraging with an acceptable toxicity profile. The study has met its primary endpoint. The depth of response improved over the treatment: 63% of patients who completed induction and ASCT achieved ≥CR with a MRD-ve rate of 55%. Disclosures Mateos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Clínica Universidad de Navarra: Employment. Ocio:AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Alegre:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Puig:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. García Mateo:Binding Site: Research Funding; Amgen: Honoraria; Celgene: Honoraria. Bladé:Janssen: Honoraria. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Novartis: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Roche: Honoraria.
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- 2018
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8. Outcomes of Cord Blood Transplantation Using Reduced Intensity Conditioning for Chronic Lymphocytic Leukemia: A Retrospective Study on Behalf of Eurocord, SFGM-TC and Cqwp-EBMT
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Jean-Henri Bourhis, Regis Peffault de la Tour, Hendrik Veelken, Eliane Gluckman, Erick Xavier, Annalisa Ruggeri, Mohamad Mohty, Nicolaus Kroeger, Anne Corby, Mauricette Michallet, Eric Deconinck, Marta Sonia Gonzalez Perez, Vanderson Rocha, Jean-Yves Cahn, Thierry de Revel, Simona Sica, Patrice Chevallier, Anna Huynh, Patrice Ceballos, Pascal Turlure, Johannes Schetelig, Stephanie Nguyen-coq, Didier Blaise, Noel Milpied, Niels Smedegaard Andersen, Irene Donnini, Christian Berthou, Jan J. Cornelissen, Natacha Maillard, and Jérôme Cornillon
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medicine.medical_specialty ,Univariate analysis ,Cyclophosphamide ,business.industry ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Chemotherapy regimen ,Fludarabine ,Surgery ,Transplantation ,Autologous stem-cell transplantation ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is performed in patients (pts) with high-risk features at diagnosis (del17p/p53 mutations) or advanced disease. Although approximately 30% of pts have matched siblings, alternative stem cell sources such as umbilical cord blood, extend the use of HSCT to pts lacking a conventional donor. However, little is known about outcomes after umbilical cord blood transplantation (UCBT) for CLL/SLL. We analyzed 68 pts (50 males) who underwent a single (n=16) or double (n=52) HLA-mismatched UCBT between 2004 and 2012 in 34 EBMT centers. Median age at UCBT was 57 years (yrs) (range, 27-68). At diagnosis, 56 pts had CLL/SLL, 8 prolymphocytic leukemia (4 B-cell and 4 T-cell) and 4 Richter transformations. Cytogenetic was available in 70% (48/68) of pts. Seventy-three percent had abnormal karyotype (36% del17p/p53, 17% del13q, 8% del11q and 12% others) and 27% normal. Median time from diagnosis to UCBT was 54 months (range, 3-358). Thirty-seven pts were in partial remission (PR) at UCBT, 23 in complete remission (CR) and 8 had refractory disease (RD). The hematopoietic stem cell comordibity index (HCT-CI) at UCBT was 0 in 60% of pts, 1-2 in 25% and 3-4 in 15%. Sixty-five percent of pts received ≥3 chemotherapy lines prior to UCBT, 28% were refractory to purine analogues and 16% underwent previous autologous stem cell transplantation (ASCT). Sixty patients received low-dose TBI (2-4 Gy) from which the Minnesota RIC regimen (TBI-Cyclophosphamide-Fludarabine: TCF) was given to 57 pts; 15 pts received ATG and GVHD prophylaxis was CsA+MMF in 61 pts. Median TNC collected was 3.7x107/Kg (1.8-7.1) for single and 5x107/Kg (2.0-9.7) for double UCBT. Units were HLA matched to the recipient at 5-6 loci in 30% of pts and at ≤4 in 70%. Median follow-up was 37 months (range, 3-98). OS and PFS at 3 yrs were, respectively, 53±7% and 45±7%. The cumulative incidences (CI) of neutrophils and platelets engraftment were 84±5% and 72±6%, respectively with a median time for engraftment of 21(range, 5-67) and 43 (range, 1-189) days, respectively. CI of acute graft-versus-host disease (aGVHD) at 100 days was 43%±6 for grade II-IV and 19±5% for grade III-IV with a median time of onset of 23 days (9-95). Three yrs CI of chronic GVHD (cGVHD) was 32±6% (12 limited and 6 extensive) with a median time of onset of 130 (range, 101-393) days. CI of relapse and NRM at 3 yrs were,16±5% and 39±6%, respectively. In a univariate analysis the use of TCF conditioning was associated with improved OS (62% vs 15%, p The use of TCF (HR: 0.34 (0.14-0.82), p=0.02), fludarabine sensitive disease at transplantation (HR: 0.41 (0.20-0.81), p=0.01) and HCT-CI ≤2 (HR: 0.38 (0.17-0.87), p=0.02) were associated with improved PFS in multivariate analysis. Acute GVHD grade III-IV was associated with lower OS (HR: 3.4 (1.6-7.4), p=0.002) and PFS (HR: 2.8 (1.4-5.8), p=0.005) in a time-dependent model. Overall, 32 patients died; 7 died of relapse and 25 of transplant related causes (10 infections, 4 post-transplant lymphoprolypherative diseases, 3 aGVHD, 3 toxicities, 1 secondary lung cancer and 4 other causes). In conclusion, RIC-UCBT appears to be a valid option for CLL/SLL patients. Strategies to optimize infection prophylaxis, use of low-dose TBI RIC conditionings and to perform the UCBT before development of fludarabine resistance may improve overall outcome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2014
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9. Clofarabine Salvage Therapy Prior To Allogeneic Hematopoietic Stem Cell Transplantation (HCT) In Patients With Relapsed Or Refractory Acute Leukemia
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Josefina Serrano, Diana Buenasmañanas, P Herrera, Mari Luz Amigo, Marisa Calabuig, Eusebio Martin, Maria-Belén Vidriales, Adolfo de la Fuente, M Santero, Silvia Negri, Jose Gonzalez-Campos, Carmen Albo, Sonia Gonzalez, Jose J. Rifon, M Cruz Viguria, V Garcia-Gutierrez, Carmen Martin, and Joaquin Sanchez-Garcia
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medicine.medical_specialty ,Acute leukemia ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Immunology ,Salvage therapy ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Fludarabine ,Surgery ,Transplantation ,Internal medicine ,medicine ,Mucositis ,Clofarabine ,business ,medicine.drug - Abstract
HCT is the only potentially curative approach that may provide long-term disease control for patients con relapsed and/or refractory acute leukemia (Re/Ref AL). However, active disease burden at HCT is associated with high relapse rates and dismal outcomes. Recently, promising results in this way have been reported using sequential treatment schedules. We performed a retrospective multicentre analysis to investigate the safety and efficacy of clofarabine (CLO) cytoreduction prior to HCT for Re/Ref AL. Spanish Agency Qualification was obtained (AAH-CLO-2013-01/EPA-OD). A total of 50 patients from 14 Spanish centres (AML 33; ALL 17) who received CLO and had an HLA-matched donor were included. Median age was 37 years (18-64); sex: 26 M, 24 F. High risk cytogenetic/molecular profile in 31.4%, Intermediate 54%, and low risk 14.6%. Patients received first-line chemotherapy (ct) regimens based on cooperative national groups (PETHEMA, CETLAM and SHOP) and 2nd lines with fludarabine-based regimens in 85%. Prior to CLO, 56.3% of patients had received 2 CT lines and 35.5% ≥ 3 lines including 6 auto-HCT and 12 allogeneic HCT. Disease status at CLO administration was primary refractoriness (29.2%) secondary refractoriness (33.3%), first relapse (10%) and ≥2nd relapse (27%). CLO was administered at 20-40 mg/m2/day for 5 consecutive days combined with ARA-C in AML cases and Citoxan-Etoposide in ALL cases. Response was assessed by IWG-2006 criteria and toxicity evaluated according to CTCAE v3. Out of 50 included patients, 16 did not underwent allogeneic HCT due to early toxic deaths (N=6) or due to lack of disease control (N=10) 1.- Response was valuable in 44 cases, achieving 11 CR and 7 PR. Effective Cytoreduction (defined as 2.- Most frequent toxicity was haematological gr.4 in 100% of cases, mucositis gr.≥ 3 in 15%, liver toxicity with bilirrubin and/or SGOT elevation gr.≥3 in 23%, infections gr.≥3 in 50% and skin toxicity gr.2 in 4% 3.- Eventually, HCT was performed in 34 patients (22 AML and 12 ALL); 19 form HLA-matched sibling donor, 7 HLA-matched unrelated donor, 4 HLA-matched umbilical cord and 4 HLA-haploidentical donor. Conditioning regimen was fludarabine-based reduced-intensity in 19 patients and myeloablative in 15 patients. Median elapsed time from CLO administration and HCT was 37 days (range: 6-105). 4.-Transplant-related mortality (TRM)at day +100 and +365 was 20.6% and 41% respectively. Acute GVHD was developed in 16 patients (grades III-IV in 6 cases) and chronic GVHD was observed in 6 patients. With a median follow-up of 14.3 months after HCT, Overall Survival was 28.5% for the global series, 39.6% for AML patients and 15% for ALL patients. Patients achieving effective cytoreduction with CLO had a significantly superior Relapse Free Survival (48% vs. 0%, P=.002). Similarly, patients receiving CLO at earlier disease status (first relapse or primary refractoriness) had a significantly better OS than those treated at more advanced disease (48% vs. 5%). Elapsed time from CLO administration and HCT shorter than 50 days was also associated to a better OS (40.2% vs. 12.2%, P =.14) ) although no statistical difference was reached. Salvage CLO-based regimens as bridge to HCT in patients with Re/Ref AL can be administered with an acceptable toxicity profile and are followed by an acceptable TRM. Achievement of effective cytoreduction and no delayed HCT procedure could identify patients with less leukemic burden capable to achieve long-lasting sustained disease control. Disclosures: No relevant conflicts of interest to declare.
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- 2013
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10. Risk Adapted-High Dose Therapies Modulate the Impact of Biological Classification in Diffuse Large B Cell Lymphoma Prognosis. Analysis of Biological Markers in Patients From Clinical Trials in Geltamo and Gotel Spanish Collaborative Groups.
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Montes-Moreno, Santiago, primary, Batlle, Ana, additional, de Villambrosia, Sonia Gonzalez, additional, Sanchez-Espiridión, Beatriz, additional, Cereceda, Laura, additional, González-Barca, Eva, additional, Noelia, Purroy, additional, Pardal, Emilia, additional, Sebastian, Elena, additional, Martin, Alejandro, additional, Grande, Carlos, additional, Mazorra, Francisco, additional, Insunza, Andrés, additional, Rueda, Antonio, additional, Llanos, Marta, additional, Codina, Jose Gomez, additional, Arroyo, Francisco Ramon Garcia, additional, Caballero, Dolores, additional, Conde, Eulogio, additional, Lopez, Andrés, additional, Provencio, Mariano, additional, and Piris, Miguel, additional
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- 2012
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11. Clofarabine in Acute Myeloid Leukemia. the Spanish Experience
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Marina Gordillo, Teresa Olave, Guillermo Deben, Juan Bergua, Jose Francisco Tomas, Angeles Fernandez, Sonia Gonzalez, Concha Bethencourt, Daniel Garcia Belmonte, Ana Belen Santos, Mar Caballero, Adolfo de la Fuente, Dolores Vilariño, Silvia Negri, Rosa Fernandez Martinez, Alejandro Román, Federico Moscardó, Jose Luis Lopez Lorenzo, Mar Tormo, Jl Sastre Moral, Silvia Solorzano, Marisa Calabuig, Pilar Martínez-Sánchez, and Pascual Fernández-Abellán
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medicine.medical_specialty ,Chemotherapy ,Anemia ,business.industry ,Incidence (epidemiology) ,medicine.medical_treatment ,Immunology ,Salvage therapy ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Refractory ,Internal medicine ,Toxicity ,medicine ,Clofarabine ,business ,medicine.drug - Abstract
Abstract 4279 Introduction: Clofarabine (CLF) is a purine nucleoside analog approved by FDA and EMA in refractory pediatric ALL patients. Phase I and II studies have reported Clofarabine activity in AML. Aims: To evaluate the experience in Spain with (CLF) in the treatment of adult AML patients, analyzing effectiveness and toxicity profile. Method: This is a multicenter retrospective study including AML patients treated in Spain with CLF by compassionate use. Main points were complete remission as IWRv2003 criteria and toxicity as CTCAE v3.0 of NCI scale. Result: Between July 2007 ans April 2011 a total of 76 AML patients were treated with CLF based chemotherapy in Spain. We obtained clinical data from 64 cases. Median age at CLF treatment 52.4 years (18–77). Male/Female: 31/33. Previous Myelodisplastic syndrome 12 (18%). Cytogenetic data was available in 58 patients (90%), and 28 of them had high-risk cytogenetic. CLF treatment: 56 patients received CLF as salvage therapy (23 in AML relapse and 33 in refractory disease), median previous lines 2 (0–7), were the remaining 8 patients were untreated patients. CLF was administered in combination with AraC in 94% patients and the 91% received a five days schedule. The most frequents CLF dose/day were: 40 mg/m2/day in 39 patients, 30 mg/m2/day in 11 patients, and 20 mg/m2/day in 9 patients. Response and outcome: Nineteen (35.8%) patients achieved complete remission and 64.1% had resistant disease. Mean survival time 14.3 ± 1.4 months. The statistical analysis shows a significant difference in the CR rate between first line therapy (CR 82%) and savage therapy in relapsed (CR 45%) and salvage therapy in refractory (CR 18%), (p0.012). Neither adverse cytogenetics nor previous MDS did influence CR. (p0.57 and p0.53 respectively). Toxicity: All patients presented grade IV hematological toxicity with grade IV neuthopenia, grade IV trombopenia and transfusion depend anemia. The incidence of extra hematological toxic effects were low, creatinine >3 mg/dL: 4 cases (6%); bilirrubine > 3mg/dL: 9 cases (14%). Eleven (17%) patients died during Induction. Conclusions(opcion1): The revised experience in Spain with CLF as compassionate used in AML confirms the effectiveness of Clofarabine as a salvage regimen. Of note was that CLF could potentially overcome some adverse known factors as cytogenetics. Disclosures: Off Label Use: Clofarabine in AML is an off-label use.
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- 2011
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