42 results on '"Isabel Krsnik"'
Search Results
2. Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center
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Juan Francisco Oteo, Pablo García-Pavía, Jesus G. Mirelis, Vanessa Moñivas, Esther Gonzalez-Lopez, Ana Briceño, Javier Segovia, Clara Salas, Isabel Krsnik, Belén Bornstein, Ángela López-Sainz, Manuel Gómez-Bueno, Aitor Hernandez-Hernandez, Francisco José Hernández-Pérez, Juan Antonio López, Maria Alejandra Restrepo-Cordoba, Fernando Domínguez, Jesús Vázquez, Marta Cobo-Marcos, Miguel A. Cavero, Luis Alonso-Pulpón, Susana Mingo Santos, and F. Javier de Haro-del Moral
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Adult ,Male ,medicine.medical_specialty ,Delayed Diagnosis ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Prealbumin ,Referral and Consultation ,Aged ,Aged, 80 and over ,Heart Failure ,Amyloid Neuropathies, Familial ,biology ,business.industry ,Myocardium ,High mortality ,Mean age ,Amyloidosis ,General Medicine ,Middle Aged ,medicine.disease ,Transthyretin ,Cardiac amyloidosis ,Heart failure ,biology.protein ,Referral center ,Female ,Cardiomyopathies ,business - Abstract
Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center.We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival.We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02).CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.
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- 2021
3. Treatment with daratumumab in patients with relapsed/refractory AL amyloidosis: a multicentric retrospective study and review of the literature
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Verónica Cánovas, Victoria Dourdil, Elham Askari, Ramón Lecumberri, Sunil Lakhwani, Mercedes Gironella, María E González-García, Luis E Tamariz, José Sarrá, Ángel Ramírez-Payer, María S Infante, Adrian Alegre, Maialen Sirvent, Virginia Pradillo, Cristina Martínez-Bilbao, M. Teresa Cibeira, Isabel Krsnik, Fernando Escalante, and Marta S González-Pérez
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Male ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,Internal Medicine ,AL amyloidosis ,Humans ,Medicine ,Immunoglobulin Light-chain Amyloidosis ,In patient ,Aged ,Retrospective Studies ,business.industry ,Antibodies, Monoclonal ,Daratumumab ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Treatment Outcome ,Drug Resistance, Neoplasm ,Relapsed refractory ,Female ,business ,030217 neurology & neurosurgery - Abstract
Management of patients with relapsed or refractory (R/R) AL amyloidosis is complex. Some initial reports have shown positive results with daratumumab in heavily pre-treated AL amyloidosis patients. In this retrospective multicentric study, 38 patients (mean age 64 ± 9 years) with R/R AL amyloidosis treated with daratumumab were included. Cardiac and renal involvement was present in 76 and 74% of patients, and 42% had ≥3 organs involved. Median number of previous lines of therapy was 2 (range 1-8). Overall hematological response was 72%, including 28% complete responses. The median time to first hematological response was 2 weeks. A high-quality response (≥very good partial response) was obtained in 65% of patients who had never achieved such depth of response previously. Hematological responses were more frequent among patients receiving daratumumab as second-line therapy compared to subsequent therapies (92 vs. 61%). Cardiac and renal organ response rates were 37 and 59%. At 12 months, overall and progression-free survival were 59% (95%CI: 0.36-0.77) and 52% (95%CI: 0.29-0.70), respectively. Daratumumab is a safe and effective drug in the treatment of R/R AL amyloidosis and should be considered early in the course of the disease.
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- 2020
4. Prevalence of cardiac amyloidosis among elderly patients with systolic heart failure or conduction disorders
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Jorge Toquero-Ramos, Enrique Lara-Pezzi, Ángela López-Sainz, Ignacio Fernández-Lozano, Pablo García-Pavía, Alejandra Restrepo-Córdoba, Aitor Hernandez-Hernandez, Fernando Dominguez, Luis Alonso-Pulpón, Esther Gonzalez-Lopez, F. Javier de Haro-del Moral, Almudena Amor-Salamanca, Marta Cobo-Marcos, Isabel Krsnik, Victor Castro, and Luis Ruiz-Guerrero
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Male ,Pacemaker, Artificial ,medicine.medical_specialty ,Conduction disorders ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Prealbumin ,Prospective Studies ,Radionuclide Imaging ,Aged ,Conduction disease ,Aged, 80 and over ,Amyloid Neuropathies, Familial ,biology ,business.industry ,Amyloidosis ,food and beverages ,Arrhythmias, Cardiac ,medicine.disease ,Survival Analysis ,Transthyretin ,Cross-Sectional Studies ,Cardiac amyloidosis ,Echocardiography ,Heart failure ,biology.protein ,Cardiology ,Female ,Hypertrophy, Left Ventricular ,Cardiomyopathies ,business ,Infiltration (medical) ,Biomarkers ,030217 neurology & neurosurgery ,Heart Failure, Systolic - Abstract
Objective: Cardiac amyloid infiltration can lead to systolic heart failure (HF) or to conduction disorders (CD). Patients with transthyretin (ATTR) amyloidosis are particularly exposed. We ...
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- 2019
5. Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis
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Ombretta Annibali, Marta Lasa, Mario Nuvolone, Leire Burgos, Pasquale Cascino, Isabel Krsnik, Sriram Ravichandran, Alice Nevone, Paolo Milani, Andrea Foli, Ashutosh D. Wechalekar, Jesús F. San-Miguel, Margherita Massa, Bruno Paiva, Ramón Lecumberri, Melania Antonietta Sesta, Giampaolo Merlini, Alberto Orfao, Pierpaolo Berti, Marco Basset, Simona Casarini, Margherita Bozzola, Giovanni Palladini, Jessica Ripepi, Noemi Puig, International Myeloma Foundation, Fondazione Cariplo, Cancer Research UK, Fundación Científica Asociación Española Contra el Cáncer, Associazione Italiana per la Ricerca sul Cancro, Ministero della Salute, Centro de Investigación Biomédica en Red Cáncer (España), and Instituto de Salud Carlos III
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Male ,medicine.medical_specialty ,Neoplasm, Residual ,Disease-free survival ,Gastroenterology ,lcsh:RC254-282 ,Article ,Internal medicine ,hemic and lymphatic diseases ,medicine ,AL amyloidosis ,Humans ,Immunoglobulin Light-chain Amyloidosis ,Multiple myeloma ,Aged ,business.industry ,Amyloidosis ,Organ dysfunction ,Hematology ,Minimal Residual Disease Negativity ,Middle Aged ,Translational research ,medicine.disease ,Flow Cytometry ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Minimal residual disease ,body regions ,Oncology ,Toxicity ,Disease Progression ,Female ,medicine.symptom ,business ,Complete Hematologic Response - Abstract
© The Author(s) 2021., Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity., This study was supported by a grant from CARIPLO “Molecular mechanisms of Ig toxicity in age-related plasma cell dyscrasias no. 2015-0591”, by a grant from the Black Swan Research Initiative from the International Myeloma Foundation “Automated multidimensional flow cytometry for high-sensitive screening and to monitor response in AL amyloidosis”, by a grant from CARIPLO “Structure–function relation of amyloid: understanding the molecular bases of protein misfolding diseases to design new treatments no. 2013-0964”, by a grant from the Amyloidosis Foundation “Investigating new therapies to treat AL amyloidosis”, and by a grant from Cancer Research UK, FCAECC and AIRC under the Accelerator Award 2017 Program “Early detection and intervention: understanding the mechanisms of transformation and hidden resistance of incurable hematological malignancies”, by a grant from CARIPLO “Harnessing the plasma cell secretory capacity against systemic light chain amyloidosis” (no. 2018-0257), by a grant from the Italian Ministry of Health “Towards effective, patient-tailored anti-plasma cell therapies in AL amyloidosis: predicting drug response and overcoming drug resistance” (GR-2018-12368387). This study has also supported the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00400, and CB16/12/00489) and the Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI13/02196). G.P. is supported in part by the Bart Barlogie Young Investigator Award from the International Myeloma Society (IMS). P.M. is supported in part by a fellowship grant form Collegio Ghislieri (Pavia). We acknowledge the study coordinator and data manager Anna Carnevale Baraglia.
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- 2021
6. Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma
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Joaquin Martinez-Lopez, Diego Alignani, Jesús Martín-Sánchez, Norma C. Gutiérrez, Juan Flores-Montero, Ibai Goicoechea, Rafael Rios, Joan Bargay, Noemi Puig, Leire Burgos, Juan José Garcés, Maria-Victoria Mateos, Juan José Lahuerta, Joan Bladé, María-Belén Vidriales, Lourdes Cordón, Maria-Jose Calasanz, Isabel Krsnik, Bruno Paiva, Miguel-Teodoro Hernández, Albert Oriol, Sara Rodriguez, Idoia Rodriguez, Maria-Teresa Cedena, Vicente Fresquet, Luis Palomera, Sarai Sarvide, J A Martinez-Climent, Amaia Vilas-Zornoza, Alberto Orfao, Javier de la Rubia, Rafael Martínez-Martínez, Ramón García-Sanz, David Lara-Astiaso, José-María Moraleda, Jesús F. San Miguel, Laura Rosiñol, Jon Celay, Josep Sarrá, María-Luisa Martín Ramos, and Daniel Alameda
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Oncology ,Adult ,Boron Compounds ,Male ,medicine.medical_specialty ,Neoplasm, Residual ,Physics::Instrumentation and Detectors ,Clinical Trials and Observations ,Immunology ,Patient subgroups ,Glycine ,Drug resistance ,Biochemistry ,Dexamethasone ,Bortezomib ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Neoplasm ,Humans ,Progression-free survival ,Treatment resistance ,Lenalidomide ,Complete response ,Multiple myeloma ,Aged ,Chromosome Aberrations ,Lymphoid Neoplasia ,business.industry ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Flow Cytometry ,Progression-Free Survival ,body regions ,Clinical trial ,Treatment Outcome ,Drug Resistance, Neoplasm ,Female ,business ,Multiple Myeloma - Abstract
PETHEMA/GEM Cooperative Group., Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species–mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252.
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- 2021
7. Analysis of minimal residual disease in bone marrow by NGF and in peripheral blood by mass spectrometry in newly diagnosed multiple myeloma patients enrolled in the GEM2012MENOS65 clinical trial
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Alberto Orfao, Rafael Rios, Isabel Krsnik, Javier de la Rubia, Anna Sureda Balari, Teresa Contreras, Hernández-Garcia Miguel Teodoro, Moraleda José María, Laura Rosiñol, M. Teresa Cedena, Jesús F. San-Miguel, Joan Bladé, Maria-Victoria Mateos, Albert Oriol, María Belén Iñigo, Noemi Puig, María Jesús Blanchard, Juan José Lahuerta, Bruno Paiva, and Joaquín Martínez
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Newly diagnosed ,medicine.disease ,Minimal residual disease ,Treatment efficacy ,Peripheral blood ,Clinical trial ,medicine.anatomical_structure ,Internal medicine ,Medicine ,Bone marrow ,business ,Multiple myeloma - Abstract
8010 Background: Analysis of minimal residual disease (MRD) in the bone marrow (BM) of patients with multiple myeloma (MM) is accepted by the IMWG to evaluate treatment efficacy and is a well-established prognostic factor. However, there is an unmet need to explore the clinical value of MRD in peripheral blood (PB). Methods: Newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial received six induction (Ind) cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous stem cell transplantation (ASCT) and 2 further cycles of consolidation (Cons) with VRD. MRD was analyzed in BM using Next Generation Flow (NGF) and in serum by Mass Spectrometry (MS) using IgG/A/M, κ, λ, free κ and free λ specific beads, both after Ind, at day 100 after ASCT, and after Cons. Sequential samples from the first 184 patients were analyzed. Results: Results of both methods were in agreement (NGF+/MS+ and NGF-/MS-) in 83% of cases post-Ind (152/184), 80% post-ASCT (139/174) and 76% post-Cons (128/169). Stratifying by the log range of MRD by NGF, discordances (NGF+/MS- and NGF-/MS+) seemed to increase at the lower MRD ranges, being 22%, 21% and 19% from ≥10−5 to −4 and 21%, 21%, 23% at ≥x10−6(post-Ind, ASCT and Cons, respectively). Analysis of discordances showed that they could be partly explained by the higher percentages of cases found to be positive by MS as compared by NGF at part of the time-points analyzed and at each log range of MRD. From ≥10−5 to −4, MRD was detected by NGF in 36%, 28%, 20% of cases post-Ind, ASCT and Cons, respectively vs MS in 37%, 29%, 21% of them; at ≥x10−6, NGF was positive in 11%, 14%, 19% of cases vs MS in 23%, 19% and 16% of them. Considering NGF as a reference, the negative predictive value (NPV) of MS per MRD range (≥10−5 to −4 and ≥x10−6, respectively) was: post-Ind: 83% (p
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- 2021
8. Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma
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Norma C. Gutiérrez, Luzalba Sanoja-Flores, Bruno Paiva, José-María Moraleda, Juan Flores-Montero, Laura Rosiñol, Luis Palomera, Jesús F. San-Miguel, Miguel-Teodoro Hernández, María-Luisa Martín-Ramos, Jacques J.M. van Dongen, Rafael Martínez-Martínez, Maria-Victoria Mateos, Javier de la Cruz, Jesús Martín, Albert Oriol, Javier de la Rubia, Lourdes Cordón, María-Belén Vidriales, Maria-Jose Calasanz, Joan Bargay, Anna Sureda, Lucia Lopez-Anglada, Noemi Puig, Alberto Orfao, Maria-Teresa Cedena, Ramón García-Sanz, Isabel Krsnik, Leire Burgos, M.J. Blanchard, Juan José Lahuerta, Roberto Maldonado, Joaquin Martinez-Lopez, Rafael Rios, Joan Bladé, Celgene, Janssen Biotech, Sanofi, Takeda Pharmaceutical Company, Amgen, Gilead Sciences, Incyte, Bristol-Myers Squibb, Prothena, and Pfizer
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Disease ,Residual ,THERAPY ,Dexamethasone ,Flow cytometry ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Meaning (existential) ,Longitudinal Studies ,Lenalidomide ,Multiple myeloma ,030304 developmental biology ,CONSOLIDATION ,Randomized Controlled Trials as Topic ,0303 health sciences ,COMPLETE RESPONSE ,medicine.diagnostic_test ,business.industry ,Middle Aged ,medicine.disease ,Flow Cytometry ,3. Good health ,Clinical trial ,PROGNOSTIC VALUE ,body regions ,MRD ,Clinical Trials, Phase III as Topic ,030220 oncology & carcinogenesis ,Female ,STEM-CELL TRANSPLANT ,business ,Multiple Myeloma ,DARATUMUMAB - Abstract
[Purpose] Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG)., [Patients and methods] In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10−6. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial., [Results] Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P < .001). Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%., [Conclusions] The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.
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- 2019
9. Compassionate Use of Belantamab Mafodotin for Treatment of Patients with Relapsed/Refractory Multiple Myeloma Heavily Treated. Spanish Experience
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Ana Morales, Isabel Krsnik, Carmen Jiménez-Montes, Carmen Martínez-Chamorro, María Jesús Blanchard, Cristina Muñoz-Linares, Adrian Alegre, Alberto Velasco, Rebeca Iglesias, Elham Askari, Concha Alaez, Arancha Alonso, Clara Cuellar, Elena Prieto, Ana Jiménez-Ubieto, Eugenio Gimenez Mesa, Gonzalo Benzo Callejo, Joaquin Martinez-Lopez, Beatriz Aguado, Laura Llorente, and Rafael Alonso Fernández
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Compassionate Use ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Internal medicine ,Relapsed refractory ,Medicine ,business ,Multiple myeloma - Abstract
Background: Heavily pretreated relapsed and refractory multiple myeloma (RR MM) constitutes a specific and unmet medical need. Median survival ranges from as little as 6 to 9 months, and responses to treatment are characteristically short (Richardson et al. 2007). Belantamab Mafodotin (BM), a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, showed single-agent activity in the phase 1 DREAMM-1 and phase 2 DREAMM-2 studies in heavily pre-treated patients with RRMM (Lonial et al, 2019 & 2021). We aim to assess efficacy and safety of BM treatment administered via the expanded access compassionate care program for triple class MMRR patients in the region of Madrid (Spain). Methods: An observational, retrospective and multicenter study has been performed including all patients who received at least one dose of BM under the expanded access program in the region of Madrid (Spain) from Nov 2019 to Jun 2021. Hematology centers provided data from the medical records and entered them in a case report form distributed to the sites. Primary endpoint was overall response rate (ORR). Secondary endpoints were progression free survival (PFS), overall survival (OS) and the incidence of treatment emergent adverse events (TEAEs), with a major focus on ocular and hematologic toxicity. Results: A total of 33 patients (pts), from 14 different centers, were included from February 2020 till May 2021. Median age was 70 (46-79) years. 55% of the pts were women. Median time from diagnosis was 71 (10-858) months. 30.3% were high-risk cytogenetic features. Median of prior therapy lines was 5 (3-8) and at least 88% of the pts were triple class refractory. The median number of BM doses per patient was 3 (1-16) and the median follow-up was 11 months (95%CI 6.34-15.66). ORR was 42.2%, and 18.2% achieved ≥VGPR. Median PFS was 3 months (95%CI 0.92-5.08). Median PFS for patients who achieved ≥PR was 11 months (HR 0,26; 95% CI 0,10-0,68). No significant differences were found in PFS according to age, cytogenetic risk and prior therapy lines. OS was 424 days (95% CI 107-740). The incidence of non-hematological TEAEs was 57.6% and the most common of which was ocular toxicity (45.5%). The incidence of ≥G3 non-hematological TEAEs was 30.3%. 51.5% of the pts were diagnosed of keratopathy and 21.2% was ≥G3. 30.3% of the pts showed a reduced visual acuity, but this event was resolved in 92.9% of the pts. The most common symptoms were blurry vision (30.3%, n=10) and dry eye (24.2%, n=8). The incidence of ≥G3 hematological TEAEs was 18.2% and thrombocytopenia was the most frequent (21.2%). Dose reductions of BM were required in 30.3% of the pts and delayed in 36.4% due to TEAEs. Main causes for treatment discontinuation (81%, n=27) were disease progression (54.5%, n=18), toxicity (15.2%, n=5), death (6.1%, n=3) and due to patient's decision (3%, n=1). Conclusion: Compassionate use of BM in heavily pretreated RR MM pts showed a relevant anti-myeloma activity with a manageable safety profile.These results are similar to those observed in the DREAMM-1 and DREAMM-2 clinical trials. Disclosures No relevant conflicts of interest to declare.
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- 2021
10. Definition and Clinical Significance of the MGUS-like Phenotype: A Study in 5,114 Patients (Pts) with Monoclonal Gammopathies
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Leire Burgos, Luis Esteban Tamariz-Amador, Noemí Puig, María Teresa Cedena, Tomas Jelinek, Sarah K Johnson, Paolo Milani, Lourdes Cordon, José J Pérez, Marta Lasa, Rosalinda Termini, Albert Oriol, Miguel-Teodoro Hernández, Luis Palomera, Rafael Martinez Martinez, Javier de la Rubia, Felipe De Arriba, Rafael Rios, Maria Esther González, Mercedes Gironella, Valentin Cabañas, Maria Casanova, Isabel Krsnik, Albert Pérez, Veronica Gonzalez De La Calle, Paula Rodríguez-Otero, Vladimir Maisnar, Roman Hajek, Frits van Rhee, Victor H Jimenez-Zepeda, Giovanni Palladini, Alberto Orfao, Laura Rosinol, Joan Bladé Creixenti, Joaquín Martínez-López, Juan-José Lahuerta, Maria-Victoria Mateos, Jesús F. San-Miguel, and Bruno Paiva
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,Monoclonal ,Medicine ,Clinical significance ,Cell Biology ,Hematology ,business ,Biochemistry ,Phenotype - Abstract
Background: Within the spectrum of monoclonal gammopathies, there are various subgroups with unique biological and clinical profiles. Namely, the presence of multiple myeloma (MM) and light-chain amyloidosis (AL) pts with MGUS-like phenotype has been hypothesized, but the criteria to identify this subgroup are poorly defined and lack clinical validation. Aim: Develop an algorithm based on a large flow cytometry dataset across the spectrum of monoclonal gammopathies, for automated identification of MM and AL pts with MGUS-like phenotype. Methods: This study included 5,114 pts with monoclonal gammopathies and available flow cytometry data on the frequency of bone marrow (BM) plasma cells (PC) and the percentages of normal and clonal PC within the BM PC compartment, at diagnosis. An algorithm to classify pts with MGUS-like phenotype was developed based on these three parameters, obtained from 548 MGUS, 393 smoldering MM (SMM) and 2,011 MM pts. Newly diagnosed MM pts were homogeneously treated according to the GEM2000 (n = 486), GEM2005MENOS65 (n = 330), GEM2005MAS65 (n = 239), GEM2010MAS65 (n = 230), GEM2012MENOS65 (n = 450) and CLARIDEX (n = 276) protocols. The prognostic value of the MGUS-like phenotype was validated in 96 SMM pts studied in Arkansas and 1,859 MM pts treated outside clinical trials in Czech Republic. The clinical significance of the algorithm was investigated in two independent series of Spanish (n = 102) and Italian (n = 105) AL pts. Results: The frequency of BM PC and of normal and clonal PC within the BM PC compartment were used to plot MGUS, SMM and MM pts in a principal component analysis (PCA). Lines defining 1.5 standard deviations of MGUS and MM pts were used as reference to classify each of the 5,114 cases. Once plotted against the dataset, individual pts were classified as MGUS-, intermediate- or MM-like, if their location in the PCA fell inside the MGUS, the overlapping or the MM reference lines, respectively. In the training SMM series, patient classification into MGUS-, intermediate- and MM-like phenotype resulted in significantly different rates of disease progression (0%, 54% and 66% at 5y, respectively; P < .001). These results were validated in the Arkansas series (8%, 27% and 71% at 5y, respectively; P < .001). Only 5% of SMM pts with high-risk disease according to Mayo or PETHEMA criteria had an MGUS-like phenotype, and these had virtually no risk of progression at 5y. In the training MM series, pts with MGUS-like phenotype showed significantly longer progression free (PFS) and overall survival (OS) vs the remaining pts. Median PFS was 10y vs 3y (hazard ratio [HR]: 0.46, P < .001) and median OS was not reached (NR) vs 6.5y (HR: 0.48, P < .001), respectively. These results were validated in the Czech Republic series with significant differences in PFS (HR: 0.45, P < .001) and OS (HR: 0.38, P < .001) between MGUS-like vs other MM pts. MGUS-like classification in the training MM series retained independent prognostic value in multivariate analyses of PFS (HR: 0.48, P < .001) and OS (HR: 0.54, P = .033), together with ISS, LDH, cytogenetics, induction regimen, transplant-eligibility and complete remission (CR). MGUS-like pts showed similar PFS (P = .932) and OS (P = .285) regardless of having standard vs high risk cytogenetics. Notably, MGUS-like transplant-eligible MM pts treated with proteasome inhibitors, immunomodulatory drugs and corticoids during induction showed PFS and OS rates at 5y of 86% and 96%, respectively. Differences in PFS among MGUS-like MM pts achieving ≥CR vs Classification of AL pts into the MGUS-, intermediate- and MM-like phenotype resulted in significantly different PFS in the Spanish (median of 28, 20 and 1 months, respectively; P = .001) and Italian (median 32, 11 and 3 months, respectively; P < .001) cohorts. Conclusions: We developed an algorithm that can be readily installed in clinical flow cytometry software, and requires three parameters that are routinely assessed at screening. Patient' automated classification using the algorithm was validated in large series across the spectrum of monoclonal gammopathies. Because pts with MGUS-like phenotype have a distinct clinical behavior, their identification could become part of the diagnostic workup in SMM, MM and AL. Disclosures Cedena: Janssen, Celgene and Abbvie: Honoraria. Milani: Celgene: Other: Travel support; Janssen-Cilag: Honoraria. Cordon: Cytognos SL: Research Funding. Oriol: Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy. de la Rubia: Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; Celgene, Takeda, Janssen, Sanofi: Honoraria; Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; GSK: Consultancy; Takeda: Consultancy; 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. Cabañas: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Honoraria. Gonzalez De La Calle: Celgene-BMS, Janssen, Amgen: Honoraria. Rodríguez-Otero: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; Kite: 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; GlaxoSmithKline: Consultancy, 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; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and other expenses. Hajek: Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jimenez-Zepeda: BMS, Amgen, Takeda, Janssen: Honoraria. Palladini: Janssen Global Services: Honoraria, Other: advisory board fees; Pfizer: Honoraria; Siemens: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Bladé Creixenti: Janssen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Mateos: Roche: 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; Regeneron: 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; Adaptive Biotechnologies: 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; Amgen: 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; AbbVie: Honoraria; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. 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.
- Published
- 2021
11. Ixazomib Plus Lenalidomide/Dexamethasone (IRd) Versus Lenalidomide /Dexamethasone (Rd) Maintenance after Autologous Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma: Results of the Spanish GEM2014MAIN Trial
- Author
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Maria-Victoria Mateos, Esther González Garcia, Yolanda Gonzalez-Montes, Antonia Sampol, Elena Cabezudo, Rafael Ríos Tamayo, Joan Blade Creixenti, María Jesús Blanchard, Jesús F. San-Miguel, Estrella Carrillo-Cruz, Felipe Casado, Joan Bargay, Anna Sureda, José M. Moraleda, Josep Martí, Luis Palomera, Laura Rosiñol, Isabel Krsnik, Joaquin Martinez-Lopez, Cristina Encinas, Felipe de Arriba, Miguel-Teodoro Hernández, Albert Oriol, Isidro Jarque, and Juan José Lahuerta
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Newly diagnosed ,medicine.disease ,Biochemistry ,Ixazomib ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,In patient ,Stem cell ,business ,Dexamethasone ,Multiple myeloma ,medicine.drug ,Lenalidomide - Abstract
Background: The Spanish Myeloma Group (GEM) demonstrated that post-transplant maintenance with thalidomide plus bortezomib was superior to thalidomide alone, although this combination was associated with a high rate of peripheral neuropathy. Lenalidomide is currently the standard postransplant maintenance treatment, and its association with ixazomib, an oral proteasome inhibitor that does not cause peripheral neuropathy, could be of interest. Aim: To assess the potential benefit of postransplant maintenance therapy with Ixazomib /lenalidomide/dexamethasone (IRd) over lenalidomide/dexamethasone (Rd). Patients: Patients who where at least with stable disease after the GEM2012menos65 trial that included VRD-GEM induction, autologous hematopoietic stem cell transplantation conditioned with either melphalan-200 or intravenous busulfan together with melphalan-140 and consolidation with VRD-GEM were randomized to receive maintenance treatment with IRd versus Rd. Each cycle lasted 28 days. Rd arm consisted of lenalidomide 15 mg/d on days 1-21 and 20mg of dexamethasone administered orally on days 1-4 and 9-12. In IRd arm ixazomib 4 mg/day on days 1, 8 and 15 of the cycle was added. At two years, patients with negative MRD discontinued maintenance treatment. Patients with positive MRD continued with Rd for 3 additional years. In this case, 20 mg of dexamethasone was only administered on days 1-4 of the cycle. From November 24, 2014 to May 18, 2017, 161 patients were allocated to Rd arm and 171 to IRd arm. Patient characteristics at screening and prognostic factors such as ISS, cytogenetics and plasmacytomas, as well as response status, were similarly distributed in the two arms. Overall, 22% of the patients had high-risk cytogenetics [t(4;14), t(14;16) and/or 17p deletion]. MRD was analyzed by using next-generation flow at a sensitivity level of 3x10 -6. Results: After a median follow-up of 56 months, there was no difference in PFS between the two maintenance arms (median not reached, PFS at 5 years: 62% vs. 63% with IRd and Rd, respectively, p=0.785) (figure 1). In the overall series, there were no significant differences in PFS or OS among patients with standard (SR) or high-risk (HR) cytogenetics. Median PFS had not been reached in patients with SR in both arms (PFS at 5 years: 66% with IRD vs. 62% with Rd, p=0.633). In patients with HR the median PFS was 62 months with IRd vs. not reached with Rd (p=0.636). No significant differences across subgroups (ISS, conditioning, cytogenetics or MRD) were observed between IRd and Rd. Negative MRD at screening overcomes the bad prognosis of cytogenetics (PFS at 5 years 78% for SR and 80% for HR; OS at 5 years was 90% for both, SR and HR). Patients with SR who had negative MRD at screening had a significantly longer PFS (PFS at 5 years 78% vs. 50%, p Conclusions: Maintenance therapy with lenalidomide and dexamethasone in patients homogeneously treated with VRD-GEM induction, ASCT and VRD-GEM consolidation resulted in a long PFS of 63% at 5 years from the start of maintenance. The addition of ixazomib did not result in a PFS benefit. This could be partially explained by the higher toxicity leading to dose reductions or discontinuation of ixazomib in the IRd arm. Figure 1 Figure 1. Disclosures Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; 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. Jarque: AbbVie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Apellis: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Beigene: Consultancy; CellTrion: Consultancy; Eusa: Consultancy; Gilead: Consultancy, Speakers Bureau; Grifols: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Shionogi: Consultancy; Sobi: Consultancy; Takeda: Consultancy, Speakers Bureau. Moraleda: Pfizer: Other: Educational Grants, Research Funding; Sanofi: Other: Educational Grants, Research Funding; MSD: Other: Educational Grants, Research Funding; ROCHE: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Takeda: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Sandoz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Educational Grants, Research Funding; NovoNordisk: Other: Educational Grants, Research Funding; Janssen: Other: Educational Grants, Research Funding; Celgene: Other: Educational Grants, Research Funding; Amgen: Other: Educational Grants, Research Funding. Sureda: Mundipharma: Consultancy; Bluebird: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. De Arriba: BMS-Celgene: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau. Mateos: 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; Adaptive Biotechnologies: 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; Amgen: 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; Bluebird bio: Honoraria; GSK: Honoraria; Sanofi: 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; Regeneron: 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; AbbVie: Honoraria; Oncopeptides: Honoraria; Janssen: 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. Lahuerta: Celgene: Other: Travel accomodations and expenses; Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy. Bladé Creixenti: Janssen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria.
- Published
- 2021
12. Flow cytometry for fast screening and automated risk assessment in systemic light-chain amyloidosis
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Alfonso García de Coca, Alberto Orfao, Albert Pérez-Montaña, Mercedes Gironella, María José Casanova, Noemi Puig, Valentin Cabañas, Isabel Krsnik, Quentin Lecrevisse, Jose-Enrique de la Puerta, Bruno Paiva, Juana Merino, Felipe Prosper, Enrique M. Ocio, Juan José Lahuerta, Cristina Moreno, Javier Verde, Felipe de Arriba, Jesús F. San Miguel, Maria-Teresa Cedena, Ramón Lecumberri, Dolores Gómez Toboso, Maria Victoria Mateos, Leire Burgos, Jorge Labrador, Luis Palomera, María Belén Vidriales, Joaquin Martinez-Lopez, José de Jesús Pérez, Javier de la Rubia, Maria-Esther Gonzalez, Marta Lasa, Albert Oriol, Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, International Myeloma Foundation, and European Research Council
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,Identification ,Plasma-cells ,Myeloma ,Translocation (11/14) ,0302 clinical medicine ,Immunophenotyping ,Bone Marrow ,Mass Screening ,Immunoglobulin Light-chain Amyloidosis ,Multiple myeloma ,Aged, 80 and over ,Amyloidosis ,Diagnosed AL amyloidosis ,Hematology ,Middle Aged ,Flow Cytometry ,Immunoglobulin Isotypes ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,CD43 expression ,Female ,Adult ,medicine.medical_specialty ,Risk Assessment ,Differential-diagnosis ,Clonal Evolution ,Multiple-myeloma ,03 medical and health sciences ,Internal medicine ,medicine ,AL amyloidosis ,Humans ,Adverse prognostic-factor ,Mass screening ,Aged ,Neoplasm Staging ,Haematological cancer ,business.industry ,Minimal residual disease ,Translational research ,medicine.disease ,Staging system ,030104 developmental biology ,Bone marrow ,Differential diagnosis ,business ,Biomarkers - Abstract
Early diagnosis and risk stratification are key to improve outcomes in light-chain (AL) amyloidosis. Here we used multidimensional-flow-cytometry (MFC) to characterize bone marrow (BM) plasma cells (PCs) from a series of 166 patients including newly-diagnosed AL amyloidosis (N = 94), MGUS (N = 20) and multiple myeloma (MM, N = 52) vs. healthy adults (N = 30). MFC detected clonality in virtually all AL amyloidosis (99%) patients. Furthermore, we developed an automated risk-stratification system based on BMPCs features, with independent prognostic impact on progression-free and overall survival of AL amyloidosis patients (hazard ratio: ≥ 2.9;P ≤.03). Simultaneous assessment of the clonal PCs immunophenotypic protein expression profile and the BM cellular composition, mapped AL amyloidosis in the crossroad between MGUS and MM; however, lack of homogenously-positive CD56 expression, reduction of B-cell precursors and a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, emerged as hallmarks of AL amyloidosis (ROC-AUC = 0.74;P, This study was supported by the Centro de Investigación Biomédica en Red – Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00400 and CB16/12/00489), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI13/02196), Asociación Española Contra el Cáncer (GCB120981SAN and Accelerator Award), the Black Swan Research Initiative of the International Myeloma Foundation, and the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT).
- Published
- 2019
13. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma
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Isabel Krsnik, Jesús F. San Miguel, Laura Rosiñol, María Jesús Blanchard, J. Bargay, Miguel T. Hernandez, Bruno Paiva, Maria-Victoria Mateos, Felipe de Arriba, Yolanda Gonzalez-Montes, Lucia Lopez-Anglada, Joan Bladé, Luis Palomera, A.-P. González, José M. Moraleda, Josep Martí, Mercedes Gironella, Rafael Rios, Anna Sureda, Maria Esther González, Albert Oriol, Luis Felipe Casado, Isidro Jarque, Juan José Lahuerta, Rafael Martínez-Martínez, and Jose M Arguiñano
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Melphalan ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Immunology ,Population ,Neutropenia ,Biochemistry ,Transplantation, Autologous ,Dexamethasone ,Bortezomib ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,education ,Lenalidomide ,Multiple myeloma ,Aged ,education.field_of_study ,Lymphoid Neoplasia ,business.industry ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,Neoadjuvant Therapy ,Transplantation ,Chemotherapy, Adjuvant ,Female ,business ,Multiple Myeloma ,medicine.drug - Abstract
Achieving and maintaining a high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients aged ≤65 years with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with IV busulfan + melphalan vs melphalan and posttransplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation. Responses deepened over time; in patients who initiated cycle 6 of induction (n = 426), the rates of a very good partial response or better were 55.6% by cycle 3, 63.8% by cycle 4, 68.3% by cycle 5, and 70.4% after induction. The complete response rate of 33.4% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (34.8%), also deepened with further treatment (44.1% after ASCT and 50.2% after consolidation). Rates of undetectable minimal residual disease (median 3 × 10(−6) sensitivity) in the ITT population also increased from induction (28.8%) to transplant (42.1%) and consolidation (45.2%). The most common grade ≥3 treatment-emergent adverse events during induction were neutropenia (12.9%) and infection (9.2%). Grade ≥2 peripheral neuropathy (grouped term) during induction was 17.0%, with a low frequency of grade 3 (3.7%) and grade 4 (0.2%) events. VRD is an effective and well-tolerated regimen for induction in NDMM with deepening response throughout induction and over the course of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01916252 and EudraCT as #2012-005683-10.
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- 2019
14. Role of Right Ventricular Strain Measured by Two-Dimensional Echocardiography in the Diagnosis of Cardiac Amyloidosis
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Jesús González-Mirelis, Alejandro Durante-López, Mario Torres Sanabria, Javier Segovia Cubero, Susana Mingo Santos, Sara M. Navarro Rico, Fernando Domínguez, Isabel Krsnik, Jorge Vazquez Lopez-Ibor, Alejandro Martínez Mingo, Vanessa Moñivas Palomero, Francisco José Hernández-Pérez, and Gibanel Cavero
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Male ,medicine.medical_specialty ,Longitudinal strain ,Ventricular Dysfunction, Right ,030204 cardiovascular system & hematology ,030218 nuclear medicine & medical imaging ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Immunoglobulin Light-chain Amyloidosis ,Prospective Studies ,Aged ,Amyloid Neuropathies, Familial ,biology ,Strain (chemistry) ,business.industry ,Amyloidosis ,Restrictive cardiomyopathy ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Transthyretin ,medicine.anatomical_structure ,Cardiac amyloidosis ,Ventricle ,Echocardiography ,Case-Control Studies ,biology.protein ,Cardiology ,Female ,Differential diagnosis ,Cardiology and Cardiovascular Medicine ,business ,Cardiomyopathies - Abstract
Cardiac amyloidosis (CA) causes restrictive cardiomyopathy usually associated with a poor prognosis. Two subtypes predominate: systemic light-chain CA (ALCA) and transthyretin-derived CA (either wild type transthyretin amyloidosis [TTRwt] or mutant transthyretin amyloidosis [TTRm]). Left ventricular (LV) apical sparing has been extensively studied using speckle-tracking echocardiography for diagnosis, but the right ventricular (RV) deformation pattern has not been described. The aims of this study were to characterize RV involvement in patients with CA and to identify parameters that may help in the differential diagnosis between ALCA and transthyretin-derived CA subtypes.Seventy-eight patients with CA (47 with ALCA, 20 with TTRwt, and 11 with TTRm) and 24 healthy control subjects were included. Global longitudinal strain (GLS) was analyzed in 16 LV and six RV segments. LV and RV apical ratios (ARs) were obtained. GLS was expressed as an absolute value.LV GLS and free-wall RV longitudinal strain were impaired in all patients (LV GLS: 11.9 ± 2.9% in ALCA, 12.5 ± 3.8% in TTRwt, 14.9 ± 2.7% in TTRm, and 21.9 ± 2.6% in control subjects [P .01]; free-wall RV longitudinal strain: 13.1 ± 6.8%, 14.9 ± 4.5%, 17.2 ± 3.4%, and 22.1 ± 3.1%, respectively [P .01]). LV and RV ARs were higher in ALCA compared with both TTRwt, TTRm, and control subjects (LV AR: 1.1 ± 0.2, 0.8 ± 0.2, 0.9 ± 0.1, and 0.7 ± 0.1, respectively [P .001]; RV AR: 1.1 ± 0.2, 0.6 ± 0.2, 0.6 ± 0.1, and 0.6 ± 0.1, respectively [P .001]). Cutoff values of LV AR0.96 and RV AR0.8 showed high accuracy to differentiate between ALCA and transthyretin-derived CA.RV dysfunction is common in patients with CA. Analysis of RV strain showed an apical sparing pattern, as previously described in the left ventricle, with a higher AR as a specific finding in patients with ALCA. RV AR may be a parameter that can differentiate the subtypes of amyloidosis on the basis of speckle-tracking echocardiographic analysis.
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- 2018
15. Prevalence of Cardiac Amyloidosis in Patients with Carpal Tunnel Syndrome
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Clara Salas, Pablo de la Cuadra, Fernando Dominguez, Isabel Zegri-Reiriz, F. Javier de Haro-del Moral, Esther Gonzalez-Lopez, Isabel Krsnik, Pablo García-Pavía, and Aresio Plaza
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0301 basic medicine ,Male ,medicine.medical_specialty ,Time Factors ,Occupational risk ,Pharmaceutical Science ,030204 cardiovascular system & hematology ,Left ventricular hypertrophy ,Ventricular Function, Left ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Genetics ,Prevalence ,Medicine ,Humans ,In patient ,Carpal tunnel syndrome ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Ventricular Remodeling ,business.industry ,Amyloidosis ,Middle Aged ,medicine.disease ,Carpal Tunnel Syndrome ,nervous system diseases ,030104 developmental biology ,Cardiac amyloidosis ,Cohort ,Cardiology ,Molecular Medicine ,Female ,Hypertrophy, Left Ventricular ,Cardiology and Cardiovascular Medicine ,business ,Attr amyloidosis - Abstract
Carpal tunnel syndrome (CTS) is a common finding among patients with cardiac amyloidosis. We sought to determine the prevalence of cardiac amyloidosis in patients who had undergone CTS surgery. From 2005 to 2014, 308 patients ≥ 60 years underwent CTS surgery. Of these, 233 (76%) agreed to participate in the study and 101 (73 ± 8 years; 68% females) showed left ventricular hypertrophy (LVH) ≥ 12 mm and underwent additional studies to diagnose AL and ATTR amyloidosis. Based on complementary studies, three patients were diagnosed with cardiac amyloidosis (two wild-type ATTR and one AL). The three patients showed bilateral CTS with no occupational risk factors. Prevalence of cardiac amyloidosis in the overall cohort was only 1.2% (3/233), but among patients with LVH and bilateral CTS, the prevalence was 5.5% (3/55) and 13.6% (3/22) if cases with an occupational risk factor were excluded. Cardiac amyloidosis should be excluded in the presence of bilateral CTS and particularly if an occupational risk factor is absent.
- Published
- 2018
16. Clinical Significance and Transcriptional Profiling of Persistent Minimal Residual Disease (MRD) in Multiple Myeloma (MM) Patients with Standard-Risk (SR) and High-Risk (HR) Cytogenetics
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Javier de la Rubia, Ramón García-Sanz, David Lara-Astiaso, María-Belén Vidriales, Alberto Orfao, Josep Sarrá, Joaquin Martinez-Lopez, Luis Palomera, Jesús F. San-Miguel, Sarai Sarvide, Rafael Rios, Diego Alignani, Maria-Victoria Mateos, Bruno Paiva, Idoia Rodriguez, Laura Rosiñol, Isabel Krsnik, Joan Bargay, María Teresa Cedena, Joan Bladé, Leire Burgos, Miguel T. Hernandez, José M. Moraleda, Juan Flores-Montero, Ibai Goicoechea, Amaia Vilas-Zornoza, Jesús Martín, Maria Luisa Martin-Ramos, Noemi Puig, Lourdes Cordón, Albert Oriol, María José Calasanz, Norma C. Gutiérrez, Rafael Martínez, and Juan José Lahuerta
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medicine.medical_specialty ,business.industry ,Immunology ,Complete remission ,Tumor cells ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Standard Risk ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical significance ,Progression-free survival ,business ,health care economics and organizations ,Multiple myeloma ,030215 immunology - Abstract
Background: Despite significant improvements in the treatment of MM, the outcome of patients with HR cytogenetics remains poor despite similar complete remission (CR) rates as compared to SR cases. Relapses among patients in CR are attributed to the persistence of MRD, but knowledge about the impact of MRD in patients with SR and HR cytogenetics, treated with modern therapies and monitored with next-generation techniques, is limited. Similarly, there is virtually no data about in vivo mechanisms of resistance in SR and HR MM; however, since MRD represents those very few cells that are resistant to treatment, it could be hypothesized that profiling MRD cells may shed light into the mechanisms of resistance in both SR and HR patients. Aim: To determine the clinical impact of MRD in MM patients with SR vs HR cytogenetics, and to identify transcriptional mechanisms determining MRD resistance by investigating the transcriptome of MRD cells in both patient subgroups. Methods: This study was conducted in a series of 390 patients enrolled in the PETHEMA/GEM2012 trial (6 induction cycles with VRD followed by ASCT and 2 courses of consolidation with VRD). FISH was analyzed on CD138 purified PCs at diagnosis. MRD was predefined to be prospectively assessed following induction, transplant and consolidation, using next-generation flow (NGF) according to EuroFlow. In 40 patients [28 with SR and 12 with HR cytogenetics: i.e., t(4;14), t(14;16) and/or del(17p)], diagnostic and MRD tumor cells persisting after VRD-induction were isolated by FACS according to patient-specific aberrant phenotypes. Due to the small number of sorted MRD cells (median of 25,600) we used a 3' end RNAseq method optimized for generating libraries from low-input starting material (MARSeq). Differential expression analyses were performed with DESeq2 R package. Results: At the latest time-point in which MRD was assessed, MRD-positive rates progressively increased (p =.006) from SR patients (148/300, 49%) to cases with t(4;14) (24/42, 57%) and del(17p) (29/38, 76%). Furthermore, MRD levels were significantly superior in patients with del(17p) compared to SR FISH (0.02% vs 0.006%, p =.009), while MRD levels in patients with t(4;14) (0.004%) were similar to those in SR MM. Only 10 patients had a t(14;16) and 4 were MRD-positive. Among patients achieving MRD-negativity (.05). Conversely, 3-year PFS rates for MRD-positive patients decreased from those having SR FISH to those with t(4;14) and del(17p) (59%, 46% and 24%, respectively), with statistically significant differences between the first and the latest subgroups (p Since clearance of MRD notably lowered the risk of relapse and persistence of MRD significantly shortened the PFS in each cytogenetic group (p ≤.001), we investigated the unique features of MRD cells persisting after VRD-induction by comparing their transcriptome to that of patient-matched tumor cells at diagnosis (n=40). Accordingly, MRD cells showed 763 genes significantly deregulated (Padj Conclusions: This is one of the largest studies integrating patients' cytogenetics and MRD status. Our results, based on intensive treatment and MRD monitoring using NGF, unveil that achieving MRD-negativity may overcome the poor prognosis of HR cytogenetics. By contrast, persistent MRD significantly reduces PFS rates, particularly in patients with del(17p). Interestingly, MRD cells from SR and HR patients may have different transcriptional mechanisms leading to VRD resistance, and further understanding of these could provide knowledge on how to eradicate MRD in both patient subgroups. Disclosures Puig: Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Garcia-Sanz:Affimed: Research Funding. Martinez-Lopez:BMS: Research Funding; Pfizer: Research Funding; Vivia: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding. Oriol:Celgene: 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; 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. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, 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; Amgen: Consultancy, Honoraria, 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. Lahuerta:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Bladé:Janssen: Honoraria. San-Miguel:Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria.
- Published
- 2018
17. Multidimensional Immunophenotyping Identifies Hallmarks of Systemic Light-Chain Amyloidosis (AL) and Maps the Disease in the Crossroad between MGUS and Multiple Myeloma (MM)
- Author
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Dolores Gómez, María-Belén Vidriales, Albert Pérez, Luis Palomera, Alfonso García de Coca, Bruno Paiva, Maria-Victoria Mateos, Joaquin Martinez Lopez, Juana Merino, Cristina Moreno, Felipe de Arriba, Jorge Labrador, Felipe Prosper, Mercedes Gironella, Albert Oriol, Ramón Lecumberri, María Teresa Cedena, Quentin Lecrevisse, Esther González Garcia, Jesús F. San-Miguel, María José Casanova, Enrique M. Ocio, Marta Lasa, José J. Pérez, Juan José Lahuerta, Javier Verde, Noemi Puig, Alberto Orfao, Jose Enrique de la Puerta, Valentin Cabañas, Isabel Krsnik, Javier de la Rubia, and Leire Burgos
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Tumor burden ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Organ damage ,Immunophenotyping ,Internal medicine ,medicine ,Organ involvement ,Diagnostic screening ,business ,Bristol-Myers ,Monoclonal gammopathy of undetermined significance ,Multiple myeloma - Abstract
Background: Since survival in AL mainly depends on the extent of organ involvement of patients at presentation, early diagnosis and risk stratification are key to improve patients' outcome. Therefore, together with surrogates of organ involvement, biomarkers identifying patients with MGUS or MM at greater risk of developing AL would be highly valuable to prevent organ damage, to maximize therapeutic efficacy and to improve outcomes in AL. Aim: To investigate the value of multidimensional flow cytometry (MFC) for simultaneous fast diagnostic screening of plasma cell (PC) clonality and risk stratification, as well as to identify immunophenotypic markers useful for the selection of patients with monoclonal gammopathies candidates for monitoring of pre-symptomatic organ damage related to AL. Methods: We used MFC to characterize a large series of patients with newly-diagnosed (ND) AL (N=94) vs MGUS (N=20) and NDMM (N=52), as well as age-matched healthy adults (HA, N=30). For each patient with AL, automated risk stratification was performed using principal component analysis (PCA) based on the relative frequency of bone marrow (BM) PCs, plus the percentage of clonal and normal PCs within the whole BM PC compartment, vs a database containing information on the same three parameters from a total of 1,774 patients, including 497 MGUS and 1,227 NDMM. In parallel, immunophenotypic protein expression profiles (iPEP) of AL patients were clustered using t-SNE, and the comparison between the iPEP of clonal PCs from patients with AL vs MGUS and MM cases was performed using canonical-correlation analysis (CCA). To identify additional immunophenotypic hallmarks of AL, the BM cellular composition in HA, MGUS, AL and MM patients was compared using 2-dimensional minimum spanning tree (MST) force-directed classification to determine the distance among individual cases. Results: PC clonality was detected by MFC in 93/94 (99%) AL patients, whereas an M-component was detectable in 96% of cases by electrophoresis, immunofixation and sFLC. PCA as defined above, identified AL patients displaying an MM-like (n=6) and an MGUS-like (n=38) signature, as well as 49 cases with an intermediate signature between the MGUS and MM reference datasets. Multivariate analysis of baseline prognostic factors for survival, including patients' age, number of organs involved, Mayo staging, the percentage of BM PCs based on cytomorphology and eligibility for ASCT, showed that having an intermediate- or an MM-like profile had an independent adverse effect on patients' progression-free (PFS) and overall survival (OS) (HR:3.4; P≤.02). t-SNE based on the iPEP of clonal PCs revealed two major clusters of AL patients with significantly different PFS, defined by opposite patterns of expression for CD45, CD56 and CD138 (P≤.02). CCA of tumor iPEP showed partial overlap between AL vs MGUS and MM, with progressively higher percentages of cases with a CD38lo, CD45-ve, CD81-ve and CD138lo iPEP being observed from MGUS to AL and MM. In contrast, AL patients displayed significantly lower reactivity for CD56 (P≤ .03). Further characterization of the BM cellular composition allowed the systematic assessment of 16 cell populations and 18 phenotypic parameters that, by MST, mapped AL in between MGUS and MM. Of note, while AL patients displayed a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, the percentage of B-cell precursors was consistently lower in AL patients than in HA, MGUS and MM (P=.004). Thus, using optimal cut-off values to discriminate between AL vs MGUS and MM, we built a scoring model based on the presence of 80% clonal PCs within total BM PCs and Conclusions: We demonstrate the value of MFC for fast diagnostic screening of PC clonality in AL and simultaneous automated patient risk-stratification, based on the BM tumor burden and PC phenotype. In addition, our results also provide new immunophenotypic markers for the identification of patients with monoclonal gammopathies that are candidates for monitoring of pre-symptomatic organ damage related to AL. Disclosures Puig: Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Ocio:Array Pharmaceuticals: Research Funding; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmamar: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Oriol:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: 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; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Martinez Lopez:Janssen: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau. Mateos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Abbvie: Consultancy, 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; Janssen: Consultancy, Honoraria, 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. Lahuerta:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria.
- Published
- 2018
18. Analysis of diagnostic and therapeutic strategies in advanced cardiac light-chain amyloidosis
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Inés Sayago, Juan Francisco Oteo, Natalia Jaramillo, Susana Mingo, Luis Alonso-Pulpón, Pablo García-Pavía, Clara Salas, Manuel Gómez-Bueno, Isabel Krsnik, and Javier Segovia
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Delayed Diagnosis ,030204 cardiovascular system & hematology ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Biopsy ,Medicine ,Humans ,030212 general & internal medicine ,Retrospective Studies ,Transplantation ,medicine.diagnostic_test ,business.industry ,Bortezomib ,Amyloidosis ,Retrospective cohort study ,medicine.disease ,Boronic Acids ,Hematologic Response ,Surgery ,Log-rank test ,Cardiac amyloidosis ,Relative risk ,Pyrazines ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Background Prognosis of advanced cardiac light-chain amyloidosis (ACAL) is ominous. Diagnosis of ACAL is frequently preceded by several biopsies of non-clinically affected tissues, which can result in dangerous treatment delays. Combinations of alkylators and steroids have a limited role in its therapy. Definitive efficacy of bortezomib in ACAL is not widely described. In this study we analyze the diagnostic yield of biopsies and compare the effect of bortezomib with other therapeutic strategies in ACAL patients. Methods This study is a retrospective analysis of 40 consecutive ACAL patients treated at our hospital (2005 to 2015). For comparison purposes, the cohort was divided into 2 groups: patients treated with bortezomib ( n = 23) and those treated with other therapeutic approaches (non-bortezomib, n = 8). Results Sensitivity of biopsies of non-clinically affected organs was 23%, as compared with 97% for affected organ biopsies ( p 2 biopsies resulted in an average delay in diagnosis of 4.1 months ( p = 0.007). Hematologic response was observed in 96% of patients in the bortezomib group compared with 25% in the non-bortezomib group (relative risk=3.8; 95% confidence interval 1.14 to 12.75; p = 0.0002). Cardiac response criteria were met by 60% of patients in the bortezomib group as compared with none in the non-bortezomib group ( p = 0.005). Survival at 6 months and 1 and 2 years for bortezomib patients was 91%, 91% and 73%, as compared with 58%, 15% and 0% for non-bortezomib patients (log rank, p Conclusion In our experience, the sensitivity of biopsies from non-affected organs in ACAL is poor and could result in diagnostic delay. Bortezomib was associated with higher hematologic and cardiac response rates as well as survival when compared with other therapies.
- Published
- 2015
19. Myocardial uptake of 99mTc-DPD in patients with AL amyloidosis
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Esther Gonzalez-Lopez, Laura Llorente, Javier Segovia, Isabel Krsnik, Carlos de Miguel, Pablo García-Pavía, and Francisco Javier de Haro-del Moral
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Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,food and beverages ,030204 cardiovascular system & hematology ,medicine.disease ,Scintigraphy ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal Medicine ,AL amyloidosis ,Medicine ,In patient ,business ,Deposition (chemistry) - Abstract
AL amyloidosis is a free light-chain (FLC) deposition disease that can affect the heart. Identification of the specific subtype is essential for treatment and prognosis. 99mTc-DPD scintigraphy has ...
- Published
- 2017
20. Cardiac Amyloidosis: The Importance of a Multidisciplinary Approach
- Author
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Isabel Krsnik, Manuel Gómez-Bueno, Javier Segovia, Víctor Sánchez-Turrión, Luis Alonso-Pulpón, Clara Salas, Pablo García-Pavía, and J.M. Barcelo
- Subjects
Male ,medicine.medical_specialty ,Poor prognosis ,Heart Diseases ,Amyloid ,medicine.medical_treatment ,Disease ,Internal medicine ,medicine ,Humans ,Ultrasonography ,Heart transplantation ,business.industry ,Myocardium ,Amyloidosis ,Restrictive cardiomyopathy ,General Medicine ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Cardiac amyloidosis ,Heart failure ,Cardiology ,Heart Transplantation ,Female ,business - Abstract
Cardiac amyloidosis is associated with the interstitial deposition of abnormal protein in the myocardium, which can lead to a form of restrictive cardiomyopathy with a poor prognosis. This protein can have a number of different origins, which give rise to various subtypes of amyloidosis that have different prognoses and that require different therapeutic approaches. Drugs commonly used in heart failure have little effect in amyloidosis and the use of heart transplantation is controversial because amyloidosis is a multi-organ disease and because there is a possibility of disease recurrence in the graft. The use of new techniques to identify the specific amyloidosis subtype, the emergence of novel ways of preventing or decreasing amyloid production, the ability to monitor responses to therapy and, above all, the introduction of multidisciplinary teams that can implement a combination of therapies, including multiple organ transplantation, have contributed to a substantial improvement in the prognosis of this disease.
- Published
- 2009
21. Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor
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Isabel Krsnik, Rosa Gonzalo-Daganzo, Rafael Fores, Isabel Millán, M N Fernández, José A. García-Marco, Elena Ruiz, Belen Navarro, Emilio Ojeda, Elena Magro, Carmen Regidor, Miguel A. Rico, Guiomar Bautista, A de Laiglesia, Trinidad Martín-Donaire, Santiago Gil, Sanjuán I, and J R Cabrera
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,CD34 ,Graft vs Host Disease ,Gastroenterology ,Umbilical cord ,Internal medicine ,medicine ,Humans ,Transplantation ,Hematology ,business.industry ,Histocompatibility Testing ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Hematopoietic Stem Cell Mobilization ,Tissue Donors ,Surgery ,Haematopoiesis ,medicine.anatomical_structure ,Cord blood ,Female ,Cord Blood Stem Cell Transplantation ,Stem cell ,business - Abstract
This open label clinical study provides updated evaluation of the strategy of single unit cord blood transplants (CBTs) with co-infusion of third-party donor (TPD) mobilized hematopoietic stem cells (MHSC). Fifty-five adults with high-risk hematological malignancies, median age 34 years (16-60 years) and weight 70 kg (43-95 kg), received CBTs (median 2.39 x 10(7) total nucleated cell (TNC) per kg and 0.11 x 10(6) CD34+ per kg) and TPD-MHSC (median 2.4 x 10(6) CD34+ per kg and 3.2 x 10(3) CD3+ per kg). Median time to ANC and to CB-ANC0.5 x 10(9)/l as well as to full CB-chimerism was 10, 21 and 44 days, with maximum cumulative incidences (MCI) of 0.96, 0.95 and 0.91. Median time to unsupported platelets20 x 10(9)/l was 32 days (MCI 0.78). MCI for grades I-IV and III-IV acute GVHD (aGVHD) were 0.62 and 0.11; 12 of 41 patients (29%) who are at risk developed chronic GVHD, becoming severely extensive in three patients. Relapses occurred in seven patients (MCI=0.17). The main causes of morbi-mortality were post-engraftment infections. CMV reactivations were the most frequent, their incidence declining after the fourth month. Five-year overall survival and disease-free survival (Kaplan-Meier) were 56 % and 47% (63% and 54% for patientsor=40 years). In conclusion, CBT with single units of relatively low cell content and 0-3 HLA mismatches is feasible as a first choice option for adult patients who lack a readily available adequate adult donor.
- Published
- 2008
22. All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia: a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies
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Miguel A, Sanz, Pau, Montesinos, Haesook T, Kim, Guillermo J, Ruiz-Argüelles, María S, Undurraga, María R, Uriarte, Lem, Martínez, Rafael H, Jacomo, Homero, Gutiérrez-Aguirre, Raul A M, Melo, Rosane, Bittencourt, Ricardo, Pasquini, Katia, Pagnano, Evandro M, Fagundes, Edo, Vellenga, Alexandra, Holowiecka, Ana J, González-Huerta, Pascual, Fernández, Javier, De la Serna, Salut, Brunet, Elena, De Lisa, José, González-Campos, José M, Ribera, Isabel, Krsnik, Arnold, Ganser, Nancy, Berliner, Raul C, Ribeiro, Francesco, Lo-Coco, Bob, Löwenberg, Eduardo M, Rego, E, de Lisa, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), and Hematology
- Subjects
Oncology ,Male ,medicine.medical_treatment ,Risk-adapted therapy ,Pharmacology ,THERAPY ,Leukemia, Promyelocytic, Acute ,immune system diseases ,Risk Factors ,Antineoplastic Combined Chemotherapy Protocols ,Cumulative incidence ,Anthracyclines ,Adolescent ,Adult ,Aged ,Daunorubicin ,Disease-Free Survival ,Female ,Humans ,Idarubicin ,Matched-Pair Analysis ,Middle Aged ,Treatment Outcome ,Tretinoin ,Young Adult ,CONSOLIDATION ,Promyelocytic ,OUTCOMES ,Leukemia ,Cytarabine ,Hematology ,General Medicine ,Cohort ,medicine.drug ,medicine.medical_specialty ,Anthracycline ,AGENT ARSENIC TRIOXIDE ,Acute ,Matched-pair analysis ,Prognostic factors ,Internal medicine ,medicine ,neoplasms ,RESPONSE CRITERIA ,Chemotherapy ,business.industry ,All-trans retinoic acid ,QUIMIOTERÁPICOS ,ANTHRACYCLINE ,medicine.disease ,Acute promyelocytic leukaemia ,business ,Settore MED/15 - Malattie del Sangue - Abstract
Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two entire cohorts. Complete remission (CR) rate was significantly higher in the PETHEMA/HOVON (94 %) than in the IC-APL cohort (85 %) (P = 0.002). The distribution of causes of induction failure and the time to achieve CR were similar in both cohorts. Patients who achieved CR had comparable cumulative incidence of relapse and disease-free survival rates, but lower overall and event-free survivals were observed in the IC-APL cohort, which was mainly due to a higher death rate during induction therapy. A higher death rate during consolidation therapy was also observed in the IC-APL. These results show that daunorubicin and idarubicin have similar antileukaemic efficacy in terms of primary resistance, molecular persistence, as well as molecular and haematological relapse rates when combined with ATRA in treatment of APL. However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov].
- Published
- 2015
23. Hemophagocytic syndrome associated with retinoic acid syndrome in acute promyelocytic leukemia
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Eduardo Reyes, J. Garcia-Suarez, Helena Bañas, Isabel Krsnik, Carmen Burgaleta, and D. De Miguel
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Acute promyelocytic leukemia ,medicine.medical_specialty ,Hematology ,business.industry ,Hepatosplenomegaly ,medicine.disease ,Pancytopenia ,Retinoic acid syndrome ,Leukemia ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Internal medicine ,Immunology ,medicine ,Idarubicin ,Bone marrow ,medicine.symptom ,business ,neoplasms ,medicine.drug - Abstract
A 56-year-old woman with an acute promyelocytic leukemia (APL) developed a severe all-trans-retinoic (ATRA) syndrome on day 17 of treatment. Shortly after, she presented a picture of pancytopenia, hepatosplenomegaly, increased triglycerides, ferritin, and liver enzymes. A bone marrow biopsy showed abundant macrophages and no evidence of leukemia. Tests for secondary hemophagocytic syndrome (HPS) were negative. A diagnosis of HPS was made. Treatment with dexamethasone and high-dose immunoglobulins was unsuccessful. Consolidation chemotherapy with idarubicin and ATRA rapidly reversed the HPS. The HPS in this patient could be related to the release of macrophage-stimulating cytokines by APL cells during ATRA syndrome.
- Published
- 2004
24. Elderly haematological patients with chemotherapy-induced febrile neutropenia have similar rates of infection and outcome to younger adults: a prospective study of risk-adapted therapy
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Eduardo Reyes, Nuria Hernanz, J. Garcia-Suarez, Carmen Burgaleta, Isabel Krsnik, Dunia de Miguel, and Mohamed Barr-Alí
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medicine.medical_specialty ,Leukopenia ,business.industry ,Incidence (epidemiology) ,Hematology ,Neutropenia ,medicine.disease ,Surgery ,Amikacin ,Internal medicine ,medicine ,Absolute neutrophil count ,medicine.symptom ,Prospective cohort study ,business ,Complication ,Febrile neutropenia ,medicine.drug - Abstract
Summary. We prospectively evaluated 131 consecutive episodes of fever and chemotherapy-induced neutropenia in 85 adults with haematological malignancies to determine whether older patients (aged
- Published
- 2003
25. The contribution of f. w. peabody to the study of pernicious anaemia
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Isabel Krsnik
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Ineffective erythropoiesis ,medicine.medical_specialty ,Pernicious anaemia ,business.industry ,Internal medicine ,Medicine ,Hematology ,business ,medicine.disease_cause ,Gastroenterology - Published
- 2001
26. Response to Proteosome Inhibitors and Immunomodulatory Drugs before and after Allogeneic Transplantation in Patients with Multiple Myeloma: A Long Term Follow up Study
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Laura Rosiñol, Gonzalo Gutierrez, Antonia Sampol, Carmen Martinez, Cristina Castilla-Llorente, Maria-Victoria Mateos, Francesc Fernández-Avilés, José Antonio Pérez-Simón, Veronica D. Gonzalez, Isabel Krsnik, Mireia Morgades, A. M. Vazquez, José M. Moraleda, José Rifón, Josep-Maria Ribera, Oriana Lopez Godino, Inmaculada Heras, Martin Cabero, Teresa Caballero Velázquez, Marta Torres Juan, Pastora Iniesta, Lucía López Corral, Montserrat Rovira, Daniel Morillo, Dolores Caballero, and Jesus San Miguel
- Subjects
Oncology ,Melphalan ,medicine.medical_specialty ,Allogeneic transplantation ,Immunology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Multiple myeloma ,030219 obstetrics & reproductive medicine ,business.industry ,Cell Biology ,Hematology ,Pomalidomide ,medicine.disease ,Carfilzomib ,Fludarabine ,Transplantation ,Calcineurin ,chemistry ,business ,030215 immunology ,medicine.drug - Abstract
Introduction: Allogeneic haematopoietic stem cell transplantation (alloHCT) is a potentially curative approach for patients (pts) with multiple myeloma (MM). The high transplant related mortality (TRM) rate with myeloablative conditioning has resulted in a shift to reduced intensity conditioning regimens (RIC). However, most MM pts who receive an alloRIC ultimately relapse and their treatment remains a challenge. Since alloHCT can modify the biology of the disease, including the immune environment, responses after alloHCT to rescue therapies previously used before alloHCT could be improved. Our main objective was to evaluate the efficacy of regimens including new drugs in MM pts relapsing after alloHCT comparing the efficacy achieved before and after alloHCT. Material and Methods: We report a retrospective multicenter analysis of 126 consecutive pts that underwent alloHCT for MM from 2010 to 2013 at 8 Spanish centers. Results: Baseline pts and transplant characteristics are shown in Table I. The median of prior therapies prior to alloHCT was 3 (1-9), 83% had received previous autologous HCT and 26% had high risk cytogenetic. 71 (56%) and 48 pts (38%) had been treated with regimens containing proteasome inhibitors (PI) and immunomodulatory drugs (IMIDs) before transplantation, respectively. Disease status at transplant was complete remission (CR) in 16 (13%) pts, partial response (PR) or very good PR in 86 (68%) and 24 (18.5%) had relapsed/progressive disease. 35 pts (28%) had active extramedullary disease at transplant. The majority of pts received peripheral blood HCT (90%), RIC (90%) with fludarabine plus melphalan based conditioning regimen (61%) and calcineurin inhibitor plus MTX as GVHD prophylaxis (68%). 19% receiving allo-HCT from an unrelated donor (91% 10/10 HLA matched). All pts engrafted. Grade II-IV acute GVHD occurred in 54% pts (grade IV 8%) and chronic GVHD in 45% (moderate 15%, severe 12%). TRM within the first 100 days after transplant was 6% (overall TRM 28%). 60% pts improved their pre-transplant response, with an overall response rate of 74% (56% CR). After a median follow-up of 92 months for pts alive (22-197), the OS was 51 and 43% at 2 and 5 years respectively. 75 pts (59.5%) relapsed after alloHCT, 57 of them with extramedullary involvement. Median time to relapse was 8 months post-transplant (1-141). The cumulative incidence of relapse was 79% at 3 years. Median OS after relapse was 22 months (8-33). Seventeen out of 75 pts who relapsed received IP both in the pre-transplant and in the post-transplant period. Sixteen pts out of 17 who received IP achieved at least PR pre-transplant while 10 out of these 16 pts responded again to PI post-HCT. Moreover, 1 patient reached a deeper response (CR) post as compared to pre alloHCT (PR) and 1 patient who was refractory pre-alloHCT did respond post-alloHCT. In addition, 6 out of 7 pts who did not respond to IP post-transplant reached stable disease with time to progression (TTP) lasting 4 to 12 months. Twelve out of 75 pts who relapsed received IMIDs both pre and post-alloHCT. Ten pts out of 12 who received IMID pre-alloHCT achieved at least PR, and 8 out of these 10 pts responded again to IMIDs post-alloHCT. Moreover, 1 patient who had been refractory to IMIDs in the pre-transplant period reached CR after alloHCT. In addition, 2 out of 4 pts who were refractory to IMIDs in the post-transplant period reached stable disease with TTP of 8 to 13 months. Remarkably, among pts who respond both in the pre and the post-transplant period to IP or IMIDs, the time to response (TTR) and time to progression (TTP) was similar despite the regimens used in the pre-transplant setting were more aggressive (TTR 3 vs 3.5 and TTP 9 vs 7 months before and after alloHCT for IP, and TTR 4 both before and after alloHCT and TTP 10 vs 9.5 months before and after alloHCT for IMIDs). All but 2 pts received first generation IP pre and post-alloHCT (two pts received carfilzomib) and all but 5 received first generation IMIDs (5 pts were treated with pomalidomide). Conclusions: MM pts relapsing after alloHCT should be considered candidates to receive new drugs, as they can achieve response rates at least in a similar proportion and durability to those observed in the pre-transplant setting. This finding is in contrast to the usual course of the disease outside the alloHCT setting, where response rates and TTP decreases with consecutive lines of treatment. Disclosures Mateos: Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria.
- Published
- 2016
27. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens
- Author
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Pau, Montesinos, Chelo, Rayón, Edo, Vellenga, Salut, Brunet, José, González, Marcos, González, Aleksandra, Holowiecka, Jordi, Esteve, Juan, Bergua, José D, González, Concha, Rivas, Mar, Tormo, Vicente, Rubio, Javier, Bueno, Félix, Manso, Gustavo, Milone, Javier, de la Serna, Inmaculada, Pérez, Manuel, Pérez-Encinas, Isabel, Krsnik, Josep M, Ribera, Lourdes, Escoda, Bob, Lowenberg, Miguel A, Sanz, M, van Marwijk Kooy, Interne Geneeskunde, RS: CARIM School for Cardiovascular Diseases, Hematology, Faculteit Medische Wetenschappen/UMCG, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)
- Subjects
Oncology ,Male ,medicine.medical_treatment ,Biochemistry ,PROGNOSTIC-FACTORS ,Leukemia, Promyelocytic, Acute ,COMPETING RISK ,immune system diseases ,Recurrence ,Risk Factors ,Antineoplastic Combined Chemotherapy Protocols ,FAILURE ,Anthracyclines ,CONSOLIDATION ,PETHEMA ,ABNORMALITIES ,hemic and immune systems ,Hematology ,CHEMOTHERAPY ,Middle Aged ,Prognosis ,CD56 Antigen ,Leukemia ,Female ,medicine.drug ,Acute promyelocytic leukemia ,Adult ,medicine.medical_specialty ,Adolescent ,Immunology ,chemical and pharmacologic phenomena ,Tretinoin ,ACUTE MYELOID-LEUKEMIA ,Young Adult ,Internal medicine ,medicine ,Idarubicin ,Humans ,Clinical significance ,INDICATOR ,neoplasms ,Mitoxantrone ,Chemotherapy ,business.industry ,Cell Biology ,medicine.disease ,RISK-ADAPTED TREATMENT ,Cytarabine ,business - Abstract
The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventy-two patients (11%) were CD56+ (expression of CD56 in ≥ 20% leukemic promyelocytes). CD56+ APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56+ APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56− APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56+ APL also showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin–derived regimens. This marker may be considered for implementing risk-adapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278.
- Published
- 2010
28. The Role of Bortezomib in Advanced Cardiac AL Amyloidosis
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Luis Alonso-Pulpón, Manuel Gómez-Bueno, Inés Sayago, Pablo García-Pavía, Isabel Krsnik, Javier Segovia, and Natalia Jaramillo
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Pulmonary and Respiratory Medicine ,Oncology ,Transplantation ,medicine.medical_specialty ,Bortezomib ,business.industry ,medicine.disease ,Internal medicine ,medicine ,AL amyloidosis ,Surgery ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Published
- 2015
29. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies
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Dunia de Miguel, J. Garcia-Suarez, Helena Bañas, Carmen Burgaleta, Ignacio Arribas, and Isabel Krsnik
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Adult ,Male ,medicine.medical_specialty ,Alkylating Agents ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Purine analogue ,Lymphoproliferative disorders ,Antineoplastic Agents ,Hematopoietic stem cell transplantation ,Gastroenterology ,History, 21st Century ,Disease-Free Survival ,Antibodies, Monoclonal, Murine-Derived ,Sex Factors ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,Univariate analysis ,Radiotherapy ,business.industry ,Progressive multifocal leukoencephalopathy ,Age Factors ,Leukoencephalopathy, Progressive Multifocal ,Antibodies, Monoclonal ,HIV ,Hematology ,History, 20th Century ,Middle Aged ,medicine.disease ,Prognosis ,Combined Modality Therapy ,Lymphoproliferative Disorders ,Lymphoma ,CD4 Lymphocyte Count ,Purines ,Immunology ,Rituximab ,Female ,business ,medicine.drug ,Stem Cell Transplantation - Abstract
The aims of this study were to evaluate the clinical characteristics of HIV-negative patients affected by lymphoproliferative disorders (LPD) who developed progressive multifocal leukoencephalopathy (PML), to delineate the risk factors, and to analyze whether the new antineoplastic therapies are changing the natural history of this infectious disease. We retrospectively analyzed 46 cases with confirmed LPD-associated PML published from 1958 to 2004. Patients were stratified according to two different time periods: group A included patients diagnosed before 1989, and group B included patients diagnosed since 1990, after introduction of purine analogues. Group A patients (n = 22) had received alkylating agents and/or radiotherapy, and the majority (63.6%) had advanced Hodgkin disease. At univariate analysis, uncontrolled Hodgkin disease was the only risk factor for PML. In group B patients (n = 24), the most frequent treatments received were purine analogues (58.3%) and high-dose therapy with hematopoietic stem cell transplantation (33.3%; HDT/HSCT). B-cell chronic lymphocytic leukemia (45.8%) and aggressive non-Hodgkin lymphoma (24.9%) were the most frequent underlying LPDs. Patients treated with purine analogues were more likely to have active LPD, lower CD4 cell counts, and to be older and male than were HSCT recipients. The median interval from purine analogues or HDT/HSCT to PML was 11 months. In HDT/HSCT recipients, this interval was delayed for 10 months when peri-transplantation rituximab was used. Univariate analysis identified age >55 years, male sex, and CD4 cell counts £0.2 · 10 9 /L as risk factors for PML in patients treated with purine analogues. Mortality rates were 95.4% (group A patients), 90% (purine analogues), and 62.5% (HDT/HSCT recipients). At univariate analysis, the only factor that significantly correlated with recovery from infection was female sex. Our findings indicate (1) the possible reduction in reported cases associated with Hodgkin disease and the increasing number of published cases associated with the new antineoplastic therapies (purine analogues and HDT/ HSCT); (2) among patients treated with purine analogues, PML is more common in male patients with CD4 cell counts £0.2 · 10 9 /L; (3) the use of rituximab after HDT/ HSCT seems to delay the onset of PML; and (4) the prognosis is slightly better in transplant recipients. Am. J. Hematol. 80:271‐281, 2005. a 2005 Wiley-Liss, Inc.
- Published
- 2005
30. Iatrogenesis or bad luck? relapse of an LMP1-positive follicular lymphoma after immunosuppression for hepatitis-associated aplastic anaemia
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Montserrat López-Rubio, J. Garcia-Suarez, Isabel Krsnik, and Alicia Santana
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Male ,medicine.medical_specialty ,Herpesvirus 4, Human ,Skin Neoplasms ,Hepatitis, Viral, Human ,medicine.medical_treatment ,Iatrogenic Disease ,Follicular lymphoma ,Gastroenterology ,Iatrogenesis ,Viral Matrix Proteins ,Fatal Outcome ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Aplastic anemia ,Lymphoma, Follicular ,Antilymphocyte Serum ,Hepatitis ,Immunosuppression Therapy ,business.industry ,Lamivudine ,Anemia, Aplastic ,Immunosuppression ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Immunology ,Cyclosporine ,Rituximab ,Virus Activation ,Complication ,business ,medicine.drug - Abstract
A 55-year-old man suffered a cutaneous relapse of an LMP1-positive follicular lymphoma after treatment with antithymocyte globulin and cyclosporine A (CSA) for a hepatitis-associated aplastic anaemia (AA). Rituximab was not effective, so CSA was tapered off. Lymphoma masses did not regress but AA relapsed. A second remission of both lymphoma and AA was achieved with high-dose cyclophosphamide, but the patient died of a bilateral pneumonia. The relationships between immunosuppression, viral reactivation and tumour growth are discussed. The use of rituximab and lamivudine in immunodepressed patients is also commented.
- Published
- 2002
31. Characteristics and Outcome Of 66 Patients With Extramedullary Plasmacytomas (EMPs) Included In a Phase III Pethema/GEM Study Of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma (MM)
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Norma C. Gutiérrez, Jose Francisco Tomas, Ma Jesús Blanchard, Isabel Krsnik, Ma Victoria Mateos, Juan José Lahuerta, Belén Iñigo, Jesús F. San Miguel, Laura Rosiñol, Miguel T. Hernandez, Luis Palomera, Ana Isabel Teruel, Javier de la Rubia, Raquel Jiménez-Segura, Dolores Hernández, and Joan Bladé
- Subjects
Cancer Research ,medicine.medical_specialty ,Intention-to-treat analysis ,business.industry ,Immunology ,Combination chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Gastroenterology ,Biochemistry ,Surgery ,Thalidomide ,Regimen ,Oncology ,Maintenance therapy ,Statistical significance ,Internal medicine ,Medicine ,business ,Multiple myeloma ,Progressive disease ,medicine.drug - Abstract
Introduction In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) initiated a randomized phase III trial (GEM05menos65) comparing induction with thalidomide/dexamethasone (TD) vs. bortezomiv/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200 and maintenance therapy with interferon vs, thalidomide alone or bortezomib/thalidomide. The results of the overall series has been previously published. However, the efficacy of novel agents in patients with extramedullary disease is not well stablished. Primary end points to describe the characteristics and outcome of patients with EMPs homogeneously treated in the GEM05menos65 trial. Patients and Methods TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1-4 and 9-12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus i.v. bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of i.v. bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. 66 patients (17%) had extramedullary plasmacytomas (median age: 54 years, M: 33, F: 33). The isotype was IgG: 41, IgA 11, Bence-Jones: 10, IgD:4; kappa:41, lambda: 25.The stage according to the ISS was I in 27 patients, II in 26 and III in 13 patients. The location of the EMPs was soft-tissue masses arising from lytic lesions in 60 patients, testicular mass with no contact with bone in 1 case and was not specified in 6 cases. Nine patients had multiple extraosseous plasmacytomas. 17 patients received induction therapy with VBMCP/VBAD/B, 23 with TD and 26 with VTD. Results Cytogenetic information was available in 51 out of the 66 cases with EMPs and 12 of them (23%) showed high-risk cytogenetics. There were no differences in the incidence of high-risk cytogenetics (t(4;14), t(14;16) and del 17p) in patients with and without EMPs (23% vs 21%). The incidence of t(4;14) in patients with and without EMP was 16% vs 23%, respectively. The incidence of del 17p was 10% and 6% in patients with and without EMPs.The IFE negative CR rate was significantly higher with VTD as compared to TD (42% vs 13%, p=0.02) while there was no significantly differences among VTD and VBMCP/VBAD/B (42% vs 29%, p=NS). Patients with EMP had a significantly higher rate of PD during induction therapy as compared to patients without EMPs (24% vs 11%, p=0.01). This higher rate of PD in patients with EMP was observed in the 3 induction arms (VBMCP/VBAD/B 24% vs 9%, TD 40% vs 19%, VTD 12% vs 6%). 43 patients received ASCT as part of the treatment design. On an intention to treat basis, the pos-ASCT CR rate was higher with VTD arm compared to TD (50% vs 22%, p=0.07) but not significantly different from VBMCP/VBAD/B (50% vs 41%, p=0.7). After a median follow-up of 46 months, there was no significant differences in PFS between patients with or without EMP (26.9 vs 39.9 months, p=0.47). Although the difference did not reach statistical significance, there was a trend towards a shorter PFS for patients with EMPs with high-risk cytogenetics (median 12.1 vs. 28.3 months, p=0.13). In patients with EMPS, the PFS was not reached in the VTD arm versus 26.9 months with VBMCP/VAB/B and 22.8 moths with TD. The OS was significantly shorter in patients with EMPs as compared to patients without EMPs (median 69.9 months vs not reached, p=0.02) Conclusion 1) In the present study the frequency of EMPs was 17%, 2) the incidence of high-risk cytogenetics in patients with EMPs was similar to that observed in patients with no extramedullary disease, 3) patients with EMPs had a higher rate of progressive disease irrespective of the induction arm as compared to patients without EMPs, being VTD the best treatment option, 4) finally, the OS was significantly shorter in patients with EMPs. Disclosures: Rosiñol: Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Mateos:Jansen: Honoraria; Celgene: Honoraria. Tomas:MedImmune: Research Funding. Gutiérrez:Jansen: Honoraria; Celgene: Honoraria. San Miguel:Celgene: Consultancy, Honoraria, 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; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.
- Published
- 2013
32. Paroxysmal Nocturnal Hemoglobinuria and Cancer: High Incidence Of Cancer In a Large Series Of PNH Patients In a Single Center
- Author
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Belen Navarro, Martin Cabero, Rafael Fores, Emilio Ojeda, José Luis Bueno, Daniel Morillo, Santiago Gil, José A. García-Marco, Almudena de Laiglesia, Guiomar Bautista, Carmen Regidor, Cristina Muñoz-Linares, Isabel Krsnik, and Jose Rafael Cabrera
- Subjects
medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Bone marrow failure ,Cancer ,Immunosuppression ,Cell Biology ,Hematology ,Eculizumab ,Liver transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Transplantation ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Aplastic anemia ,business ,medicine.drug - Abstract
Since 1964, a total of 56 patients with Paroxysmal Nocturnal Hemoglobinuria clone (PNH) were evaluated in our Hematology Unit. The PNH was evaluated with Ham’s and/or sucrose tests until 1993, when the firsts cytometric analysis of PNH were performed in our Laboratory with CD55 and CD59 markers on granulocytes mainly, and since 2011 also with the FLAER technique. According with PNH Parker´s Classification, most of the patients were Classical PNH type (28 patients), and the remaining included in the other subsets such as 21 PNH in the setting of another bone marrow failure syndrome (BMFS) and 7 PNH subclinical. Most of the patients (70%) displayed an Aplastic Anemia (AA) before or concomitantly with the diagnosis of PNH, and received immunosuppressant drugs (Steroids with/out antithymocyte globulin & Cyclosporine). In four patients an Allogeneic Hematopoietic Transplantation was performed due to a Severe Aplastic Anemia (2 patients), a Classical Severe PNH (before Eculizumab era) or a Myelodysplastic Syndrome. Another patient received a Liver Transplantation because of advanced Hepatitis C related liver failure. In our PNH series, an unexpected high incidence of cancer has appeared, with 8 patients (14,5%) displaying different hematological or non-hematological cancers in the lasts years:SexAge Diagnosis PNHParker’s ClassificationYear Diagnosis PNHYear Diagnosis CancerPrevious ImmunosuppressionCancerYear Death♂16Classical19692011YesLymphoma2011AA & Liver Tx♀30Classical19732003NonePancreatic2006♂38Classical19741995NoneGastric20122012Pulmonary♂26Classical19892013Yes, SteroidsCerebralAlive♀25Classical19942005YesLymphoma2006AA & Cord-Blood Tx♂40BMFS19951995Yes, SteroidsLiver1995♂75BMFS20112009NoneSeminoma2012*♂56Subclinical20101999Yes, SteroidsProstaticAlive*Dead because bone marrow failure. In our PNH series, cancer reports as one of the most frequent final cause of death, with thrombosis with similar incidence (11 patients of the 56 are dead, with 5 patients dead because thrombosis), although the high incidence and severity of thrombosis episodes in this cohort of patients (20 patients experienced thrombosis with a total of 40 events). As displayed supra, some of the cancers could be attributed to the therapy applied in particular patients: The two secondary lymphomas after organ transplantation could be explained by the immunosuppression employed in these procedures. Only three patients did not received immunosuppressant drugs before cancer diagnosis. This high mortality cancer rate precludes the indiscriminate use of steroids in PNH patients. This result, never reported before in PNH, merits an investigational survey of cancer incidence in PNH patients in the PNH International Registry. Disclosures: Ojeda: Alexion Pharmaceuticals: Consultancy, Speakers Bureau.
- Published
- 2013
33. Use of Romiplostim to Facilitate Platelet Engraftment in Allogeneic Hematopoietic Transplantation
- Author
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Emilio Ojeda, Santiago Gil, Almudena DelaIglesia, Sanjuán I, Amelia Sanchez-Guerrero, Belen Navarro, Gracia Bravo, Rosa Gonzalo-Daganzo, Martin Cabero, Carmen Regidor, Pilar Beltran, Jose Rafael Cabrera, Trinidad Martín-Donaire, Rocio Sanchez, Rafael Fores, José A. García-Marco, Guiomar Bautista, Isabel Krsnik, and Nuria Claros
- Subjects
Thrombopoietin receptor ,medicine.medical_specialty ,Romiplostim ,Platelet Engraftment ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Platelet transfusion refractoriness ,Transplantation ,Platelet transfusion ,Internal medicine ,Anesthesia ,medicine ,Platelet ,business ,medicine.drug ,Hemorrhagic cystitis - Abstract
Abstract 1947 Background: Thrombocytopenia requiring platelet transfusions is a constant in the hematopoietic transplantation (HT). In some situations, like the adult non-related donor and cord blood HT, the platelet engraftment is delayed for a long time. Hemorrhagic cystitis, venooclusive disease, graft-vs-host disease could to worse these procedures with a very high risk of bleeding and to increase the transplantation morbi-mortality. The agonists of thrombopoietin receptor (TRAs) have demonstrated to increase the platelet production in different pathological situations, like in the ITP and MDS patients. Thus, these new drugs could have a potential benefit in other clinical situations with low platelet production. Methods: We describe our experience in seven patients with Allogeneic HT using Romiplostim (NPlate®, Amgen Inc.), a parenteral TRA peptide, to accelerate the platelet engraftment or to increase the platelet level in the thrombocytopenia induced by HT conditioning or HT related complications. We have administrated Romiplostim in a compassionate basis (off-label). In all cases the drug was administered subcutaneously at a dose of 250 mcg. Most of the patients received only one dose, with the exception of patients #1 and 7, whom received two doses separated by seven days. The first case, a woman diagnosed as Acute Lymphoblastic Leukemia (ALL) with severe HLA platelet refractoriness acquired in the induction and consolidation chemotherapy treatments previous to HT, received two doses of 250 mcg of Romiplostim on days +4 and +12 after peripheral blood progenitor cells infusion from an HLA matched brother. Results: In the first case, a rapid and sustained platelet level increase was obtained, without platelet transfusional support. Encouraged by this successful result, we have used Romiplostim in six more patients with platelet refractoriness to platelet transfusions with or without bleeding. In all the patients the spleen was present. The patient #6, obtained a previous platelet engraftment that was loosed with the beginning of severe cGVHD. (see table) Conclusion: The use of Romiplostim could be very useful in HT complicated by severe platelet transfusions refractoriness. Our data encourages the realization of a randomized prospective study with this drug in HT. Graphic evolution of platelet count over time is depicted in the next figure: Days after Romiplostim administration. Number of platelets x109/L. Disclosures: Ojeda: Amgen Inc.: Consultancy, Honoraria. Off Label Use: Romiplostim (Nplate)is an agonist of thrombopoietin receptor (TRAs) that have demonstrated to increase the platelet production in different pathological situations, like in the ITP and MDS patients.
- Published
- 2011
34. Analysis of Procoagulants Phospholipids in Plasma of Paroxysmal Nocturnal Hemoglobinuria Patients,Processed in Differents Preanalytic Conditions
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Isabel Krsnik, Beatriz Azcoitia, Carmen Regidor, Jose Rafael Cabrera, Martin Cabero, Isabel San Juan, Rafael Fores, Mirian Santero, Isabel Millán, Emilio Ojeda, Belen Navarro, Santiago Gil, Daniel Morillo, Almudena de Laiglesia, Pilar Beltran, Nuria Claros, Cristina Muñoz, Miguel A. Piris, Guiomar Bautista, José A. García-Marco, Rosa Gonzalo, and Trinidad Martin
- Subjects
medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Gastroenterology ,Pathophysiology ,Coagulative necrosis ,Internal medicine ,Fibrinolysis ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Platelet ,Platelet activation ,business ,Complication ,medicine.drug - Abstract
Abstract 5258 Background: Paroxysmal Nocturnal Hemoglobinuria (PNH) is an infrequent hematopoietic stem cell disorder characterized by a higher risk of Tromboembolic disease. This complication is associated with hemolysis, Fibrinolysis and platelet activation. The increase in plasma of procoagulants microparticles from platelets has been incriminated in the pathophysiology of this complication. Up to now the analysis of microparticles has been made by Cytometry, ELISA, Electronic Microscope and thrombin generation, all of them very time-consuming and expensive techniques. Recently, an automatic quantification of microparticles has been introduced for procoagulant phospholipids time coagulation measurement. The objective of this study is to compare the procoagulant phospholipids levels in PNH and Aplasia/PNH overlap disease patients compared with twenty healthy subjects, in samples processed by different preanalytic conditions. Patients and Methods: After an informed consent, twenty healthy subjects (blood donors) matched for age and sex were selected as controls. Eighteen patients (15 PNH and 3 AA /PNH) followed in our Reference Unit. From these, 15 were men and 3 women. Median age of 45,5 yrs. (16–68), 12 were treated with different types of treatments (five of them with Eculizumab) and 6 were not treated. To measure microparticles, after double centrifugation 2500 g × 15 min, and separation in three aliquots, were stored at −80°C and −40°C, and a third sample was processed in fresh. A FXa based coagulative technique was used. Results: The media in controls was 86,3±11,0 seg in fresh, 78,3±13,5 seg at −40°C and 79,3±12,3 seg at −80°C. These differences were significant between the fresh samples at −40°C (p Conclusions: Through this automated coagulative technique based of FXa, a significant increased of microparticles has been observed in controls, at – 40°C and in less significance at −80°C respect fresh samples. In not treatment PNH patients a no significant microparticles levels increased has been measured (because of the reduced sample size) about controls. These differences disappear in treatment PNH patients. There is an increased in microparticles levels in PNH patients before treatment, that becomes normal in treatment patients. Moreover the freezing show an increasing of the plasma procoagulant activity higher at −40°C about −80°C. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2011
35. MYELOFIBROSIS IN PRIMARY MYELODYSPLASTIC SYNDROMES
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Villegas A, E. Del Potro, Isabel Krsnik, A. Gonzalez Fernandez, Rafael Martínez, and M. Lopez Rubio
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Oncology ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Internal medicine ,medicine ,Hematology ,Myelofibrosis ,medicine.disease ,business - Published
- 2008
36. Use of Third Party Ancillary Cells for Enhancement of Full Donor Chimerism and Immunomodulation in Cord Blood Transplants
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Santiago Gil, José A. García-Marco, Elena Ruiz, Sanjuán I, Manuel N. Fernandez, Rosa Gonzalo, Rafael Fores, Guiomar Bautista, Isabel Millán, Emilio Ojeda, Isabel Krsnik, Jose Rafael Cabrera, Carmen Regidor, and Belen Navarro
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Human leukocyte antigen ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,HLA Mismatch ,Haematopoiesis ,Median follow-up ,Internal medicine ,Cord blood ,Medicine ,Stem cell ,business ,Adverse effect - Abstract
We have pioneered co-infusion of a low number of T-cell highly depleted mobilized hematopoietic stem cells (MHSC) from a third party donor (TPD) as a tool to increase rates of cord blood transplant (CBT) engraftment and full chimerism in adults with high risk hematologic malignancies (“dual transplant”, Haematologica2006; 9:640–8). The conditioning regimes used have been myeloablative although of reduced extra-hematological toxicity. After achieving very favourable results regarding both engraftment and full chimerism, we have started using this approach to evaluate the addition of other TPD cells to the purpose of optimizing CBT immune reconstitution. Results on CBT engraftment, chimerism and survival are available for analysis at this time on 53 patients (M/F 33/20, median age 35 years, range 16–60) who received units with a total cell count (TCC) of 1.1 to 4.3 x 107/Kg (median 2.3) and 0–3/6 HLA disparities, who have received TPD MHSC: 38 from an haploidentical donor, 15 from a related or unrelated donor not sharing an HLA haplotype. Days to ANC>500/uL ranged 9–36 (P50: 11; P90: 20). Initially most of the ANC was predominantly from the TPD with increasing proportions of granulocytes of CB source. Days to full CB chimerisms ranged from 11 to 97 (P50: 37; P90: 93). With a median follow up of 15 months, 3 year OS and DFS of these 53 patients are 60% and 53%. OS for patients older and younger than 40 years are 50% and 64% respectively (p= 0,37). Five patients relapsed, 2 of them achieved new complete remission maintaining full CB chimerism. Acute GVHD occurred in 19 patients, most of them grade I-II with favorable response to treatment. Four cases were grade III-IV, causing death to 3 patients. Other were toxic (VOD 2, MOF 3 and cerebral hemorrhage 1) or infections (all but one CMV). These have been the main cause of morbidity after post-transplant neutropenia and were favoured by a slow recovery of the protective immunity. Reconstitution of lymphocyte subpopulations (detailed data available for 31) is similar to what has been described for single unit CBT: prompt recovery of NK cells (1 month), followed by recovery of B cells (3 months) and slower recovery of T cells subpopulations: T8 in about one year, T4 and T-regs within the second year. No adverse effects due to the co-infusion of the TPD MHSC have been observed. Ex-vivo expanded MSC from the same TPD have been co-infused to 8 patients in addition to the MHSC. The number of co-infused MSC has ranged 1.16–3.24 x 106 cells/kg (median 1.38) without adverse effects observed so far: ANC has occurred as in the other patients and only one had signs of aGVHD, who did nor achieve stable response to antivirals for CMV, achieving continued control of both after the infusion of a new dose of 1.12 x106 cells/kg. Conclusion: These results consolidate our previous description of the “dual transplant” strategy as an approach that may allow high rates of engraftment, full chimerisms and survival of HLA mismatch CBT of relatively low cell content for adults of a wide age range with haematological malignancies, with the possibility of adding other subpopulations of the same TPD as cell therapy tools.
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- 2007
37. Cord blood transplantation supported by co-infusion of CD133-positive hematopoietic stem cells from a third party donor: Preliminary results
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Rafael Cabrera, Isabel Krsnik, Rafael Fores, Carmen Regidor, José A. García-Marco, Isabel Millán, and M.N. Fernández
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Oncology ,Transplantation ,medicine.medical_specialty ,Haematopoiesis ,Third party ,business.industry ,Internal medicine ,medicine ,Hematology ,Stem cell ,business ,Cord blood transplantation - Published
- 2006
38. Sustained granulocyte recovery after G-CSF in a patient with ticlopidine-induced severe aplastic anemia
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M. A. Calero, J. Garcia-Suarez, M. López‐Rubio, J. F. Del Campo, Isabel Krsnik, and K. Arribalzaga
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medicine.medical_specialty ,medicine.anatomical_structure ,business.industry ,Internal medicine ,medicine ,Hematology ,Ticlopidine ,Granulocyte ,business ,Severe Aplastic Anemia ,medicine.drug ,Granulocyte colony-stimulating factor ,Surgery - Published
- 1995
39. Risk-Adapted Treatment of Acute Promyelocytic Leukemia: Results of the PETHEMA LPA2005 Trial Using All-Trans Retinoic Acid and Anthracycline with Cytarabine for High-Risk Patients
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Javier de la Serna, José D. González, Aleksandra Holowiecka, Gustavo Milone, Marcos González, Pau Montesinos, Joaquín Díaz Mediavilla, Salut Brunet, Angel Leon, Chelo Rayon, Javier Bueno, José M. Ribera, Juan Bergua, Elena de Lisa, Concha Rivas, José González, Miguel A. Sanz, and Isabel Krsnik
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Acute promyelocytic leukemia ,medicine.medical_specialty ,Mitoxantrone ,Anthracycline ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,AIDA Regimen ,Biochemistry ,Gastroenterology ,Mercaptopurine ,Surgery ,Maintenance therapy ,Internal medicine ,medicine ,Cytarabine ,Idarubicin ,business ,medicine.drug - Abstract
Background: A previous report of the PETHEMA Group (Sanz et al, Blood 2004) showed that a risk-adapted strategy combining ATRA and anthracycline monochemotherapy for induction and consolidation (LPA99 trial), followed by ATRA and low dose methotrexate and mercaptopurine for maintenance therapy, resulted in high antileukemic efficacy, moderate toxicity, and a high degree of compliance. A critical analysis of this study led us to consider the following opportunities for improvement in a new trial: the observation of a lack of relapses in non high-risk patients (WBC counts Thus, a new risk-adapted PETHEMA trial (LPA 2005) was designed and initiated in July 2005. Methods: AIDA regimen (ATRA 45 mg/m2/d ATRA until CR and idarubicin 12 mg/m2/d on days 2, 4, 6 and 8) was given as induction therapy. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: i.”low-risk” patients (WBC 40×109/l) received ATRA (45 mg/m2/d × 15) simultaneously with idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 3 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3); ii.”intermediaterisk” patients (WBC 10×109/l) < 60 years received ATRA (45 mg/m2/d × 15) and idarubicin in courses #1 and #3 at the same dose than for low-risk patients but with the addition of cytarabine (1000 mg/m2/d × 4 in course #1 and 150 mg/m2/8 h days 1 to 4 in course #3) and 2 more days of mitoxantrone in course #2 (5 days instead of 3). Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 25 mg/m2/d ATRA for 15 days every three months during 2 years. Results: Of 319 patients enrolled in the LPA 2005 trial between July 2005 and July 2008, data on baseline characteristics and induction outcome was available from 290 patients. CR was achieved in 268 patients (92%). No resistant cases were observed. Toxicity was manageable during consolidation and there were 2 deaths in CR during consolidation. The median follow-up of the cohort was 21 months (range, 2–38). Six patients presented hematological relapse and 3 molecular relapse. Overall, the 2-year cumulative incidence of relapse (CIR), disease-free survival, and overall survival were 5%, 94%, and 92%, respectively. The 2-year CIR for low-, intermediate- and high-risk patients were 0%, 6% and 8%, respectively. A comparison of these results with those obtained with the LPA99 trial show a statistically significant lower CIR in high-risk patients (p=0.047). Conclusions: The significant improvement of the outcome observed in high-risk patients suggests a synergistic effect of the triple combination of ATRA, anthracycline and cytarabine.
40. Acute Myeloid Leukemia and Erythroleukemia
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M.T. Ferro, J. Diaz Media Villa, Isabel Krsnik, Espinós D, E. Del Potro, and Villegas A
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Oncology ,Leukemia ,medicine.medical_specialty ,business.industry ,hemic and lymphatic diseases ,Internal medicine ,Internal Medicine ,medicine ,Myeloid leukemia ,macromolecular substances ,General Medicine ,medicine.disease ,business - Abstract
Excerpt To the editor: The French-American-British (FAB) Group (1) has proposed several revisions in an attempt to improve their classification of acute myeloid leukemia. For Bloomfield and Brunnin...
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- 1986
41. ECTOPIC PRODUCTION OF CALCITONIN AND HYPOCALCAEMIA IN ACUTE LEUKAEMIA
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Joaquín Díaz-Mediavilla, E. Bordiu, H. Rico, Isabel Krsnik, and M. A. Peńtalver
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Calcitonin ,medicine.medical_specialty ,Leukemia ,Hypocalcemia ,business.industry ,Hematology ,medicine.disease ,Endocrinology ,Internal medicine ,Acute Disease ,Hormones, Ectopic ,Medicine ,Humans ,Hypocalcaemia ,business - Published
- 1987
42. Post-engraftment infections in adult patients transplanted with single cord blood units supported by co-infusion of mobilized purified hematopoietic stem cells from a third party donor
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Jorge Gayoso, Guiomar Bautista, José A. García-Marco, Rafael Fores, Emilio Ojeda, Elena Ruiz, Carmen Regidor, Belen Navarro, Santiago Gil, Manuel N. Fernandez, Sanjuán I, Rafael Cabrera, and Isabel Krsnik
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medicine.medical_specialty ,HBsAg ,Transplantation ,Cyclophosphamide ,business.industry ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,Azithromycin ,medicine.disease ,Biochemistry ,Fludarabine ,Serology ,Cord blood ,Internal medicine ,medicine ,business ,Busulfan ,Hemorrhagic cystitis ,medicine.drug - Abstract
We have co-infused mobilized purified hematopoietic stem cells (HSC) from a third party donor to shorten neutropenia in single unit cord blood transplantation (CBT). We describe post-engraftment infectious complications in 33 consecutive adults with high-risk hematologic malignancies. Median age was 30 (range 16–59), 22 were male. Patients were conditioned with TBI or busulfan, fludarabine, cyclophosphamide and ATG. GVHD prophylaxis included CyA and steroids. Non-bacterial prophylaxis included fluconazol, acyclovir, trimethoprim-sulfamethoxazole and azithromycin or Fansidar (toxopositive cases). Median total infused CB cell dose was 2.26 x 107/kg (1.31–3.7). Pre-CBT toxoplasma serology was positive in 12, negative in 13 (4 received HSC from a seropositive donor) and unknown in 8 cases. Pre-CBT CMV serology was positive in 30 cases. Pre-CBT, 7 patients were HBsAb(+), HBsAg(−) and 1 HBsAg(+) HBsAb(−). ANC>500/uL was achieved by 32/33, median time 10 days (9–36). Full CB chimerism was achieved in 32/33 cases. Most clinically significant infections occurred after ANC recovery (no major neutropenic infections).There were 34 episodes of CMV reactivation (3 patients developed CMV peumonitis and died Short and long term results in adult CBT are improving. However we and others are reporting high incidence of post-engraftment unusual infections which seem related to delayed recovery of cell-mediated immunity. CMV, for which early diagnostic techniques and antiviral agents are available, heads the list. Our toxoplasma cases have prompted us to use prophylaxis in seropositive patients. HBV reactivation among HBsAb(+) HBsAg(−) patients raises the issue of prophylaxis during CBT versus close serological monitoring and pre-emptive therapy. Leishmaniasis is endemic among our city’s dogs, so we actively search for it in FUO (BM examination and culture). Polyomavirus can be found in the urine of up to 50% of BM recipients, viruria preceding symptoms. The value of prospective monitoring and the role of antivirals are unknown. Other unusual infections (as tripanosomiasis in our country) require high index of awareness and consideration in FUO protocols (BM, PB smears). Adult CB recipients are at very high risk of fastidious non-bacterial infections requiring wide pre-BMT screening, close analytical and clinical monitoring, prophylactic/preemptive strategies or early aggressive therapy and innovative immunotherapeutic approaches.
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