45 results on '"Rafael Fores"'
Search Results
2. Treatment of Myeloid Neoplasms with HLA-Mismatched Stem Microtransplantation: Real-Life Single-Center Experience
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Rosalia Alonso Trillo, Almudena de Laiglesia, María Esther Martínez-Muñoz, Carlos de Miguel, Jose Luis Bueno, Guiomar Bautista, Nuria Panadero, Miguel García, Carlos Vilches, Rafael Fores, and Rafael F. Duarte
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
3. Use of defibrotide to treat adult patients with transplant-associated thrombotic microangiopathy
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Rafael F. Duarte, Belen Navarro, José Luis Bueno, Guiomar Bautista, J R Cabrera, Rafael Fores, A Sánchez-Guerrero, A de Laiglesia, María Esther Martínez-Muñoz, C. de Miguel, and Ana Lario
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Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Thrombotic microangiopathy ,Adolescent ,medicine.medical_treatment ,MEDLINE ,Transplants ,Hematopoietic stem cell transplantation ,Defibrotide ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Transplantation ,Adult patients ,Thrombotic Microangiopathies ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Allografts ,medicine.disease ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,Female ,business ,030215 immunology ,medicine.drug - Published
- 2018
4. Extravascular hemolysis and complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing eculizumab treatment
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Héctor Martín Merinero, Fernando A. González-Fernández, Santiago Rodríguez de Córdoba, Rafael Fores, Ana Villegas, Emilio Ojeda, A. López, Jaouad Anter, Margarita López-Trascasa, Marta Subías Hidalgo, Sheila Pinto García, UAM. Departamento de Medicina, Ministerio de Economía y Competitividad (España), and Comunidad de Madrid
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Cytotoxicity, Immunologic ,Male ,0301 basic medicine ,PNH ,Complement receptor 1 ,Hemoglobinuria, Paroxysmal ,0302 clinical medicine ,Immunology and Allergy ,Child ,Complement Activation ,Complement component 5 ,biology ,Complement C5 ,Complement C3 ,Hematology ,Eculizumab ,Hemolysis ,Treatment Outcome ,Child, Preschool ,Female ,medicine.drug ,Genotype ,Medicina ,Immunology ,Complement ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,Acquired hemolytic anemia ,business.industry ,Genetic Variation ,Infant ,Complement System Proteins ,medicine.disease ,Complement system ,extravascular hemolysis ,Complement Inactivating Agents ,030104 developmental biology ,Receptors, Complement 3b ,Alternative complement pathway ,Paroxysmal nocturnal hemoglobinuria ,biology.gene ,business ,030215 immunology - Abstract
35 p.-3 fig.-4 tab. Subías, Marta et al., Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n=12) for signs of hemolysis and assessed complement biomarkers. Patients were also genotyped for complement receptor 1 (CR1, CD35) and C5 polymorphisms and evaluated for free eculizumab in plasma. We report that 10 patients (83%) present parameters suggesting persistent hemolysis, although they did not require additional transfusions. Seven of them (58%) become direct Coombs-test positive as a consequence of treatment, including all patients carrying the low-expression CR1-L allele. CH50 and sC5b-9 assays demonstrate that the persistent low-level hemolysis identified in our treated patients is not a consequence of incomplete C5 blockade, supporting that this hemolysis, as has been suggested previously, results from the extravascular removal of C3 opsonized PNH erythrocytes. We also show that continuous alternative pathway activation in eculizumab-treated individuals carrying the CR1-L allele results in abnormally decreased levels of C3 in plasma that could, potentially, increase their susceptibility to bacterial infections. Finally, we encourage a routine evaluation of free eculizumab levels and terminal pathway activity to personalize eculizumab administration., S.RdeC is supported by the Spanish “Ministerio de Economía y Competitividad” (SAF2011-26583) and the Autonomous Region of Madrid (S2010/BMD-2316).
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- 2017
5. Mesenchymal stromal cells for steroid-refractory acute GvHD
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Ana Royuela, Rosa Gonzalo-Daganzo, M García-Berciano, José Luis Bueno, J R Cabrera-Marín, A De Liglesia, Rafael Fores, Rafael F. Duarte, Guiomar Bautista, C Fernández-Maqueda, Y Gutiérrez, Rocio Sanchez, M N Fernández, Carmen Regidor, and Trinidad Martín-Donaire
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Adult ,Pathology ,medicine.medical_specialty ,Adolescent ,Graft vs Host Disease ,Mesenchymal Stem Cell Transplantation ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Transplantation, Homologous ,Medicine ,Young adult ,Salvage Therapy ,Transplantation ,business.industry ,Mesenchymal stem cell ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,030220 oncology & carcinogenesis ,Immunology ,Steroids ,Steroid refractory ,business ,030215 immunology - Published
- 2017
6. Haplo-Cord Transplantation Using CD34+ Cells from a Third-Party Donor to Speed Engraftment in High-Risk Patients with Hematologic Disorders
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Rafael F. Duarte, Jorge Gayoso, Rosario de Pablo, David P. Serrano, Rafael Fores, Rafael Cabrera, Ismael Buño, Mi Kwon, Guiomar Bautista, Javier Anguita, José Luis Díez-Martín, M.N. Fernández, Carmen Regidor, Isabel Sánchez-Ortega, Pascual Balsalobre, José A. García Marco, and Carlos Vilches
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Adult ,Graft Rejection ,Male ,medicine.medical_specialty ,Time Factors ,Cord blood transplantation ,Platelet Engraftment ,CD34 ,Graft vs Host Disease ,Antigens, CD34 ,Haploidentical ,Gastroenterology ,Disease-Free Survival ,Alternative donor ,Interquartile range ,Internal medicine ,Humans ,Medicine ,Cumulative incidence ,Transplantation ,Neutrophil Engraftment ,business.industry ,Stem Cells ,Graft Survival ,Hematology ,Middle Aged ,Surgery ,Survival Rate ,surgical procedures, operative ,Hematologic Neoplasms ,Cord blood ,Female ,Cord Blood Stem Cell Transplantation ,Stem cell ,business ,Follow-Up Studies - Abstract
Among the strategies to optimize engraftment of cord blood (CB) stem cell transplantation (SCT), single CB with the coinfusion of CD34+ stem cells from an HLA-mismatched auxiliary donor (haplo-cord) provides a valid alternative for adult patients without a suitable donor. A total of 132 high-risk adult patients with hematological malignancies from 3 Spanish institutions underwent myeloablative haplo-cord SCT. The median age was 37 years and median weight was 70 kg; 37% had active disease. The median number of postprocessing CB total nucleated and CD34+ cells was 2.4 × 107/kg (interquartile range [IQR], 1.8 to 2.9) and 1.4 × 105/kg (IQR, .9 to 2), respectively. Neutrophil engraftment occurred in a median of 11.5 days (IQR, 10.5 to 16.5) and platelet engraftment at 36 days (IQR, 25.5 to 77). Graft failure was 2% overall and only 9% for CB. Cumulative incidence of acute graft-versus-host disease (GHVD) grades II to IV was 21% and cumulative incidence of chronic GVHD was 21%. Median follow-up was 60 months (range, 3.5 to 163). Overall survival was 43.5%, event-free survival was 38.3%, nonrelapse mortality was 35%, and relapse was 20% at 5 years. Myeloablative haplo-cord SCT results in fast engraftment of neutrophils and platelets, low incidences of acute and chronic GVHD, and favorable long-term outcomes using single CB units with relatively low cell content. Moreover, CB cell dose had no impact on CB engraftment and survival in this study. Therefore, haplo-cord SCT expands donor availability while reducing CB cell dose requirements.
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- 2014
7. HLA-Mismatched Microtransplant in Older Patients Newly Diagnosed With Acute Myeloid Leukemia: Results From the Microtransplantation Interest Group
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Kai-Xun Hu, Jian-Hui Qiao, Hui-Sheng Ai, Bo Cai, Hong-Li Zuo, Anthony D. Sung, Lin-Hua Yang, Xuliang Shen, Wei-Wei Liu, Yang-Yi Bao, Wan-Jun Sun, Elizabeth F. Krakow, Depei Wu, Rafael Fores, Qi-Yun Sun, Xinrong Zhan, Li Liu, Ann Mohrbacher, David A. Rizzieri, Jian-Yong Li, Si-Xuan Qian, Nelson J. Chao, Juan Wang, Zhiqing Liu, Ya-Jing Huang, Zheng Dong, Bo Yao, Hong-Xia Zhao, Tie-Qiang Liu, Jun-Xiao Qiao, Chang-Lin Yu, Rafael F. Duarte, Min Zhou, and Mei Guo
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Cancer Research ,medicine.medical_specialty ,Myeloid ,business.industry ,Induction chemotherapy ,Myeloid leukemia ,medicine.disease ,Microtransplantation ,Surgery ,03 medical and health sciences ,Leukemia ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,hemic and lymphatic diseases ,Clinical endpoint ,medicine ,Age of onset ,business ,Survival analysis ,030215 immunology ,Original Investigation - Abstract
Importance The outcome of older patients with acute myeloid leukemia (AML) remains unsatisfactory. Recent studies have shown that HLA-mismatched microtransplant could improve outcomes in such patients. Objective To evaluate outcomes in different age groups among older patients with newly diagnosed AML who receive HLA-mismatched microtransplant. Design, Setting, and Participants This multicenter clinical study included 185 patients with de novo AML at 12 centers in China, the United States, and Spain in the Microtransplantation Interest Group. Patients were divided into the following 4 age groups: 60 to 64 years, 65 to 69 years, 70 to 74 years, and 75 to 85 years. The study period was May 1, 2006, to July 31, 2015. Exposures Induction chemotherapy and postremission therapy with cytarabine hydrochloride with or without anthracycline, followed by highly HLA-mismatched related or fully mismatched unrelated donor cell infusion. No graft-vs-host disease prophylaxis was used. Main Outcomes and Measures The primary end point of the study was to evaluate the complete remission rates, leukemia-free survival, and overall survival in different age groups. Additional end points of the study included hematopoietic recovery, graft-vs-host disease, relapse rate, nonrelapse mortality, and other treatment-related toxicities. Results Among 185 patients, the median age was 67 years (range, 60-85 years), and 75 (40.5%) were female. The denominators in adjusted percentages in overall survival, leukemia-free survival, relapse, and nonrelapse mortality are not the sample proportions of observations. The overall complete remission rate was not significantly different among the 4 age groups (75.4% [52 of 69], 70.2% [33 of 47], 79.1% [34 of 43], and 73.1% [19 of 26). The 1-year overall survival rates were 87.7%, 85.8%, and 77.8% in the first 3 age groups, which were much higher than the rate in the fourth age group (51.7%) ( P = .004, P = .008, and P = .04, respectively). The 2-year overall survival rates were 63.7% and 66.8% in the first 2 age groups, which were higher than the rates in the last 2 age groups (34.2% and 14.8%) ( P = .02, P = .03, P P Conclusions and Relevance Microtransplant achieved a high complete remission rate in AML patients aged 60 to 85 years and higher 1-year overall survival in those aged 60 to 74 years.
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- 2017
8. Paroxysmal nocturnal hemoglobinuria: a single Spanish center’s experience over the last 40 yr
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Guiomar Bautista, Rafael Fores, Isolina Baños, Ana Villegas, Carmen Monteserín, Jose Rafael Cabrera, Esther Jaro, Pilar Bravo, Martin Cabero, Daniel Morillo, Cristina Muñoz-Linares, Emilio Ojeda, Miguel Pastrana, Teresa Cedena, and Juan Luis Steegmann
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,paroxysmal nocturnal hemoglobinuria ,Adolescent ,medicine.medical_treatment ,Hemoglobinuria, Paroxysmal ,Hematopoietic stem cell transplantation ,Liver transplantation ,Antibodies, Monoclonal, Humanized ,Immunophenotyping ,Young Adult ,Quality of life ,Bone Marrow ,Pregnancy ,Neoplasms ,medicine ,Humans ,Transplantation, Homologous ,Renal Insufficiency ,Young adult ,thrombosis ,secondary cancer ,Aged ,Retrospective Studies ,Aged, 80 and over ,liver transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,General Medicine ,Original Articles ,Eculizumab ,Middle Aged ,medicine.disease ,Thrombosis ,Magnetic Resonance Imaging ,Surgery ,Treatment Outcome ,Paroxysmal nocturnal hemoglobinuria ,eculizumab ,Female ,business ,medicine.drug ,Follow-Up Studies - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease. To date, many reviews and series have been described. We report the experience of our center by presenting a review of 56 PNH patient cases with an average age at diagnosis of 38 yr and follow-ups beginning at approximately 40 yr; the median survival rate was 11 yr. The average clonal size upon diagnosis was 48%, presenting a variable evolution. Thrombotic episodes and cancer were five each, and the main causes of death among our patients were equal at 8.9%. Radiological study by magnetic resonance imaging is presented as a fundamental technique for estimating the deposit of iron levels in the liver and kidney, as well as in some decisive cases at the start of eculizumab therapy. Sixteen patients have been treated with eculizumab so far in our series, and being a safe drug, it provides improvement in the patients’ quality of life, and the disappearance of clinical symptoms, and avoids the emergence of new thrombosis.
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- 2014
9. Toxoplasmosis in cord blood transplantation recipients
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Rafael Fores, Guiomar Bautista, Rafael Cabrera, Antonio Ramos, J. Bravo, Elena Ruiz, A de Laiglesia, Carmen Regidor, Belen Navarro, F. Portero, M N Fernández, and Sanjuán I
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Transplantation ,medicine.medical_specialty ,Pediatrics ,Opportunistic infection ,business.industry ,medicine.medical_treatment ,Congenital cytomegalovirus infection ,Cord Blood Stem Cell Transplantation ,Hematopoietic stem cell transplantation ,medicine.disease ,Toxoplasmosis ,Serology ,Surgery ,Infectious Diseases ,Graft-versus-host disease ,medicine ,Disseminated disease ,business - Abstract
Toxoplasmosis is a devastating opportunistic infection that can affect immunocompromised patients such as cord blood transplantation (CBT) recipients. The clinical characteristics of 4 toxoplasmosis CBT patients treated at our institution are reviewed, together with 5 cases collected from the literature. The rate of toxoplasmosis in our hospital was 6% in CBT recipients and 0.2% in other types of allogeneic hematopoietic stem cell transplantation (P
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- 2012
10. Rhodotorula species fungaemia causes low mortality in haematopoietic stem-cell transplantation. A case report and review
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Rafael Cabrera, Antonio Ramos, Julio Bravo, Almudena de Laiglesia, Rafael Fores, Beatriz Orden, Guiomar Bautista, Martin Cabero, Belen Navarro, Elena Múñez, and Isabel Sánchez-Romero
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biology ,business.industry ,medicine.medical_treatment ,Dermatology ,General Medicine ,Hematopoietic stem cell transplantation ,Rhodotorula ,biology.organism_classification ,medicine.disease ,Transplantation ,Haematopoiesis ,Infectious Diseases ,B-cell chronic lymphocytic leukaemia ,Immunology ,Rhodotorula species ,Medicine ,Stem cell ,business ,Fungemia - Published
- 2012
11. Immune reconstitution after cord blood transplants supported by coinfusion of mobilized hematopoietic stem cells from a third party donor
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Rafael Cabrera, Isabel Krsnik, Miguel A. Rico, Belen Navarro, Guiomar Bautista, M N Fernández, Rosa Gonzalo-Daganzo, N Pérez-Sanz, Isabel Millán, Carmen Regidor, Santiago Gil, José A. García-Marco, Emilio Ojeda, Rafael Fores, N. Panadero, Rocio Sanchez, Sanjuán I, Elena Ruiz, Trinidad Martín-Donaire, and Elena Magro
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Adult ,Male ,Transplantation Conditioning ,medicine.medical_treatment ,Graft vs Host Disease ,Kaplan-Meier Estimate ,Cord Blood Stem Cell Transplantation ,Hematopoietic stem cell transplantation ,Lymphocyte Activation ,Disease-Free Survival ,Young Adult ,Immune system ,Transplantation Immunology ,Living Donors ,medicine ,Humans ,Hematopoietic Stem Cell Mobilization ,Transplantation ,business.industry ,Histocompatibility Testing ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Haematopoiesis ,Hematologic Neoplasms ,Cord blood ,Immunology ,Female ,Stem cell ,business - Abstract
Low severity of GVHD, substantial graft vs tumor (GVT) and slow development of protective immunity are well-documented features of cord blood transplants (CBT). We have evaluated the immune reconstitution of adult recipients of single-unit CBT supported by the coinfusion of third party donor (TPD) mobilized hematopoietic stem cells (MHSC), a procedure-'dual CB/TPD-MHSC transplant'-that results in early recovery of circulating granulocytes, high rates of CB engraftment and full chimerism. Cumulative recovery of natural killer and B cells at or above the median values of normal controls were 1.0 and 0.76 by the sixth and ninth months. Recovery of T cells was much slower, naive cells lagging behind those of memory and effector (committed) immunophenotypes. Serial analyses of signal joint TCR excision circles showed a general pattern of very low levels by the third month after CBT, followed by recovery to levels persistently similar or higher than those observed before transplantation and in normal controls. Our results are consistent with the clinical observations of substantial GVT effect together with low incidence of serious GVHD and slow development of protective immunity and suggest that thymic function contributes substantially to the recovery of T-cell populations in adults receiving dual CB/TPD-MHSC transplants.
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- 2009
12. 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
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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.
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- 2008
13. Severe infections after single umbilical cord blood transplantation in adults with or without the co-infusion of CD34(+) cells from a third-party donor: results of a multicenter study from the Grupo Espanol de Trasplante Hematopoyetico (GETH)
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Carmen Regidor, Rafael Fores, José A. García-Marco, Rafael F. Duarte, Francisco J. Márquez-Malaver, Montserrat Rovira, J R Cabrera, Pere Barba, Lourdes Vázquez, Guiomar Bautista, Inmaculada Heras, Silvana Saavedra, David P. Serrano, J. Sierra, I Sánchez-Ortega, Rodrigo Martino, Albert Esquirol, Rocío Parody, and I. García
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Male ,Transplantation Conditioning ,Lymphoma ,CD34 ,Antigens, CD34 ,Gastroenterology ,Severity of Illness Index ,Cohort Studies ,Risk Factors ,Granulocyte Colony-Stimulating Factor ,allogeneic ,Leukopenia ,Leukemia ,Incidence (epidemiology) ,Bacterial Infections ,Middle Aged ,Infectious Diseases ,Virus Diseases ,Cord blood ,Cyclosporine ,Female ,Cord Blood Stem Cell Transplantation ,medicine.symptom ,Immunosuppressive Agents ,Vidarabine ,Whole-Body Irradiation ,Adult ,medicine.medical_specialty ,Adolescent ,severe infections ,cord blood transplantation ,Young Adult ,Internal medicine ,medicine ,Humans ,Busulfan ,Retrospective Studies ,Transplantation ,Peripheral Blood Stem Cell Transplantation ,Neutrophil Engraftment ,business.industry ,Umbilical Cord Blood Transplantation ,Retrospective cohort study ,Myeloablative Agonists ,Surgery ,Mycoses ,Multivariate Analysis ,business ,Thiotepa - Abstract
Background Umbilical cord blood transplantation (CBT) is an established alternative source of stem cells in the setting of unrelated transplantation. When compared with other sources, single-unit CBT (sCBT) is associated with a delayed hematologic recovery, which may lead to a higher infection-related mortality (IRM). Co-infusion with the sCBT of CD34+ peripheral blood stem cells from a third-party donor (TPD) (sCBT + TPDCD34+) has been shown to markedly accelerate leukocyte recovery, potentially reducing the IRM. However, to our knowledge, no comparative studies have focused on severe infections and IRM with these 2 sCBT strategies. Methods A total of 148 consecutive sCBT (2000–2010, median follow-up 4.5 years) were included in a multicenter retrospective study to analyze the incidence and risk factors of IRM and severe viral and invasive fungal infections (IFIs). Neutrophil engraftment occurred in 90% of sCBT (n = 77) and 94% sCBT + TPDCD34+ (n = 71) recipients at a median of 23 and 12 days post transplantation, respectively (P
- Published
- 2015
14. Unrelated umbilical cord blood transplants in adults: Early recoveryof neutrophils by supportive co-transplantation of a low number of highlypurified peripheral blood CD34+ cells from an HLA-haploidentical donor
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Sanjuán I, Carmen Regidor, Rafael Cabrera, Rafael Fores, Jorge Gayoso, Elena Ruiz, Alejandro Madrigal, Ann Margaret Little, M.N. Fernández, Santiago Gil, José A. García-Marco, and A.J. McWhinnie
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Adult ,Male ,Cancer Research ,Neutropenia ,Neutrophils ,Antigens, CD34 ,Opportunistic Infections ,Umbilical cord ,Peripheral blood mononuclear cell ,Transplantation Immunology ,Genetics ,medicine ,Humans ,Transplantation, Homologous ,Molecular Biology ,Peripheral Blood Stem Cell Transplantation ,business.industry ,Histocompatibility Testing ,Graft Survival ,Cell Biology ,Hematology ,medicine.disease ,Survival Analysis ,Transplantation ,Haematopoiesis ,medicine.anatomical_structure ,Haplotypes ,Hematologic Neoplasms ,Cord blood ,Immunology ,Absolute neutrophil count ,Female ,Cord Blood Stem Cell Transplantation ,Stem cell ,business - Abstract
Objective, Methods, and Results. To reduce the period of posttransplant neutropenia and related early morbidity and mortality of cord blood (CB) transplants, we assessed the feasibility of co-infusion of a low number of highly purified peripheral blood CD34 + cells from a related haploidentical donor with a CB graft. Between March 1999 and May 2002, 11 patients with high-risk hematologic malignancies were transplanted using this strategy. The seven patients who received a haploidentical peripheral blood graft and a CB graft from a sibling (6) or the father (1) had prompt recovery (9–17 days, median 10) of the absolute neutrophil count (ANC) to greater than 0.5×10 9 /L. Analysis of DNA polymorphisms showed initial predominance of the haploidentical genotype both in granulocytes and in mononuclear cells, and subsequent progressive replacement by cells of CB genotype until final complete CB chimerism was achieved by patients who survived for sufficient periods of time. The four patients who received maternal haploidentical cells had no significant contribution of these to blood leukocytes, although complete CB chimerism was achieved by three of them and two reached engraftment of the CB on days +20 and +36. Morbidity due to early bacterial or fungal infections was remarkably low in patients with prompt ANC recovery. Conclusion. Our data show that co-infusion of a CB unit and a low number of haploidentical CD34 + cells may result in a shortened period of posttransplant neutropenia. This is likely the result of prompt and transient engraftment of the haploidentical hematopoietic stem cells that may provide the patient antimicrobial protection until the later engraftment of the CBhematopoietic stem cells.
- Published
- 2003
15. Cord blood transplants: early recovery of neutrophils from co-transplanted sibling haploidentical progenitor cells and lack of engraftment of cultured cord blood cells, as ascertained by analysis of DNA polymorphisms
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Rafael Cabrera, Rafael Fores, Carmen Regidor, A.J. McWhinnie, José A. García-Marco, Sergio Querol, M N Fernández, Sanjuán I, M Briz, Alejandro Madrigal, and J. Garcia
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Adult ,Graft Rejection ,Male ,Neutrophils ,CD34 ,Cell Separation ,Nuclear Family ,Blood cell ,medicine ,Humans ,Progenitor cell ,Cells, Cultured ,Transplantation Chimera ,Transplantation ,Polymorphism, Genetic ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Fetal Blood ,Haematopoiesis ,medicine.anatomical_structure ,Haplotypes ,Leukopoiesis ,Leukemia, Myeloid ,Cord blood ,Acute Disease ,Immunology ,Absolute neutrophil count ,Female ,Stem cell ,business - Abstract
The number of infused cells is a very important factor in cord blood transplant (CBT) engraftment. Prior ex vivo expansion of aliquots of transplanted cord blood (CB) units is being investigated as a procedure to increase engraftment potential, but results are difficult to evaluate due to a lack of markers for assessing the contribution of expanded cells. We transplanted five patients, infusing the best available CB unit and cells from a second donor simultaneously. In two patients, these cells were obtained from another frozen CB unit by CD34+positive selection and culture expansion; the other three patients received uncultured highly purified haploidentical CD34+ cells. The first two patients had DNA from the culture expanded CB cells detected only for a few days around day +11 when the absolute neutrophil count (ANC) was >200/μl; thereafter and when the ANC was
- Published
- 2001
16. Umbilical cord blood banking for unrelated transplantation
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Manuel-Nicolás Fernández, Carmen Regidor, Manuel Posada, Rafael Fores, Dolores Monteagudo, Nieves Somolinos, M Briz, and Carlos Garaulet
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Cancer Research ,medicine.medical_specialty ,Chromatography ,Ficoll ,Cell Biology ,Hematology ,Fractionation ,Biology ,Hydroxyethyl starch ,Umbilical cord ,Cryopreservation ,Surgery ,Transplantation ,medicine.anatomical_structure ,Genetics ,medicine ,Cell separation ,Molecular Biology ,Percoll ,medicine.drug - Abstract
Cost-efficient umbilical cord blood (UCB) banking requires well-standardized methods of volume reduction and storage. To compare UCB fractionation using a technique of hydroxyethyl starch (HES) sedimentation with the Ficoll (double) and Percoll methods, 50 whole units was allocated randomly to each procedure. HES resulted in a significantly better recovery of mononuclear cells (87.5%), granulocyte/macrophage colony-forming units (CFU-GM) (88.4%), and CD34 + cells (87.4%) and lesser volume reduction (85.5%). HES was the least laborious, time consuming, and expensive of the three procedures, costing 3.4- and 4.4-fold less than the Ficoll and Percoll methods, respectively. Five units processed by each method was frozen in 4.5-mL cryotubes under optimal conditions. After thawing, the greatest degree of recovery of viable nucleated cells and number of CFU-GM per unit were obtained using the HES procedure. Using 4.5-mL cryotubes, the calculated number of units that could be stored in 600-L containers was 3.8- and 2.2-fold higher for Ficoll- and Percoll-separated than for HES-separated units, respectively. Nevertheless, the higher direct costs of the density gradient separation procedures outweighed their lower storage cost. For long-term cryopreservation, we assessed the freezing of HES-processed units in 50-mL cryobags and their specifically designed canisters. We found cell recoveries similar to those obtained with cryotubes, but storage capacity was decreased. Special racks designed for these canisters resulted in a 5-fold increase over the number of units stored in standard cryobags. This system also is feasible for Percoll- and Ficoll-separated units, resulting in comparable storage costs for the three separation methods. We conclude that this HES procedure and the 50-mL cryobags constitute a cost-efficient system for large-scale UCB banking.
- Published
- 1999
17. Epstein‐Barr virus associated B‐cell lymphoma after autologous bone marrow transplantation for T‐cell acute lymphoblastic leukaemia
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M Briz, Jose Luis Díez, Maria‐José Busto, Rafael Fores, Santiago Ramón y Cajal, Carmen Regidor, Manuel-Nicolás Fernández, Rafael Cabrera, and Sanjuán I
- Subjects
Male ,Herpesvirus 4, Human ,Lymphoma, B-Cell ,Gene Rearrangement, B-Lymphocyte, Heavy Chain ,Gene Rearrangement, T-Lymphocyte ,medicine.disease_cause ,hemic and lymphatic diseases ,Acute lymphocytic leukemia ,medicine ,Humans ,B-cell lymphoma ,Aged ,Bone Marrow Transplantation ,business.industry ,Herpesviridae Infections ,Hematology ,Gene rearrangement ,medicine.disease ,Burkitt Lymphoma ,Epstein–Barr virus ,Bone marrow purging ,Lymphoma ,Non-Hodgkin's lymphoma ,Blotting, Southern ,Tumor Virus Infections ,medicine.anatomical_structure ,Immunology ,Bone marrow ,business - Abstract
Epstein-Barr virus associated lymphoproliferative disease after autologous bone marrow transplantation (ABMT) has rarely been reported. We report a case of B-cell lymphoma following ABMT for T-acute lymphoblastic leukaemia; bone marrow was purged in vitro with monoclonal antibodies to remove T cells. Immunoglobulin and T-cell receptor gene rearrangement studies were used to demonstrate clonality and to show that this patient developed a second neoplasm after ABMT. EBV proteins and genome (type A) were present in post-transplantation lymphoma, suggesting a causative role in its development.
- Published
- 1997
18. Eculizumab Treatment in a Patient with Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy and Steroid-Refractory Acute Graft Versus Host Disease
- Author
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Rafael Fores, Ana Lario, Cristina Fernández, and Rafael Cabrera
- Subjects
medicine.medical_specialty ,Thrombotic microangiopathy ,Bilirubin ,medicine.medical_treatment ,Case Report ,Hematopoietic stem cell transplantation ,Gastroenterology ,chemistry.chemical_compound ,Refractory ,immune system diseases ,Internal medicine ,medicine ,acute graft versus host disease ,lcsh:RC633-647.5 ,business.industry ,Microangiopathy ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,Eculizumab ,medicine.disease ,thrombotic microangiopathy ,Diarrhea ,surgical procedures, operative ,chemistry ,Immunology ,medicine.symptom ,Stem cell ,business ,medicine.drug - Abstract
A 30-year-old man with acquired aplastic anemia underwent an HLA-identical bone marrow transplant. He developed a grade III acute graft versus host disease (GVHD) refractory to various lines of treatment. On post-transplant day 196, he was diagnosed with stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and he received treatment with eculizumab 900 mg iv weekly for 4 doses followed by a single dose of 1200 mg 2 weeks later. After the first dose of eculizumab, the patient ceased to require transfusions and a progressive improvement in analytical parameters for microangiopathy was observed until their complete normalization. Coinciding with the improved of HSCT-TMA, the patient presented a clear response to his acute GVHD with disappearance of the diarrhea and bilirubin normalization. He was discharged eight weeks after the start of treatment. Unfortunately, one month later, the patient was readmitted for a GVHD relapse and he died two weeks later by an acute respiratory distress syndrome. In our case, the rapid clinical and analytical response to early treatment with eculizumab supports the implication of the complement in HSCT-TMA and suggests that the drug has a beneficial effect when used as coadjuvant therapy in acute GVHD.
- Published
- 2015
19. High Cardiac Output By Microfistulas: A New Pulmonary Hypertension Mechanism in Patients with Myelofibrosis and the Impact of the Treatment with Ruxolitinib
- Author
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Francisco Javier Haro, Gomez-Bueno Manuel Francisco, Rafael Fores, Jose Maria Segovia, Isabel Salcedo, José A. García-Marco, Carlos DeMiguel, and Emilio Ojeda
- Subjects
medicine.medical_specialty ,Ruxolitinib ,Cardiac output ,medicine.diagnostic_test ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Scintigraphy ,Biochemistry ,Pulmonary hypertension ,Surgery ,Polycythemia vera ,Internal medicine ,medicine ,Cardiology ,Complication ,Prospective cohort study ,Myelofibrosis ,business ,medicine.drug - Abstract
Background: Pulmonary Hypertension (PH) is a well-known complication of the advanced phase of Myeloproliferative Diseases (MPD) such as Polycythemia Vera (PV), Essential Thrombocytopenia (ET) and Myelofibrosis (MF). Although initially attributed to increased pulmonary vascular resistance (group 1 PH of the WHO classification), this entity was classified in 2009 in group 5 PH (unknown mechanism and miscellaneous PH). Our aim was to describe the prevalence and possible causes of PH in a series of patients with MF. Methods: We studied a series of patients with Primary MF or Secondary MF to other MPD with cardiac ultrasound, right heart catheterization and scintigraphy after intraarterial infusion of Tc99-labeled albumin macroaggregates. Results: We studied 11 consecutive patients with MF (7 male, mean age 58 years, 4 with MF post-PV, 4 post-TE and 3 Primary MF) during the period 2009-2014. All of them had mutations of JAK-2 gene, fibrosis in bone marrow biopsy and visceromegaly (all with intermediate-2 or higher IPSS). Median NTproBNP levels were 4597 pg/ml (range 175-5700). Echocardiogram showed high systolic pulmonary pressure in most cases, with a mean of 54 ± 17 mmHg (range 35-80). Right heart catheterization showed high cardiac output (HCO) in all patients (table 1). After ruling out other causes of HCO, a scintigraphy was performed after administration of Tc99-labeled albumin macroaggregates in descending thoracic aorta. In every case, a percentage of the labeled macroaggregates (6.1 ± 2.0% of the radioactivity) were plugged in the pulmonary capillary bed, what is diagnostic of the presence of microfistulas in infradiaphragmatic territory. In two of these patients, scintigraphies were performed at diagnosis and after been treated with the anti-JAK drug Ruxolitinib (Novartis Pharma). A favourable impact of this drug was obtained in the two cases, probably due to a reduction of spleen volume. Conclusion: Most patients with MF show pulmonary hypertension associated with high cardiac output caused by microfistulas, without significant increase in pulmonary resistance. This finding has important clinical implications, because pulmonary vasodilators (once recommended) should be contraindicated, since they could cause worsening of the clinical picture. Ruxolitinib could resolve PH in MF and a prospective study in this sense could be indicated. Table 1. Patient 1 2 3 4 5 6 7 8 9 10 11 Pulmonary Artery Pres. (S/D/Mean) 58/38/ 42 69/41/ 50 48/29/ 40 84/26/ 45 57/17/ 30 22/17 / 19 51/16 / 28 22/9 / 13 25/8 / 14 71/23 / 39 30/7 / 15 Pulmonary wedge pres. 28 37 27 13 9 7 13 7 8 12 6 Cardiac output (l/min) 12.5 8.0 11 7.1 8 7.3 8.7 6.7 7.45 6 7.8 Cardiac index (l/m/m2) 5.5 4.0 6.6 3.6 5 4 4.8 4.0 4.5 3.9 5.1 Pulmonary vascular resistance (Wood U.) 1.2 1.4 1.2 4.5 2.6 3 1.7 0.9 0.8 4.5 1.1 Disclosures Ojeda: Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fores:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.
- Published
- 2015
20. Complement Genotype and Multiparametric Laboratory Analysis to Predict Response to Eculizumab and to Adjust Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria
- Author
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José A. García-Marco, Jaouad Anter, Rafael Fores, Santiago Rodriguez-Cordoba, Marta Subías-Hidalgo, Ana Maria Villegas-Martinez, Laura Llorente, A. López, Emilio Ojeda, Fernando A. González-Fernández, and Sheila Pinto
- Subjects
Hemosiderinuria ,business.industry ,Immunology ,Cell Biology ,Hematology ,CD59 ,Eculizumab ,Complement Hemolytic Activity Assay ,medicine.disease ,Biochemistry ,Hemolysis ,Complement system ,medicine ,Paroxysmal nocturnal hemoglobinuria ,medicine.symptom ,business ,medicine.drug ,Cause of death - Abstract
Background: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a disorder caused by the proliferation of hematopoietic stem cells carrying a somatic mutation in the gene PIG-A, which is necessary for the biosynthesis of the glycosyl phosphatidyl-inositol anchor. As a consequence, PNH erythrocytes lack, among other proteins, the complement regulators CD55 and CD59 and become susceptible to complement-mediated intravascular hemolysis. Before Eculizumab, a monoclonal antibody that prevents C5 cleavage, life expectancy of PNH patients was about 10-15 years from diagnosis, being thrombotic events the main cause of death. Despite the unquestionable success of Eculizumab therapy to treat PNH, the responses among PNH patients show heterogeneity, with some patients remaining transfusion-dependent for reasons not completely understood. Methods: To get further insight into the different responses to Eculizumab treatment among patients, we have generated a PNH cohort including 12 PNH patients treated with Eculizumab. All patients included in the study had previously a minimum of ≥12 months on treatment with the drug (ten receiving 900 mg every 14 days, and two patients on 1200 mg every 14 days because breakthrough hemolysis). We have collected samples during two Eculizumab cycles (4 weeks) at different points during treatment: before and after Eculizumab injection and in the intermediate week. We have searched for correlations between clinical and hematological parameters, complement genetic findings, and deposition of C3 fragments on erythrocytes and plasma levels of complement activation components. Results: We report the CR1 genotypes, complement and hematological determinations in 12 PNH patients during their treatment with Eculizumab. We have established that concentrations of free Eculizumab above 110 µg/mL completely inhibit serum hemolytic activity. Consistent with this, in our patient cohort, most patients with levels of free Eculizumab close or below 110 µg/mL exhibited traces of C5b9 and/or CH50. In general, lowest levels of free Eculizumab correlate with higher levels of C5b9. Our results indicate that proper monitoring of PNH patients would be useful to optimize Eculizumab dosage. We have 3 patients that showed symptoms of intravascular hemolysis (high LDH and hemosiderinuria) despite having a negative CH50 accompanied with sufficient free Eculizumab levels. Further studies are currently being done to elucidate the causes. We have found a correlation between CR1 haplotype, red cellsopsonization and C3 plasma levels: H/L individuals present higher % of C3 positive erythrocytes and low C3 plasma levels. Two of these patients also had low C4 plasma levels, one of them presenting also low levels of FH. These individuals are currently being studied to determine whether these low levels are due to genetic factors or consumption. We found a correlation between levels of bilirubin and % of reticulocytes; patients who had more than the 30% of their erythrocytes opsonized presented higher percentage of reticulocytes and bilirubin in plasma, which could be taken as indicatives of slight extravascular hemolysis. In this regard, individuals carrying the CR1 L allele might require special attention. Disclosures Ojeda: Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fores:Alexion Pharmaceuticals: Consultancy, Speakers Bureau. Villegas-Martinez:Alexion Pharmaceuticals: Consultancy, Speakers Bureau. Rodriguez-Cordoba:Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
- Published
- 2015
21. Results of a pilot study on the use of third-party donor mesenchymal stromal cells in cord blood transplantation in adults
- Author
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Rafael Cabrera, José A. García-Marco, Isabel Krsnik, Nuria Valverde Pérez, Santiago Gil, Belen Navarro, Yolanda Gutiérrez, N. Panadero, Sanjuán I, Trinidad Martín-Donaire, Rafael Fores, Rosa Gonzalo-Daganzo, Emilio Ojeda, Rocio Sanchez, Guiomar Bautista, Miguel García-Berciano, Carmen Regidor, Isabel Millán, M.N. Fernández, and Miguel A. Rico
- Subjects
Adult ,Male ,Cancer Research ,Neutrophils ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,Cell Count ,Pilot Projects ,Hematopoietic stem cell transplantation ,Mesenchymal Stem Cell Transplantation ,Chimerism ,Cell therapy ,Bone Marrow ,Immunology and Allergy ,Medicine ,Humans ,Transplantation, Homologous ,Genetics (clinical) ,Transplantation ,business.industry ,Mesenchymal stem cell ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Mesenchymal Stem Cells ,Cell Biology ,Middle Aged ,medicine.disease ,Fetal Blood ,Hematopoietic Stem Cell Mobilization ,Tissue Donors ,Haematopoiesis ,surgical procedures, operative ,Graft-versus-host disease ,medicine.anatomical_structure ,Oncology ,Cord blood ,Hematologic Neoplasms ,Acute Disease ,Female ,Bone marrow ,Stem cell ,Stromal Cells ,business - Abstract
Cord blood (CB) transplants with co-infusion of third-party donor (TPD) mobilized hematopoietic stem cells (MHSC) have been shown to result in 'bridge' engraftment with prompt neutrophil recovery and high final rates of CB engraftment and full chimerism. This strategy overcomes the limitation posed by low cellularity of CB units for unrelated transplants in adults. Enhancement of adaptive immunity reconstitution without increasing risks of graft-versus-host disease (GvHD) is required to optimize results further. Our objectives were to evaluate co-infusion of mesenchymal stromal cells (MSC) from the same TPD regarding tolerance, CB engraftment and effects on acute (a)GvHD, both preventive and therapeutic.Ex vivo-expanded bone marrow MSC were infused at the time of the transplant or the in case of refractory aGvHD.Nine patients received 1.04 - 2.15 x 10(6)/kg (median 1.20) MSC immediately after CB and TPD MHSC. Neither immediate adverse side-effects nor significant differences regarding CB engraftment or aGvHD development were observed. Four patients developed grade II aGvHD, refractory to steroids in two. These reached complete remission after therapeutic infusions of MSC.In recipients of 'dual CB/TPD MHSC transplants', MSC infusions were therapeutically effective for severe aGvHD but no significant differences in CB engraftment and incidence of severe aGvHD were observed following their prophylactic use. Although results of this study alone cannot conclusively determine the application of MSC in CB transplantation, we believe that, in this setting, the best use of MSC could be as pre-emptive treatment for aGvHD.
- Published
- 2009
22. Flow cytometric analysis of decay-accelerating factor (CD55) on neutrophils from aplastic anaemia patients
- Author
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Maria Alcocer, Rafael Fores, José Luis Díez-Martín, and Manuel N. Fernandez
- Subjects
Adult ,Male ,Neutropenia ,Neutrophils ,Neutrophile ,CD58 ,CD59 Antigens ,CD59 ,Granulocyte ,Flow cytometry ,Antigens, CD ,Humans ,Medicine ,Aplastic anemia ,Decay-accelerating factor ,Aged ,Complement Inactivator Proteins ,Membrane Glycoproteins ,CD55 Antigens ,medicine.diagnostic_test ,business.industry ,Anemia, Aplastic ,Hematology ,Middle Aged ,CD58 Antigens ,Flow Cytometry ,medicine.disease ,medicine.anatomical_structure ,Immunology ,Female ,business - Abstract
Using a flow cytometric analysis, CD55 (decay-accelerating factor), CD59 and CD58 have been measured on neutrophils from 12 aplastic anaemia (AA) patients who were long-term survivors after immunosuppressive therapy (IS), 17 healthy individuals, four patients with PNH, and six patients with other haematological disorders. The neutrophils from normal control patients and the six patients with other haematological disorders showed 98 +/- 2% (mean +/- SD) positive granulocytes for CD55. Corresponding values were low (12%, 26%, 51% and 58%) on the primarily PNH patients. Among the 12 AA patients examined, seven had normal and five low values (59% in two, 70%, 71% and 82%). Among the five AA patients who showed CD55 neutrophil deficiency, four had showed an incomplete response after the initial IS treatment and the other relapsed following an initial haematological complete response; three cases had a positive Ham's test and two were negative. Our data suggest that the development of PNH clones is a frequent finding in AA long-term survivors, mainly in those who had shown an incomplete response following IS. Neutrophil CD55 expression analysis by flow cytometry could be useful to detect clonal evolution in these patients.
- Published
- 1995
23. Paroxysmal Nocturnal Hemoglobinuria and Magnetic Resonance Imaging
- Author
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José Luis Bueno, José A. García-Marco, Martin Cabero, Isabel Krsnik, Emilio Ojeda, Santiago Gil, Almudena de Laiglesia, Carmen Regidor, Daniel Morillo, Rafael Fores, Beatriz Brea, Belen Navarro, Miguel Pastrana, Jose Rafael Cabrera, Cristina Muñoz-Linares, and Guiomar Bautista
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Immunology ,Bone marrow failure ,Magnetic resonance imaging ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Thrombosis ,Surgery ,Atheromatosis ,medicine.anatomical_structure ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Abdomen ,Radiology ,business ,Rare disease ,medicine.drug - Abstract
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare and complex disease characterized by a severe prothrombotic state caused by a complement system mediated hemolysis. The introduction of the anti-C5 antibody, Eculizumab, has been conducted in many Hematology units worldwide to adopt new diagnostic tools to evaluate new and old PNH patients in order to consider the adequacy of the adoption of this new drug in each case. Magnetic Resonance Imaging (MRI) allows a more adequate and profitable approach in PNH that other radiology techniques used for this purpose. In the last four years Hematology and Radiology units in our Hospital have collaborate in the clinical evaluation of PNH patients performing MRI (cranioencephalic, thoracic and/or abdominal) in acute complications of PNH patients (9 patients) or as a programmed protocoled evaluation previous to consider Eculizumab treatment (14 patients). The protocoled evaluation consists in thoracic and abdominal MRI evaluations in all cases, and cranioencephalic MRI (with independence of the presence of neurological symptoms) in 9 cases. The PNH patients were examined with 1.5 Teslas magnet for cranioencephalic,thoracic and abdominal MRI and with 3.0 Teslas magnet for some cranioencephalic MRI (Achieva Magnets; Philips Healthcare, Best, The Netherlands). Different protocols designed for the study of this pathology, using morphological sequences with different empowerment, functional sequences and angiographic studies after administration of intravenous contrast (gadobutrol) have been used. In the abdominal explorations had been performed calculations of T2 * for the quantification of deposit of iron in liver and kidney. The first group of patients (incidental studies in acute/chronic situations) included Classical and with other bone marrow failure syndrome (BMFS) Parker’s types. The second group (protocoled studies previous consideration of Eculizumab therapy) consisted on 11 Classical Parker’s type patients with active hemolysis (LDH increased 3-13 times over normal levels) and elevated PNH clone (73-99% negative GPI granulocytes by FLAER cytometry); and 3 with BMFS Parker’s type patients (LDH increased 2-6 times over normal levels) with lower PNH clone (43-50% negative GPI granulocytes by FLAER cytometry). Thrombosis was found in four cases, one in the inferior cava and and three arterial (two cerebral and one in descendent aorta). In three patients this finding implied to initiate Eculizumab therapy. Minor ischemic brain changes were displayed by three patients. None of the eighteen patients explored with thoracic MRI, displayed pulmonary hypertension signs despite the elevation of pro-BNP in eight of them. Iron overload in the liver and/or kidneys were very frequent. The finding of a reversal of the normal cortical and medullary intensities on T1 and T2 weighted images of both kidneys was evident in the majority of patients with severe PNH types. Interestingly, one patient with a chronic PNH severe form displayed no renal iron cortical after two years on Eculizumab therapy. This finding was also evident in patients with active hemolysis in the past but with very low PNH clones and clinical remission of the disease. Many other incidental discoveries includes cholelithiasis, splenomegaly, kidney arterial vessel constriction, vascular anomalies, kidney and vesical stones, adrenal adenoma, atheromatosis at different levels, Tornwaldt cyst, hamartoma, hemangiomas and abnormal bone marrow signal. MRI is the best imaging technique to diagnose thrombosis in PNH patients and to control evolution. Moreover, in the cerebrovascular setting allows a more fine and precise diagnosis of the minor pathologic thrombotic changes. MRI is the only imaging technique that permits to evaluate the iron overload that in some PNH cases could be underestimated and needs quelation therapy. In our opinion all new patients with classical severe hemolytic PNH must be evaluated prospectively with MRI. The collaboration of the Radiology team with the Hematologist is fundamental to acquire expertise in this rare disease. Disclosures: Pastrana: Alexion Pharmaceuticals: Speakers Bureau. Ojeda:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.
- Published
- 2013
24. Paroxysmal Nocturnal Hemoglobinuria and Thrombosis Before and After Eculizumab
- Author
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Belen Navarro, Santiago Gil, Daniel Morillo, Almudena de Laiglesia, José Luis Bueno, Carmen Regidor, Jose Rafael Cabrera, José A. García-Marco, Rafael Fores, Guiomar Bautista, Miguel Pastrana, Cristina Muñoz-Linares, Isabel Krsnik, Martin Cabero, and Emilio Ojeda
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Bone marrow failure ,Warfarin ,Atrial fibrillation ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Thrombosis ,Pancytopenia ,Surgery ,medicine.anatomical_structure ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Vein ,business ,medicine.drug - Abstract
Thrombosis, mainly venous but also arterial, is the leading threat in Paroxysmal Nocturnal Hemoglobinuria (PNH) patients, caused by the continuous hemolysis. It constitutes the first cause of death in all reported series. Since 1964, a total of 56 patients with PNH clone were evaluated in our Hematology Unit. According with PNH Parker´s Classification, most of the patients were Classical type (28 patients), and the remaining included in the other subsets: 21 in the setting of another bone marrow failure syndrome (BMFS) and 7 subclinical. Since November 2007, Eculizumab (an anti-C5 antibody) is employed in the disease to abrogate the hemolysis in our patients. In the last years, sixteen patients have been treated with this drug in our series. PNH patients previously anticoagulated with warfarin because thrombosis, continued on therapy after the addition of Eculizumab. Also, patients with more than 50 % PNH clone (established by Cytometry with FLAER on granulocytes) and platelets >50 x109/L received oral anticoagulation. The incidence and localization of thrombotic events in the patients without Eculizumab was as follows:Parker’s ClassificationClassicalBMFSSubclinical28216Thrombosis cases (%)14 (50)4 (20)2 (33)Thrombotic episodes:2675Deep calf642Multiple cerebral ischemic infarcts212 (1 death)Large Cerebrovascular311Budd-Chiari11 (1 death)Portal2 (1 death)Retinal2Cava1Pulmonary thromboembolism2 (1 death)Myocardial infarction3 (1 death)Arterial ischemia2 (1 amputation)Skin ischemic2 (vasculitis, livedo reticularis) After introduction of Eculizumab, sixteen patients have been treated with this drug and active thrombosis resolved in all cases, as was the case of a patient with a large persistent thrombosis in the inferior cava vein despite the isolated anticoagulation therapy. Only one patient on Eculizumab therapy experienced a thrombotic event and suffered a transient ischemic attack with aphasia after a prolonged catheter ablation procedure for an atrial fibrillation. This patient had previous signs of small vessel disease in MR imaging techniques. The episode occurs despite heparin anticoagulation and anticipated additional Eculizumab dose and resolves thereafter. Eculizumab had a clear favourable impact in preventing thrombosis complications in our series of PNH patients. Careful monitoring of LDH levels and shortening the Eculizumab interval doses it is indicated in any chirurgical or invasive procedures in these patients. Disclosures: Pastrana: Alexion Pharmaceuticals: Speakers Bureau. Ojeda:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.
- Published
- 2013
25. 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
26. Infusion of lymphocytes obtained from a donor immunised with the paraprotein idiotype as a treatment in a relapsed myeloma
- Author
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M N Fernández, F. DÍAz‐Espada, Rafael Cabrera, Y. Barrios, M Briz, Rafael Fores, L Barbolla, FJ Peñalver, Sanjuán I, and Carmen Regidor
- Subjects
Melphalan ,Idiotype ,Male ,Lymphocyte Transfusion ,Myeloma protein ,Lymphocyte ,T-Lymphocytes ,Salvage therapy ,Blood Donors ,Immunotherapy, Adoptive ,Dexamethasone ,Immunoglobulin kappa-Chains ,Immunoglobulin Idiotypes ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Antineoplastic Agents, Alkylating ,Multiple myeloma ,Bone Marrow Transplantation ,Salvage Therapy ,Transplantation ,business.industry ,Chimera ,Graft Survival ,Remission Induction ,Hematology ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Immunoglobulin A ,medicine.anatomical_structure ,Myeloma Proteins ,Doxorubicin ,Vincristine ,Immunology ,Immunization ,business ,Multiple Myeloma ,medicine.drug - Abstract
A 48-year-old patient with IgA k multiple myeloma received a BMT from his HLA-matched sibling. After transplantation, the disease relapsed. Melphalan therapy followed by reinfusion of haemopoietic blood stem cells collected from the patient led to the improvement of the clinical status, although mixed chimerism and an elevated serum IgA persisted. Successful donor immunisation against an immunogenic preparation of the recipient monoclonal protein was performed before the infusion of donor T lymphocytes (DLI) into the patient. Ten weeks after the lymphocyte infusions, no monoclonal band was evidenced and donor complete chimerism was detected. The patient did not develop GVHD. Once complete remission was achieved, the idiotype vaccine was administered to the patient. Nineteen months after DLI, the patient remains in remission. Bone Marrow Transplantation (2000).
- Published
- 2000
27. Rhinocerebral mucormycosis following donor leukocyte infusion: successful treatment with liposomal amphotericin B and surgical debridement
- Author
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M N Fernández, Carmen Regidor, Rafael Cabrera, JL Díez-Martin, FJ Peñalver, Rafael Fores, and R Romero
- Subjects
Adult ,Male ,medicine.medical_specialty ,Antifungal Agents ,medicine.medical_treatment ,Blood product ,Amphotericin B ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Mucormycosis ,Transplantation, Homologous ,Mycosis ,Transplantation ,Chemotherapy ,Brain Diseases ,Drug Carriers ,business.industry ,Myeloid leukemia ,Hematology ,medicine.disease ,Surgery ,Leukocyte Transfusion ,Methylprednisolone ,Liposomes ,Complication ,business ,medicine.drug - Abstract
A 24-year-old male developed cytogenetic relapse of chronic myeloid leukemia (CML) four years after allogeneic BMT. After a year of treatment with IFN-alpha, he achieved a partial cytogenetic response. Treatment with donor leukocyte infusions (DLI) was given (total dose 1 x 10(8) T lymphocytes/kg). Two months later, he developed acute GVHD (skin and liver), that improved with CsA and methylprednisolone and resulted in cytogenetic remission with complete donor chimerism. One month later he developed rhinocerebral mucormycosis and was successfully treated with surgical debridement and liposomal amphotericin B (total dose 12 g). This is the first case of mucormycosis described after DLI.
- Published
- 1998
28. Chagas disease in a recipient of cord blood transplantation
- Author
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José A. García-Marco, Guiomar Bautista, Elena Ruiz, Carlos Vallejo, Isabel Krsnik, M Linares, Rafael Fores, Carmen Regidor, R López-Vélez, J R Cabrera, Emilio Ojeda, Santiago Gil, F Portero, Sanjuán I, and M N Fernández
- Subjects
Chagas disease ,Transplantation ,Pediatrics ,medicine.medical_specialty ,Blood transfusion ,biology ,business.industry ,medicine.medical_treatment ,Public health ,Hematology ,Disease ,biology.organism_classification ,medicine.disease ,Organ transplantation ,parasitic diseases ,Immunology ,medicine ,Congenital transmission ,Trypanosoma cruzi ,business ,Cord blood transplantation - Abstract
American trypanosomiasis, or Chagas' disease, is caused by a protozoan, Trypanosoma cruzi. It is endemic in Latin America where it represents a major public health problem. Chagas' disease also occurs in non-endemic areas where it can be acquired by blood transfusion, congenital transmission and organ transplantation. The disease can be fatal in immunosuppressed patients.1 We report a case of reactivation of Chagas' disease (acute form) in a patient who underwent cord blood transplantation in a non-endemic European country.
- Published
- 2007
29. Detection of maternal DNA in umbilical cord blood by polymerase chain reaction amplification of minisatellite sequences
- Author
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M Posada, C Garaulet, M Briz, N Somolinos, Rafael Fores, M N Fernández, Carmen Regidor, and D Monteagudo
- Subjects
Genotype ,Graft vs Host Disease ,Minisatellite Repeats ,Biology ,Umbilical cord ,Polymerase Chain Reaction ,Sensitivity and Specificity ,law.invention ,Blood cell ,Andrology ,law ,Pregnancy ,medicine ,Humans ,Transplantation, Homologous ,Maternal-Fetal Exchange ,Polymerase chain reaction ,Transplantation ,Chimera ,Hematopoietic Stem Cell Transplantation ,Infant, Newborn ,Hematology ,DNA ,Fetal Blood ,Hypervariable region ,medicine.anatomical_structure ,Minisatellite ,Fetal circulation ,Cord blood ,Immunology ,Female - Abstract
One of the concerns about the use of cord blood as a source of hematopoietic stem cells for allogeneic transplantation is the possibility of contamination by maternal cells which could cause life-threatening GVHD. We have assessed cord blood contamination using PCR analysis of several minisatellite regions to detect maternal DNA. Eighty mother-cord pairs were obtained for this study. In one case there were no specific maternal alleles at any loci and, therefore, cord blood could not be evaluated. Thus, there was a total of 79 informative cases for the detection of maternal cells in the fetal circulation. In most cases, the level of detection was between 0.5 and 1%. We detected maternal DNA in the cord blood sample in only one case (1.26%), and the analysis of dilution experiments led to an estimate of 0.5-1% maternal cells. In conclusion, using PCR amplification of hypervariable regions, maternal DNA is very rarely detected in the cord blood collected at birth, although this approach has a relatively low level of sensitivity.
- Published
- 1998
30. Diagnosis of transfusion-associated graft-versus-host disease by polymerase chain reaction in fludarabine-treated B-chronic lymphocytic leukaemia
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Rafael Fores, Jose Luis Díez, M.N. Fernández, Miguel Herrero, Rafael Cabrera, Sanjuán I, Carmen Regidor, M Briz, and Manuel Algora
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medicine.medical_treatment ,Chronic lymphocytic leukemia ,Splenectomy ,Graft vs Host Disease ,Antineoplastic Agents ,Blood irradiation therapy ,Polymerase Chain Reaction ,law.invention ,Transfusion-associated graft versus host disease ,immune system diseases ,law ,hemic and lymphatic diseases ,medicine ,Humans ,Polymerase chain reaction ,Chemotherapy ,business.industry ,Transfusion Reaction ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Fludarabine ,surgical procedures, operative ,Graft-versus-host disease ,Immunology ,Female ,business ,Vidarabine ,medicine.drug - Abstract
Transfusion-associated graft-versus-host disease (TA-GVHD), has rarely been reported associated with B-chronic lymphocytic leukaemia (B-CLL). We report a patient diagnosed with B-CLL, previously treated with fludarabine, who developed TA-GVHD after being transfused during surgery for splenectomy. Diagnosis was confirmed by polymerase chain reaction (PCR) detection of donor DNA in the patient, by amplification of Y-chromosome sequence and analysis of minisatellite polymorphisms. B-CLL patients treated with fludarabine appear to be at risk for TA-GVHD and should be regarded as candidates for transfusions with irradiated blood products. This case illustrates that PCR is a rapid technique for the early diagnosis of TA-GVHD.
- Published
- 1995
31. Use of Romiplostim to Facilitate Platelet Engraftment in Allogeneic Hematopoietic Transplantation
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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
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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
32. 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
33. Alemtuzumab as a Single Agent or Combined with Methylprednisolone (MPD) or Fludarabine (FDR) for the Treatment of CLL Patients with p53 and ATM Deletions
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Elena Ruiz, A. Sebrango, Belen Navarro, Rafael Fores, Felix Carbonell, Pedro Sánchez-Godoy, Jose A. Garcia-Vela, José A. García-Marco, M N Fernández, Secundino Ferrer, and A. De la Iglesia
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medicine.medical_specialty ,Cyclophosphamide ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Fludarabine ,Methylprednisolone ,Internal medicine ,Toxicity ,medicine ,Alemtuzumab ,Progression-free survival ,Stage (cooking) ,business ,Progressive disease ,medicine.drug - Abstract
Genetic abnormalities are one of the most important prognostic factors in CLL. Indeed, p53 deletions/mutations are associated with progressive disease, refractoriness to alkylating or fludarabine (FDR) based regimes and short survival. Similarly, ATM deletion/mutations at chromosome band 11q22.3 are associated with shorter treatment free interval from diagnosis and decreased overall survival. Alemtuzumab (Alem) has shown to be effective in CLL patients (pts) with p53/ATM deletions, when used as a single agent especially in cases with p53 abnormalities. The aim of this study was to evaluate the efficacy of Alem alone or in combination with FDR or MPD in CLL pts with p53/ATM deletions. Materials and Methods: Since Feb/02 to March/07 we have treated 21 pts (15M/6F, median age: 59 yrs, range:48–72) with p53 del (13/21) and ATM del (9/21). Two cases had both types of abnormality. Twenty cases had refractory disease to alkylating or FDR combinations, with a median number of 3 prior regimes. One pts was treated in first line with Alem+MPD. Seven cases had bulky lymphadenopathy (≥7cm). Fifteen pts had Rai stage II, 1 pts stage III and 5 stage IV disease. Eleven pts were treated with Alem 30mg thrice week up to 12 weeks (CAM30), 3 pts with FDR (20mg/m2iv ×3d) + cyclophosphamide (200mg/m2iv ×3d)+ Alem (20mg thrice week iv ×4weeks) every 28d ×2 cycles (FLUCYCAM) and 7 pts with concurrent Alem (30mg thrice week iv ×4weeks) and iv methylprednisolone 1g/m2 days 1–5 every 28d up to 4 cycles (CAMPRED). Hematological responses were evaluated in PB and BM by four color flow cytometry. Genetic abnormalities were screened by G-banding and FISH. P53 mutations were analysed by direct sequencing. Results: Overall, 18(85.7)/21 pts responded to Alem based therapy (6CR, 3nPR, 9PR, 3SD). P53 del was detected at diagnosis in 11/13 cases and ATM del in 6/9 pts. Out of 13 cases with p53del, 5 achieved CR, 1 nPR, 6PR and 1SD. 6 cases also showed associated mutations, but there were no differences in terms of response. Of 9 cases with ATM del, 1 reached CR, 1nPR, 5PR and 2SD. Clinical response according to treatment was as follow: CAM30 (2CR, 1nPR, 7PR, 1SD), FLUCYCAM (1PR, 2SD), CAMPRED (5CR, 3 of them MRD neg, and 2PR). Progression free survival (PFS) was 6 months, 3 months and not reached for CAM30, FLUCYCAM and CAMPRED regimes respectively. Infusional side effects were present in 80% of cases, myelotoxicity was more frequent with FLUCYCAM (100%) than CAM30 (30%) and CAMPRED (25%). Infections were seen in 42% of cases and CMV reactivation in 34%. 2 pts died of gram- sepsis. Richter transformation EBV+ was seen in 6(28%)21 pts and did not correlate with the number of prior treatments or with the type of genetic abnormality. Conclusion: Alemtuzumab in monotherapy demonstrates clinical activity in CLL patients with p53 and ATM deletions, although this response is transient in most cases and less effective in patients with lymphadenopathy. The association with fludarabine shows similar effects but more toxicity. However, the combination with methilprednisolone is more effective in eradicating PB and BM lymphocytes and also on bulky lymphadenopathy in patients with p53 and ATM abnormalities.
- Published
- 2007
34. 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.
- Published
- 2007
35. Secondary effects after belantamab treatment: A new anti‐B‐cell maturation antigen monoclonal antibody for multiple myeloma
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Sara Garrido Paniagua, Pablo Prieto Martínez, Rafael Forés Cachón, Guiomar Bautista Carrascosa, Rafael F. Duarte, and Isabel Krsnik
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
- Full Text
- View/download PDF
36. Single Unit Cord Blood Transplant Supported by Third Party Highly Purified Mobilized Hematopoietic Stem Cells: Immune Reconstitution Studies
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Elena Magro, Adria Prieto, Elena Ruiz, Rosa Gonzalo-Daganzo, Guiomar Bautista, PJ Travers, N. Panadero, Isabel Millán, Rafael Fores, Alejandro Madrigal, Carlos Vallejo, José A. García-Marco, Emilio Ojeda, Rocio Sanchez, Carmen Regidor, Trinidad Martín-Donaire, Manuel N. Fernandez, Sanjuán I, Rafael Cabrera, and Isabel Krsnik
- Subjects
T cell ,Immunology ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Andrology ,Transplantation ,Haematopoiesis ,Immune system ,medicine.anatomical_structure ,Immunophenotyping ,Cord blood ,medicine ,Cytotoxic T cell ,CD8 - Abstract
Background and Objectives: Following cord blood transplants (CBT) there is a period of severe and often prolonged immune deficiency that results in long term susceptibility to infections. Immune reconstitution is an important factor for long term survival. We analyzed the immune reconstitution of adult recipients of a single unit CBTs supported by a low number of third party donor highly purified mobilized hematopoietic stem cells (dual CB/TPD transplants), as previously described (Magro et al. Haematologica2006;91:640–8). This strategy results in transient double chimerism of CB and TPD cells and early granulocyte recovery, initially of TPD predominance. Complete CB chimerism is regularly achieved within 100 days.The objective of this study is to evaluate immune reconstitution in this CBT. Patients and Methods: Data were obtained from 19 patients between July 2004 and July 2006. Data collection was initiated at different intervals (from day −7 to +720, quartiles Q1=35, Q2=90 and Q3=210). Samples were obtained on days +15, +35, +55, +90 and monthly thereafter up to two years. By four-color flow cytometric immunophenotyping we analyzed the subsets of peripheral blood lymphocytes: CD3+/CD4+ (T helper/inducer), CD3+/CD8+ (T suppressor/cytotoxic), NK cells (CD3−/CD56+/CD16+) and B cells, as well as cells with naïve, memory and effector T-cell immunophenotypes. TREC bearing cells were analyzed by quantitative PCR in sorted CD4+ and CD8+ T cells collected from 3 months post-transplant onwards. Results: CD56+ cells recovered early after transplantation, with median absolute number counts (ANC) of 69 (range 18–307), 170 (0–366) and 159 (32–531) cells/uL in days +15, +35 and +55 samples [normal controls 153 (71–438)], representing the largest subset within the first two months (decreasing proportions of 60%, 50% and 40%, respectively). ANC of CD4 and CD8 T cells remained low for several months, progressively increasing to reach normal ranges at different intervals. Naïve CD4 and CD8 cells (CD45RO−/CD27+) start to be detected by immunophenotyping after three months post-transplantation with median ANC of 17 (12–79) and 12 (5–103) cells/uL respectively and increasing thereafter [normal controls 860 (552–1072) and 331 (227–521)]. By the end of the first year values of T cell subsets were: CD4+, 823 (16–1123) cells/uL [normal controls 872 (470–1093)]; CD8 934 (56–1174) [normal controls 371 (208–808)], with persisting predominance of the naive phenotypes and proportions of memory phenotypes slowly increasing. B cells became detectable around day +90 with median ANC of 249 (0–1934) cells/uL, rapidly reaching values within the normal range [275 (133–684)]. Transient acute GVHD was developed by six of the 19 patients. All showed a transient drop in absolute numbers of NK, T and B cells. Chimerism analysis showed initial transient double chimerism of CB and TPD cells. Complete CB chimerism was achieved between days +15 and +94 (median, +35). Results of chimerism of lymphocyte subsets and TREC are not yet available. Conclusions: Following dual CB/TPD transplants we have observed early recovery of NK and B-cells and slow development of T cells subsets and of non-naive immunophenotypes.
- Published
- 2006
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. Management of thrombotic microangiopathy following allogeneic transplantation: what is the role of plasma exchange?
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Rafael Cabrera, R Romero, Rafael Fores, Pilar Llamas, M N Fernández, and Sanjuán I
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Adult ,Male ,medicine.medical_specialty ,Thrombotic microangiopathy ,Allogeneic transplantation ,Adolescent ,medicine.medical_treatment ,Thrombotic thrombocytopenic purpura ,Gastroenterology ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Bone Marrow Transplantation ,Transplantation ,Plasma Exchange ,business.industry ,Thrombosis ,Hematology ,medicine.disease ,Hemolysis ,Surgery ,Cyclosporine ,Female ,Plasmapheresis ,Complication ,business - Abstract
Thrombotic microangiopathy (TMA) is an infrequent but serious complication of allogeneic transplantation. The success rate of plasma exchange (PE) reported in the treatment of this entity is a controversial subject. We report the outcome of 10 patients with TMA post-allogeneic transplantation after treatment with PE. Two out of the 10 patients have not responded, five had a partial response, but died of acute GVHD or interstitial pneumonitis, and three have responded and recovered. Our study suggests that there are different degrees of TMA severity. Only mild multifactorial cases with no severe hemolysis (LDH activity
- Published
- 1997
39. Secondary Malignancies after Hematopoietic Stem Cell Transplantation in Patients Treated with Total Body Irradiation
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Carmen Regidor, Maria I. Berrocal, J. Rafael Cabrera, Alejandro de la Torre, Isabel Millán, Rafael Fores, Sanjuán I, Luis Nunez, Manuel N. Fernandez, Cristina De La Fuente, C.A. Regueiro, and Francisco Valcárcel
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Incidence (epidemiology) ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Total body irradiation ,Cervical intraepithelial neoplasia ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Lymphoma ,Internal medicine ,medicine ,Carcinoma ,Cumulative incidence ,Risk factor ,business - Abstract
We have analyzed the incidence and risk factors of developing a secondary malignancy after total body irradiation (TBI) and hematopoietic stem cell transplantation (HSCT). From March 1986 to December 2002, 205 patients received TBI as a part of the HSCT conditioning regimen. TBI was administered in 6 fractions, twice a day, up to a total dose of 12 Gy, with a median dose rate of 11.44 cGy/min. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 119 patients and the other 86 patients received an autologous hematopoietic stem cell transplantation (AHSCT). Median age was 30 years (5–63). We have calculated the cumulative incidence of solid tumors and secondary hematologic malignancies among these patients. Death due to noncancerous causes and patients lost to follow-up were entered as a competitive risk. With a median follow-up of 32 months (0.2–229)- including patients deceased in the first three months- 13 (6.3%) developed a secondary malignancy, 7 of them (3.4%) developed a solid tumor and 6 (2.9%) developed a secondary hematologic malignancy. The 7 patients who developed a solid tumor-1 glioblastoma, 2 head and neck carcinoma, 2 basocelular carcinoma, 1 osteosarcoma and 1 cervical intraepithelial neoplasia- had received an allo-HSCT. The 6 patients that developed a secondary hematologic malignancy- 5 therapy-related leukemia/myelodisplasia (t-AML/MDS) and 1 B cell non Hodgkin’s lymphoma- had received an AHSCT. The overall probability of developing a secondary malignancy after HSCT is 2.5% at 3 years (95% confidence interval (CI) 1.1– 6); 5% at 10 years (95% CI 2.6–9.3), and 9% at 15 years (95% CI 5–16.5). The probability of developing a solid tumor after HSCT is 0.5% at 3 years (95% CI 0.1–3.6), 1.8 % at 10 years (95% CI 0.6–5.5), and 6 % at 15 years (95% CI 2.6–13.7) and the probability of developing a secondary hematologic malignancy is 2 % at 3 years (95% CI 0.8–5.3), and 3,1 % at 10 and 15 years (95% CI 1.4–6.9). Median time to develop a solid tumor was 134 months (29–229). Median time to develop a secondary hematologic malignancy was 31 (3–60) months. Multivariate analysis proved that allo-HSCT was the only risk factor of developing a solid tumor, and that AHSCT and advanced age were risk factors of developing secondary hematologic malignancy (mean age 30 vs. 50 years ). To conclude, the probability of developing a solid tumor after HSCT is higher if an allo-HSCT has been performed and increases with time. AHSCT and advanced age are risk factors for the development of a secondary hematologic malignancy, a risk that decreases 5 years after AHSCT.
- Published
- 2005
40. Unrelated Single Cord Blood Transplant Supported by Co-Infusion of a Low Number of Mobilized Peripheral Blood Highly Purified CD34+ Cells from a Third Party Donor after Low Toxicity Myeloablative Conditioning. a Strategy That Makes Cord Blood Transplant Feasible for Most Patients. (An 'Allostem' Study)
- Author
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Elena Magro, Santiago Gil, Belen Navaro, José A. García-Marco, Jorge Gayoso, Sanjuán I, Rafael Fores, Guiomar Bautista, Manuel N. Fernandez, Elena Ruiz, Carmen Regidor, and Rafael Cabrera
- Subjects
business.industry ,Immunology ,CD34 ,Cell Biology ,Hematology ,Human leukocyte antigen ,Neutropenia ,medicine.disease ,Biochemistry ,Fludarabine ,Leukemia ,Haematopoiesis ,Cord blood ,medicine ,Stem cell ,business ,medicine.drug - Abstract
We report results of single unit Cord Blood (CB) transplants and co-infusion of a low number of highly purified mobilized PB CD34+ (MPB) cells from a 3rd party donor in 22 consecutive adults with high risk leukemia, median age 29 (16–63) and weight 66 (53–85) Kg. Basic conditioning regimen was Fludarabine, TBI, CTX and ALG, with modifications in 6 patients because of circumstancial factors. The CB units had 2.3 (1.31–3.7) x107 TNC/Kg and 0.1 (0.049–0.37) x106 CD34+ cells/Kg and were 0–2 HLA mismatches to the recipient. The 3rd party donor was an HLA haploidentical relative for 18 (sibling 10; mother 4; father 2; son 1; nephew 1), a higher HLA mm relative for 3 and a fully HLA mm unrelated donor for 1; infused cells were 2.3 (1.05–2.54) x106 CD34+/Kg and 0.23 (0.05–0.98) x104 CD3+/Kg. Post-transplant all patients received CsA and low dose Prednisone for GVHD prophylaxis. G-CSF was started on day +1 in all but 1 on day +5 and continued as required for ANC>1.5x109/L. For the 18 patients receiving MPB-SC from a non-maternal donor, median time to ANC>0.5x109/L was 10 days (9–12 days for 16; 16 and 17 for the other 2, 1 with G-CSF started on day +5). Analysis of DNA polymorphisms showed initial predominance of the 3d party donor both in granulocytes and mononuclear cells and subsequent progressive replacement by CB cells. Final complete CB chimerism was achieved in 17 patients between days 23 and 96 (median 56); 1, transplanted with residual disease, died on day 56 because of CMV Pn with 95% CB cells. The 4 who received maternal cells had no significant engraftment of these, although 3 had exclusive CB chimerism, 2 of which reached full CB engraftment (days 20 and 36). This different behaviour was not related to the non-inherited maternal antigens. Current clinical data suggest that replacement of the 3rd party graft by the CB engraftment may be due to rejection by the CB derived immune system. Morbidity due to early bacterial or fungal infections was remarkably low. Severe GVHD (grade>II) occurred in 2 patients resulting in death (1 did not receive ALG); another 8 had less severe GVHD that responded to treatment. Third party donor cells were not detected in biopsy material of GVHD skin lesions. Deaths were toxic in 2 (1 had received “full intensity” TBI conditioning) and primarily due to opportunistic infections in 4 (2 CMV and 2 Toxoplasmosis, on days 64, 72, 96 and 241). Regression analyses show number of CB-CD34+ cells/Kg as the main factor influencing time to CB engraftment, with no significant effect of number of 3rd party donor CD34+ infused cells. Five years OS and DFS are 57 % for all patients and 80% for those under 40 receiving non-maternal 3rd party cells. No relapses have been observed. Our data show that the strategy of single unit CB transplant supported by 3rd party donor highly purified MPB CD34+ cells results in a short period of post-transplant neutropenia (as a consequence of prompt and transient engraftment of the 3rd party donor cells), significant GVL effect and high rates of OS and DFS, which makes CB transplant a favorable option for almost any patient requiring a hematopoietic unrelated stem cell transplant.
- Published
- 2004
41. Chronic myeloid leukaemia and allogenic bone marrow transplantation in a patient with toxic oil syndrome
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Fernández Mn, Rafael Cabrera, Rafael Fores, P. Llamas-Sillero, Díez Jl, and M. Gómez-Roncero
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Letter ,Fatal outcome ,Bone marrow transplantation ,business.industry ,Immunology ,medicine ,General Medicine ,medicine.disease ,business ,Chronic myeloid leukaemia ,Toxic oil syndrome - Published
- 1995
42. Typical Chronic Myelogenous Leukemia With e19a2 Junction BCR/ABL Transcript
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Rafael Fores, M Briz, Manuel N. Fernandez, Rafael Cabrera, and Carlos Vilches
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Messenger RNA ,ABL ,Immunology ,Breakpoint ,breakpoint cluster region ,Chromosomal translocation ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,hemic and lymphatic diseases ,Cancer research ,medicine ,Bcr-Abl Tyrosine Kinase ,Chromosome 22 ,Chronic myelogenous leukemia - Abstract
To the Editor : In the vast majority of patients diagnosed as having chronic myelogenous leukemia (CML) and t(9; 22), the breakpoint on chromosome 22 occurs in the M-BCR region of the BCR gene; this translocation usually results in a hybrid BCR/ABL mRNA with a b2a2 and/or b3a2 junction, which
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- 1997
43. Eculizumab treatment in a patient with hematopoietic stem cell transplantation-associated thrombotic microangiopathy and steroid-refractory acute graft versus host disease
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Cristina Fernández, Ana Lario, Rafael Forés, and Rafael Cabrera
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Eculizumab ,thrombotic microangiopathy ,acute graft versus host disease ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
A 30-year-old man with acquired aplastic anemia underwent an HLA-identical bone marrow transplant. He developed a grade III acute graft versus host disease (GVHD) refractory to various lines of treatment. On post-transplant day 196, he was diagnosed with stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and he received treatment with eculizumab 900 mg iv weekly for 4 doses followed by a single dose of 1200 mg 2 weeks later. After the first dose of eculizumab, the patient ceased to require transfusions and a progressive improvement in analytical parameters for microangiopathy was observed until their complete normalization. Coinciding with the improved of HSCT-TMA, the patient presented a clear response to his acute GVHD with disappearance of the diarrhea and bilirubin normalization. He was discharged eight weeks after the start of treatment. Unfortunately, one month later, the patient was readmitted for a GVHD relapse and he died two weeks later by an acute respiratory distress syndrome. In our case, the rapid clinical and analytical response to early treatment with eculizumab supports the implication of the complement in HSCT-TMA and suggests that the drug has a beneficial effect when used as coadjuvant therapy in acute GVHD.
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- 2015
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44. Hypophosphatemia During Imatinib Treatment of Newly Diagnosed Chronic Myeloid Leukemia Patients Is Associated with Better Response
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Juan Luis Steegmann, Manuel Pérez-Encinas, Luis Felipe Casado, Luis Palomera, Isabel Massague, Carmen Burgaleta, Joaquin Martinez-Lopez, Pilar Giraldo, María Jesús Peñarrubia, Raquel de Paz, Begoña Maestro, Santiago Osorio, Rafael Fores, and Maria José Requena
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Prognostic variable ,medicine.medical_specialty ,Anemia ,business.industry ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Surgery ,Cancer registry ,Imatinib mesylate ,Median follow-up ,Internal medicine ,medicine ,business ,Complete Hematologic Response ,Hypophosphatemia - Abstract
Abstract 1121 Poster Board I-143 The Spanish Registry on CML ( RELMC ) is a multicentric, hospital-based cancer registry whose aim is to describe what is the actual treatment received by patients with CML in Spain, its outcome, and the variables which influence it. Aim To study the variables which could influence the outcome in newly diagnosed CML patients treated with Imatinib, including classic and new variables, such as phosphate serum levels, which are diminished in a substantial number of patients ( Osorio et al,2007) Patients 207 CP-CML patients, newly diagnosed, were included in 17 Spanish hospitals. Sex: 131 M,76F( 63%,37%). Age: Median: 51,5 (18,7-87,5).The risk group distribution was as follows: Sokal L/I/H: ((47%;35%;18%). Hasford ( 44%,49%,7%). The variables studied at diagnosis were sex, Sokal and Hasford group. During the treatment: dose of Imatinib, anemia, neutropenia, thrombocytopenia and hypophosphatemia. Results Median follow up of the series have been 19,1 months. Among 207 patients, frequency values for anemia, neutropenia, and thrombocytopenia were 21%, 29% and 11%, respectively. Ninety-one patients had serum phosphate measured during the treatment. Among them, 49(54%) had hypophosphatemia. Complete hematologic response ( CHR) was obtained in 94,6%.No significant association was found between Sokal or Hasford group and the achievement of complete HR. Complete cytogenetic response (CCR ) was obtained in 73%. A significant association was found between obtaining CCR and Low or intermediate Hasford group (p=0,013) or having hypophosphatemia during the treatment ( p=0,04). The probability of obtaining CCR was higher in patients having hypophosphatemia in the 9th month of therapy (Log Rank (Mantel-Cox) Chi2: 6,21 (p=0,013).Patients who had hypophosphatemia during the treatment also showed a trend for higher probability of CCR (p=0,096). Major and complete molecular response (MMR, CMR) were obtained in 71% and 48%, respectively. MMR was significant worse in Hasford high-risk patients (Pearson Chi-Square:6,909 (p=0,009), and the probability of MMR was higher in patients developing hypophosphatemia ( p=0,175). Regarding CMR, Hasford high risk had a significant association with worse rate of CMR (Chi-Square: 4,419; p=0,036. Also, the probability of CMR was significantly higher in patients having hypophosphatemia ( p=0,045). Conclusion In our series, Hasford risk system has a stronger predictive value than the Sokal classification. It is interesting to note that half of our patients had hypophosphatemia during the treatment with Imatinib. Intriguingly, having low serum levels of phosphate during treatment is associated with better response, and it invites to further study of the biological basis of this finding and its relevance as prognostic variable. This study has received the grant PI07/91015 from the Instituto de Salud Carlos III. Disclosures No relevant conflicts of interest to declare.
45. 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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