26 results on '"Rodríguez-Macías G"'
Search Results
2. PLZF-RAR(alpha), NPM1-RAR(alpha), and other acute promyelocytic leukemia variants: the PETHEMA registry experience and systematic literature review
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Sobas, M. (Marta), Talarn-Forcadell, M.C. (Maria Carme), Martínez-Cuadron, D. (David), Escoda, L. (Lourdes), García-Pérez, M.J. (María J.), Mariz, J. (José), Mela-Osorio, M.J. (María J.), Fernandez, I. (Isolda), Alonso-Domínguez, J.M. (Juan M.), Cornago-Navascués, J. (Javier), Rodríguez-Macías, G. (Gabriela), Amutio, E. (Elena), Rodríguez-Medina, C. (Carlos), Esteve, J. (Jordi), Sokól, A. (Agniezska), Murciano-Carrillo, T. (Thais), Calasanz-Abinzano, M.J. (Maria Jose), Barrios, M. (M.), Barragán, E. (Eva), Sanz, M.A. (Miguel A.), and Montesinos, P. (Pau)
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Characteristics ,Acute promyelocytic leukemia ,Systematic review ,Outcomes ,Variant ,neoplasms - Abstract
It has been suggested that 1-2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RAR alpha) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RAR(alpha) being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RAR(alpha) and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RAR(alpha) and 2 NPM1-RAR(alpha)), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 x 10(9)/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.
- Published
- 2020
3. Haplo-identical bone marrow transplantation with post-grafting cyclophosphamide: multi-centre experience with an alternative salvage strategy: O407
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Tuve, S., Gayoso, J., Scheid, C., Radke, J., Kiani, A., Serrano, D., Platzbecker, U., Rodríguez-Macías, G., Wermke, M., Holtick, U., Balsalobre, P., Middeke, J. M., Shayegi, N., Chemnitz, J. M., Krause, A., Gruner, N., Füssel, M., Schetelig, J., Ehninger, G., Hallek, M., Martín, Díez J.L., and Bornhäuser, M.
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- 2011
4. Allogeneic hematopoietic stem cell transplantation in patients 50 years of age and older
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La Cámara, R., Alonso, A., Luis Steegmann, J., Arranz, R., Granados, E., Rodríguez-Macías, G., Sanz-Rodríguez, C., Soria, V. G., Figuera, A., and Fernández-Rañada, J. M.
5. Evolving patterns and clinical outcome of genetic studies performed at diagnosis in acute myeloid leukemia patients: Real life data from the PETHEMA Registry.
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Labrador J, Martínez-Cuadrón D, Boluda B, Serrano J, Gil C, Pérez-Simón JA, Bernal T, Bergua JM, Martínez-López J, Rodríguez-Medina C, Vidriales MB, García-Boyero R, Algarra L, Polo M, Sayas MJ, Tormo M, Alonso-Domínguez JM, Herrera P, Lavilla E, Ramos F, Amigo ML, Vives-Polo S, Rodríguez-Macías G, Mena-Durán A, Pérez-Encinas MM, Arce-Fernández O, Cuello R, Sánchez-García J, Gómez-Casares MT, Chillón MC, Calasanz MJ, Ayala R, Rodriguez-Veiga R, Barragán E, and Montesinos P
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- Humans, Middle Aged, Male, Female, Aged, Adult, Aged, 80 and over, Genetic Testing statistics & numerical data, Genetic Testing methods, Young Adult, Adolescent, Mutation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute diagnosis, Nucleophosmin, Registries, fms-Like Tyrosine Kinase 3 genetics, High-Throughput Nucleotide Sequencing
- Abstract
Background: There are no studies assessing the evolution and patterns of genetic studies performed at diagnosis in acute myeloid leukemia (AML) patients. Such studies could help to identify potential gaps in our present diagnostic practices, especially in the context of increasingly complex procedures and classifications., Methods: The REALMOL study (NCT05541224) evaluated the evolution, patterns, and clinical impact of performing main genetic and molecular studies performed at diagnosis in 7285 adult AML patients included in the PETHEMA AML registry (NCT02607059) between 2000 and 2021., Results: Screening rates increased for all tests across different time periods (2000-2007, 2008-2016, and 2017-2021) and was the most influential factor for NPM1, FLT3-ITD, and next-generation sequencing (NGS) determinations: NPM1 testing increased from 28.9% to 72.8% and 95.2% (p < .001), whereas FLT3-ITD testing increased from 38.1% to 74.1% and 95.9% (p < .0001). NGS testing was not performed between 2000-2007 and only reached 3.5% in 2008-2016, but significantly increased to 72% in 2017-2021 (p < .001). Treatment decision was the most influential factor to perform karyotype (odds ratio [OR], 6.057; 95% confidence interval [CI], 4.702-7.802), and fluorescence in situ hybridation (OR, 2.273; 95% CI, 1.901-2.719) studies. Patients ≥70 years old or with an Eastern Cooperative Oncology Group ≥2 were less likely to undergo these diagnostic procedures. Performing genetic studies were associated with a favorable impact on overall survival, especially in patients who received intensive chemotherapy., Conclusions: This unique study provides relevant information about the evolving landscape of genetic and molecular diagnosis for adult AML patients in real-world setting, highlighting the increased complexity of genetic diagnosis over the past 2 decades., (© 2024 American Cancer Society.)
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- 2024
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6. Oral decitabine/cedazuridine versus intravenous decitabine for acute myeloid leukaemia: A randomised, crossover, registration, pharmacokinetics study.
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Geissler K, Koristek Z, Del Castillo TB, Novák J, Rodríguez-Macías G, Metzelder SK, Illes A, Mayer J, Arnan M, Keating MM, Krauter J, Lunghi M, Fracchiolla NS, Platzbecker U, Santini V, Sano Y, Oganesian A, Keer H, and Lübbert M
- Abstract
This study compared decitabine exposure when administered IV (DEC-IV) at a dose of 20 mg/m
2 for 5-days with orally administered decitabine with cedazuridine (DEC-C), as well as the clinical efficacy and safety of DEC-C in patients with acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy. In all, 89 patients were randomised 1:1 to DEC-IV or oral DEC-C (days 1-5 in a 28-day treatment cycle), followed by 5 days of the other formulation in the next treatment cycle. All patients received oral DEC-C for subsequent treatment cycles until treatment discontinuation. Equivalent systemic decitabine exposures were demonstrated (5-day area under the curve ratio between the two decitabine formulations of 99.64 [90% confidence interval 91.23%, 108.80%]). Demethylation rates also were similar (≤1.1% difference). Median overall survival (OS), clinical response and safety profile with oral DEC-C were consistent with those previously observed with DEC-IV. Next-generation sequencing was performed to identify molecular abnormalities that impact OS and TP53 mutations were associated with a poor outcome. These findings support the use of oral DEC-C in patients with AML., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2024
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7. Clinical outcomes after CPX-351 in patients with high-risk acute myeloid leukemia: A comparison with a matched cohort from the Spanish PETHEMA registry.
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Bernal T, Moreno AF, de LaIglesia A, Benavente C, García-Noblejas A, Belmonte DG, Riaza R, Salamero O, Foncillas MA, Roldán A, Concepción VN, González LL, Bergua Burgués JM, Lorente de Uña S, Rodríguez-Macías G, de la Fuente Burguera A, García Pérez MJ, López-Lorenzo JL, Martínez P, Aláez C, Callejas M, Martínez-Chamorro C, Roca JR, Barciela LA, Mena Durán AV, Gómez Correcha K, Lavilla Rubira E, Amigo ML, Vall-Llovera F, Garrido A, García-Fortes M, de Miguel Llorente D, Leonardo AA, Cervero C, Jordá RC, Pérez-Encinas MM, Zarzuela MP, Figuera A, Rad G, Martínez-Cuadrón D, and Montesinos P
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- Humans, Aged, Retrospective Studies, Remission Induction, Cytarabine therapeutic use, Leukemia, Myeloid, Acute
- Abstract
Background: CPX-351 is approved for the treatment of therapy related acute myeloid leukemia (t-AML) and AML with myelodysplastic related changes (MRC-AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real-life patients., Methods: Retrospective analysis of AML patients treated with CPX-351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry., Results: Median age of 79 patients treated with CPX-351 was 67 years old (interquartile range 62-71), 53 were MRC-AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX-351 was 52%, 60-days mortality 18%, measurable residual disease <0.1% in 54% (12 out of 22) of them. Stem cell transplant (SCT) was performed in 27 patients (34%), median OS was 10.3 months, and 3-year relapse incidence was 50%. Using PSM, we obtained two comparable cohorts treated with CPX-351 (n = 52) or IC (n = 99), without significant differences in CR/CRi (60% vs. 54%) and median OS (10.3 months vs. 9.1 months), although more patients were bridged to SCT in the CPX-351 group (35% vs. 12%). The results were confirmed when only 3 + 7 patients were included in the historical cohort. In multivariable analyses, SCT was associated with better OS (HR 0.33 95% CI: 0.18-0.59), p < 0.001., Conclusion: Larger post-authorization studies may provide evidence of the clinical benefits of CPX-351 for AML in the real-life setting., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2023
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8. Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy.
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Rodríguez-Macías G, Briz O, Cives-Losada C, Chillón MC, Martínez-Laperche C, Martínez-Arranz I, Buño I, González-Díaz M, Díez-Martín JL, Marin JJG, and Macias RIR
- Abstract
Despite its often low efficacy and high toxicity, the standard treatment for acute myeloid leukemia (AML) is induction chemotherapy with cytarabine and idarubicin. Here, we have investigated the role of transporters and drug-metabolizing enzymes in this poor outcome. The expression levels (RT-qPCR) of potentially responsible genes in blasts collected at diagnosis were related to the subsequent response to two-cycle induction chemotherapy. The high expression of uptake carriers (ENT2), export ATP-binding cassette (ABC) pumps (MDR1), and enzymes (DCK, 5-NT, and CDA) in the blasts was associated with a lower response. Moreover, the sensitivity to cytarabine in AML cell lines was associated with ENT2 expression, whereas the expression of ABC pumps and enzymes was reduced. No ability of any AML cell line to export idarubicin through the ABC pumps, MDR1 and MRP, was found. The exposure of AML cells to cytarabine or idarubicin upregulated the detoxifying enzymes (5-NT and DCK). In AML patients, 5-NT and DCK expression was associated with the lack of response to induction chemotherapy (high sensitivity and specificity). In conclusion, in the blasts of AML patients, the reduction of the intracellular concentration of the active metabolite of cytarabine, mainly due to the increased expression of inactivating enzymes, can determine the response to induction chemotherapy.
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- 2023
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9. Novel Candidate loci and Pathogenic Germline Variants Involved in Familial Hematological Malignancies Revealed by Whole-Exome Sequencing.
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Andrés-Zayas C, Suárez-González J, Chicano-Lavilla M, Bastos Oreiro M, Rodríguez-Macías G, Font López P, Osorio Prendes S, Oarbeascoa Royuela G, García Ramírez P, Nieves Salgado R, Gómez-Centurión I, Carbonell Muñoz D, Muñiz P, Kwon M, Díez-Martín JL, Buño I, and Martínez-Laperche C
- Abstract
The familial occurrence of hematological malignancies has been underappreciated. Recent studies suggest that up to 15% of adults with myeloid neoplasms carry germline pathogenic variants in cancer-predisposing genes. This study aimed to identify the underlying germline predisposition variant in patients with a strong family or personal onco-hematological history using whole exome sequencing on sixteen uncharacterized individuals. It was carried out in two groups of patients, one with samples available from two affected relatives (Cohort A) and one with available samples from the index case (Cohort B). In Cohort A, six families were characterized. Two families shared variants in genes associated with DNA damage response and involved in cancer development ( CHEK2 and RAD54L ). Pathogenic or likely pathogenic germline variants were also found in novel candidate genes ( NFATC2 and TC2N ). In two families, any relevant pathogenic or likely pathogenic genomic variants were identified. In Cohort B, four additional index cases were analyzed. Three of them harbor clinically relevant variants in genes with a probable role in the development of inherited forms of hematological malignancies ( GATA1 , MSH4 and PRF1 ). Overall, whole exome sequencing is a useful approach to achieve a further characterization of these patients and their mutational spectra. Moreover, further investigations may help improve optimization for disease management of affected patients and their families.
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- 2023
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10. Azacitidine vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the PETHEMA Registry.
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Labrador J, Martínez-Cuadrón D, de la Fuente A, Rodríguez-Veiga R, Serrano J, Tormo M, Rodriguez-Arboli E, Ramos F, Bernal T, López-Pavía M, Trigo F, Martínez-Sánchez MP, Rodríguez-Gutiérrez JI, Rodríguez-Medina C, Gil C, Belmonte DG, Vives S, Foncillas MÁ, Pérez-Encinas M, Novo A, Recio I, Rodríguez-Macías G, Bergua JM, Noriega V, Lavilla E, Roldán-Pérez A, Sanz MA, Montesinos P, and On Behalf Of Pethema Group
- Abstract
The hypomethylating agents, decitabine (DEC) and azacitidine (AZA), allowed more elderly acute myeloid leukemia (AML) patients to be treated. However, there are little direct comparative data on AZA and DEC. This multicenter retrospective study compared the outcomes of AZA and DEC in terms of response and overall survival (OS). Potential predictors associated with response and OS were also evaluated. A total of 626 AML patients were included (487 treated with AZA and 139 with DEC). Response rates were similar in both groups: CR was 18% with AZA vs. 23% with DEC (p = 0.20), CR/CRi was 20.5% vs. 25% (p = 0.27) and ORR was 32% vs. 39.5% (p = 0.12), respectively. Patients with leukocytes < 10 × 109/L, bone marrow blasts < 50% and ECOG ≥ 2 had higher ORR with DEC than with AZA. OS was similar in both groups: 10.4 months (95% CI: 9.2−11.7) vs. 8.8 months (95% CI: 6.7−11.0, p = 0.455), for AZA and DEC, respectively. Age (≥80 years), leukocytes (≥ 10 × 109/L), platelet count (<20 × 109/L) and eGFR (≥45 mL/min/1.73 m2) were associated with higher OS with AZA compared to DEC. In conclusion, we found no differences in response and OS rates in AML patients treated with AZA or DEC.
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- 2022
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11. Implementation of a hospital-at-home (HAH) unit for hematological patients during the COVID-19 pandemic: safety and feasibility.
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Gómez-Centurión I, Oarbeascoa G, García MC, López Fresneña MC, Martínez Carreño MJ, Escudero Vilaplana V, González-Haba E, Bailén R, Dorado N, Juárez LM, Rodríguez Macías G, Font López P, Encinas C, Bastos-Oreiro M, Anguita J, Sanjurjo M, Díez-Martin JL, and Kwon M
- Subjects
- Adult, Aged, Aged, 80 and over, Disease Management, Feasibility Studies, Female, Hematopoietic Stem Cell Transplantation, Hospitalization, Humans, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Multiple Myeloma therapy, Myelodysplastic Syndromes therapy, Retrospective Studies, Transplantation, Autologous, Young Adult, COVID-19 epidemiology, Continuity of Patient Care, Hematologic Neoplasms therapy
- Abstract
Background: "Hospital-at-home" (HAH) programs have been shown to optimize resource utilization, shorten hospitalization and prevent nosocomial infection., Methods: We retrospectively analysed data regarding implementation of an HAH unit for caring patients with hematological malignancies in our center, during the COVID-19 pandemic., Results: Between January and November 2020, 105 patients were treated in the HAH unit for a total of 204 episodes. Nine patients with multiple myeloma (MM) received autologous HSCT (auto-HSCT). Three patients with acute myeloid leukemia (AML) received consolidation therapy, 32 patients underwent clinical and analytical monitoring, 20 were transplant recipients early discharged (5 auto-HSCT and 15 allo-HSCT) and 2 had received CART cells therapy. Azacitidine, bortezomib and carfilzomib were administered at home to 54 patients with AML, myelodysplastic syndrome (MDS) or MM. A median of 17 (IQR 13-19) days of admission per patient and a total of 239 visits to the Hematology day-care hospital were avoided. Overall, 28 patients (14% of all episodes) needed admission to the hospital, 4 of them due to COVID-19., Conclusions: Implementation of a Hematology HAH unit was feasible and safe, and provided thorough advanced care to a high-risk population. Advanced care-at-home strategies can be crucial during times of COVID-19 to minimize treatment interruptions and reduce the risk of cross-infections., (© 2021. Japanese Society of Hematology.)
- Published
- 2022
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12. Clinical utility of targeted next-generation sequencing for the diagnosis of myeloid neoplasms with germline predisposition.
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Andrés-Zayas C, Suárez-González J, Rodríguez-Macías G, Dorado N, Osorio S, Font P, Carbonell D, Chicano M, Muñiz P, Bastos M, Kwon M, Díez-Martín JL, Buño I, and Martínez-Laperche C
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- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Hematologic Neoplasms genetics, Humans, Male, Middle Aged, Young Adult, Genetic Predisposition to Disease, Germ-Line Mutation, Hematologic Neoplasms diagnosis, High-Throughput Nucleotide Sequencing methods
- Abstract
Myeloid neoplasms (MN) with germline predisposition (MNGP) are likely to be more common than currently appreciated. Many of the genes involved in MNGP are also recurrently mutated in sporadic MN. Therefore, routine analysis of gene panels by next-generation sequencing provides an effective approach to detect germline variants with clinical significance in patients with hematological malignancies. Gene panel sequencing was performed in 88 consecutive and five nonconsecutive patients with MN diagnosis. Disease-causing germline mutations in CEBPα, ASXL1, TP53, MPL, GATA2, DDX41, and ETV6 genes were identified in nine patients. Six out of the nine patients with germline variants had a strong family history. These patients presented great heterogeneity in the age of diagnosis and phenotypic characteristics. In our study, there were families in which all the affected members presented the same subtype of disease, whereas members of other families presented various disease phenotypes. This intrafamiliar heterogeneity suggests that the acquisition of particular somatic variants may drive the evolution of the disease. This approach enabled high-throughput detection of MNGP in patients with MN diagnosis, which is of great relevance for both the patients themselves and the asymptomatic mutation carriers within the family. It is crucial to make a proper diagnosis of these patients to provide them with the most suitable treatment, follow-up, and genetic counseling., (© 2021 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
- Published
- 2021
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13. Evolving treatment patterns and outcomes in older patients (≥60 years) with AML: changing everything to change nothing?
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Martínez-Cuadrón D, Serrano J, Gil C, Tormo M, Martínez-Sánchez P, Pérez-Simón JA, García-Boyero R, Rodríguez-Medina C, López-Pavía M, Benavente C, Bergua J, Lavilla-Rubira E, Amigo ML, Herrera P, Alonso-Domínguez JM, Bernal T, Colorado M, Sayas MJ, Algarra L, Vidriales MB, Rodríguez-Macías G, Vives S, Pérez-Encinas MM, López A, Noriega V, García-Fortes M, Ramos F, Rodríguez-Gutiérrez JI, Costilla-Barriga L, Labrador J, Boluda B, Rodríguez-Veiga R, Martínez-López J, Sanz MA, and Montesinos P
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- Aged, Aged, 80 and over, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Prognosis, Retrospective Studies, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation mortality, Leukemia, Myeloid, Acute mortality
- Abstract
There are no studies analyzing how therapeutic changes impact on outcomes of older AML patients. This study analyzes patient´s and disease characteristics, treatment patterns, and outcomes of 3637 AML patients aged ≥60 years reported to the PETHEMA registry. Study periods were 1999-2006 (before hypomethylating agents-HMAs availability) vs 2007-2013, and treatments were intensive chemotherapy (IC), non-intensive, clinical trial (CT), and supportive care only (SC). Median age was 72 (range, 60-99), 57% male, median ECOG 1 (range, 0-4), secondary AML 914 (30%), with adverse-risk genetic in 720 (32%). Treatment differed between study periods (1999-2006 vs 2007-2013): IC 58% vs 32%, non-intensive 1 vs 23%, CT 0 vs 2%, SC 27 vs 28% (p < 0.001). Median OS was 4.7 months (1-year OS 29% and 5-years 7%, without differences between periods), 1.2 for SC, 7.8 for non-intensive, 8.6 for IC, and 10.4 for CT (p < 0.001). OS improved in the 2007-2013 period for IC patients (10.3 vs 7.5 months, p = 0.004), but worsened for SC patients (1.2 vs 1.6 months, p = 0.03). Our real-life study shows that, despite evolving treatment for elderly patients during the last decade, OS has remained unchanged. Epidemiologic registries will critically assess whether novel therapies lead to noteworthy advances in the near future (#NCT02606825).
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- 2021
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14. Genetic biomarkers identify a subgroup of high-risk patients within low-risk NPM1 -mutated acute myeloid leukemia.
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Carbonell D, Suárez-González J, Chicano M, Andrés-Zayas C, Díez-Díez M, Rodríguez-Macías G, Muñiz P, Kwon M, Anguita J, Díez-Martín JL, Buño I, and Martínez-Laperche C
- Subjects
- Humans, Mutation, Nucleophosmin, Prognosis, Recurrence, Risk, fms-Like Tyrosine Kinase 3 genetics, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Nuclear Proteins genetics
- Abstract
Although acute myeloid leukemia (AML) with NPM1
mut /FLT3 -ITDneg is a low-risk entity, its relapse rate remains high. Out of 333 AML patients, 27 were NPM1mut , and were analyzed in greater detail in order to find associations between clinical and molecular features and cumulative incidence of relapse. Next-generation sequencing (NGS) was performed on diagnosis and remission samples using two capture-based panels. The presence of the FLT3D835 variant at diagnosis and a qPCR value of NPM1mut ≥0.1% after induction chemotherapy were associated with an increased probability of relapse, especially if both conditions are present together. By contrast, patients in which the main clone found at diagnosis harbored NPM1 variant had a lower risk of relapse. Nineteen of the 85 variants found at diagnosis were detected by NGS in remission. AML Subgroup with NPM1mut / FLT3 -ITDneg is a heterogeneous entity, which can be further risk-stratified based on molecular biomarkers.- Published
- 2021
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15. COVID-19 coagulopathy: An in-depth analysis of the coagulation system.
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Martín-Rojas RM, Pérez-Rus G, Delgado-Pinos VE, Domingo-González A, Regalado-Artamendi I, Alba-Urdiales N, Demelo-Rodríguez P, Monsalvo S, Rodríguez-Macías G, Ballesteros M, Osorio-Prendes S, Díez-Martín JL, and Pascual Izquierdo C
- Subjects
- Aged, Aged, 80 and over, Biomarkers blood, Blood Coagulation Tests, Blood Platelets pathology, Blood Platelets virology, COVID-19, Coronavirus Infections diagnosis, Coronavirus Infections mortality, Coronavirus Infections virology, Cytokine Release Syndrome diagnosis, Cytokine Release Syndrome mortality, Cytokine Release Syndrome virology, Disseminated Intravascular Coagulation diagnosis, Disseminated Intravascular Coagulation mortality, Disseminated Intravascular Coagulation virology, Female, Fibrin Fibrinogen Degradation Products metabolism, Humans, Lung blood supply, Lung drug effects, Lung pathology, Lung virology, Male, Middle Aged, Pandemics, Pneumonia, Viral diagnosis, Pneumonia, Viral mortality, Pneumonia, Viral virology, Prognosis, Protein S metabolism, Retrospective Studies, SARS-CoV-2, Severity of Illness Index, Survival Analysis, Venous Thrombosis diagnosis, Venous Thrombosis mortality, Venous Thrombosis virology, Betacoronavirus pathogenicity, Coronavirus Infections complications, Cytokine Release Syndrome complications, Disseminated Intravascular Coagulation complications, Factor VIII metabolism, Pneumonia, Viral complications, Venous Thrombosis complications
- Abstract
Background: Abnormal coagulation parameters have been reported in COVID-19-infected patients. Although the underlying mechanism of COVID-19 coagulopathy remains unknown, it has been suggested to be a form of disseminated intravascular coagulation (DIC)., Objectives: The aim of our study was to analyze the coagulation parameters of patients with COVID-19, determine whether coagulation factors consumption occurs and identify potential prognostic biomarkers of the disease., Patients/methods: Blood samples from hospitalized patients with COVID-19 pneumonia were collected. We performed basic coagulation tests and quantification of coagulation factors and physiological inhibitor proteins. Laboratory data were compared with clinical data and outcomes., Results: The study involved 206 patients (63.6% male). D-dimer was particularly elevated (median 450 ng/mL; IQR 222.5-957.3). Free protein S levels were below the normal range (median 56.6%; IQR: 43.6-68.9), and factor VIII showed an increasing trend (median 173.4%; IQR: 144.1-214.9). However, all coagulation factors were within normal limits. We found no correlation between abnormal coagulation parameters and thrombosis, except for higher D-dimer (HR 1.99; 95% CI 1.3-3.1; P = .002)., Conclusions: COVID-19 is associated with coagulopathy that correlates with poor prognosis. However, we did not demonstrate a consumption of coagulation factors, as seen in DIC., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2020
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16. Exome sequencing reveals heterogeneous clonal dynamics in donor cell myeloid neoplasms after stem cell transplantation.
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Suárez-González J, Triviño JC, Bautista G, García-Marco JA, Figuera Á, Balas A, Vicario JL, Ortuño FJ, Teruel R, María Álamo J, Carbonell D, Andrés-Zayas C, Dorado N, Rodríguez-Macías G, Kwon M, Díez-Martín JL, Martínez-Laperche C, Buño I, and Spanish Group For Hematopoietic Transplantation Geth
- Subjects
- Exome, Humans, Stem Cell Transplantation, Exome Sequencing, Hematopoietic Stem Cell Transplantation, Neoplasms
- Published
- 2020
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17. A retrospective cohort of invasive fusariosis in the era of antimould prophylaxis.
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Fernández-Cruz A, Semiglia MA, Guinea J, Martínez-Jiménez MDC, Escribano P, Kwon M, Rodríguez-Macías G, Chamorro-de-Vega E, Rodríguez-González C, Navarro R, Galar A, Sánchez-Carrillo C, Díez-Martín JL, and Muñoz P
- Subjects
- Chemoprevention, Fusariosis mortality, Fusarium, Humans, Incidence, Invasive Fungal Infections mortality, Microbial Sensitivity Tests, Neutropenia complications, Retrospective Studies, Risk Factors, Spain epidemiology, Tertiary Care Centers, Antifungal Agents administration & dosage, Fusariosis drug therapy, Invasive Fungal Infections drug therapy
- Abstract
Mould-active prophylaxis is affecting the epidemiology of invasive mycoses in the form of a shift toward less common entities such as fusariosis. We analyze the characteristics of invasive fusariosis and its association to antifungal prophylaxis in a retrospective cohort (2004-2017) from a tertiary hospital in Madrid, Spain. Epidemiological, clinical, microbiological, and antifungal consumption data were retrieved. Isolates were identified to molecular level, and antifungal susceptibility was tested. Eight cases of invasive fusariosis were diagnosed. Three periods were identified according to incidence: <2008 (three cases), 2008-2013 (zero cases), >2014 (five cases). All except one case involved breakthrough fusariosis. During the earliest period, the episodes occurred while the patient was taking itraconazole (two) or fluconazole (one); more recently, while on micafungin (three) or posaconazole (one). Early cases involved acute leukemia at induction/consolidation, recent cases relapsed/refractory disease (P = .029). Main risk factor for fusariosis (62.5%) was prolonged neutropenia (median 44 days). Galactomannan and beta-D-glucan were positive in 37.5% and 100% of cases, respectively. All isolates except F. proliferatum presented high minimal inhibitory concentrations (MICs) against the azoles and lower MIC to amphotericin B. Most patients received combined therapy. Mortality at 42 days was 62.5%. Resolution of neutropenia was associated with survival (P = .048). Invasive fusariosis occurs as breakthrough infection in patients with hematologic malignancy, prolonged neutropenia, and positive fungal biomarkers. Recent cases were diagnosed in a period of predominant micafungin use in patients who had more advanced disease and protracted neutropenia and for whom mortality was extremely high. Resolution of neutropenia was a favorable prognostic factor., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)
- Published
- 2020
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18. Practical Considerations for Treatment of Relapsed/Refractory FLT3-ITD Acute Myeloid Leukaemia with Quizartinib: Illustrative Case Reports.
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Martínez-Cuadrón D, Rodríguez-Macías G, Rodríguez-Veiga R, Boluda B, and Montesinos P
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Mutation, Protein Kinase Inhibitors therapeutic use, Benzothiazoles administration & dosage, Leukemia, Myeloid, Acute drug therapy, Phenylurea Compounds administration & dosage, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Quizartinib is a tyrosine kinase inhibitor selectively targeting the FMS-like tyrosine kinase 3 (FLT3) receptor that has been developed for the treatment of acute myeloid leukaemia (AML). The Phase 3 QuANTUM-R study investigated the efficacy of quizartinib monotherapy in patients with relapsed/refractory FLT3-ITD mutation-positive AML. The clinical course of four QuANTUM-R participants exemplifies issues specific to quizartinib treatment and is described here. Patient 1 was FLT3-ITD mutation-negative at AML diagnosis, but became FLT3-ITD mutation-positive during treatment that included several lines of chemotherapy and was therefore a suitable candidate for quizartinib. Because of the clonal shifts of AML during treatment, retesting genetic alterations at each relapse or resistance may help to identify candidates for targeted treatment options. Patient 2 developed QTc prolongation during quizartinib treatment, but the QTc interval normalised after dose reduction, allowing the patient to continue treatment and eventually resume the recommended dose. Patient 3 responded to quizartinib and was scheduled for haematopoietic stem cell transplant (HSCT), but developed febrile neutropenia and invasive aspergillosis during conditioning and subsequently died (to avoid drug-drug interactions, no azole antifungal was administered concomitantly). Care is required when selecting concomitant medications, and if there is potential for interactions (e.g. if prophylactic azole antifungals are required) the quizartinib dose should be reduced to minimise the risk of QTc prolongation. Patient 4 was able to undergo HSCT after responding to quizartinib and experienced a durable response after HSCT while on quizartinib maintenance therapy. Together, these cases illustrate the main issues to be addressed when managing patients under quizartinib, allowing for adequate scheduling and tolerability, bridging to HSCT, and durable remission on maintenance therapy in some patients.
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- 2020
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19. Next-Generation Sequencing Improves Diagnosis, Prognosis and Clinical Management of Myeloid Neoplasms.
- Author
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Carbonell D, Suárez-González J, Chicano M, Andrés-Zayas C, Triviño JC, Rodríguez-Macías G, Bastos-Oreiro M, Font P, Ballesteros M, Muñiz P, Balsalobre P, Kwon M, Anguita J, Díez-Martín JL, Buño I, and Martínez-Laperche C
- Abstract
Molecular diagnosis of myeloid neoplasms (MN) is based on the detection of multiple genetic alterations using various techniques. Next-generation sequencing (NGS) has been proved as a useful method for analyzing many genes simultaneously. In this context, we analyzed diagnostic samples from 121 patients affected by MN and ten relapse samples from a subset of acute myeloid leukemia patients using two enrichment-capture NGS gene panels. Pathogenicity classification of variants was enhanced by the development and application of a custom onco-hematology score. A total of 278 pathogenic variants were detected in 84% of patients. For structural alterations, 82% of those identified by cytogenetics were detected by NGS, 25 of 31 copy number variants and three out of three translocations. The detection of variants using NGS changed the diagnosis of seven patients and the prognosis of 15 patients and enabled us to identify 44 suitable candidates for clinical trials. Regarding AML, six of the ten relapsed patients lost or gained variants, comparing with diagnostic samples. In conclusion, the use of NGS panels in MN improves genetic characterization of the disease compared with conventional methods, thus demonstrating its potential clinical utility in routine clinical testing. This approach leads to better-adjusted treatments for each patient.
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- 2019
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20. A Case-Control Study of Real-Life Experience with Ceftolozane-Tazobactam in Patients with Hematologic Malignancy and Pseudomonas aeruginosa Infection.
- Author
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Fernández-Cruz A, Alba N, Semiglia-Chong MA, Padilla B, Rodríguez-Macías G, Kwon M, Cercenado E, Chamorro-de-Vega E, Machado M, Pérez-Lago L, García de Viedma D, Díez Martín JL, and Muñoz P
- Subjects
- Bacteremia drug therapy, Bacteremia microbiology, Case-Control Studies, Cross Infection drug therapy, Cross Infection microbiology, Drug Resistance, Multiple, Bacterial genetics, Female, Hematologic Neoplasms, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Pseudomonas Infections mortality, Anti-Bacterial Agents adverse effects, Anti-Bacterial Agents therapeutic use, Cephalosporins adverse effects, Cephalosporins therapeutic use, Pseudomonas Infections drug therapy, Pseudomonas aeruginosa drug effects, Tazobactam adverse effects, Tazobactam therapeutic use
- Abstract
We present our experience in patients with hematologic malignancy and Pseudomonas aeruginosa infection treated with ceftolozane-tazobactam. We performed a single-center case-control study comparing patients with hematologic malignancy and P. aeruginosa infection treated with ceftolozane-tazobactam (study group) with similar patients not treated with ceftolozane-tazobactam (control group) to assess safety and efficacy. Nineteen cases and 38 controls were analyzed. Cases were younger (45.6 years versus 57.6 years; P = 0.012) and less frequently had bacteremia (52.6% versus 86.8%; P = 0.008). They also had worse Multinational Association for Supportive Care in Cancer (MASCC) scores (10.2 versus 16.1; P = 0.0001), more hospital-acquired infections (78.9% versus 47.4%; P = 0.013), and more extremely drug-resistant (XDR) P. aeruginosa infections (47.4% versus 21.1%; P = 0.015). Cases received a median of 14 days (7 to 18 days) of ceftolozane-tazobactam (monotherapy in 11 cases [57.9.6%]). Ceftolozane-tazobactam was mostly used as targeted therapy (16 cases; 84.2%) because of resistance (9 cases; 47.4%), failure (4 cases; 21.1%), and toxicity (3 cases; 15.8%). Ten cases had bacteremia (52.6%). The sources were pneumonia (26.3%), catheter-related bacteremia (21.1%), primary bacteremia (21.1%), and perianal/genital (15.7%), urinary (10.5%), and skin/soft tissue (5.3%) infection. No toxicity was attributed to ceftolozane-tazobactam. More than 60% had neutropenia, and 15.8% fulfilled the criteria for sepsis. There were no significant differences in clinical cure at day 14 (89.5% versus 71.1%; P = 0.183) or recurrence (15.8% versus 10.5%; P = 0.675). Thirty-day mortality was lower among cases (5.3% versus 28.9%; P = 0.045). Ceftolozane-tazobactam was well tolerated and at least as effective as other alternatives for P. aeruginosa infection in patients with hematologic malignancy, including neutropenic patients with sepsis caused by XDR strains., (Copyright © 2019 American Society for Microbiology.)
- Published
- 2019
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21. Whole-exome sequencing reveals acquisition of mutations leading to the onset of donor cell leukemia after hematopoietic transplantation: a model of leukemogenesis.
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Suárez-González J, Martínez-Laperche C, Martínez N, Rodríguez-Macías G, Kwon M, Balsalobre P, Carbonell D, Chicano M, Serrano D, Triviño JC, Piris MÁ, Gayoso J, Díez-Martín JL, and Buño I
- Subjects
- Adult, Cell Transformation, Neoplastic, Female, Graft vs Host Disease diagnosis, Graft vs Host Disease etiology, Humans, Leukemia etiology, Leukemia genetics, Models, Biological, Prognosis, Biomarkers, Tumor genetics, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia diagnosis, Mutation, Tissue Donors, Transplantation Conditioning adverse effects, Exome Sequencing methods
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- 2018
- Full Text
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22. Donor Cell-Derived Hematologic Neoplasms after Hematopoietic Stem Cell Transplantation: A Systematic Review.
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Suárez-González J, Martínez-Laperche C, Kwon M, Balsalobre P, Carbonell D, Chicano M, Rodríguez-Macías G, Serrano D, Gayoso J, Díez-Martín JL, and Buño I
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Hematologic Neoplasms pathology, Humans, Infant, Infant, Newborn, Male, Middle Aged, Tissue Donors, Young Adult, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation methods, Transplantation Conditioning methods
- Abstract
Development of de novo hematologic malignancies in donor cells after allogeneic stem cell transplantation (allo-SCT) provides a useful in vivo model to study the process of leukemogenesis. A systematic analysis of the cases reported in the literature was performed to identify risk factors and mechanisms involved in the pathogenesis of donor cell-derived hematologic neoplasms (DCHN) and leukemogenic transformation. Relevant data were extracted from 137 cases. Cases of DCHN show a wide heterogeneity with regard to recipient/donor age, sex mismatch, and conditioning regimen. Some characteristics, such as the type of primary disease, the type of hematologic malignancy of the DCHN, and the stem cell source used in the transplant procedure, differ from those expected. Mechanisms involved in the pathogenesis of DCHN are complex, and several hypotheses have been proposed, such as pre-existing hematologic neoplasms or premalignant clones in the donor, decreased immune surveillance, and damage to bone marrow microenvironment in the recipient. Most likely several if not all these mechanisms play a role in DCHN development. Novel approaches, such as next-generation sequencing to study consecutive samples after allo-SCT in these patients, appear to be promising to decipher the mechanisms of leukemogenesis., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
23. Role of drug transporters in the sensitivity of acute myeloid leukemia to sorafenib.
- Author
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Macias RIR, Sánchez-Martín A, Rodríguez-Macías G, Sánchez-Abarca LI, Lozano E, Herraez E, Odero MD, Díez-Martín JL, Marin JJG, and Briz O
- Abstract
Background: Chemoresistance often limits the success of the pharmacological treatment in acute myeloid leukemia (AML) patients. Although positive results have been obtained with tyrosine kinase inhibitors (TKIs), such as sorafenib, especially in patients with Fms-like tyrosine kinase 3 (FLT3)-positive AML, the success of chemotherapy is very heterogeneous. Here we have investigated in vitro whether the transportome (set of expressed plasma membrane transporters) is involved in the differential response of AML to sorafenib., Methods: The sensitivity to sorafenib-induced cell death (MTT test and anexin V/7-AAD method) was evaluated in five different cell lines: MOLM-13, OCI-AML2, HL-60, HEL and K-562. The transportome was characterized by measuring mRNA using RT-qPCR. Drug uptake/efflux was determined by flow cytometry using specific substrates and inhibitors., Results: The cytostatic response to sorafenib was: MOLM-13>>OCI-AML2>HL-60>HEL≈K-562. Regarding efflux pumps, MDR1 was highly expressed in HEL>K-562≈MOLM-13, but not in OCI-AML2 and HL-60. BCRP and MPR3 expression was low in all cell lines, whereas MRP4 and MRP5 expression was from moderate to high. Flow cytometry studies demonstrated that MRP4, but not MRP5, was functional. The expression of the organic cation transporter 1 (OCT1), involved in sorafenib uptake, was MOLM-13>OCI-AML2≈HL-60 and non detectable in HEL and K-562. Transfection of HEL cells with OCT1 increased the sensitivity of these cells to sorafenib, whereas inactive genetic variants failed to induce this change., Conclusion: Together with changes in the expression/function of receptors targeted by TKIs, the expression of plasma membrane transporters involved in sorafenib uptake/efflux may affect the response of leukemia cells to this drug., Competing Interests: CONFLICTS OF INTEREST None.
- Published
- 2018
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24. [Disseminated bullous lesions and supraclavicular adenopathy in a nonagenarian patient].
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Hidalgo Gamarra M, Rodríguez-Macías G, Escudero Soto A, Ortiz FJ, and Vidán Astiz MT
- Subjects
- Aged, 80 and over, Clavicle, Female, Hodgkin Disease complications, Humans, Lymphadenopathy etiology, Skin Diseases, Vesiculobullous etiology, Hodgkin Disease diagnosis
- Published
- 2015
- Full Text
- View/download PDF
25. Mutation of the NPM1 gene contributes to the development of donor cell-derived acute myeloid leukemia after unrelated cord blood transplantation for acute lymphoblastic leukemia.
- Author
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Rodríguez-Macías G, Martínez-Laperche C, Gayoso J, Noriega V, Serrano D, Balsalobre P, Muñoz-Martínez C, Díez-Martín JL, and Buño I
- Subjects
- Adult, Female, Humans, In Situ Hybridization, Fluorescence, Mutation, Nucleophosmin, Precursor Cell Lymphoblastic Leukemia-Lymphoma surgery, Real-Time Polymerase Chain Reaction, Transplantation, Homologous adverse effects, Unrelated Donors, Cord Blood Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute genetics, Nuclear Proteins genetics
- Abstract
Donor cell leukemia (DCL) is a rare but severe complication after allogeneic stem cell transplantation. Its true incidence is unknown because of a lack of correct recognition and reporting, although improvements in molecular analysis of donor-host chimerism are contributing to a better diagnosis of this complication. The mechanisms of leukemogenesis are unclear, and multiple factors can contribute to the development of DCL. In recent years, cord blood has emerged as an alternative source of hematopoietic progenitor cells, and at least 12 cases of DCL have been reported after unrelated cord blood transplantation. We report a new case of DCL after unrelated cord blood transplantation in a 44-year-old woman diagnosed as having acute lymphoblastic leukemia with t(1;19) that developed acute myeloid leukemia with normal karyotype and nucleophosmin (NPM1) mutation in donor cells. To our knowledge, this is the first report of NPM1 mutation contributing to DCL development., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
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26. Allogeneic hematopoietic stem cell transplantation in patients 50 years of age and older.
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de la Cámara R, Alonso A, Steegmann JL, Arranz R, Granados E, Rodríguez-Macías G, Sanz-Rodríguez C, de Soria VG, Figuera A, and Fernández-Rañada JM
- Subjects
- Adult, Contraindications, Female, Graft Rejection epidemiology, Graft vs Host Disease epidemiology, Humans, Incidence, Male, Middle Aged, Multivariate Analysis, Recurrence, Stem Cell Transplantation mortality, Survival Rate, Transplantation, Homologous mortality, Aging physiology, Stem Cell Transplantation adverse effects, Transplantation, Homologous adverse effects
- Abstract
Background and Objectives: The population of elderly patients with hematologic malignancies is increasing and so will the activity of stem cell transplantation (SCT) in this population. The aim of this study was to analyze the toxicity and survival of allogeneic SCT in patients 50 years and older (elderly group), and compare the results with a standard adult population (young group)., Design and Methods: Thirty-two elderly patients (median age 52.5, range 50-59 years) and 97 young patients (median 32, range 20-40) received a myeloablative, allogeneic SCT from HLA-identical siblings at a single institution, and formed the basis of this retrospective study. The majority of transplants in both groups were performed with non-T-cell-depleted bone marrow, conditioned with busulfan + cyclophosphamide and received cyclosporine + methotrexate as graft-versus-host disease (GVHD) prophylaxis. The percentage of high-risk patients was nearly double in the elderly group (41% vs. 23%, p = 0.06)., Results: We observed a low incidence of toxicities in the elderly group, including veno-occlusive disease, acute and chronic GVHD, transplant-related mortality, time to engraftment, and relapse incidence, without significant differences compared within the young group. The 3-year survival rates were not statistically different between the elderly and young groups: 51% vs. 55% for all patients; 87% vs. 69% in chronic myeloid leukemia; 79% vs. 62% in standard risk patients and 13% vs. 31% in high risk ones. In multivariate analyses no significant difference in overall survival was found between age groups., Interpretation and Conclusions: According to our experience, age alone (between 50-59), should not be considered a contraindication to a conventional HLA identical sibling transplant.
- Published
- 2002
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