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1.
Blood Adv ; 5(5): 1442-1451, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33666653

RESUMO

We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.

4.
Leuk Lymphoma ; 60(14): 3493-3502, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31359808

RESUMO

Ruxolitinib was recently approved for the treatment of patients with polycythemia vera who are resistant/intolerant to hydroxyurea based on data from the RESPONSE studies. This phase 3b, Expanded Treatment Protocol study (NCT02292446) of ruxolitinib for hydroxyurea-resistant/intolerant patients with polycythemia vera (N = 161: median exposure = 25.1 weeks) further evaluated the safety of ruxolitinib. Adverse events (AEs) led to dose adjustment/interruption in 37.9% of patients and study drug discontinuation in 8.7% of patients. The most common hematologic AEs included anemia and thrombocytosis; while headache and diarrhea were the most frequent nonhematologic AEs. At week 24, 45.3% of patients achieved hematocrit control; hematologic remission was seen in 18% of patients. At least, 50% of reduction in spleen length was achieved in 86.7% of patients from baseline at any time. The observed safety profile of ruxolitinib was consistent and the efficacy results were similar to the observed values in the RESPONSE studies.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Hidroxiureia/farmacologia , Policitemia Vera/tratamento farmacológico , Pirazóis/uso terapêutico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/patologia , Prognóstico , Taxa de Sobrevida
5.
Blood ; 134(3): 277-290, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31151987

RESUMO

Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.


Assuntos
Mutação , Fatores de Alongamento de Peptídeos/genética , Fatores de Iniciação de Peptídeos/biossíntese , Ribonucleoproteína Nuclear Pequena U5/genética , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/metabolismo , Adolescente , Animais , Células Cultivadas , Análise Mutacional de DNA , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Linhagem , Fatores de Alongamento de Peptídeos/química , Fatores de Alongamento de Peptídeos/metabolismo , Fenótipo , Conformação Proteica , Ribonucleoproteína Nuclear Pequena U5/química , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Síndrome de Shwachman-Diamond/diagnóstico , Relação Estrutura-Atividade , Sequenciamento Completo do Genoma
6.
Haematologica ; 103(8): 1278-1287, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29724903

RESUMO

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.


Assuntos
Deficiência de GATA2/epidemiologia , Mutação em Linhagem Germinativa , Adulto Jovem , Adolescente , Adulto , Bélgica , Criança , Pré-Escolar , França , Deficiência de GATA2/complicações , Deficiência de GATA2/genética , Deficiência de GATA2/terapia , Neoplasias Hematológicas/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Infecções/etiologia , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Inquéritos e Questionários
7.
Haematologica ; 103(3): 438-446, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29217781

RESUMO

We have previously described the safety and efficacy of pegylated interferon-α2a therapy in a cohort of 62 patients with myeloproliferative neoplasm-associated myelofibrosis followed in centers affiliated to the French Intergroup of Myeloproliferative neoplasms. In this study, we report their long-term outcomes and correlations with mutational patterns of driver and non-driver mutations analyzed by targeted next generation sequencing. The median age at diagnosis was 66 years old, the median follow-up since starting pegylated interferon was 58 months. At the time of analysis, 30 (48.4%) patients were alive including 16 still being treated with pegylated interferon. The median survival of patients with intermediate and high-risk prognostic Lille and dynamic International Prognostic Scoring System scores treated with pegylated interferon was increased in comparison to that of historical cohorts. In addition, overall survival was significantly correlated with the duration of pegylated interferon therapy (70 versus 30 months after 2 years of treatment, P<10-12). JAK2V617F allele burden was decreased by more than 50% in 58.8% of patients and two patients even achieved complete molecular response. Next-generation sequencing analyses performed in 49 patients showed that 28 (57.1%) of them carried non-driver mutations. The presence of at least one additional mutation was associated with a reduction of both overall and leukemia-free survival. These findings in a large series of patients with myelofibrosis suggest that pegylated interferon therapy may provide a survival benefit for patients with intermediate- or high-risk Lille and dynamic International Prognostic Scoring System scores. It also reduced the JAK2V617F allele burden in most patients. These results further support the use of pegylated interferon in selected patients with myelofibrosis.


Assuntos
Interferon-alfa/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/mortalidade , Mielofibrose Primária/genética , Mielofibrose Primária/mortalidade , Prognóstico , Proteínas Recombinantes/uso terapêutico , Medição de Risco , Análise de Sobrevida
8.
Leuk Res ; 63: 34-40, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29096334

RESUMO

Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n=89) and without (n=329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count <100×109/L (moderate 51-100×109/L; severe ≤50×109/L), was associated with anemia (76% vs. 45%, p<0.001), leukopenia (29% vs. 11%, p<0.001), and need for red blood cell transfusion (35% vs. 19%, p=0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p<0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p=0.04), leukopenia (40% vs. 20%, p=0.04), and transfusion requirements (51% vs. 20%, p=0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies.


Assuntos
Determinação de Necessidades de Cuidados de Saúde , Mielofibrose Primária/diagnóstico , Índice de Gravidade de Doença , Avaliação de Sintomas , Trombocitopenia/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/epidemiologia , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários , Trombocitopenia/epidemiologia
9.
Haematologica ; 102(1): 85-93, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27540137

RESUMO

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.


Assuntos
Transtornos Mieloproliferativos/epidemiologia , Fenótipo , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/mortalidade , Prognóstico , Fatores Sexuais , Inquéritos e Questionários , Adulto Jovem
11.
J Clin Oncol ; 34(2): 151-9, 2016 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-26598745

RESUMO

PURPOSE: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. PATIENTS AND METHODS: Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). RESULTS: The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). CONCLUSION: The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.


Assuntos
Antineoplásicos/efeitos adversos , Hidroxiureia/efeitos adversos , Flebotomia , Policitemia Vera/complicações , Policitemia Vera/tratamento farmacológico , Esplenomegalia/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Fadiga/etiologia , Feminino , Febre/etiologia , Humanos , Hidroxiureia/administração & dosagem , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Palpação , Prognóstico , Estudos Prospectivos , Prurido/etiologia , Índice de Gravidade de Doença , Sudorese , Perda de Peso
13.
Br J Haematol ; 162(6): 783-91, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23848933

RESUMO

Myeloproliferative neoplasm-related myelofibrosis is associated with cytopenic or proliferative phases, splenomegaly and constitutional symptoms. Few effective treatments are available and small series suggested that interferon could be an option for myelofibrosis therapy. We performed a retrospective study of pegylated-interferon α-2a (Peg-IFNα-2a) therapy in myelofibrosis. Sixty-two patients treated with Peg-IFNα-2a at 17 French and Belgian centres were included. Responses were determined based on the criteria established by the International Working Group for Myelofibrosis Research and Treatment. Mean follow-up was 26 months. Sixteen of 25 anaemic patients (64%) (eight concomitantly receiving recombinant erythropoietin) achieved a complete response and transfusion-independence was obtained in 5/13 patients (38·5%). Constitutional symptoms resolved in 82% of patients. All five leucopenic patients normalized their leucocyte counts, whereas a normal platelet count was obtained in 5/8 thrombocytopenic patients. Splenomegaly was reduced in 46·5% of patients, and complete resolution of thrombocytosis and leucocytosis were observed in 82·8% and 68·8% of patients, respectively. Side effects (mostly haematological) were mainly of grade 1-2. The only factor independently associated with treatment failure was a spleen enlargement of more than 6 cm below the costal margin. In conclusion, Peg-IFNα-2a induced high response rates with acceptable toxicity in a large proportion of patients with primary and secondary myelofibrosis, especially in early phases.


Assuntos
Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Mielofibrose Primária/patologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
14.
J Clin Oncol ; 30(33): 4098-103, 2012 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-23071245

RESUMO

PURPOSE: Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. PATIENTS AND METHODS: The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. RESULTS: MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P<.001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) for patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, respectively. The MPN-SAF TSS strongly correlated with overall quality of life (QOL; r=0.59; P<.001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) functional scales (all P<.001 and absolute r≥0.50 except social functioning r=0.48). No significant trends were present when comparing therapy subgroups. The MPN-SAF TSS had excellent internal consistency (Cronbach's α=.83). Factor analysis identified a single underlying construct, indicating that the MPN-SAF TSS is an appropriate, unified scoring method. CONCLUSION: The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptom study to date. This new prospective scoring method may be used to assess MPN symptom burden in both clinical practice and trial settings.


Assuntos
Transtornos Mieloproliferativos/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/patologia , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Perfil de Impacto da Doença , Inquéritos e Questionários , Adulto Jovem
15.
Blood Cells Mol Dis ; 46(3): 235-8, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21306925

RESUMO

Essential thrombocythemia and polycythemia vera are myeloproliferative disorders (MPD) with an elevated thrombotic risk. Leukocytosis has recently emerged as a new risk factor and there is increasing evidence that polymorphonuclear neutrophils (PMN) are involved. Procoagulant activity (PCA) of PMN in MPD has not yet been investigated. PCA of PMN from 22 patients with JAK2(V617F) positive MPD and 26 healthy subjects was studied using calibrated automated thrombography: in vitro thrombin generation induced with 1 pM tissue factor in the presence of added procoagulant phospholipids. There were no differences between patients and controls regarding the ability of PMN to increase thrombin generation. More surprisingly, basal thrombin generation in acellular MPD-plasma was found decreased for as yet unknown reasons. The presence of an active protein C pathway or platelets might provide a better insight into the coagulation phenotype in MPD.


Assuntos
Testes de Coagulação Sanguínea , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/fisiopatologia , Neutrófilos/patologia , Trombofilia/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Policitemia Vera/metabolismo , Policitemia Vera/fisiopatologia , Trombina/metabolismo , Trombocitemia Essencial/metabolismo , Trombocitemia Essencial/fisiopatologia
17.
Transfusion ; 50(12): 2676-85, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20663114

RESUMO

BACKGROUND: The short-term effects of granulocyte-colony-stimulating factor (G-CSF) have been extensively studied, but recent reports of G-CSF-induced genetic perturbations raised concerns regarding its long-term safety. In this respect, duration of G-CSF-induced perturbations has been less studied than short-term effects and needs to be evaluated. STUDY DESIGN AND METHODS: G-CSF mobilization-induced immunologic alterations were prospectively analyzed in a cohort of 24 healthy donors. Blood samples were taken before G-CSF administration; at the time of administration; and at 1, 3, 6, and 12 months and analyzed for blood cell counts and in vitro cytokines (interleukin [IL]-2, -8, and -10) and immunoglobulin production, quantified in the culture supernatant of peripheral blood mononuclear cells (PBMNCs) after, respectively, phytohemagglutinin and pokeweed mitogen stimulation. RESULTS: Platelet, granulocyte, monocyte, B, and dendritic blood cell counts as well as the IL-2, -8, and -10 secretion by PBMNCs, perturbed at the time of G-CSF mobilization, returned to baseline values at 1 month, with T-cell and natural killer cell counts recovering at 3 months. In vitro immunoglobulin production was increased up to 6 months after mobilization. CONCLUSION: Although assessment of the potential long-term risk of G-CSF administration will require prolonged observation of larger cohorts, our data show that the duration of immunologic perturbations may be more persistent than previously anticipated, especially for B-cell functional alterations. Most perturbations remain, however, transient with a return to baseline values within 1 year.


Assuntos
Doadores de Sangue , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Doenças do Sistema Imunitário/fisiopatologia , Leucaférese/métodos , Linfócitos/fisiologia , Adulto , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/fisiologia , Humanos , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/imunologia , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Recuperação de Função Fisiológica/imunologia , Fatores de Tempo , Adulto Jovem
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