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1.
Ann Hematol ; 98(2): 321-330, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30446802

RESUMO

Bosutinib is a second-generation tyrosine kinase inhibitor (2GTKI) approved at 400 mg once daily (QD) as first-line therapy in patients with chronic myeloid leukemia (CML) patients and at 500 mg QD in patients who are resistant to or intolerant of prior therapy. In clinical practice, bosutinib is often given to patients who have failed imatinib, nilotinib, and dasatinib (i.e., as fourth-line treatment), despite the limited data on its clinical benefit in this setting. We have retrospectively evaluated the results of bosutinib in a series of 62 CML patients who have failed to prior treatment with all three, imatinib, nilotinib, and dasatinib. Median time on TKI treatment before bosutinib start was 105 (9-163) months, and median duration on bosutinib was 9 months (1-30). Overall, probabilities to achieve complete cytogenetic response (CCyR) and major molecular response (MMR) were 25% and 24% respectively. After a median follow-up period of 14 months, the event-free survival and progression-free survival were 68 and 85%, respectively. Sixty-four percent of patients in CCyR at the time of bosutinib start were able to achieve MMR. In contrast, patients without CCyR, probabilities to obtain CCyR and MMR were 25% and 14%. Bosutinib was well tolerated in this heavily pretreated patients' cohort. Pleural effusions and diarrhea were the most frequent grade II-IV side effects, leading to treatment discontinuation in 16% of patients. Bosutinib is an effective treatment option for patients who have failed previous 2GTKIs due to intolerance. However, efficacy seems to be related to the molecular response that the patient achieved prior to bosutinib.


Assuntos
Compostos de Anilina/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilos/administração & dosagem , Quinolinas/administração & dosagem , Adulto , Compostos de Anilina/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Nitrilos/efeitos adversos , Quinolinas/efeitos adversos , Estudos Retrospectivos , Taxa de Sobrevida
2.
Haematologica ; 104(3): 576-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30262568

RESUMO

Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lymphocytic leukemia. We, therefore, analyzed the clinical and biological characteristics of chronic lymphocytic leukemia patients with mutations in this pathway and investigated the in vitro response of primary cells to BRAF and ERK inhibitors. Putative damaging mutations were found in 25 of 452 patients (5.5%). Among these, BRAF was mutated in nine patients (2.0%), genes upstream of BRAF (KITLG, KIT, PTPN11, GNB1, KRAS and NRAS) were mutated in 12 patients (2.6%), and genes downstream of BRAF (MAPK2K1, MAPK2K2, and MAPK1) were mutated in five patients (1.1%). The most frequent mutations were missense, subclonal and mutually exclusive. Patients with these mutations more frequently had increased lactate dehydrogenase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12 and unmutated immunoglobulin heavy-chain variable region genes and had a worse 5-year time to first treatment (hazard ratio 1.8, P=0.025). Gene expression analysis showed upregulation of genes of the MAPK pathway in the group carrying RAS-BRAF-MAPK-ERK pathway mutations. The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells. In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that the RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, is associated with adverse clinical features and could be pharmacologically inhibited.

3.
Biol Blood Marrow Transplant ; 24(10): 2088-2093, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29753162

RESUMO

This study examined the impact of prednisone (PDN) on cytomegalovirus (CMV) infection after allogeneic stem cell transplantation (allo-SCT) according to donor and recipient CMV serostatus. Seventy-five patients underwent allo-SCT from June 2010 to July 2012. The risk of CMV infection according to donor and recipient serostatus was defined as follows: high risk (HR; D-/R+), intermediate risk (IR; D+/R+ and D+/R-), and low risk (D-/R-). Forty-five patients (60%) developed CMV infection, and 46 patients (61%) received steroids (PDN ≥ 1 mg/kg/day) to treat acute graft-versus-host disease. CMV infection was more common in those treated with steroids than in those not treated with steroids (70% versus 44%, respectively, P < .05). Overall, 40% of patients had recurrent CMV infection (50% PDN versus 24% no PDN, P < .05). Steroids had no impact on the incidence of CMV infection or its recurrence in HR patients; however, steroids did prolong the need for antiviral treatment. The incidence of CMV infection in IR patients was higher in those receiving PDN (80% PDN versus 41% no PDN, P = .01); recurrence rates were also higher (55% PDN versus 18% no PDN, P = .02). We analyzed CMV-specific immune reconstitution in the first 22 patients of the series and observed that patients on steroids had lower levels of CMV-specific lymphocytes TCD8 (P < .05 on days +60, +100, and +180) and that CMV-specific immune reconstitution (defined as lymphocytes CD8/IFN ≥ 1 cell/µL) was achieved later (after day +100 post-SCT) in the steroid group.


Assuntos
Antivirais/administração & dosagem , Infecções por Citomegalovirus , Citomegalovirus , Doença Enxerto-Hospedeiro , Esteroides/efeitos adversos , Doadores de Tecidos , Adolescente , Adulto , Idoso , Aloenxertos , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/induzido quimicamente , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/epidemiologia , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Esteroides/administração & dosagem
4.
Leuk Lymphoma ; 59(10): 2318-2326, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29115891

RESUMO

Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated-IGHV, CD38high, ZAP-70high, CD49dhigh, +12, alterations in genes of NOTCH1, cell cycle, RNA metabolism, and NFkB pathways than CLL. During the follow-up, 46% of SLL patients developed CLL. Time to first treatment (TTFT) was shorter in SLL (10-year: 75% vs 62%; p = .006). Binet stage, SLL, and IGHV were independent predictive factors for TTFT. Transformation to diffuse large B-cell lymphoma was higher (10-year: 12% vs 6%; p = .003), and overall survival was shorter in SLL (10-year: 55% vs 66%; p = .004). When A0 CLL patients were excluded, only CD38 and CD49d expression, +12, and 10-year TTFT remained different between the SLL and CLL patients. In summary, SLL showed only minor clinicobiological differences when compared with CLL in similar clinical stages.


Assuntos
Genoma Humano/genética , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Tempo para o Tratamento/estatística & dados numéricos , Adulto Jovem
6.
Med. clín (Ed. impr.) ; 149(8): 339-342, oct. 2017. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-167659

RESUMO

Antecedentes y objetivo: Los linfomas con reordenamiento de MYC (MYC-R) diferentes al linfoma de Burkitt (LB) son muy agresivos, con un pronóstico desfavorable cuando se tratan con regímenes estándar. El objetivo del estudio fue investigar las características y el resultado de una serie de linfomas MYC-R, comparando los resultados del tratamiento de los regímenes basados en R-CHOP y un régimen intensivo específico para LB (BURKIMAB). Pacientes y métodos: Estudio retrospectivo de pacientes diagnosticados de MYC-R. Se evaluaron las translocaciones de MYC, BCL2 y BCL6 mediante hibridación in situ fluorescente. Se trató a los pacientes, bien con inmunoquimioterapia basada en R-CHOP, bien con el régimen tipo Burkitt, BURKIMAB. Resultados: Se estudiaron 34 casos de linfomas MYC-R: 21 tratados con R-CHOP y 13 tratados con BURKIMAB. No se produjeron diferencias en cuanto a tasa de RC; 45% (9/20) para R-CHOP y 42% (5/12) para BURKIMAB (p=0,99). Aunque la supervivencia global (SG) y la supervivencia libre de progresión (SLP) de los pacientes tratados con BURKIMAB fueron mejores que las de los pacientes tratados con R-CHOP (SG a 3 años: 46 frente a 24%; SLP a 3 años: 46 frente a 10%), las diferencias no fueron estadísticamente significativas. Conclusión: Los linfomas MYC-R muestran resultados desfavorables, aun cuando se tratan con inmunoquimioterapia intensiva para LB (AU)


Background and objective: MYC-rearranged (MYC-R) lymphomas other than Burkitt lymphoma (BL) are very aggressive, with poor prognosis when treated with standard regimens. We aimed to study the characteristics and outcome of a series of MYC-R lymphomas comparing the treatment results between R-CHOP based and a specific intensive regimen for BL (BURKIMAB). Patients and methods: Retrospective study of patients diagnosed with MYC-R. Translocations of MYC, BCL2 and BCL6 were evaluated by fluorescent in situ hybridization. Patients were treated with either, R-CHOP based immunochemotherapy or the Burkitt type regimen, BURKIMAB. Results: Thirty-four MYC-R lymphoma cases were studied: 21 treated with R-CHOP and 13 treated with BURKIMAB. There were no differences in CR rate; 45% (9/20) for R-CHOP and 42% (5/12) for BURKIMAB (P=.99). Although overall survival (OS) and progression free survival (PFS) of BURKIMAB-treated patients were better than those of R-CHOP-treated (3y-OS: 46 vs. 24%; 3y-PFS: 46 vs. 10%), the differences were not statistically significant. Conclusion: MYC-R lymphomas show poor outcomes even when treated with intensive immunochemotherapy for BL (AU)


Assuntos
Humanos , Linfoma de Burkitt/tratamento farmacológico , Genes myc , Antineoplásicos/uso terapêutico , Rearranjo Gênico , Estudos Retrospectivos , Resultado do Tratamento , Conduta do Tratamento Medicamentoso
7.
Med Clin (Barc) ; 149(8): 339-342, 2017 Oct 23.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28648593

RESUMO

BACKGROUND AND OBJECTIVE: MYC-rearranged (MYC-R) lymphomas other than Burkitt lymphoma (BL) are very aggressive, with poor prognosis when treated with standard regimens. We aimed to study the characteristics and outcome of a series of MYC-R lymphomas comparing the treatment results between R-CHOP based and a specific intensive regimen for BL (BURKIMAB). PATIENTS AND METHODS: Retrospective study of patients diagnosed with MYC-R. Translocations of MYC, BCL2 and BCL6 were evaluated by fluorescent in situ hybridization. Patients were treated with either, R-CHOP based immunochemotherapy or the Burkitt type regimen, BURKIMAB. RESULTS: Thirty-four MYC-R lymphoma cases were studied: 21 treated with R-CHOP and 13 treated with BURKIMAB. There were no differences in CR rate; 45% (9/20) for R-CHOP and 42% (5/12) for BURKIMAB (P=.99). Although overall survival (OS) and progression free survival (PFS) of BURKIMAB-treated patients were better than those of R-CHOP-treated (3y-OS: 46 vs. 24%; 3y-PFS: 46 vs. 10%), the differences were not statistically significant. CONCLUSION: MYC-R lymphomas show poor outcomes even when treated with intensive immunochemotherapy for BL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Genes myc/genética , Fatores Imunológicos/uso terapêutico , Linfoma/tratamento farmacológico , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Linfoma/genética , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Retrospectivos , Rituximab , Análise de Sobrevida , Resultado do Tratamento , Vincristina/uso terapêutico
8.
Leuk Res ; 59: 20-25, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28544905

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with heterogeneous outcomes. To improve accuracy of the international prognostic index score, new biological variables are being investigated. The aim of this study was to determine the prognostic significance of serum levels of different cytokines, namely soluble interleukin-2 receptor (sIL2-R), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF). We analyzed 197 de novo DLBCL patients (91 M/106 F; median age 66 years) treated with immunochemotherapy in a single institution. Serum cytokine determination was performed with ELISA, using the upper normal values as cut-offs. sIL-2R, IL-6 and TNF were elevated in 133, 130 and 144 cases, respectively. Elevation of each of these cytokines correlated with worse performance status, presence of B symptoms, advanced stage, elevated LDH and ß2-microglobulin (P<0.03) and lower complete remission rate (P<0.001). Elevated levels of serum sIL-2R and TNF were significantly associated with shorter progression-free (PFS) and overall survival (OS), while elevated IL-6 only with shorter PFS. Early death (<4months from diagnosis) strongly correlated with elevated cytokines. Determination of serum cytokines levels is simple and adds information regarding risk of early death, response to therapy, and outcome.


Assuntos
Interleucina-6/sangue , Linfoma Difuso de Grandes Células B/diagnóstico , Receptores de Interleucina-2/sangue , Fator de Necrose Tumoral alfa/sangue , Idoso , Citocinas/sangue , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Taxa de Sobrevida
10.
Leuk Lymphoma ; 58(4): 842-850, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27687692

RESUMO

We have analyzed in lymph nodes at diagnosis of 75 patients with follicular lymphoma (FL) the relationship between different T-cell subpopulations, assessed by immunohistochemistry (IHC) and flow cytometry (FC), with the outcome. CD4+ cells were the most abundant T-cells in tumor tissue sections, whilst CD57+ cells were the less frequent. In addition to nonambulatory performance status, advanced stage and FLIPI, low CD4+CD57+/CD4+ ratio (p = .041), and low CD4+/CD8+ ratio (p = .008) predicted poor overall survival (OS). Multivariate analysis showed that CD4+CD57+/CD4+ ratio was the most important variable for OS. In conclusion, T-cell subpopulations, including CD4+CD57+/CD4+ ratio analyzed by FC, could identify FL patients with favorable outcome.


Assuntos
Linfonodos/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/mortalidade , Subpopulações de Linfócitos T/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Feminino , Humanos , Imunofenotipagem , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
12.
Clin Cancer Res ; 22(11): 2755-64, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26792260

RESUMO

PURPOSE: Mutations in MYD88 are found in different lymphoproliferative disorders associated with particular biologic characteristics and clinical impact. The aim of this study was to analyze the incidence of MYD88 mutations and its clinical impact in diffuse large B-cell lymphoma (DLBCL). EXPERIMENTAL DESIGN: The incidence, clinicobiological features, and outcome of 213 patients (115 M/98 F; median age, 65 years) with DLBCL treated with immunochemotherapy in a single institution according to MYD88 mutational status as assessed by an allele-specific PCR assay were analyzed. The cell of origin (COO) was determined in 129 cases by gene expression. RESULTS: MYD88 mutations were found in 47 cases (22%), including L265P in 39 and S219C and M232F in 4 cases, respectively. Patients with MYD88 L265P were older, presenting frequent extranodal involvement, and mostly corresponded to activated B-cell like (ABC) subtype, whereas no preference in COO was observed in patients with other MYD88 mutations. Five-year overall survival (OS) for MYD88 wild-type, MYD88 L265P, and other variants was 62%, 52%, and 75%, respectively (P = 0.05). International Prognostic Index (IPI) (HR, 2.71; P < 0.001) and MYD88 L265P (HR, 1.786; P = 0.023) were independent variables predicting OS in the multivariate analysis. However, MYD88 L265P lost its independent value when COO was included in the model. CONCLUSIONS: Our findings indicate that MYD88 L265P mutations, but no other variants, identify a subgroup of DLBCL mainly of ABC origin, with extranodal involvement and poor outcome. Clin Cancer Res; 22(11); 2755-64. ©2016 AACR.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Fator 88 de Diferenciação Mieloide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Ativação Linfocitária , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Resultado do Tratamento , Adulto Jovem
13.
Leuk Lymphoma ; 57(1): 120-4, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25944376

RESUMO

This study has retrospectively analyzed the efficacy of single-agent prednisone, usually given after failure of other therapies, in 30 patients with myelofibrosis (MF) and severe anemia. Initial dose was 0.5-1 mg/kg daily, with tapering to the minimum effective dose in responders. Twelve patients (40%) achieved anemia response according to the revised International Working Group for Myelofibrosis Research and Treatment criteria, after a median time of 1.1 months on treatment. Median response duration was 12.3 months. Patients with constitutional symptoms or > 2% circulating blasts had a trend for a lower response rate. A platelet increase > 50 × 10(9)/L was observed in three out of 11 patients with baseline counts < 100 × 10(9)/L. Median survival from prednisone start was significantly longer in anemia responders (5.0 years, 95% CI = 3.5-6.5, vs 1.5 years, 95% CI = 0.2-2.8; p = 0.002). Prednisone can improve the anemia and thrombocytopenia in selected MF patients after failure to standard therapies.


Assuntos
Anemia/tratamento farmacológico , Anemia/etiologia , Anti-Inflamatórios/uso terapêutico , Imunossupressores/uso terapêutico , Prednisona/uso terapêutico , Mielofibrose Primária/complicações , Idoso , Anemia/diagnóstico , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Medula Óssea/patologia , Índices de Eritrócitos , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Estudos Retrospectivos , Resultado do Tratamento
14.
Am J Surg Pathol ; 40(2): 192-201, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26426381

RESUMO

Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is considered an indolent neoplasm and its pathogenesis is not well known. We investigated the molecular characteristics of 19 SDRPL patients, 5 of them with progressive disease. IGHV genes were mutated in 9/13 (69%). Cytogenetic and molecular studies identified complex karyotypes in 2 cases, and IGH rearrangements in 3, with PAX5 and potentially TCL1 as partners in each one of them. Copy number arrays showed aberrations in 69% of the tumors, including recurrent losses of 10q23, 14q31-q32, and 17p13 in 3, and 9p21 in 2 cases. Deletion of 7q31.3-q32.3 was present in only 1 case and no trisomies 3 or 18 were detected. NOTCH1 and MAP2K1 were mutated in 2 cases each, whereas BRAF, TP53, and SF3B1 were mutated each in single cases. No mutations were found in NOTCH2 or MYD88. Four of the 5 patients with aggressive disease had mutations in NOTCH1 (2 cases), TP53 (1 case), and MAP2K1 (1 case). The progression-free survival of patients with mutated genes was significantly shorter than in the unmutated (P=0.011). These findings show that SDRPL share some mutated genes but not chromosomal alterations, with other splenic lymphomas, that may confer a more aggressive behavior.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Células B/genética , MAP Quinase Quinase 1/genética , Mutação , Receptor Notch1/genética , Neoplasias Esplênicas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Biomarcadores Tumorais/análise , Biópsia , Chile , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Progressão da Doença , Intervalo Livre de Doença , Europa (Continente) , Feminino , Deleção de Genes , Dosagem de Genes , Rearranjo Gênico , Genes de Cadeia Pesada de Imunoglobulina , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Linfoma de Células B/química , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , Neoplasias Esplênicas/química , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/terapia , Fatores de Tempo
15.
Br J Haematol ; 172(1): 48-55, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26559905

RESUMO

We investigated CD49d (also termed ITGA4) expression and its biological and clinical correlations in 415 patients with chronic lymphocytic leukaemia. CD49d expression was stable over the course of the disease. A high expression of CD49d (>30%) was found in 142/415 (34%) patients and was associated with progressive disease (advanced clinical stage, high serum lactate dehydrogenase or ß2 -microglobulin levels; all p < 0·05) and aggressive disease biology (increased ZAP70 or CD38, unmutated IGHV, trisomy 12, mutations of NOTCH1 and SF3B1; all P < 0·05). A higher CD49d expression was also associated with a lower blood lymphocyte count and a higher number of lymphoid areas involved by the disease. Patients with high CD49d expression were treated more frequently (55% vs. 27%; P < 0·001) and earlier (median time to treatment [TTT] 65·4 months vs. not reached; P < 0·001) than those with low CD49d expression. However, no significant differences in response rates were observed. In the subgroup of patients with mutated IGHV, high CD49d expression was predictive of a shorter TTT while other markers, such as ZAP70 and CD38, were not. In conclusion, in this study CD49d expression correlated with high-risk CLL biomarkers and proved to be useful for separating patients with mutated IGHV into two different prognostic groups.


Assuntos
Biomarcadores Tumorais/sangue , Cadeias Pesadas de Imunoglobulinas/genética , Integrina alfa4/sangue , Leucemia Linfocítica Crônica de Células B/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/terapia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Fatores de Tempo
16.
Best Pract Res Clin Haematol ; 28(4): 253-63, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26614904

RESUMO

Hairy cell leukaemia-variant (HCL-V) is a rare B-cell malignancy that affects elderly males and manifests with splenomegaly, lymphocytosis and cytopenias without monocytopenia. The neoplastic cells have morphological features of prolymphocytes and hairy cells. The immunophenotype is that of a clonal B-cell CD11c and CD103 positive but, unlike classical HCL, CD25, CD123 and CD200 negative. The spleen histology is similar to classical HCL and the pattern of bone marrow infiltration is interstitial and/or intrasinusoidal. Mutations of the immunoglobulin heavy chain (IGVH) are seen in two thirds of cases with a preferential VH4-34 family usage. There is no distinct chromosomal abnormality but del17p13 and mutations of the TP53 gene are frequent. Mutations in the MAP2K1 gene have been documented in half of the cases. The course is chronic with median survivals of 7-9 years. Patients are refractory to purine analogues and the most effective therapy is the combination of 2-chlorodeoxyadenosine and Rituximab.


Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Linfocitose/tratamento farmacológico , Rituximab/uso terapêutico , Esplenomegalia/tratamento farmacológico , Idoso , Antígenos CD/genética , Antígenos CD/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Deleção Cromossômica , Cromossomos Humanos Par 17 , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/mortalidade , Leucemia de Células Pilosas/patologia , Linfocitose/genética , Linfocitose/mortalidade , Linfocitose/patologia , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/imunologia , Masculino , Mutação , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Esplenomegalia/genética , Esplenomegalia/mortalidade , Esplenomegalia/patologia , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
17.
Am J Hematol ; 90(5): 429-33, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25683327

RESUMO

The role of bosutinib as rescue treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) patients after failing three previous tyrosine kinase inhibitors (TKIs) is currently unknown. We report here the largest series (to our knowledge) of patients treated with bosutinib in fourth-line, after retrospectively reviewing 30 patients in chronic phase, and pretreated with imatinib, nilotinib, and dasatinib. With a median follow up of 11.1 months, the probability to either maintain or improve their CCyR response was 56.6% (17/30) and 11 patients (36.7%) achieved or maintained their baseline MMR. In patients not having baseline CCyR, the probabilities of obtaining CCyR, MMR, and MR4.5 were 13, 11, and 14%, respectively. The probabilities of obtaining MMR and deep molecular response MR4.5 in patients with baseline CCyR were 40.0% (6/15) and 20.0% (3/15). At 20 months, progression-free survival was 73%. Grade 3-4 hematological toxicities were more frequent in resistant than intolerant patients (45.4 vs. 0.0%). Nonhematological toxicities were also more frequent in resistant patients, being diarrhea the most conspicuous one. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKI's.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Ensaios de Uso Compassivo , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Nitrilos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Adulto , Idoso , Benzamidas/uso terapêutico , Dasatinibe , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crônica/enzimologia , Leucemia Mieloide de Fase Crônica/mortalidade , Leucemia Mieloide de Fase Crônica/patologia , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Espanha , Análise de Sobrevida , Tiazóis/uso terapêutico
18.
Ann Hematol ; 94(5): 803-12, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25501975

RESUMO

A retrospective study was performed to assess the outcome of patients with diffuse large B cell lymphoma (DLBCL) who did not achieve complete response or who relapsed before and after the use of rituximab. Clinical features and outcome of 816 (425 M/391 F; median age 63 years) patients diagnosed from 1991 to 2001 (pre-rituximab era, N = 348) and from 2002 to 2012 (rituximab era, N = 468) in a single institution were evaluated. Five hundred fifty-three patients achieved complete remission (CR), 57 partial response (PR), and 206 were refractory with a median overall survival of 15, 1.5, and 0.4 years, respectively. Patients receiving rituximab had lower risk of refractoriness or relapse. In primarily refractory and PR patients, there was not a difference in survival depending on whether patients received or not rituximab-containing frontline treatment. Early death rate was 11%, including 3.6% due to infectious complications. Rituximab did not modify these figures. In the relapse setting, 5-year survival from relapse was 25% for patients who never received rituximab, 54% for those who received rituximab only at relapse, and 48% for those treated with immunochemotherapy both as frontline and at relapse. In conclusion, relapsed/refractory patients with DLBCL show poor prognosis despite the use of frontline immunochemotherapy. New therapeutic approaches are needed in this group of patients.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Rituximab , Adulto Jovem
20.
Ann Hematol ; 93(12): 2037-43, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24981691

RESUMO

Therapeutic options for patients with polycythemia vera (PV) and essential thrombocythemia (ET) resistant or intolerant to hydroxyurea are limited. Busulfan is effective as first-line therapy, but there is scarce information on this drug as second-line treatment. The efficacy of busulfan in patients with advanced PV or ET refractory or intolerant to hydroxyurea was assessed in 36 patients (PV n = 15, ET n = 21) treated for a median of 256 days. Complete hematological response (CHR) was achieved in 83 % of patients, after a median time of 203 days (range 92-313). The probability of sustained CHR at 1 and 2 years was 87 and 62 %, respectively. Time to CHR was shorter in patients treated with ≥14 mg of busulfan per week than with lower doses (141 versus 336 days, p = 0.01). Partial molecular response was achieved in three out of nine (33 %) patients. Busulfan was stopped in 27 patients (75 %) due to CHR achievement in 18 cases (67 %), hematological toxicity in 8 cases (30 %), and disease transformation in 1 case. With a median follow-up of 721 days, six patients have died, with the probability of survival at 2 years being 85 %. The probability of thrombosis at 2 years was 11 %. Transformation into acute leukemia or myelodysplastic syndrome was observed in three cases, all of them in a JAK2V617F-negative clone carrying additional mutations. Busulfan, at a dose of 2 mg/day, is an effective option for elderly patients with PV or ET who fail to hydroxyurea, but a significant rate of transformation was observed.


Assuntos
Alquilantes/uso terapêutico , Bussulfano/uso terapêutico , Policitemia Vera/tratamento farmacológico , Trombocitemia Essencial/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Comorbidade , Progressão da Doença , Resistência a Medicamentos , Substituição de Medicamentos , Feminino , Hematócrito , Hemorragia/etiologia , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Janus Quinase 2/genética , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Policitemia Vera/complicações , Policitemia Vera/genética , Indução de Remissão , Fatores de Risco , Trombocitemia Essencial/complicações , Trombocitemia Essencial/genética , Trombose/etiologia , Resultado do Tratamento
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