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1.
Chemotherapy ; 64(3): 155-162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31715597

RESUMO

Bendamustine is a cytostatic drug with a unique structure, combining the features of purine nucleoside analogs and alkylating agents. In patients with chronic lymphocytic leukemia (CLL) it is commonly used in combination with rituximab (BR protocol) both in the first-line as well as subsequent lines of therapy, and in clinical trials it is often combined with new targeted therapies. Therefore, the data on its real-life safety and efficacy are of clinical significance. As the Polish Lymphoma Research Group (PLRG), we retrospectively analyzed the efficacy and tolerability of bendamustine monotherapy in 96 patients with CLL. The median number of bendamustine cycles was 5, and 44 patients did not complete the planned 6 cycles (46%). Among the adverse events associated with the earlier termination of bendamustine treatment, infections were the most common (20.5%), followed by neutropenia (15.9%) and thrombocytopenia (15.9%). Dose reductions and/or delays occurred in 31% of treatment cycles (132 of 425) with neutropenia (17.9%) as the most frequent cause. Efficacy analysis showed an overall response rate of 88.2% with complete remission and partial remission achieved in 43.8 and 41.7% of patients, respectively. At the 24th month of follow-up, progression-free survival was 52% and overall survival was 69.7%. Bendamustine in monotherapy was found to be safe and efficacious, at least in terms of early response. Special attention should be paid to infectious complications, and especially that immune disorders are characteristic in the clinical course of CLL. Our observations suggest efforts must be made to ensure the proper timing and proper dose in the administration of the drug, and to avoid the premature termination of the treatment.


Assuntos
Cloridrato de Bendamustina/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Cloridrato de Bendamustina/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Estudos Retrospectivos , Taxa de Sobrevida , Trombocitopenia/etiologia , Resultado do Tratamento
2.
Ann Hematol ; 98(12): 2749-2760, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31745601

RESUMO

After analyzing treatment patterns in chronic lymphocytic leukemia (CLL) (objective 1), we investigated the relative effectiveness of ibrutinib versus other commonly used treatments (objective 2) in patients with treatment-naïve and relapsed/refractory CLL, comparing patient-level data from two randomized registration trials with two real-world databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using a multivariate Cox proportional hazards model, adjusted for differences in baseline characteristics. Rituximab-containing regimens were often prescribed in clinical practice. The most frequently prescribed regimens were fludarabine + cyclophosphamide + rituximab (FCR, 29.3%), bendamustine + rituximab (BR, 17.7%), and other rituximab-containing regimens (22.0%) in the treatment-naïve setting (n = 604), other non-FCR/BR rituximab-containing regimens (38.7%) and non-rituximab-containing regimens (28.5%) in the relapsed/refractory setting (n = 945). Adjusted HRs (95% CI) for progression-free survival (PFS) and overall survival (OS), respectively, with ibrutinib versus real-world regimens were 0.23 (0.14-0.37; p < 0.0001) and 0.40 (0.22-0.76; p = 0.0048) in the treatment-naïve setting, and 0.21 (0.16-0.27; p < 0.0001) and 0.29 (0.21-0.41; p < 0.0001) in the relapsed/refractory setting. When comparing real-world use of ibrutinib (n = 53) versus other real-world regimens in relapsed/refractory CLL (objective 3), adjusted HRs (95% CI) were 0.37 (0.22-0.63; p = 0.0003) for PFS and 0.53 (0.27-1.03; p < 0.0624) for OS. This adjusted analysis, based on nonrandomized patient data, suggests ibrutinib to be more effective than other commonly used regimens for CLL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bases de Dados Factuais , Leucemia Linfocítica Crônica de Células B , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Cloridrato de Bendamustina/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Rituximab/administração & dosagem , Taxa de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
3.
Orv Hetil ; 160(38): 1487-1494, 2019 Sep.
Artigo em Húngaro | MEDLINE | ID: mdl-31537095

RESUMO

Immune status was investigated in 186 patients with chronic lymphoid leukaemia between January 2012 and March 2015. Incidences of infections and mortality were analysed in patients who did not receive prophylactic immunoglobulin therapy. Immunoglobulin G (IgG) levels were normal (7-17.8 g/L) or decreased in 62.37% and 35.48% of patients, respectively. We measured high immunoglobulin levels only in a few cases (2.15%). Immunoglobulin levels became increasingly lower in more advanced disease stages (Rai stages). The number of infections was inversely proportional to that. Hypogammaglobulinaemia proved to be more important than disease progression in terms of the development of infections. The most common infections were upper respiratory tract (33.07%) and sepsis (18.90%). Two months after chemotherapy, initially normal immunoglobulin levels decreased by an average of 21%, and at the same time the incidence of infections increased. The most common cause of death was sepsis: 30% occurred at low immunoglobulin levels, while 20% at normal immunoglobulin levels. According to literature, prophylactic immunoglobulin treatment is indicated in patients with chronic lymphoid leukaemia and immunodeficiency for decreasing both morbidity and mortality. According to recommendations in literature, replacement treatment must be administered in severe or moderately severe recurrent bacterial infections. Immunoglobulin prophylaxis may be provided as low dose (10 g), fix dose (18 g) or individually customized higher dose (300-400 mg/kg body weight) treatment. According to recommendations, higher dose immunoglobulin prophylaxis, administered every three weeks on six occasions, is more efficient when customized. With this dose, infection-free condition may be achieved in 50% of patients. Orv Hetil. 2019; 160(38): 1487-1494.


Assuntos
Agamaglobulinemia/tratamento farmacológico , Agamaglobulinemia/mortalidade , Imunoglobulinas Intravenosas/uso terapêutico , Imunoglobulinas/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sepse/mortalidade , Agamaglobulinemia/complicações , Relação Dose-Resposta a Droga , Feminino , Humanos , Hungria/epidemiologia , Imunoglobulina G/sangue , Imunoglobulinas Intravenosas/administração & dosagem , Controle de Infecções , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Sepse/diagnóstico , Resultado do Tratamento
4.
J Cancer Res Clin Oncol ; 145(11): 2823-2834, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31468122

RESUMO

PURPOSE: The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown. METHODS: We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC. RESULTS: The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS. CONCLUSION: Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Linfocítica Crônica de Células B/mortalidade , Condicionamento Pré-Transplante/mortalidade , Adulto , Idoso , Bussulfano/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Incidência , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Adulto Jovem
5.
Med Oncol ; 36(9): 79, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375939

RESUMO

Chronic lymphocytic leukemia (CLL) is one of the most frequent lymphoproliferative diseases. CLL is characterized by unusual heterogeneity, which probably reflects its biological and genetic lack of homogeneity. Clonal chromosome aberrations belong to the most important prognostic and predictive factors in CLL. This research was aimed at observing clonal evolution in CLL at the chromosomal level, and assessing its clinical significance in relation to selected prognostic factors. The study involved 72 untreated patients with CLL. The preliminary investigations using cytogenetic banding analysis (CBA) and FISH were performed at the time of diagnosis, and again after about 24 months to observe clonal changes (clonal evolution). In addition, other parameters were evaluated, i.e., the expression of ZAP-70 kinase, CD38 antigen, and the mutation statuses of IGVH and NOTCH1 genes. Classic prognostic factors, i.e., categorized ZAP70 and CD38 expressions as well as mutations in IGVH and NOTCH1 genes did not influence the course of clonal evolution in the examined group of patients. Clonal evolution was detected in 45.8% of patients by means of CBA, and in 19.4% patients with FISH. Analysis of chromosomal aberrations in the examined group of patients showed that the incidence of 17p deletions and translocations in karyotypes has a negative impact on overall survival. CE was found to be a risk factor for the occurrence of disease progression (OR = 2.22). Our observations indicate that combined CBA and FISH are the most optimal techniques for monitoring clonal evolution in the course of CLL.


Assuntos
Evolução Clonal/genética , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Bandeamento Cromossômico , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de Sobrevida
6.
N Engl J Med ; 381(5): 432-443, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31365801

RESUMO

BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited. METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis. RESULTS: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001). CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Rituximab/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Rituximab/efeitos adversos , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados
7.
Lancet Haematol ; 6(9): e470-e479, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31324600

RESUMO

BACKGROUND: In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients. METHODS: We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up. FINDINGS: Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1-2 in months 1-9 and in 43 [33%] of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred. INTERPRETATION: Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed. FUNDING: Roche, Janssen.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Gastroenteropatias/etiologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Taxa de Sobrevida , Trombocitopenia/etiologia , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética
9.
Eur J Haematol ; 103(3): 190-199, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31210368

RESUMO

OBJECTIVES: We aimed to describe treatment patterns of chronic lymphocytic leukaemia (CLL) patients in routine practice settings, compare overall survival and time-to-next-treatment among patients treated in different time periods (2005-2008, 2009-2013, 2014-2015), and explore associated factors. METHODS: This retrospective cohort study included adult CLL patients from the Finnish Hematology Registry. RESULTS: In total, 124 and 64 CLL patients received first- and second-line treatments, respectively. The use of first- and second-line treatments with bendamustine-rituximab (BR) increased, while chlorambucil-based treatments decreased over time. Patients treated in more recent years showed a trend towards longer first- and second-line survival. A trend towards inferior overall survival was detected in first- and second-line treatment with B/BR. First-line time-to-next-treatment was longer for patients treated in the later years towards 2015, while second-line time-to-next-treatment did not improve over time. CONCLUSIONS: This study identified that improved treatment outcomes over time were likely influenced by patient characteristics and treatments, but also through other factors unexplored in this study. Hence, further research on the factors influencing patients' survival over time is needed. In particular, research on using B/BR in clinical practice is warranted.


Assuntos
Leucemia Linfocítica Crônica de Células B/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Finlândia/epidemiologia , História do Século XXI , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/história , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Vigilância em Saúde Pública , Sistema de Registros , Estudos Retrospectivos , Análise de Sobrevida , Tempo para o Tratamento
10.
N Engl J Med ; 380(23): 2225-2236, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31166681

RESUMO

BACKGROUND: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known. METHODS: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated. RESULTS: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% in the venetoclax-obinutuzumab group and 7.9% in the chlorambucil-obinutuzumab group. These differences were not significant. CONCLUSIONS: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Clorambucila/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Clorambucila/efeitos adversos , Comorbidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Intervalo Livre de Progressão , Sulfonamidas/efeitos adversos
11.
Blood ; 134(5): 432-444, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151986

RESUMO

Chronic lymphocytic leukemia (CLL) occurs in 2 major forms: aggressive and indolent. Low miR-29b expression in aggressive CLL is associated with poor prognosis. Indiscriminate miR-29b overexpression in the B-lineage of mice causes aberrance, thus warranting the need for selective introduction of miR-29b into B-CLL cells for therapeutic benefit. The oncofetal antigen receptor tyrosine kinase orphan receptor 1 (ROR1) is expressed on malignant B-CLL cells, but not normal B cells, encouraging us with ROR1-targeted delivery for therapeutic miRs. Here, we describe targeted delivery of miR-29b to ROR1+ CLL cells leading to downregulation of DNMT1 and DNMT3A, modulation of global DNA methylation, decreased SP1, and increased p21 expression in cell lines and primary CLL cells in vitro. Furthermore, using an Eµ-TCL1 mouse model expressing human ROR1, we report the therapeutic benefit of enhanced survival via cellular reprograming by downregulation of DNMT1 and DNMT3A in vivo. Gene expression profiling of engrafted murine leukemia identified reprogramming of cell cycle regulators with decreased SP1 and increased p21 expression after targeted miR-29b treatment. This finding was confirmed by protein modulation, leading to cell cycle arrest and survival benefit in vivo. Importantly, SP1 knockdown results in p21-dependent compensation of the miR-29b effect on cell cycle arrest. These studies form a basis for leukemic cell-targeted delivery of miR-29b as a promising therapeutic approach for CLL and other ROR1+ B-cell malignancies.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Leucemia Linfocítica Crônica de Células B/genética , MicroRNAs/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , MicroRNAs/administração & dosagem , MicroRNAs/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Taxa de Sobrevida , Nanomedicina Teranóstica , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Lancet Haematol ; 6(7): e366-e374, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31109827

RESUMO

BACKGROUND: Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies. METHODS: In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0-1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (idelalisib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination. FINDINGS: The derived model consisted of four factors (one point each; serum ß2-microglobulin ≥5 mg/dL, lactate dehydrogenase >upper limit of normal, haemoglobin <110 g/L for women or <120 g/L for men, and time from initiation of last therapy <24 months), separating patients into low (score 0-1), intermediate (score 2-3), and high risk (score 4) groups. The risk score was prognostic for overall survival in the training dataset (CS=0·74, 95% CI 0·60-0·85, log-rank p<0·0001), and in the internal-validation (CS=0·79, 0·56-0·97, log-rank p=0·0003), and all three external-validation cohorts (idelalisib or chemoimmunotherapy: CS=0·71, 0·59-0·81, log-rank p<0·0001; venetoclax or chemoimmunotherapy: CS =0·76, 0·66-0·85, log-rank p=0·014; MCCD cohort: CS=0·61, 0·56-0·66), log-rank p<0·0001). The risk score is available on Calculate by QxMD. INTERPRETATION: We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need. FUNDING: Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia , Leucemia Linfocítica Crônica de Células B/terapia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Bases de Dados Factuais , Feminino , Hemoglobinas/análise , Humanos , L-Lactato Desidrogenase/sangue , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de Risco , Sulfonamidas/uso terapêutico , Taxa de Sobrevida , Microglobulina beta-2/sangue
13.
Blood ; 134(6): 534-547, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31010847

RESUMO

Targeted therapy is revolutionizing the treatment of cancers, but resistance evolves against these therapies and derogates their success. The phosphatidylinositol 3-kinase delta (PI3K-δ) inhibitor idelalisib has been approved for treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma, but the mechanisms conferring resistance in a subset of patients are unknown. Here, we modeled resistance to PI3K-δ inhibitor in vivo using a serial tumor transfer and treatment scheme in mice. Whole-exome sequencing did not identify any recurrent mutation explaining resistance to PI3K-δ inhibitor. In the murine model, resistance to PI3K-δ inhibitor occurred as a result of a signaling switch mediated by consistent and functionally relevant activation of insulin-like growth factor 1 receptor (IGF1R), resulting in enhanced MAPK signaling in the resistant tumors. Overexpression of IGF1R in vitro demonstrated its prominent role in PI3K-δ inhibitor resistance. IGF1R upregulation in PI3K-δ inhibitor-resistant tumors was mediated by functional activation and enhanced nuclear localization of forkhead box protein O1 transcription factors and glycogen synthase kinase 3ß. In human CLL, high IGF1R expression was associated with trisomy 12. CLL cells from an idelalisib-treated patient showed decreased sensitivity to idelalisib in vitro concomitant with enhanced MAPK signaling and strong upregulation of IGF1R upon idelalisib exposure. Thus, our results highlight that alternative signaling cascades play a predominant role in the resistance and survival of cancer cells under PI3K-δ inhibition. We also demonstrate that these pathway alterations can serve as therapeutic targets, because inhibition of IGF1R offered efficacious salvage treatment of PI3K-δ inhibitor-resistant tumors in vitro and in vivo.


Assuntos
Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Receptor IGF Tipo 1/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Análise Mutacional de DNA , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Mutação , Receptor IGF Tipo 1/genética , Resultado do Tratamento , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Exp Oncol ; 41(1): 39-45, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30932419

RESUMO

AIM: The IGHV mutational status is one of the most important markers for chronic lymphocytic leukemia (CLL) prognostication. Lipoprotein lipase (LPL) gene expression was found to correlate with IGHV status and was suggested as its surrogate marker. Recent data reported that LPL expression might be influenced by pivotal signalling pathways in CLL. This study aimed to assess LPL gene expression in relation to key immunogenetic and molecular markers of CLL, including IGHV mutational status, B-cell receptor (BCR) stereotypy, TP53, NOTCH1, and SF3B1 gene mutations. Materials and Methods: Expression of LPL mRNA was measured in peripheral blood mononuclear cells of 73 CLL patients by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). IGHV, NOTCH1, TP53, and SF3B1 gene mutation analysis was performed by PCR amplification and direct sequencing. RESULTS: 44 of 73 (60%) CLL cases were categorized as LPL-positive based on the cut-off value established by ROC (receiver operating characteristic) curve analysis. LPL expression was significantly associated with IGHV mutation status (r = 0.684; p < 0.0001) and tended to correlate with presence of NOTCH1 gene mutations (p = 0.113). BCR stereotyped cases showed higher LPL expression values in comparison to unstereotyped cases in the LPL-positive group of patients (p = 0.041). LPL expression was associated with a shorter overall survival in the entire СLL group (median 107 vs 143, p = 0.048) as well as in Binet A patients, albeit with borderline significance (median 139 vs not reached, p = 0.086). CONCLUSION: LPL expression was found to be closely correlated with IGHV gene mutational status and overall survival, proving LPL as prognostic marker in CLL. Our results also indicate a possible relationship between aberrant expression of LPL and BCR- and NOTCH1-dependent signalling pathways.


Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Lipase Lipoproteica/genética , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Rearranjo Gênico do Linfócito B , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico
15.
Blood ; 134(2): 111-122, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31023700

RESUMO

To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Intervalo Livre de Progressão
17.
Hematol Oncol ; 37(3): 261-269, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30916804

RESUMO

Survival rates of patients with non-Hodgkin lymphoma (NHL) have improved over the last decade. However, cardiotoxicities remain important adverse consequences of treatment with chemotherapy and radiation, although the burden of cardiovascular mortality (CVM) in such patients remains unknown. We conducted a retrospective cohort study of patients greater than or equal to 20 years of age diagnosed with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) between 2000 and 2013 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. Our primary endpoint was CVM. The association between NHL and CVM was evaluated using multivariable Cox regression analysis after adjusting for other patient characteristics. We calculated standardized mortality ratios (SMRs) for CVM, comparing NHL patients with the general population. We identified 153 983 patients who met the inclusion criteria (69 329 with DLBCL, 48 650 with CLL/SLL, and 36 004 with FL). The median follow-up was 37 months (interquartile range, 10-78 months); the mean patient age was 66.24 (±14.69) years; 84 924 (55.2%) were men; 134 720 (87.5%) were White, and 131 912 (85.7%) did not receive radiation therapy. Overall, 9017 patients (5.8%) died from cardiovascular disease, and we found that NHL patients had a higher risk of CVM than the general population, after adjusting for age (SMR 15.2, 95% confidence interval: 14.89-15.52). The rates of CVM were 5.1%, 8%, and 4.4% in patients with DLBCL, CLL/SLL, and FL, respectively. Furthermore, across all NHL subtypes, older age, higher stage at the time of diagnosis (particularly stage 4), male sex, and living in the south were associated with higher risks of CVM. Our data suggest that risk assessment and careful cardiac monitoring are recommended for NHL patients, particularly those with the CLL/SLL subtypes.


Assuntos
Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , Linfoma não Hodgkin/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Linfoma Folicular/complicações , Linfoma Folicular/epidemiologia , Linfoma Folicular/mortalidade , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/epidemiologia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Mortalidade , Estadiamento de Neoplasias , Estudos Retrospectivos , Medição de Risco , Programa de SEER , Resultado do Tratamento , Estados Unidos , Adulto Jovem
19.
Oncol Rep ; 41(5): 3127-3136, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896840

RESUMO

The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG­3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro­apoptotic effects of the compounds were found to be reactive oxygen species and caspase­dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3­kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co­cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Nitrocompostos/farmacologia , Estirenos/farmacologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Concentração Inibidora 50 , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Nitrocompostos/química , Nitrocompostos/uso terapêutico , Cultura Primária de Células , Prognóstico , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Relação Estrutura-Atividade , Estirenos/química , Estirenos/uso terapêutico
20.
Blood ; 133(19): 2031-2042, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-30842083

RESUMO

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS vs without these factors. Median duration of ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as #NCT01578707.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Tempo
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