RESUMO
PURPOSE: Targeting CD79B using antibody-drug conjugates (ADC) is an effective therapeutic strategy in B-cell non-Hodgkin lymphoma (B-NHL). We investigated DCDS0780A, an anti-CD79B ADC with THIOMAB technology (TDC) that consistently conjugates two anti-neoplastic molecules per antibody, in contrast with ADCs with heterogeneous loads. PATIENTS AND METHODS: This phase 1 study enrolled 60 patients with histologically confirmed B-NHL that had relapsed/failed to respond following ≥1 prior treatment regimens; 41 (68%) had diffuse large B-cell lymphoma (DLBCL). Fifty-one patients received DCDS0780A monotherapy once every 3 weeks (0.3-4.8 mg/kg); 9 received combination therapy (3.6-4.8 mg/kg) with rituximab. RESULTS: Fifty-four (90%) patients experienced adverse events related to study drug, the most common of which were blurred vision, fatigue, corneal deposits, neutropenia, nausea, and peripheral neuropathy. 4.8 mg/kg was the highest dose tested and the recommended phase II dose. The pharmacokinetic profile was linear at doses ≥1.2 mg/kg. Response rate in all-treated patients (N = 60) was 47% (n = 28), including 17 complete responses (28%) and 11 partial responses (18%). The median duration of response (15.2 months) was the same for all responders (n = 28) and patients with DLBCL (n = 20). CONCLUSIONS: DCDS0780A as the TDC format for CD79B was tested at higher doses than its ADC counterpart investigated earlier, leading to deep responses. However, dose intensity was limited by ocular toxicities seen at the higher doses indicating that the TDC format was unable, in the current study, to expand the therapeutic index for the CD79B target. The encouraging antitumor activity advocates continuation of investigations into novel ADC technologies.
Assuntos
Imunoconjugados , Linfoma Difuso de Grandes Células B , Neutropenia , Terapia Combinada , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Neutropenia/induzido quimicamente , Rituximab/efeitos adversosRESUMO
Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma Folicular , Anticorpos Monoclonais Humanizados , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas , Pirazóis , Pirimidinas/efeitos adversosRESUMO
PURPOSE: Mantle-cell lymphoma (MCL) is an incurable mature B-cell neoplasm with high initial response rates followed almost invariably by relapse. Prognosis for patients following relapse is poor, and treatment choices are limited. We evaluated the efficacy and safety of zanubrutinib, an investigational selective Bruton's tyrosine kinase (BTK) inhibitor. PATIENTS AND METHODS: Patients with relapsed/refractory MCL were enrolled in this ongoing phase II, single-arm, open-label study, and treated with oral zanubrutinib 160 mg twice daily. The primary endpoint is overall response rate (ORR) assessed by an independent review committee (per Lugano 2014 classification); secondary endpoints include duration of response (DOR), time to response, progression-free survival (PFS), and safety. RESULTS: Eighty-six patients (median age, 60.5 years) were enrolled after a median of 2 prior lines of therapy, received ≥1 dose of the study drug, and were evaluable for safety and efficacy. After a median follow-up of 18.4 months, 72 (84%) patients achieved an objective response, with 59 (68.6%) achieving a complete response (CR). Median DOR and PFS were 19.5 and 22.1 months, respectively; 12-month event-free estimates for DOR and PFS are 78% and 76%, respectively. Most common grade ≥3 adverse events (AE) were neutropenia (19.8%) and lung infection/pneumonia (9.3%). Three patients experienced major bleeding events, and there were no reports of atrial fibrillation. Eight (9.3%) patients discontinued zanubrutinib for AEs. CONCLUSIONS: These results demonstrate high and durable ORR and CR rates in patients with relapsed/refractory MCL. Zanubrutinib was generally well tolerated; grade ≥3 BTK inhibitor-associated toxicities (hemorrhage, rash, hypertension, diarrhea, atrial fibrillation) were uncommon.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Linfoma de Célula do Manto/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Tirosina Quinase da Agamaglobulinemia/genética , Idoso , Feminino , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Resultado do TratamentoRESUMO
Prognosis is poor for patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) after failure of or who are ineligible for autologous stem cell transplant. We evaluated the efficacy and safety of tislelizumab, an investigational anti-PD-1 monoclonal antibody, in phase 2, single-arm study in Chinese patients with R/R cHL. The primary endpoint was overall response rate as assessed by an independent review committee, according to the Lugano 2014 Classification. Seventy patients were enrolled in the study and received at least one dose of tislelizumab. After median follow-up of 9.8 months, 61 (87.1%) patients achieved an objective response, with 44 (62.9%) achieving a complete response (CR). The estimated 9-month progression-free survival rate was 74.5%. Most common grade ≥3 adverse events (AEs) were upper respiratory tract infection and pneumonitis. Infusion-related reactions occurred in 27 (38.6%) patients, and 27 patients (38.6%) experienced an immune-related AE, the most common of which was thyroid dysfunction. Eleven (15.7%) patients experienced at least one treatment-emergent AE leading to dose interruption or delay. No deaths occurred due to AEs. Treatment of patients with R/R cHL with tislelizumab was generally well tolerated and resulted in high overall response and CR rates, potentially translating into more durable responses for these patients.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Linfoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adolescente , Adulto , Idoso , Feminino , Doença de Hodgkin/metabolismo , Humanos , Linfoma/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Intervalo Livre de Progressão , Indução de Remissão/métodos , Adulto JovemRESUMO
Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
Assuntos
Leucemia de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia de Células B/metabolismo , Leucemia de Células B/patologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Refractory and/or relapsed diffuse large B cell lymphoma (RR-DLBCL) patients are incurable with conventional chemotherapy due to the aggressiveness and the chemorefractory state of these tumors. DNA hypermethylation and histone deacetylation are two major epigenetic modifications by which aggressive DLBCL maintain their oncogenic state. We have previously reported that DNA methyltransferase inhibitors (DNMTI) affect RR-DLBCL growth and improve chemosensitivity. Here, we hypothesized that the combination of DNMTI with histone deacetylase inhibitor (HDI) would be an active and feasible therapeutic strategy in RR-DLBCL. Thus, we evaluated the anti-lymphoma activity of the HDI vorinostat (VST) in combination with the DNMTI azacitidine (AZA) or decitabine (DAC) in pre-clinical models of RR-DLBCL, and we determined the feasibility of the combination by conducting a phase Ib trial in RR-DLBCL patients. RESULTS: Concurrent combination of DNMTI and HDI resulted in synergistic anti-lymphoma effect toward RR-DLBCL cells in vitro and in vivo, with no significant toxicity increase. In a phase Ib trial, a total of 18 patients with a median of three prior therapies were treated with four different dose levels of AZA and VST. The most common toxicities were hematological, followed by gastrointestinal and metabolic. The clinical benefit was low as only one subject had a partial response and three subjects had stable disease. Interestingly, two of the seven patients that received additional chemotherapy post-study achieved a complete response and three others had a significant clinical benefit. These observations suggested that the combination might have a delayed chemosensitization effect that we were able to confirm by using in vitro and in vivo models. These studies also demonstrated that the addition of VST does not improve the chemosensitizing effect of DAC alone. CONCLUSIONS: Our data supports the strategy of epigenetic priming by employing DNMTI in RR-DLBCL patients in order to overcome resistance and improve their outcomes.
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azacitidina/administração & dosagem , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Decitabina , Epigênese Genética/efeitos dos fármacos , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/farmacologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , VorinostatRESUMO
The two major subtypes of diffuse large B cell lymphoma (DLBCL)--activated B cell-like (ABC) and germinal center B cell-like (GCB)--arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling. The ABC subtype has a â¼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies. We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. In a phase 1/2 clinical trial that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib produced complete or partial responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB DLBCL (P = 0.0106). ABC tumors with BCR mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%), a result that is consistent with in vitro cooperation between the BCR and MYD88 pathways. However, the highest number of responses occurred in ABC tumors that lacked BCR mutations (9/29; 31%), suggesting that oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by non-genetic mechanisms. These results support the selective development of ibrutinib for the treatment of ABC DLBCL.
Assuntos
Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/fisiologia , Transdução de Sinais/efeitos dos fármacos , Adenina/análogos & derivados , Adulto , Idoso , Sequência de Bases , Antígenos CD79/genética , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Fator 88 de Diferenciação Mieloide/genética , PiperidinasRESUMO
The standard treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in frail elderly patients has not been established. A variation was made on rituximab (R), cyclophosphamide (C), etoposide (E), procarbazine and prednisone (P), substituting vorinostat (V) for procarbazine. Patients ≥aged 60 years with relapsed/refractory DLBCL, not candidates for autologous stem cell transplantation, were treated R-CVEP [R 375 mg/m(2) intravenously (IV), day 1; C 600 mg/m(2) IV days 1, 8: E 70 mg/m(2) IV day 1, 140 mg/m(2) days 2, 3 orally (PO); V (300 vs. 400 mg) PO and P 60 mg/m(2) PO days 1-10] every 28 d for six cycles. Quality of life (QoL) was assessed in addition to response. Thirty patients (median age 76 years, 69-88) were enrolled (one died before treatment). Maximum tolerated dose (MTD) for V was 300 mg. For 23 patients at MTD (six phase I + 17 phase II), two were discontinued for toxicity, one withdrew consent, eight achieved complete response (35%), five achieved partial response (22%) and seven progressed (25%). Median overall survival was 17·5 months. Median progression-free survival was 9·2 months. Nine patients are alive. QoL declined during treatment but improved above baseline for patients who completed treatment. In conclusion, R-CVEP was tolerated at MTD and produced durable responses with improved QoL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Cuidados Paliativos , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Dose Máxima Tolerável , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Recidiva , Rituximab , Transplante de Células-Tronco , Taxa de Sobrevida , VorinostatRESUMO
Radioimmunotherapy (RIT) is effective treatment for indolent non-Hodgkin lymphomas (NHLs), but response durations are usually limited, especially in aggressive NHL. We hypothesized that administration of bortezomib as a radiosensitizer with RIT would be tolerable and improve efficacy in NHL. This phase 1 dose-escalation study evaluated escalating doses of bortezomib combined with 131I-tositumomab in patients with relapsed/refractory NHL. Twenty-five patients were treated. Treatment was well tolerated, with primarily hematologic toxicity. The maximum tolerated dose (MTD) was determined to be 0.9 mg/m2 bortezomib, in combination with a standard dose of 75 cGy 131I-tositumomab. Sixteen patients responded (64%), including 44% complete responses (CRs), with 82% CR in patients with follicular lymphoma (FL). At a median follow-up of 7 months, median progression-free survival was 7 months, and seven of 11 patients with FL remained in remission at a median of 22 months. In conclusion, bortezomib can be safely administered in combination with 131I-tositumomab with promising response rates.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Bortezomib/uso terapêutico , Radioisótopos do Iodo/uso terapêutico , Linfoma não Hodgkin/terapia , Radioimunoterapia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Bortezomib/efeitos adversos , Calafrios/etiologia , Terapia Combinada , Intervalo Livre de Doença , Fadiga/etiologia , Feminino , Humanos , Radioisótopos do Iodo/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neutropenia/etiologia , Radiossensibilizantes/efeitos adversos , Radiossensibilizantes/uso terapêutico , Radioimunoterapia/efeitos adversos , Indução de Remissão , Trombocitopenia/etiologia , Resultado do TratamentoRESUMO
Adults with newly diagnosed or persistent immunothrombocytopenia frequently relapse upon tapering steroids; adults and children with chronic disease have an even lower likelihood of lasting response. In adults with newly-diagnosed immunothrombocytopenia, two studies showed that dexamethasone 40 mg/day × four days and 4 rituximab infusions were superior to dexamethasone alone. Studies have also shown three cycles of dexamethasone are better than one and patients with persistent/chronic immunothrombocytopenia respond less well to either dexamethasone or rituximab. Therefore, 375 mg/m(2) × 4 rituximab was combined with three 4-day cycles of 28 mg/m(2) (max. 40 mg) dexamethasone at 2-week intervals and explored in 67 ITP patients. Best long-term response was assessed as complete (platelet count ≥ 100 × 10(9)/L) or partial (50-99 × 10(9)/L). Only 5 patients had not been previously treated. Fifty achieved complete (n=43, 64%) or partial (n=7, 10%) responses. Thirty-five of 50 responders maintained treatment-free platelet counts over 50 × 10(9)/L at a median 17 months (range 4-67) projecting 44% event-free survival. Duration of immunothrombocytopenia less than 24 months, achieving complete responses, and being female were associated with better long-term response (P<0.01). Adverse events were generally mild-moderate, but 3 patients developed serum sickness and 2 colitis; there were no sequelae. Dexamethasone could be difficult to tolerate. Fourteen patients became hypogammaglobulinemic and half had increased frequency of minor infections; 9 of 12 evaluable patients recovered their IgG levels. Rituximab combined with three cycles of dexamethasone provides apparently better results to reported findings with rituximab alone, dexamethasone alone, or the combination with one cycle of dexamethasone. The results suggest medical cure may be achievable in immunothrombocytopenia, especially in women and in patients within two years of diagnosis. (clinicaltrials.gov identifier:02050581).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/cirurgia , Esplenectomia , Adolescente , Adulto , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Púrpura Trombocitopênica Idiopática/mortalidade , Estudos Retrospectivos , Rituximab , Resultado do Tratamento , Adulto JovemRESUMO
Positron emission tomography (PET) using 18fluoro-2-deoxyglucose (FDG) has become a standard clinical tool for staging and response assessment in aggressive lymphomas. The use of PET scans in clinical trials is still under exploration, however. In this review, we examine current data regarding PET in DLBCL, and its potential applicability to development of a surrogate endpoint to expedite clinical trial conduct. Interim PET scanning in DLBCL shows mixed results, with qualitative assessment variably associated with outcome. Addition of quantitative assessment might improve predictive power of interim scans. Data from multiple retrospective studies support that PET-defined response at end of treatment correlates with outcome in DLBCL. Optimal technical criteria for standardization of acquisition and criteria for interpretation of scans require further study. Prospective studies to define the correlation of PET-defined response and time-dependent outcomes such as progression free survival (PFS) and overall survival (OS), critical for development of PET as a surrogate endpoint for clinical trials, are ongoing. In conclusion, evolving data regarding utility of PET in predictcing outcome of patients with DLBCL show promise to support the use of PET as a surrogate endpoint in clinical trials of DLBCL in the future.
Assuntos
Fluordesoxiglucose F18 , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Ensaios Clínicos como Assunto , Humanos , Linfoma Difuso de Grandes Células B/terapiaRESUMO
UNLABELLED: Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemoresistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTI) reprogrammed chemoresistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemoresistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was conducted evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk patients newly diagnosed with DLBCL. The combination was well tolerated and yielded a high rate of complete remission. Pre- and post-azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs. SIGNIFICANCE: The problem of chemoresistant DLBCL remains the most urgent challenge in the clinical management of patients with this disease. We describe a mechanism-based approach toward the rational translation of DNMTIs for the treatment of high-risk DLBCL.
Assuntos
Azacitidina/uso terapêutico , Metilação de DNA/genética , Metilases de Modificação do DNA/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/efeitos adversos , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Humanos , Pessoa de Meia-Idade , Interferência de RNA , RNA Interferente Pequeno , Proteína Smad1/genética , Adulto JovemRESUMO
BACKGROUND: Metronomic therapy is the application of continuous, low dose chemotherapy. The doses of chemotherapy are usually not sufficient to destroy neoplastic cells, but impact the milieu, particularly angiogenesis. OBJECTIVE: To determine if the oral PEP-C regimen, consisting of prednisone 20 mgm, etoposide 50 mgm, procarbazine 50 mgm, and cyclophosphamide 50 mgm given in either a daily, alternate day, or fractionated basis, is effective in a variety of lymphomas. METHODS: One hundred twenty two patients were studied although the majority had low grade or mantle cell lymphoma. All had received at least two or more prior therapies. RESULTS: Overall, 75% achieved an objective response (OR) with 38% complete responses (CRs) or CRs unconfirmed, and 37% partial responses. ORs were achieved in mantle cell (85%), follicular (88%), marginal zone (71%), and small lymphocytic (67%) lymphomas. Chemosensitive disease was more responsive. Toxicity was minimal. CONCLUSION: The PEP-C regimen is an easily administered highly effective treatment for heavily pretreated mantle cell and low grade lymphomas.
Assuntos
Antineoplásicos/uso terapêutico , Ciclofosfamida/uso terapêutico , Etoposídeo/uso terapêutico , Linfoma/tratamento farmacológico , Prednisona/uso terapêutico , Procarbazina/uso terapêutico , Antineoplásicos/administração & dosagem , Ciclofosfamida/administração & dosagem , Quimioterapia Combinada , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Etoposídeo/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma/genética , Linfoma/imunologia , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Prevenção Secundária , Fator A de Crescimento do Endotélio Vascular/sangueAssuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin/cirurgia , Terapia de Salvação , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Bases de Dados Factuais , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/mortalidade , Masculino , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Condicionamento Pré-Transplante , Transplante Autólogo , Resultado do TratamentoRESUMO
Patients with relapsed or refractory diffuse large B-cell lymphoma may experience extended survival with second-line chemotherapy and autologous stem cell transplant (ASCT). Since a major determinant of outcome after ASCT is responsiveness to second-line therapy, the development of more effective second-line treatments is desirable. We investigated the addition of bortezomib to rituximab, dexamethasone, ifosfamide, cisplatin and etoposide (VIPER). Fifteen patients were enrolled, of whom seven were refractory to first-line chemotherapy and only three had maintained first response for 1 year. Nine (60%) patients achieved objective responses, of which three (20%) were IWC-PET (International Workshop Criteria positron emission tomography) complete responses. Median progression-free survival was 3 months, and median overall survival was 10 months. At a median follow-up of 26 months, five patients (33%) remained alive. Treatment was well tolerated with no unexpected toxicity. Although response rates did not meet predefined criteria, activity was at least comparable to other second-line approaches despite a poor-prognosis patient population.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Cisplatino/administração & dosagem , Dexametasona/administração & dosagem , Etoposídeo/administração & dosagem , Ifosfamida/administração & dosagem , Imunoterapia/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pirazinas/administração & dosagem , Adulto , Idoso , Bortezomib , Terapia Combinada/métodos , Intervalo Livre de Doença , Humanos , Pessoa de Meia-Idade , Complexo de Endopeptidases do Proteassoma/metabolismo , Recidiva , Rituximab , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Subcutaneous injections of anti-CD20 antibodies may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies. DESIGN AND METHODS: A pilot study was undertaken to evaluate the potential for subcutaneous dosing with 2(nd) generation anti-CD20 antibody veltuzumab in patients with CD20(+) indolent non-Hodgkin's lymphoma. Patients with previously untreated or relapsed disease received 4 doses of 80, 160, or 320 mg veltuzumab injected subcutaneously every two weeks. Responses were assessed by computed tomography scans, with other evaluations including adverse events, safety laboratories, B-cell blood levels, serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers. RESULTS: Seventeen patients (14 follicular lymphoma; 13 stage III or IV disease; 5 treatment-naive) completed treatment with only occasional, mild-moderate, transient injection reactions and no other safety issues. Subcutaneous veltuzumab demonstrated a slow release pattern over several days, achieving a mean Cmax of 19, 25 and 63 µg/mL at 80, 160, and 320 mg doses for a total of 4 administrations, respectively. Depletion of circulating B cells occurred after the first injection. The objective response rate (partial responses plus complete responses plus complete responses unconfirmed) was 47% (8/17) with a complete response/complete response unconfirmed rate of 24% (4/17); 4 of 8 objective responses continued for 60 weeks or more. All serum samples evaluated for human anti-veltuzumab antibody were negative. CONCLUSIONS: Subcutaneous injections of low-dose veltuzumab are convenient, well tolerated, and capable of achieving sustained serum levels, B-cell depletion, and durable objective responses in indolent non-Hodgkin's lymphoma. (Clinicaltrials.gov identifier: NCT00546793).
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos CD20/metabolismo , Antineoplásicos/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Feminino , Testes Hematológicos , Humanos , Injeções Subcutâneas , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
PURPOSE: The proteasome inhibitor bortezomib may enhance activity of chemoimmunotherapy in lymphoma. We evaluated dose-escalated bortezomib plus standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R) in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). PATIENTS AND METHODS: Seventy-six subjects with untreated DLBCL (n = 40) and MCL (n = 36) received standard CHOP every 21 days (CHOP-21) with R plus bortezomib at 0.7 mg/m(2) (n = 4), 1.0 mg/m(2) (n = 9), or 1.3 mg/m(2) (n = 63) on days 1 and 4 for six cycles. RESULTS: Median age was 63 years (range, 20 to 87), and International Prognostic Index (IPI) scores were generally unfavorable (39% with IPI of 2, and 49% with IPI of 3 to 5), as were Mantle Cell Lymphoma International Prognostic Index scores in patients with MCL (28% intermediate risk and 39% high risk). Toxicity was manageable, including neuropathy in 49 subjects (8% grade 2 and 4% grade 3) and grade 3/4 anemia (13%), neutropenia (41%), and thrombocytopenia (25%). For DLBCL, the evaluable overall response rate (ORR) was 100% with 86% complete response (CR)/CR unconfirmed (CRu; n = 35). Intent-to-treat (ITT, n = 40) ORR was 88% with 75% CR/CRu, 2-year progression-free survival (PFS) of 64% (95% CI, 47% to 77%) and 2-year overall survival (OS) of 70% (95% CI, 53% to 82%). For MCL, the evaluable ORR was 91% with 72% CR/CRu (n = 32). The ITT (n = 36) ORR was 81% with 64% CR/CRu, 2-year PFS 44% (95% CI, 27% to 60%) and 2-year OS 86% (95% CI, 70% to 94%). IPI and MIPI correlated with survival in DLBCL and MCL, respectively. Unlike in DLBCL treated with R-CHOP alone, nongerminal center B cell (non-GCB) and GCB subtypes had similar outcomes. CONCLUSION: Bortezomib with R-CHOP-21 can be safely administered and may enhance outcomes, particularly in non-GCB DLBCL, justifying randomized studies.