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In addition to complications of acute diseases, chronic viral infections are linked to both malignancies and autoimmune disorders. Lack of adequate treatment options for Epstein-Barr virus (EBV), Human T-lymphotropic virus type 1 (HTLV-1), and human papillomavirus (HPV) remains. The NexImmune Artificial Immune Modulation (AIM) nanoparticle platform can be used to direct T cell responses by mimicking the dendritic cell function. In one application, AIM nanoparticles are used ex vivo to enrich and expand (E+E) rare populations of multi-antigen-specific CD8+ T cells for use of these cells as an AIM adoptive cell therapy. This study has demonstrated using E+E CD8+ T cells, the functional relevance of targeting EBV, HTLV-1, and HPV. Expanded T cells consist primarily of effector memory, central memory, and self-renewing stem-like memory T cells directed at selected viral antigen peptides presented by the AIM nanoparticle. T cells expanded against either EBV- or HPV-antigens were highly polyfunctional and displayed substantial in vitro cytotoxic activity against cell lines expressing the respective antigens. Our initial work was in the context of exploring T cells expanded from healthy donors and restricted to human leukocyte antigen (HLA)-A*02:01 serotype. AIM Adoptive Cell Therapies (ACT) are also being developed for other HLA class I serotypes. AIM adoptive cell therapies of autologous or allogeneic T cells specific to antigens associated with acute myeloid leukemia and multiple myeloma are currently in the clinic. The utility and flexibility of the AIM nanoparticle platform will be expanded as we advance the second application, an AIM injectable off-the-shelf nanoparticle, which targets multiple antigen-specific T cell populations to either activate, tolerize, or destroy these targeted CD8+ T cells directly in vivo, leaving non-target cells alone. The AIM injectable platform offers the potential to develop new multi-antigen specific therapies for treating infectious diseases, cancer, and autoimmune diseases.
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Purpose People with HIV are living longer as a result of effective antiretroviral therapy. Cancer has become a leading cause of morbidity and mortality in this patient population. However, studies of novel cancer therapeutics have historically excluded patients with HIV. Critical review of eligibility criteria related to HIV is required to accelerate development of and access to effective therapeutics for HIV-infected patients with cancer and make studies more generalizable to this patient population. Methods From January through April 2016, the HIV Working Group conducted a series of teleconferences; a review of 46 New Drug Applications from registration studies of unique agents studied in adults with cancer that led to the initial US Food and Drug Administration approval of that agent from 2011 to 2015; and a review of HIV-related eligibility criteria from National Cancer Institute-sponsored studies. Results were discussed and refined at a multistakeholder workshop held May 12, 2016. The HIV Working Group developed recommendations for eligibility criteria that focus on pharmacologic and immunologic considerations in this patient population and that balance patient safety, access to appropriate investigational agents, and study integrity. Results Exclusion of patients with HIV remains common in most studies of novel cancer agents. Models for HIV-related eligibility criteria in National Cancer Institute-sponsored studies are instructive. HIV infection itself should no longer be an exclusion criterion for most studies. Eligibility criteria related to HIV infection that address concurrent antiretroviral therapy and immune status should be designed in a manner that is appropriate for a given cancer. Conclusion Expanding clinical trial eligibility to be more inclusive of patients with HIV is justified in most cases and may accelerate the development of effective therapies in this area of unmet clinical need.
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Ensaios Clínicos como Assunto/métodos , Definição da Elegibilidade/métodos , Infecções por HIV/diagnóstico , HIV/patogenicidade , Pesquisa Biomédica , Humanos , Estados UnidosRESUMO
Kaposi sarcoma-associated herpesvirus (KSHV) is the cause of several tumors, including Kaposi sarcoma and primary effusion lymphoma (PEL). Most viruses have evolved means of escaping immune recognition. KSHV downregulates MHC-I expression during lytic infection, and expression of ICAM-1 and B7-2 (CD86) during latent infection, allowing evasion of T cell and natural killer immunity respectively. These effects are largely mediated by two KSHV-encoded proteins, K3 and K5. We show here that lenalidomide (Len) and pomalidomide (Pom) prevent down-regulation of MHC-I during lytic activation, and restore ICAM-1 and B7-2 surface expression in latently infected PEL cells. Importantly, these changes occurred at clinically achievable concentrations and prior to any cytotoxic effects. Exploration of the mechanism revealed that Pom blocked lytic down-regulation of MHC-I induced by transfection with K3 but not K5. Although Pom alone did not significantly increase HLA mRNA expression in PEL cells, it did blunt the butyrate-induced decrease in MHC-I mRNA expression and decreased the upregulation of K3 mRNA in lytic cells. Virus-induced tumors express foreign antigens, but immunotherapy can be thwarted by viral strategies to evade immune recognition. The effects of Pom and Len described here can prevent these strategies and support the use of these drugs to treat KSHV-induced tumors.
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Purpose Kaposi's sarcoma (KS) is a multicentric tumor caused by Kaposi's sarcoma-associated herpesvirus. Unmet needs include therapies that are oral, anthracycline sparing, and deliverable in resource-limited settings. We evaluated pomalidomide, an oral immune modulatory agent, in patients with symptomatic KS. Methods The primary objectives were to assess tolerability, pharmacokinetics, and activity. Initial dosage level was 5 mg once per day for 21 days per 28-day cycle, with a de-escalated level of 3 mg if not tolerable, and aspirin 81 mg once per day thromboprophylaxis. HIV-infected patients required controlled viremia with either persistent KS despite 3 months of antiretroviral therapy (ART) or progressive KS despite 2 months of ART. Evaluations included tumor response and health-related quality of life (HRQL). Results Twenty-two patients were treated; 15 (68%) were HIV infected, 17 (77%) had advanced (T1) disease, and 19 (86%) previous KS therapy excluding ART. All were treated with 5 mg because no dose-limiting toxicities occurred. Over 156 cycles, the grade 3/4 adverse events possibly attributable to therapy were neutropenia (23 cycles, 10 patients), infection (1 cycle), and edema (1 cycle). Sixteen patients responded (73%; 95% CI, 50% to 89%): nine of 15 HIV-infected patients (60%; 95% CI, 32% to 84%) and all seven HIV-uninfected patients (100%; 95% CI, 59% to 100%). Median time to response was 4 weeks (range, 4 to 36 weeks). HRQL showed no impairment during therapy and improved satisfaction with appearance at end therapy ( P = .03). Significant increases in CD4+ and CD8+ cells were seen in patients with and without HIV, together with a transient increase in Kaposi's sarcoma-associated herpesvirus viral load at week 4 ( P = .05). Conclusion Pomalidomide is well tolerated and active in KS regardless of HIV status. Responses were rapid, with improved self-reported outcomes, and occurred in advanced and heavily pretreated disease. Correlative studies support, at least in part, an immunologic mechanism of activity.
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Inibidores da Angiogênese/uso terapêutico , Infecções por HIV/complicações , Sarcoma de Kaposi/tratamento farmacológico , Talidomida/análogos & derivados , Administração Oral , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Talidomida/administração & dosagem , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVES: Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. METHODS: A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. RESULTS: Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits. CONCLUSIONS: Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment.
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Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Animais , Antituberculosos/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Isoniazida/administração & dosagem , Inibidores da Fosfodiesterase 4/administração & dosagem , CoelhosRESUMO
Pomalidomide is a second generation IMiD (immunomodulatory agent) that has recently been granted approval by the Food and Drug Administration for treatment of relapsed multiple myeloma after prior treatment with two antimyeloma agents, including lenalidomide and bortezomib. A simple and robust HPLC assay with fluorescence detection for pomalidomide over the range of 1-500ng/mL has been developed for application to pharmacokinetic studies in ongoing clinical trials in various other malignancies. A liquid-liquid extraction from human plasma alone or pre-stabilized with 0.1% HCl was performed, using propyl paraben as the internal standard. From plasma either pre-stabilized with 0.1% HCl or not, the assay was shown to be selective, sensitive, accurate, precise, and have minimal matrix effects (<20%). Pomalidomide was stable in plasma through 4 freeze-thaw cycles (<12% change), in plasma at room temperature for up to 2h for samples not pre-stabilized with 0.1% HCl and up to 8h in samples pre-stabilized with 0.1% HCl, 24h post-preparation at 4°C (<2% change), and showed excellent extraction recovery (â¼90%). This is the first reported description of the freeze/thaw and plasma stability of pomalidomide in plasma either pre-stabilized with 0.1% HCl or not. The information presented in this manuscript is important when performing pharmacokinetic analyses. The method was used to analyze clinical pharmacokinetics samples obtained after a 5mg oral dose of pomalidomide. This relatively simple HPLC-FL assay allows a broader range of laboratories to measure pomalidomide for application to clinical pharmacokinetics.
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Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Fluorescência/métodos , Talidomida/análogos & derivados , Bioensaio/métodos , Estabilidade de Medicamentos , Fluorescência , Humanos , Extração Líquido-Líquido/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Talidomida/sangue , Talidomida/farmacocinéticaRESUMO
A previous interim report of MM-011, the first study that combined lenalidomide with anthracycline-based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long-term outcomes of all 76 treated patients with follow-up ≥ 5 years. This single-center phase I/II study administered lenalidomide (10 mg on days 1-21 of every 28-day cycle), intravenous liposomal doxorubicin (40 mg/m(2) on day 1), dexamethasone (40 mg on days 1-4), and intravenous vincristine (2 mg on day 1). After 4-6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1-7); 49 (64.5%) patients had refractory disease. Forty-three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment-related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression-free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline-based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM (ClinicalTrials.gov number, NCT00091624).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Doenças Hematológicas/induzido quimicamente , Humanos , Controle de Infecções , Estimativa de Kaplan-Meier , Cariotipagem , Lenalidomida , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Modelos de Riscos Proporcionais , Indução de Remissão , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Trombose/prevenção & controle , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversosAssuntos
Amiloidose , Inibidores da Angiogênese/efeitos adversos , Segunda Neoplasia Primária , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/tratamento farmacológico , Amiloidose/mortalidade , Amiloidose/patologia , Inibidores da Angiogênese/administração & dosagem , Feminino , Seguimentos , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/patologia , Estudos Retrospectivos , Fatores de Risco , Talidomida/administração & dosagem , Talidomida/efeitos adversosRESUMO
We report results of a phase II trial of combination of melphalan, lenalidomide, and dexamethasone for the treatment of immunoglobulin light chain (AL) amyloidosis. The primary objectives were tolerability and hematologic response rate; secondary objectives were organ responses and survival. Treatment protocol consisted of melphalan 5 mg/m(2)/day for four days, lenalidomide 10 mg/day for 21 days and dexamethasone 20-40 mg once a week every 28 days for a total of 12 cycles. Sixteen subjects were enrolled of whom 14 completed at least 3 cycles and were evaluable for response. Grade 3/4 toxicities were experienced by 88% (n=14), the most common being myelosuppression (n=7). Dose reductions occurred in 85% (n=12 of 14) of subjects. Hematologic partial and complete responses were achieved by 43% (n=6 of 14) and 7% (n=1 of 14), respectively. The median overall survival has not been reached and median progression-free survival is 24 months. In conclusion, this combination is associated with significant myelosuppression leading to dose modifications and producing minor hematologic responses in AL amyloidosis. http://clinicaltrials.gov/ct2/show/NCT00679367.
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Amiloidose/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cadeias Leves de Imunoglobulina , Idoso , Idoso de 80 Anos ou mais , Amiloidose/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Progressão da Doença , Feminino , Humanos , Lenalidomida , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Resultado do TratamentoRESUMO
BACKGROUND: The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. METHODS: Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of each 28-day cycle. 375 mg/m(2) intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00294632. FINDINGS: 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3-4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached [NR]). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response. INTERPRETATION: Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL. FUNDING: Celgene.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida , Linfoma de Célula do Manto/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva , Rituximab , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivadosRESUMO
Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-α and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment.
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Antituberculosos/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Isoniazida/uso terapêutico , Pulmão/patologia , Ativação de Macrófagos/efeitos dos fármacos , Talidomida/análogos & derivados , Tuberculose Pulmonar/prevenção & controle , Animais , Western Blotting , Ensaio de Unidades Formadoras de Colônias , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Citocinas/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Pulmão/efeitos dos fármacos , Masculino , Metaloproteinases da Matriz/metabolismo , Mycobacterium tuberculosis/patogenicidade , Inibidores da Fosfodiesterase 4/uso terapêutico , Fibrose Pulmonar/enzimologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle , RNA Mensageiro/genética , Coelhos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Talidomida/uso terapêutico , Tuberculose Pulmonar/enzimologia , Tuberculose Pulmonar/patologiaRESUMO
BACKGROUND: In patients with chronic lymphocytic leukemia (CLL), treatment with lenalidomide induces a unique, previously uncharacterized, immune response called tumor flare reaction (TFR). The clinical significance of this reaction remains unknown. METHODS: Forty-five patients with CLL who were treated with lenalidomide in a phase 2 clinical trial were evaluated for the clinical features, intensity, and duration of TFR. Correlation was made with tumor response and the immune cellular microenvironment. Steroids for the prophylaxis of TFR was not given to patients in Group A (n = 29) whereas patients in Group B (n = 16) received low-dose prednisone as well as a slow dose escalation of lenalidomide for the prevention of TFR. RESULTS: Thirty (67%) patients experienced a TFR, with a grade 2 or 3 reaction (according to National Cancer Institute Common Toxicity Criteria [version 3.0]) observed in 33% of patients (47% in Group A and 9% in Group B; P = .05). The median time to onset of the TFR was 6 days, and was longer in the patients receiving prophylaxis (4 days vs 9 days, respectively; P = .01). A complete response was observed in 7 of 30 (23%) patients with TFR and 1 of 15 (7%) patients without TFR. The median progression-free survival was 19.9 months and 19.4 months, respectively, for patients with versus those without TFR (P = .92). CONCLUSIONS: TFR is a unique immune-mediated phenomenon noted with lenalidomide treatment only in patients with CLL that correlates with clinical response. It can be effectively managed with anti-inflammatory agents.
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Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/imunologia , Talidomida/análogos & derivados , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Feminino , Humanos , Imunidade Celular/efeitos dos fármacos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Talidomida/efeitos adversos , Resultado do TratamentoRESUMO
Lenalidomide (REVLIMID), an immunomodulatory compound targeting both cancer cells and their microenvironment, has substantial activity in several difficult-to-manage hematological malignancies. In previously treated multiple myeloma, lenalidomide produces high-quality responses combined with sustained disease control. Recently, several randomized studies have demonstrated a clinical benefit of continuous lenalidomide treatment in newly diagnosed multiple myeloma. In many patients with refractory anemia associated with lower risk myelodysplastic syndromes and a 5q chromosome deletion, lenalidomide leads to transfusion independence, considerably improving quality of life. It has a manageable safety profile, and its oral formulation reduces the burden on patients. Several phase III trials are ongoing in other indications currently underserved by conventional therapy, such as chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and prostate cancer. Several early-stage studies are exploring lenalidomide alone and in combination across different hematological malignancies, solid tumors, and immune-related disorders.
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Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Talidomida/análogos & derivados , Descoberta de Drogas/história , Descoberta de Drogas/tendências , História do Século XX , História do Século XXI , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/síntese química , Lenalidomida , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Talidomida/efeitos adversos , Talidomida/síntese química , Talidomida/farmacologia , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: In two randomized phase III trials (MM-009 and MM-010), lenalidomide plus dexamethasone significantly prolonged time to progression and overall survival (OS) in patients with relapsed/refractory multiple myeloma compared with dexamethasone alone. In both trials the treatment was continued until disease progression or unacceptable toxicity. We conducted a subanalysis to determine if continuing therapy after achieving≥partial response (PR) improved survival. PATIENTS AND METHODS: Data were collected on 212 patients who were treated with lenalidomide plus dexamethasone and achieved≥PR. Kaplan-Meier survival estimates were compared between patients on continued treatment versus patients discontinuing therapy because of adverse events, withdrawal of consent, or other reasons. Time-dependent multivariate regression analyses were used to determine the benefit of continuing treatment with lenalidomide. RESULTS: A total of 174 patients received continued treatment until disease progression or death, and 38 patients discontinued therapy without progression. There was a trend toward longer median OS in patients who continued therapy (50.9 months vs. 35.0 months; P=.0594). When controlling for the number of previous antimyeloma therapies, ß2-microglobulin levels, and Durie-Salmon stage (which adversely affected survival in these patients), continued lenalidomide treatment (HR, 0.137; 95% CI, 0.045-0.417; P=.0005) or each additional cycle of lenalidomide (HR, 0.921; 95% CI, 0.886-0.957; P<.0001) were both associated with longer survival. CONCLUSION: Continued lenalidomide treatment until disease progression after achievement of ≥PR is associated with a significant survival advantage when controlling for patient characteristics. These findings should be confirmed in a prospectively designed trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Resultado do TratamentoRESUMO
BACKGROUND: Lenalidomide is an immunomodulatory agent used to treat plasma cell dyscrasias. We previously observed worsening of kidney function in a high proportion of patients with AL amyloidosis during lenalidomide treatment. The objective of this study is to characterize alterations in kidney function among patients with AL amyloidosis undergoing treatment with lenalidomide. METHODS: This is a secondary analysis of an ongoing clinical trial at a single referral centre. Forty-one patients with AL amyloidosis received lenalidomide with or without dexamethasone in monthly cycles. Kidney dysfunction was defined as ≥ 50% increase in serum creatinine. Severe kidney dysfunction was defined as ≥ 100% increase in serum creatinine. Recovery of renal function was defined as a return of serum creatinine to within 25% of the pre-treatment value or discontinuation of dialysis. RESULTS: Twenty-seven of 41 patients (66%) developed kidney dysfunction during lenalidomide treatment. The kidney dysfunction was severe in 13 of these patients (32%); four of whom required initiation of dialysis (10%). The median time to kidney dysfunction after starting lenalidomide was 44 days (interquartile range 15-108 days). Four of eight patients without underlying renal amyloidosis developed kidney dysfunction. Patients with severe kidney dysfunction were older and had a higher frequency of underlying renal amyloidosis, greater urinary protein excretion, and lower serum albumin. Recovery of renal function occurred in 12 patients (44%). CONCLUSIONS: Among patients with AL amyloidosis, worsening of kidney function occurs frequently during lenalidomide treatment. While a causal role of the drug has not been established, our findings suggest that kidney function should be monitored closely during treatment with this drug.
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Amiloidose/tratamento farmacológico , Antineoplásicos/efeitos adversos , Insuficiência Renal/induzido quimicamente , Talidomida/análogos & derivados , Adulto , Idoso , Feminino , Humanos , Testes de Função Renal , Lenalidomida , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Talidomida/efeitos adversos , Resultado do TratamentoAssuntos
Amiloidose/tratamento farmacológico , Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Peptídeo Natriurético Encefálico/sangue , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Feminino , Coração/efeitos dos fármacos , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/efeitos dos fármacos , Estudos Retrospectivos , Talidomida/uso terapêuticoAssuntos
Amiloidose/tratamento farmacológico , Talidomida/análogos & derivados , Amiloidose/sangue , Antineoplásicos/uso terapêutico , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Quimioterapia Combinada , Glucocorticoides/uso terapêutico , Humanos , Cadeias Leves de Imunoglobulina/sangue , Lenalidomida , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outcomes of patients who achieved a complete response or very good partial response to treatment with lenalidomide plus dexamethasone with the outcomes of those who only achieved a partial response. DESIGN AND METHODS: Patients (n=353) received lenalidomide (25 mg/day for 21 days of each 28-day cycle) plus dexamethasone (40 mg on days 1-4, 9-12, and 17-20 for four cycles, and only on days 1-4 after the first four cycles). Time to response, duration of response, time-to-progression, overall survival, and adverse events were investigated for patients who had a complete or very good partial response and compared with those of patients who had a partial response. RESULTS: At the time of unblinding, 32% of patients had achieved a complete or very good partial response and 28% had a partial response. Half (50.5%) of the patients who had a partial response as their initial response achieved a complete or very good partial response with further treatment. The probability of achieving a complete or very good partial response with continued lenalidomide treatment decreased with delayed achievement of a partial response (by cycle 4 versus later); however, it remained clinically significant. With an extended follow-up of 48 months, the median response duration, time-to-progression, and overall survival were longer in patients with a complete or very good partial response than in those with a partial response (24.0 versus 8.3 months, P<0.001; 27.7 versus 12.0 months, P<0.001; not reached versus 44.2 months, P=0.021, respectively). The benefit of a complete or very good partial response was independent of when it was achieved. CONCLUSIONS: Continuing treatment with lenalidomide plus dexamethasone to achieve best response, in the absence of disease progression and toxicity, provided deeper remissions and greater clinical benefit over time for patients in this study.
Assuntos
Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Terapia de Salvação/métodos , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Talidomida/administração & dosagem , Resultado do TratamentoRESUMO
IMPORTANCE OF THE FIELD: Lenalidomide and other new agents are improving survival of multiple myeloma patients. This review describes current data on lenalidomide in myeloma and how the unique properties of lenalidomide may lend its use in new settings, such as maintenance and preventive therapy. AREAS COVERED IN THIS REVIEW: This review covers the activity of lenalidomide in multiple myeloma, efficacy in both newly diagnosed and relapsed/refractory patients, how to manage effectively common adverse events observed with lenalidomide, and its potential use in new settings based on clinical trials published up to 2009. WHAT THE READER WILL GAIN: This review describes the mechanism of action of lenalidomide in myeloma which provides the basis for its clinical use in newly diagnosed, relapsed/refractory, and high-risk smoldering myeloma in combination with other agents. Strategies to reduce or effectively manage myelosuppression and thromboembolic events, the main adverse events associated with lenalidomide plus dexamethasone therapy, are also described. TAKE HOME MESSAGE: Lenalidomide is an oral immunomodulatory drug that is highly effective in treating multiple myeloma, has a favorable safety profile and is now being evaluated as maintenance therapy, preventive therapy and in combination with other new agents.