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1.
Rinsho Ketsueki ; 60(10): 1468-1470, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31695009

RESUMO

A 50-year-old male was diagnosed with multiple myeloma (MM) and treated by high-dose melphalan followed by autologous stem cell transplantation in April 2014. However, he relapsed and received non-myeloablative bone marrow transplantation from an unrelated HLA-matched donor (UR-BMT) in July 2016. After 100 days of UR-BMT, the disease remained stable disease and the patient was treated with carfilzomib, lenalidomide, and dexamethaonse (KRd) therapy. After 10 cycles of KRd, he obtained stringent complete response without exacerbation of graft-versus-host disease. We concluded that KRd after allogeneic stem cell transplantation is one of the useful treatment regimens for relapsed refractory MM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Lenalidomida/uso terapêutico , Mieloma Múltiplo/terapia , Oligopeptídeos/uso terapêutico , Transplante de Medula Óssea , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Transplante Autólogo
2.
Rinsho Ketsueki ; 60(9): 1199-1204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597844

RESUMO

The treatment of follicular lymphoma (FL) continues to evolve. Those patients who present with minimal symptoms often are observed without therapy until significant progression occurs. When treatment is needed, initial options include single agent rituximab (R, anti-CD20), or various forms of chemoimmunotherapy including either R or the newer anti-CD20 monoclonal antibody obinutuzumab (O), with or without maintenance administration. Recent data suggest that the immunomodulatory agent lenalidomide can also be effective in combination with rituximab in both the upfront and relapsed setting. Patients with recurrent disease are frequently treated with chemoimmunotherapy or phosphoinositol-3-kinase (PI3K) inhibitors. Current information suggests that the most important prognostic feature of FL is the presence or absence of early progression (within 2 years of initial treatment/diagnosis). Ongoing efforts are focused on biomarkers to optimally match treatment to patient populations and further improve clinical outcomes.


Assuntos
Linfoma Folicular/terapia , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD20 , Humanos , Imunoterapia , Lenalidomida/uso terapêutico , Rituximab/uso terapêutico
3.
Lancet Haematol ; 6(8): e429-e437, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31296423

RESUMO

BACKGROUND: Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma. METHODS: In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0-2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2-22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual. FINDINGS: Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2-2·8). 68 (79%) of 86 evaluable patients (95% CI 69-87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51-72), progression-free survival 65% (95% CI 54-74), duration of response 70% (95% CI 57-79), and overall survival 87% (95% CI 78-93). Complete response was achieved by 33 (38%, 95% CI 28-50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72-89) and 72 (84%, 74-91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia. INTERPRETATION: Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted. FUNDING: Lymphoma Academic Research Organisation, and Celgene and Roche.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Lenalidomida/efeitos adversos , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Recidiva , Taxa de Sobrevida , Resultado do Tratamento
4.
Rinsho Ketsueki ; 60(4): 308-313, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31068561

RESUMO

We report three cases of POEMS syndrome treated with lenalidomide and dexamethasone who presented with peripheral neuropathy. All of them had markedly elevated serum vascular endothelial growth factor (VEGF) levels treated with lenalidomide and dexamethasone for severe peripheral neuropathy, which normalized serum VEGF levels and improved peripheral neuropathy. The standard treatment of POEMS syndrome has not been established, but has been effectively treated with high-dose chemotherapy with autologous stem cell transplantation. Newer agents currently used for plasma cell dyscrasias include bortezomib and immunomodulatory drugs, such as thalidomide and lenalidomide. A randomized controlled trial on thalidomide plus dexamethasone for POEMS syndrome showed reduced serum VEGF levels after therapy; however, the incidence of peripheral neuropathy, a well-known side effect of both thalidomide and bortezomib, increased. Lenalidomide is associated with lower incidence of peripheral neuropathy compared to thalidomide and bortezomib, making it a reasonable treatment option for POEMS syndrome.


Assuntos
Dexametasona/uso terapêutico , Lenalidomida/uso terapêutico , Síndrome POEMS/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante Autólogo , Fator A de Crescimento do Endotélio Vascular/sangue
5.
J Dermatol ; 46(7): 618-621, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31144726

RESUMO

Eosinophilic dermatosis of hematological malignancy is a paraneoplastic skin eruption associated with chronic lymphocytic leukemia and other B-cell malignancies. It clinically resembles an insect bite reaction and it can precede the symptoms of the hematological malignancy or be related to a more aggressive course. Different treatments have been proposed, but partial response and recurrence are frequent. Herein, we describe a case of eosinophilic dermatosis associated with mantle cell lymphoma with remission after lenalidomide therapy.


Assuntos
Eosinofilia/tratamento farmacológico , Exantema/tratamento farmacológico , Lenalidomida/uso terapêutico , Linfoma de Célula do Manto/complicações , Síndromes Paraneoplásicas/tratamento farmacológico , Prurido/tratamento farmacológico , Eosinofilia/etiologia , Eosinofilia/patologia , Exantema/etiologia , Exantema/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Paraneoplásicas/etiologia , Síndromes Paraneoplásicas/patologia , Prurido/etiologia , Prurido/patologia , Pele/patologia , Resultado do Tratamento
6.
Nat Commun ; 10(1): 1911, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015454

RESUMO

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Cadeias lambda de Imunoglobulina/genética , Mieloma Múltiplo/diagnóstico , Proteínas do Mieloma/genética , Translocação Genética , Antineoplásicos/uso terapêutico , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/imunologia , Elementos Facilitadores Genéticos , Loci Gênicos , Genoma Humano , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Plasmócitos/imunologia , Plasmócitos/patologia , Prognóstico , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Recidiva , Análise de Sobrevida , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Sequenciamento Completo do Genoma
7.
Brain Nerve ; 71(4): 350-353, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-30988219

RESUMO

Skin changes, including peripheral edema, hyperpigmentation, hypertrichosis, and hemangioma are frequent and early manifestations of POEMS (polyneuropathy, organomegaly, enndocrinopathy, M-protein, and skin changes) syndrome. Hemangiomata is presumably caused by overproduction of the vascular endothelial growth factor, and hypertrichosis results from the deposition of melanin; however, the pathogenesis of the skin symptoms are poorly understood. Nevertheless, recognition of the skin changes facilitates early diagnosis and treatment. Novel treatments, such as autoplantation, thalidomide/lenalidomide, and proteasome inhibitors have been availoble since 2000, and outcomes of the disorder have significantly improved. Appropriate understanding of the skin manifestations is clinically important for the early diagnosis of this intractable disorder.


Assuntos
Síndrome POEMS/patologia , Pele/patologia , Humanos , Lenalidomida/uso terapêutico , Síndrome POEMS/tratamento farmacológico , Talidomida/uso terapêutico , Fator A de Crescimento do Endotélio Vascular
8.
Ann Hematol ; 98(6): 1441-1447, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30874851

RESUMO

Pomalidomide dexamethasone is a standard of care for relapsed multiple myeloma (MM) patients who received at least two prior lines of therapy, including both lenalidomide and proteasome inhibitors (PI). We report here a real-life single-center series of 49 consecutive patients with relapsed and refractory MM treated with the triplet pomalidomide cyclophosphamide dexamethasone (PCD) combination. The median of prior lines of therapy was 3 and all patients were previously exposed to proteasome inhibitors and lenalidomide. The overall response rate was 76%, including 27% very good partial response or better. With a median follow-up of 16 months, the median progression-free survival (PFS) was 7.3 months and the median overall survival was not reached. Regarding safety, most frequent toxicity was hematologic, including 37% grade 3-4 cytopenias. Nine patients (18%) discontinued therapy due to adverse event. Our study confirms that PCD combination is feasible and results in favorable response rate and PFS in comparison with pomalidomide dexamethasone alone.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Terapia de Salvação , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Avaliação de Medicamentos , Substituição de Medicamentos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Lenalidomida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteases/uso terapêutico , Recidiva , Estudos Retrospectivos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados
10.
Mater Sci Eng C Mater Biol Appl ; 98: 419-436, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30813043

RESUMO

In the present investigation, FePt alloy nanoparticles were synthesized with controlled size and elemental composition followed by surface modification using (3-Aminopropyl) triethoxysilane (APTES). Lenalidomide was covalently bound to FePt-NH2 by pH sensitive hydrazone bonding. Hyaluronic acid was conjugated to amino groups of APTES while lactoferrin (Lf) was directly conjugated to excess carboxylic group present on hyaluronic acid (HA) to form surface modified pH sensitive alloy-drug nanoconjugates (SPANs). The multifunctional nanoconjugates were characterized and evaluated using extensive in vitro and in vivo techniques. The nanoconjugates demonstrated excellent heating ability on exposure to alternating magnetic field and near-infrared laser irradiation. The acidic microenvironment of lysozome triggered release of LND from SPANs. Owing to leaching of Fe and Pt contents, SPANs demonstrated ability to generate reactive oxygen species (ROS) in U87MG cell line which further enhanced therapeutic effect of SPANs. Significant difference in cell viability suppression was observed in in vitro photothermal, chemo-photothermal and chemo-magnetophotothermal killing of cancer cells using SPANs in U87MG cell lines. Significant difference in heating ability and cell cytotoxicity of SPANs in comparison to alternative magnetic field and NIR irradiation was observed for DUAL-mode exposure of SPANs. The results of cellular internalization study showed efficient internalization of SPANs inside U87MG cells. The in vivo results (both qualitative and quantitative) confirmed enhanced uptake of SPANs in brain after intranasal administration with enhanced nasal and mucus penetration owing to presence of Lf. No significant interaction was observed with ECM and mucin due to presence of carboxyl group on SPANs.


Assuntos
Ligas/química , Glioblastoma/terapia , Ácido Hialurônico/química , Nanoconjugados/química , Administração Intranasal , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cães , Liberação Controlada de Fármacos , Endocitose , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Concentração de Íons de Hidrogênio , Hipertermia Induzida , Ferro/química , Lactoferrina/química , Lenalidomida/administração & dosagem , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Masculino , Mucinas/metabolismo , Nanoconjugados/ultraestrutura , Ácido Oleico/química , Espectroscopia Fotoeletrônica , Fototerapia , Platina/química , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Suínos
11.
Leukemia ; 33(8): 2006-2021, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30760870

RESUMO

Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation, and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.


Assuntos
Subunidades alfa de Fatores de Ligação ao Core/fisiologia , Fator de Transcrição Ikaros/metabolismo , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Linhagem Celular Tumoral , Subunidades alfa de Fatores de Ligação ao Core/antagonistas & inibidores , Subunidades alfa de Fatores de Ligação ao Core/química , Humanos , Peptídeo Hidrolases/fisiologia
12.
Neoplasma ; 66(3): 499-505, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30784289

RESUMO

Lenalidomide (LEN) is an immunomodulator with clinical activity against myeloma cells. Based on the pivotal phase 3 trials MM-009 and MM010, the combination of lenalidomide and dexamethasone(DEX) was approved for patients with multiple myeloma who received at least one prior therapy. Here, we evaluated LEN/DEX therapy in unselected population and subsequently in selected sub-groups of patients with relapsed/refractory multiple myeloma followed in the Registry of Monoclonal Gammopathies of the Czech Myeloma Group. Altogether 858 patients were treated with LEN/DEX in the Czech Republic and Slovakia until end of 2017. The analyzed sub-groups were defined as patients with high risk cytogenetic aberrations and patients with relapsed and refractory MM. The overall response rate (ORR; partial remission or better response, PR) in the whole group of patients was 46.3% for all lines of therapy, 26.4% for high-risk group and 32.1% for relapsed and refractory group. Medians of overall survival (OS) in the same cohorts were as follows: 25.6, 15.7 and 18.5 months, progression free survival (PFS) was: 11.2, 6.4 and 9.0 months respectively. The most common adverse events were hematologic and infectious. In conclusion we found that our results correlated with those found in other studies in terms of response rates, survival measures, and also of treatment toxicity.


Assuntos
Dexametasona , Lenalidomida , Mieloma Múltiplo , Sistema de Registros , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , República Tcheca , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Humanos , Lenalidomida/efeitos adversos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Sistema de Registros/estatística & dados numéricos , Eslováquia , Análise de Sobrevida , Resultado do Tratamento
14.
Int J Hematol ; 109(6): 731-736, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30680670

RESUMO

A 67-year-old female was referred to our hospital with a sternal fracture in March 2008. She received a diagnosis of multiple myeloma (MM) BJP-κ type (ISS stage III). G-banding karyotype revealed 46, XX, t(11;22)(q23.3;q11.2) (Hubacek, Gene 592:193-9, 2016), which was later confirmed to be congenital. After repeated rounds of chemotherapy with bortezomib and lenalidomide, she obtained a very good partial response in August 2014, and she was followed up with no treatment. However, she relapsed in February 2016. At that time, fluorescence in situ hybridization identified del(13q) and t(4;14)(p16;q32), which are associated with a poor prognosis. Furthermore, PCR analysis showed that the chromosome 11 breakpoint was at the APOA5/APOA4 locus at 11q23.3, which is associated with malignancy, and that the chromosome 22 breakpoint was at the SEPT5 intron 1 locus, which also plays a role in leukemogenesis through formation of a fusion gene with MLL. Although she was treated with three further lines of therapy, she died from disease progression in August 2017. Synergism between t(11;22) and t(4;14) may have induced the double-refractory phenotype to proteasome inhibitor and lenalidomide, at least during the chemorefractory phase. We present a biological analysis of this case and a review of the literature.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Proteínas de Fusão Oncogênica/genética , Idoso , Bortezomib/uso terapêutico , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 4/genética , Progressão da Doença , Quimioterapia Combinada , Evolução Fatal , Feminino , Humanos , Lenalidomida/uso terapêutico
15.
Blood ; 133(10): 1096-1107, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30670446

RESUMO

The heterogeneous nature of myelodysplastic syndromes (MDS) demands a complex and personalized variety of therapeutic approaches. Among them, allogeneic hematopoietic stem cell transplantation remains the only potentially curative option and is accessible to only a small number of fit patients. For the majority of patients with MDS, treatment strategies are nonintensive and risk-adapted (by the revised version of the International Prognostic Scoring System), ranging from iron chelation and growth factors to lenalidomide and hypomethylating agents. These approaches are noncurative and aimed instead at improving cytopenias and quality of life and delaying disease progression. These limitations underpin the need for more translational research-based clinical trials in well-defined subgroups of patients with MDS. Indeed, much progress has been made over the past decade in understanding the complex molecular mechanisms underlying MDS. Unfortunately, this has not yet translated into approval of novel treatment options. There is a particularly urgent medical need in patients failing current first-line therapies, such as with erythropoiesis-stimulating or hypomethylating agents. Nevertheless, actual developments are expected to pave the way for exciting novel therapeutic opportunities. This review provides an overview of the current therapeutic landscape in MDS focusing on recent advances in clinical and translational research.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes Mielodisplásicas/terapia , Progressão da Doença , Eritropoese , Hematologia/métodos , Hematologia/normas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Quelantes de Ferro/uso terapêutico , Lenalidomida/uso terapêutico , Metilação , Prognóstico , Risco , Índice de Gravidade de Doença , Pesquisa Médica Translacional , Transplante Homólogo
16.
Expert Opin Pharmacother ; 20(5): 487-494, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30608891

RESUMO

INTRODUCTION: Although a variety of therapeutic schemes for Mantle Cell Lymphoma (MCL) have been attempted, the clinical outcome of patients continues to be unsatisfactory especially among patients with a very high-risk profile and in the relapsed/refractory setting. For this reason, recent clinical trials have explored novel approaches, either by the use of biological agents in chemotherapy-free schedules or by integrating them with chemoimmunotherapy regimens. Areas covered: The efficacy of lenalidomide monotherapy and combination therapy established in clinical studies mainly involving relapsed/refractory MCL is reviewed. The mechanism of action of lenalidomide is also discussed. Furthermore, the current position of lenalidomide in the MCL treatment algorithm is debated. Expert opinion: Lenalidomide demonstrated high efficacy and tolerability in several clinical trials as well as in retrospective real-world reports, even in patients who relapsed or were resistant to bortezomib and ibrutinib. In 2013, lenalidomide was approved by the Food and Drug Administration (FDA) for relapsed/refractory MCL after two prior therapies including at least one prior treatment with bortezomib. However, the potential synergistic anti-neoplastic effects of lenalidomide in combination with other biological agents, i.e. ibrutinib and venetoclax, especially in the management of p53-mutated cases, still remain an open issue.


Assuntos
Antineoplásicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Humanos , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Resultado do Tratamento
17.
Leukemia ; 33(3): 588-596, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692596

RESUMO

Three randomized controlled trials and a meta-analysis reported lenalidomide given after high-dose therapy and an autologous hemopoietic cell transplantation is associated with increase in progression-free survival (PFS) and survival in persons with plasma cell myeloma (PCM). Based on these data, posttransplant lenalidomide is considered by many a standard-of-care in this setting. However, decisions on the use of new therapies should consider not only results of such trials and meta-analyses but also other factors including quality-of-evidence, anticipated desired and undesired effects of the drug, costs and feasibility of the therapy option. In this review, we critically analyzed evidence on posttransplant lenalidomide in PCM, and we identified criteria which should be considered in designating posttransplant lenalidomide the standard-of-care. Using Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach we judged posttransplant lenalidomide improves PFS with high-quality evidence. However, we identified inconsistency and imprecision as limitations in the conclusions regarding a survival benefit rating the quality-of-evidence for a survival benefit moderate. We also highlighted inconsistency in claims of an increased risk of new cancers associated with posttransplant lenalidomide. We emphasize the need for a value-based reasoning which considers PFS and survival as well as health-related quality-of-life and costs. We conclude the decision to use posttransplant lenalidomide should be individualized based on pre- and posttransplant variables such as remission state, risk category and/or posttransplant measurable residual disease (MRD)-test results. Validity of these variables in estimating benefits and risks of posttransplant lenalidomide should be tested in randomized clinical trials.


Assuntos
Autoenxertos/efeitos dos fármacos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Intervalo Livre de Doença , Humanos , Metanálise como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante Autólogo/métodos
18.
Medicine (Baltimore) ; 98(1): e14011, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30608448

RESUMO

RATIONALE: The gene deletion (5)(q22q35) is reported in 10-20% of myelodysplastic syndrome (MDS) cases and is associated with response to lenalidomide and favorable prognosis. The authors report here a clinical case of MDS transformation to B-cell acute lymphocytic leukemia (B-ALL) with an associated accrual of an additional mutation following treatment with lenalidomide. PATIENT CONCERNS: A 69-year-old man presented with progressive anemia, normal white blood cell count, and thrombocytopenia consistent with MDS. He was administered lenalidomide for 27 months, then developed acute B-cell lymphocytic leukemia and acquired a previously unreported mutation in the gene enhancer of zeste homolog 2 (EZH2). DIAGNOSES: After 27 months of therapy with lenalidomide, a surveillance bone marrow aspiration (BMA) revealed 90% cellularity with persistent multilineage dysplasia and a population of blasts comprising 54% of all bone marrow elements by morphology, consistent with B-ALL, even though the patient was asymptomatic. Conventional karyotype showed no signs of del(5)(q22q35) MDS, however bone marrow next-generation sequencing (NGS) demonstrated the accrual of a nonsense mutation (c.211del pL71*) in exon 3 of EZH2. A confirmatory BMA yielded 70% blasts and clinical features indicative of B-ALL. INTERVENTIONS: Mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m × 4 doses) was administered for 21 days. OUTCOMES: A follow-up BMA was performed 2 months after mini-hyper-CVD therapy, showing dysplastic features with 25% ring sideroblasts, but no evidence of B-ALL. The patient is currently receiving monthly-low dose decitabine, ofatumumab, and dexamethasone, and is transfusion independent and asymptomatic after 7 cycles. LESSONS: The present study shows an extremely rare progression of del(5)(q22q35) MDS to B-ALL with accompanying NGS data and a newly described acquisition of an EZH2 frameshift mutation. This case highlights the importance of NGS as a diagnostic and surveillance tool for MDS.


Assuntos
Linfócitos B/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Síndromes Mielodisplásicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Idoso , Anemia/complicações , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Medula Óssea/patologia , Deleção Cromossômica , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Progressão da Doença , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Masculino , Mutação , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Trombocitopenia/complicações , Resultado do Tratamento
19.
Internist (Berl) ; 60(1): 23-33, 2019 01.
Artigo em Alemão | MEDLINE | ID: mdl-30552458

RESUMO

Within the last two decades the therapeutic options for newly diagnosed multiple myeloma have changed dramatically. The implementation of high-dose chemotherapy with melphalan and subsequent autologous blood stem cell transplantation initially led to prolonged survival in younger, fit patients. Furthermore, recent data suggest that patients with high-risk disease seem to benefit most from tandem transplantation approaches. Therefore, risk stratification at initiation of first-line treatment is of great importance. With the advent and integration of the so-called novel agents, such as thalidomide, lenalidomide and bortezomib into first-line treatment, both transplant eligible and ineligble patients gained new therapeutic perspectives. In Germany, the combination of bortezomib with cyclophosphamide and dexamethasone is currently considered the standard of care as induction regimen before high-dose treatment and transplantation; however, the combination of lenalidomide, bortezomib and dexamethasone is increasingly being used, but is still not yet approved in Germany. For patients where high-dose therapy and stem cell transplantation are not feasible, bortezomib and lenalidomide are available as backbone agents of various combination regimens. Recently, the anti-CD38 antibody daratumumab has been approved in combination with bortezomib, melphalan and prednisone as primary treatment for newly diagnosed patients. An allogeneic stem cell transplantation can be considered for younger patients without relevant comorbidities and with high-risk disease or early relapse after autologous blood stem cell transplantation but should only be performed within controlled clinical trials and in specialized centers.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/cirurgia , Transplante de Células-Tronco/métodos , Talidomida/uso terapêutico , Antineoplásicos/provisão & distribução , Alemanha , Humanos , Recidiva Local de Neoplasia , Transplante Autólogo/métodos , Transplante Homólogo/métodos
20.
Ann Dermatol Venereol ; 145 Suppl 7: VIIS47-VIIS55, 2018 Dec.
Artigo em Francês | MEDLINE | ID: mdl-30583757

RESUMO

The therapeutic revolution in the management of inflammatory dermatoses is under way. The therapeutic arsenal is expanding in the field of psoriasis, including biologics (TNF blockers, anti-IL12/IL23, anti-IL17, and anti-IL23 antibodies), new small molecules (tyrosine kinase inhibitor), and a new biologic for generalized pustular psoriasis (anti-IL36 receptor). New biologics will be soon available in the field of atopic dermatitis in addition to anti-IL4/IL13 antibodies. New targeted treatments of pruritus are also coming (biologics and small molecules). A first randomized placebo-controlled trial has confirmed the interest of JAK inhibitors in alopecia areata. These molecules seem to be also promising in dermatomyositis. Another therapeutic revolution will be technological with the development of new therapeutic agents: small interfering RNA. Recent clinical trials confirmed their efficacy in hereditary amyloidosis.


Assuntos
Dermatopatias/terapia , Anticorpos Monoclonais/uso terapêutico , Capecitabina/uso terapêutico , Ensaios Clínicos como Assunto , Fármacos Dermatológicos/uso terapêutico , Dermatologia/tendências , Receptores ErbB/antagonistas & inibidores , Humanos , Fatores Imunológicos/uso terapêutico , Interleucinas/antagonistas & inibidores , Lenalidomida/uso terapêutico , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptores de Interleucina/antagonistas & inibidores , Ácido Tranexâmico/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
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