RESUMO
Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized by a T follicular helper cell phenotype expressing PD-1 (programmed cell death-1). AITL exhibits a poor response to conventional chemotherapy, with a median 5-year overall survival of 44% and a progression-free survival of 32%. Relapse is common, resulting in a median overall survival of 6 months. Recurrent mutations are detected in genes regulating DNA methylation, including TET2, DNMT3A, and IDH2 variants, along with the prevalent RHOA G17V mutation. In this context, patients treated with the hypomethylating agent 5-azacytidine achieved overall response and complete response rates of 75% and 41%, respectively. We hypothesized that targeted therapies combining anti-PD-1 checkpoint blockers with hypomethylating agents could be efficient in AITL patients and less toxic than standard chemotherapy. Methods: Here, we report the efficacy of a regimen combining 5-azacytidine and nivolumab in nine relapsed or refractory AITL patients. Results: This regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses (44%) and three complete responses (33%). Allogeneic hematopoietic stem cell transplantation was performed in two patients who reached complete response. Discussion: These preliminary favorable results may serve as a basis for further investigation in prospective studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Nivolumabe , Humanos , Nivolumabe/uso terapêutico , Azacitidina/uso terapêutico , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/mortalidade , Resultado do Tratamento , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversosRESUMO
Patients with high-risk lymphoma have a poor prognosis when treated with standard chemoimmunotherapy. This retrospective study included 23 high-risk lymphoma patients with a median age at diagnosis of 59 (range, 35-68) years. They received 2 cycles of R-COPADM and 2 cycles of CYVE, completed by ASCT for fit patients. With a median follow-up of 46 (range, 3-78) months, three (13%) patients in the cohort died. Nearly half of the patients had an ECOG performance status of 2 or 3. Most patients in the cohort (91%, n = 21) had Ann Arbor stage III-IV disease, and 88% (n = 20) had an IPI of 3 to 5. LDH levels were elevated in 83% (n = 19) of patients. Overall, 30% of patients were identified as having double-expressor lymphoma and 22% as having DHL, while two patients (9%) had THL. The origin of the lymphoma was GC B-cell-like in 15 patients (65%) and ABC-like in 8 patients (35%). Cumulative incidence of relapse at 46 months was 14% (95% CI, 5-37), while overall survival was 87% (95% CI, 64-95) and progression-free survival was 83% (95% CI, 60-93). These results showed the efficacy and an acceptable safety profile of the R-COPADM/CYVE/ASCT regimen in high-risk lymphoma, including patients with DHL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células B , Linfoma , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Seguimentos , Estudos Retrospectivos , Intervalo Livre de Doença , Recidiva Local de Neoplasia , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Células B/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante AutólogoRESUMO
In multiple myeloma, atypical forms with extramedullary involvement exhibit poor survival. The poly-chemotherapeutic regimen D(T)-PACE has shown high activity in relapsed or refractory multiple myeloma. In this large monocentric retrospective study, we addressed the activity of D(T)-PACE-based regimens in 43 heavily pretreated patients with relapsed/refractory multiple myeloma and extramedullary disease.Median age at initiation was 57 years. Four patients had a t(4;14) translocation, 3 had a t(11;14) translocation and 7 had a del(17p). Extramedullary sites were mostly the skin (15 patients), central nervous system (10 patients), and thorax or abdomen (10 patients each). Overall response was achieved in 25 (58%) patients, including 6 (14%) with a complete response. Median progression-free survival was 5.0 months. Median overall survival was 9.0 months. Fourteen patients subsequently underwent stem-cell transplantation. Cytogenetics had no impact on response rate, overall survival and progression-free survival.In the era of several new immunotherapies, D(T)-PACE-based regimens still remain a useful treatment option for a selected group of heavily pretreated myeloma patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Recidiva Local de Neoplasia , Estudos RetrospectivosAssuntos
Adenina/análogos & derivados , COVID-19/epidemiologia , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/epidemiologia , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , SARS-CoV-2 , Adenina/efeitos adversos , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Comorbidade , Humanos , MasculinoAssuntos
Púrpura Trombocitopênica Idiopática , Púrpura Trombocitopênica Trombótica , Rituximab/administração & dosagem , Adulto , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/prevenção & controle , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/prevenção & controleRESUMO
OBJECTIVES: Relapsed/refractory peripheral T-cell lymphomas (PTCL) have a poor prognosis. We aimed at assessing efficacy of ifosfamide, carboplatin, etoposide (ICE) regimen, a known therapeutic option, to which we added brentuximab-vedotin (BV). METHODS: In this study, we retrospectively analyzed patients with PTCL treated with BV-ICE in our center between July 2014 and March 2018. RESULTS: Fourteen patients received BV-ICE. Median age was 62 years (range, 31-73). Main histological subtypes were PTCL-not otherwise specified (29%), angioimmunoblastic T-cell lymphoma (21%), follicular-T helper (21%), or anaplastic large-cell (15%) lymphomas, all were CD30 positive. Overall response was seen in four (29%) patients, and complete response (CR) in two (14%). Most frequent adverse events were infections, and cytopenia. 2-year progression-free and overall survival were 14% and 17.5%, respectively. CONCLUSION: Patients with relapsed/refractory PTCL treated with BV-ICE can achieve CR, but few had a sustained response. This association should preferably be used as a bridge to stem cell transplant or be followed by maintenance therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin/administração & dosagem , Carboplatina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/mortalidade , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Prognóstico , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: More than one-third of patients with acute myeloid leukemia (AML) will relapse after allogenic hematopoietic cell transplant (allo-HCT). The main challenge is to overcome disease resistance to achieve a new complete remission while avoiding excessive toxicity. Gemtuzumab ozogamicin (GO), a conjugate of calicheamicin linked to the humanized monoclonal anti-CD33 antibody, has been used for refractory or relapsed AML with promising response rates, but liver toxicity of GO has long been considered a limiting factor. PATIENTS AND METHODS: We included 18 consecutive patients with AML relapsing after a first allo-HCT and treated with fractioned GO (fGO) and intensive chemotherapy. The median age was 40 years (range, 18-65). RESULTS: The overall response rate was 72% (13/18), including 7 complete remissions. No death was attributed to treatment toxicity. The main liver toxicity was transient and consisted of transaminase level elevation and hyperbilirubinemia. No cases of veno-occlusive disease were observed after the GO treatment. From the time of salvage treatment initiation, 1- and 2-year OS rates were 54% (95% confidence interval, 28%-74%) and 42% (95% confidence interval, 19%-63%), respectively. CONCLUSIONS: Our study suggests the feasibility, efficacy, and safety of an fGO-based salvage regimen combined with intensive chemotherapy in patients with CD33+ AML in the case of early relapse after an allo-HCT.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gemtuzumab/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Transplante Homólogo/métodos , Adolescente , Adulto , Idoso , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Gemtuzumab/farmacologia , Humanos , Pessoa de Meia-Idade , Recidiva , Adulto JovemAssuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Doenças Hematológicas/complicações , Transtornos Linfoproliferativos/complicações , Pandemias , Pneumonia Viral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/isolamento & purificação , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Infecções por Coronavirus/transmissão , Infecção Hospitalar/etiologia , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Síndromes Mielodisplásicas/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Pneumonia Viral/transmissão , Respiração Artificial , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , SARS-CoV-2 , Resultado do TratamentoRESUMO
Varicella zoster virus (VZV) primo-infection can be severe in the elderly and in immunocompromised patients. Atypical presentations are not uncommon and may mislead the diagnosis and delay adequate treatment. Valacyclovir prophylaxis should be systematically proposed in immunocompromised patients.
RESUMO
Lymphoblastic lymphoma (LBL) is a rare disease associated with favourable prognosis in childhood but with poor prognosis in adults when treated with conventional non-Hodgkin lymphoma regimens. Improvements in long-term outcome have been made since the use of acute lymphoblastic leukaemia (ALL) regimens. We report here the feasibility of a double-delayed intensification paediatric protocol in 12 adult LBL patients. There were no relapses and no deaths, with a median follow-up of 4.7 years. Using the same protocol, overall survival was significantly longer in LBL patients versus ALL patients (100% vs 75%, p = 0.05). Overall tolerance was acceptable and better in ALL patients. We have shown the feasibility and the good results of using this paediatric protocol in LBL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adulto , Idoso , Criança , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: A major issue in the treatment of acute myeloid leukemia is resistance to chemotherapeutic drugs. An increasing number of ATP-Binding-Cassette transporters have been demonstrated to cause resistance to cancer drugs. The aim of this study was to highlight the putative role of other ATP-Binding-Cassette transporters in primary chemoresistant acute myeloid leukemia. DESIGN AND METHODS: In the first part of this study, using taqman custom arrays, we analyzed the relative expression levels of 49 ATP-Binding-Cassette genes in 51 patients divided into two extreme cohorts, one very sensitive and one very resistant to chemotherapy. In the second part of this study, we evaluated the prognostic impact, in a cohort of 281 patients, of ATP-Binding-Cassette genes selected in the first part of the study. RESULTS: In the first part of the study, six genes (ATP-Binding-CassetteA2, ATP-Binding-CassetteB1, ATP-Binding-CassetteB6, ATP-Binding-CassettC13, ATP-Binding-CassetteG1, and ATP-Binding-CassetteG2) were significantly over-expressed in the resistant group compared with the sensitive group. In the second cohort, overexpression of 5 of these 6 ATP-Binding-Cassette genes was correlated with outcome in univariate analysis, and only the well-known ATP-Binding-CassetteB1 and G2, and the new ATP-Binding-CassetteG1 in multivariate analysis. Prognosis decreased remarkably with the number of these over-expressed ABC genes. Complete remission was achieved in 71%, 59%, 54%, and 0%, (P=0.0011) and resistance disease in 21%, 37%, 43%, and 100% (P<0.0001) of patients over-expressing 0, 1, 2, or 3, ABC genes, respectively. The number of ATP-Binding-Cassette genes expressed, among ATP-Binding-CassetteB1, G1, and G2, was the strongest prognostic factor correlated, in multivariate analysis, with achievement of complete remission (P=0.01), resistant disease (P=0.01), and overall survival (P=0.02). CONCLUSIONS: Using expression profiling, we have emphasized the diversity of ATP-Binding-Cassette transporters that cooperate to promote chemoresistance rather than overexpression of single transporters and the putative role of new ATP-Binding-Cassette tranporters, such as ATP-Binding-CassetteG1. Modulation of these multiple transporters might be required to eradicate leukemic cells.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Adulto JovemRESUMO
Adolescents ALL have a better outcome when treated with pediatric protocol compared to adult protocol. We have tested the feasibility of pediatric protocol to treat 40 consecutive adults ALL. DFS and OS were 73±7%, and 72±7%, and were significantly longer in patients under 40 yo (81±9% vs 51±15%, p=0.05 [DFS] and 83±7.8% vs 45±15%, p=0.003 [OS], respectively) or cortico/chemo-sensitive (86±9% vs 36±16%, p=0.001 [DFS] and 95±4.4% vs 28±13%, p<0.0001 [OS]) than in other patients. Overall tolerance was acceptable. We have shown the feasibility of using this unmodified pediatric protocol to treat adult with ALL up to 40 years.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Adulto JovemRESUMO
Immune reconstitution was analyzed in 140 consecutive patients who were 2-year disease-free and who underwent myeloablative allogeneic transplantation. A CD4 and CD8 defect was observed involving naive, terminally differentiated, memory and competent cells and above limits values for activated subsets. Natural killer cells normalize at six months while we observed expansion of CD19(+)/CD5(+) B cells after three months and a persisting defect of memory B cells. Chronic graft-versus-host disease did not influence significantly those parameters for CD8 subsets while the naïve and competent CD4 subsets were strongly affected. But the most profound impact of chronic graft-versus-host disease was on B-cell subsets, especially on the memory B population. The cumulative incidence of late severe infections was low (14% at four years). Using Cox's models, only low B-cell counts at 12 (P=0.02) and 24 (P=0.001) months were associated with the hazard of developing late infection, in particular if patients did not develop chronic graft-versus-host disease.
Assuntos
Linfócitos B/imunologia , Infecções por Citomegalovirus/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Síndromes de Imunodeficiência/imunologia , Adulto , Linfócitos B/patologia , Linfócitos B/virologia , Criança , Doença Crônica , Infecções por Citomegalovirus/patologia , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/virologia , Humanos , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/virologia , Masculino , Estudos Prospectivos , Fatores de Tempo , Transplante HomólogoRESUMO
BACKGROUND: AVE9633 is a new immunoconjugate comprising a humanized monoclonal antibody, anti-CD33 antigen, linked through a disulfide bond to the maytansine derivative DM4, a cytotoxic agent and potent tubulin inhibitor. It is undergoing a phase I clinical trial. Chemoresistance to anti-mitotic agents has been shown to be related, in part, to overexpression of ABC proteins. The aim of the present study was to investigate the potential roles of P-gp, MRP1 and BCRP in cytotoxicity in AVE9633-induced acute myeloid leukaemia (AML). METHODS: This study used AML cell lines expressing different levels of P-gp, MRP1 or BCRP proteins and twenty-five samples from AML patients. Expression and functionality of the transporter protein were analyzed by flow cytometry. The cytotoxicity of the drug was evaluated by MTT and apoptosis assays. RESULTS: P-gp activity, but not MRP1 and BCRP, attenuated AVE9633 and DM4 cytotoxicity in myeloid cell lines. Zosuquidar, a potent specific P-gp inhibitor, restored the sensitivity of cells expressing P-gp to both AVE9633 and DM4. However, the data from AML patients show that 10/25 samples of AML cells (40%) were resistant to AVE9633 or DM4 (IC(50) > 500 nM), and this was not related to P-gp activity (p-Value: 0.7). Zosuquidar also failed to re-establish drug sensitivity. Furthermore, this resistance was not correlated with CD33 expression (p-Value: 0.6) in those cells. CONCLUSION: P-gp activity is not a crucial mechanism of chemoresistance to AVE9633. For patients whose resistance to conventional anthracycline AML regimens is related to ABC protein expression, a combination with AVE9633 could be beneficial. Other mechanisms such as microtubule alteration could play an important role in chemoresistance to AVE9633.