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The immunosuppressive treatment of immune-mediated thrombotic thrombocytopenic purpura (iTTP) in patients with intolerance or refractoriness to the B-cell depleting monoclonal antibody rituximab remains debated. Daratumumab, a plasma cell-directed monoclonal antibody targeting CD38, represents a therapeutic option, but data are scarce. The French Thrombotic Microangiopathies Reference Center conducted a nationwide survey on iTTP patients treated with daratumumab. Nine episodes from seven patients were identified. Treatment was administered for A Disintegrin And Metalloproteinase with ThromboSpondin-1 motifs, 13th member (ADAMTS13) relapses while patients were otherwise in clinical response (N = 8), or during the acute phase of the disease following rituximab intolerance (N = 1). Patients have received a median of three previous therapeutic lines. ADAMTS13 activity improved in eight cases following daratumumab administration, including three cases where ADAMTS13 normalized. ADAMTS13 relapses occurred in three patients; in two cases, retreatment with daratumumab was successful. Median ADAMTS13 relapse-free survival was not reached; 12-month ADAMTS13 relapse-free survival was 56%. Daratumumab-related adverse events occurred in five cases and were non-severe infusion-related reactions in all cases. These results suggest that daratumumab may be an effective treatment option for iTTP patients with intolerance or refractoriness to rituximab.
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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.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células T Periférico/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brentuximab Vedotina/administración & dosificación , Carboplatino/administración & dosificación , Resistencia a Antineoplásicos , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/mortalidad , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Pronóstico , Recurrencia , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Púrpura Trombocitopénica Idiopática , Púrpura Trombocitopénica Trombótica , Rituximab/administración & dosificación , Adulto , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/prevención & control , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/prevención & controlRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Nivolumab , Humanos , Nivolumab/uso terapéutico , Azacitidina/uso terapéutico , Femenino , Masculino , Anciano , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/mortalidad , Resultado del Tratamiento , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversosRESUMEN
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.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B , Linfoma , Humanos , Adulto , Persona de Mediana Edad , Anciano , Estudios de Seguimiento , Estudios Retrospectivos , Supervivencia sin Enfermedad , Recurrencia Local de Neoplasia , Trasplante de Células Madre Hematopoyéticas/métodos , Linfoma de Células B/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante AutólogoRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Adulto , Anciano , Niño , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estadificación de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pronóstico , Inducción de Remisión , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
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.
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Transportadoras de Casetes de Unión a ATP/genética , Resistencia a Antineoplásicos/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis por Conglomerados , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Pronóstico , Adulto JovenRESUMEN
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.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Recurrencia Local de Neoplasia , Estudios RetrospectivosRESUMEN
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.
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Linfocitos B/inmunología , Infecciones por Citomegalovirus/inmunología , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Síndromes de Inmunodeficiencia/inmunología , Adulto , Linfocitos B/patología , Linfocitos B/virología , Niño , Enfermedad Crónica , Infecciones por Citomegalovirus/patología , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/patología , Enfermedad Injerto contra Huésped/virología , Humanos , Síndromes de Inmunodeficiencia/patología , Síndromes de Inmunodeficiencia/virología , Masculino , Estudios Prospectivos , Factores de Tiempo , Trasplante HomólogoRESUMEN
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.
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Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gemtuzumab/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Trasplante Homólogo/métodos , Adolescente , Adulto , Anciano , Antineoplásicos Inmunológicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Gemtuzumab/farmacología , Humanos , Persona de Mediana Edad , Recurrencia , Adulto JovenRESUMEN
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.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Inmunoconjugados/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Maitansina/análogos & derivados , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/metabolismo , Anticuerpos Monoclonales/farmacología , Antígenos CD/biosíntesis , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Antígenos de Diferenciación Mielomonocítica/inmunología , Dibenzocicloheptenos/farmacología , Resistencia a Antineoplásicos , Células HL-60 , Humanos , Inmunoconjugados/farmacocinética , Células K562 , Maitansina/farmacocinética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Quinolinas/farmacología , Lectina 3 Similar a Ig de Unión al Ácido SiálicoRESUMEN
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.
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Adenina/análogos & derivados , COVID-19/epidemiología , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/epidemiología , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , SARS-CoV-2 , Adenina/efectos adversos , Adenina/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Anciano , Comorbilidad , Humanos , MasculinoAsunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Enfermedades Hematológicas/complicaciones , Trastornos Linfoproliferativos/complicaciones , Pandemias , Neumonía Viral/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus/aislamiento & purificación , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/transmisión , Infección Hospitalaria/etiología , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Síndromes Mielodisplásicos/complicaciones , Neumonía Viral/diagnóstico , Neumonía Viral/terapia , Neumonía Viral/transmisión , Respiración Artificial , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/terapia , SARS-CoV-2 , Resultado del TratamientoRESUMEN
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.