T-cell lymphomas(TCLs)represent a group of lymphoid neoplasms characterized by an aggressive clinical course,even after an anthracycline-containing regimen.Novel agents for patients with relapsed/refractory TCL are ur...T-cell lymphomas(TCLs)represent a group of lymphoid neoplasms characterized by an aggressive clinical course,even after an anthracycline-containing regimen.Novel agents for patients with relapsed/refractory TCL are urgently needed.Lenalidomide is an oral drug with immunomodulatory,antiangiogenic and direct antineoplastic effects.These peculiar mechanisms of action make TCL an attractive target for lenalidomide.We have identified five clinical trials in which lenalidomide monotherapy was investigated to treat TCL,including cutaneous TCL(CTCL)and adult T-cell lymphoma/leukemia(ATLL).In the ATLL-002 study,the overall response rate(ORR)was 42%and median progression-free survival(PFS)and overall survival were 3.8 mo and 20.3 mo,respectively.In a phase II trial for CTCL,ORR was 28%and median PFS and overall survival were 8 mo and 43 mo,respectively.For nodal peripheral TCL,ORR was between 10%and 43%in three clinical trials,with a median PFS of about 4 mo,even if some patients had a durable response.Overall toxicity is manageable and grade 3-4 events are mainly hematological and reversible.Combination strategies did not improve PFS.In conclusion,lenalidomide could represent a suitable treatment option for relapsed/refractory TCL,especially for neoplasms with a T-follicular helper origin,such as angioimmunoblastic TCL.展开更多
Novel drug availability has increased the depth of response and revolutionised the outcomes of multiple myeloma patients.Minimal residual disease evaluation is a surrogate for progression-free survival and overall sur...Novel drug availability has increased the depth of response and revolutionised the outcomes of multiple myeloma patients.Minimal residual disease evaluation is a surrogate for progression-free survival and overall survival and has become widely used not-only in clinical trials but also in daily patient management.Bone marrow aspiration is the gold standard for response evaluation,but due to the patchy nature of myeloma,false negatives are possible.Liquid biopsy and blood-based minimal residual disease evaluation consider circulating plasma cells,mass spectrometry or circulating tumour DNA.This approach is less invasive,can provide a more comprehensive picture of the disease and could become the future of response evaluation in multiple myeloma patients.展开更多
Great progress has been made in improving survival in multiple myeloma(MM)patients over the last 30 years.New drugs have been introduced and complete responses are frequently seen.However,the majority of MM patients d...Great progress has been made in improving survival in multiple myeloma(MM)patients over the last 30 years.New drugs have been introduced and complete responses are frequently seen.However,the majority of MM patients do experience a relapse at a variable time after treatment,and ultimately the disease becomes drug-resistant following therapies.Recently,minimal residual disease(MRD)detection has been introduced in clinical trials utilizing novel therapeutic agents to measure the depth of response.MRD can be considered as a surrogate for both progression-free and overall survival.In this perspective,the persistence of a residual therapy-resistant myeloma plasma cell clone can be associated with inferior survivals.The present review gives an overview of drug resistance in MM,i.e.,mutation ofβ5 subunit of the proteasome;upregulation of pumps of efflux;heat shock protein induction for proteasome inhibitors;downregulation of CRBN expression;deregulation of IRF4 expression;mutation of CRBN,IKZF1,and IKZF3 for immunomodulatory drugs and decreased target expression;complement protein increase;sBCMA increase;and BCMA down expression for monoclonal antibodies.Multicolor flow cytometry,or next-generation flow,and next-generation sequencing are currently the techniques available to measure MRD with sensitivity at 10-5.Sustained MRD negativity is related to prolonged survival,and it is evaluated in all recent clinical trials as a surrogate of drug efficacy.展开更多
Recent advances in multiple myeloma therapy have increased the depth of response and ultimately survivals;however,the prognosis remains poor.The BCMA antigen is highly expressed in myeloma cells,thus representing a ta...Recent advances in multiple myeloma therapy have increased the depth of response and ultimately survivals;however,the prognosis remains poor.The BCMA antigen is highly expressed in myeloma cells,thus representing a target for novel therapies.Several agents that target BCMA through different mechanisms,including bispecific T cell engagers drug conjugated to antibody and CAR-T cells,are now available or under development.Immunotherapies targeting BCMA have shown good results in efficacy and safety in multiple myeloma patients previously treated with several lines of therapy.This review will discuss the recent development of anti-BCMA targeted treatments in myeloma,with a special focus on currently available agents.展开更多
Aim:Diffuse large B-cell lymphoma(DLBCL)is the most common B-cell non-Hodgkin lymphoma(NHL).Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis,in up to 30%-40%of pati...Aim:Diffuse large B-cell lymphoma(DLBCL)is the most common B-cell non-Hodgkin lymphoma(NHL).Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis,in up to 30%-40%of patients,intrinsic or acquired drug resistance occurs.Constitutional genetics may help to predict R-CHOP resistance.This study aimed to validate previously identified single nucleotide polymorphisms(SNPs)in the literature as potential predictors of R-CHOP resistance in DLBCL patients,SNPs.Methods:Twenty SNPs,involved in R-CHOP pharmacokinetics/pharmacodynamics or other pathobiological processes,were investigated in 185 stage Ⅰ-Ⅳ DLBCL patients included in a multi-institution pharmacogenetic study to validate their previously identified correlations with resistance to R-CHOP.Results:Correlations between rs2010963(VEGFA gene)and sex(P=0.046),and rs1625895(TP53 gene)and stage(P=0.003)were shown.After multivariate analyses,a concordant effect(i.e.,increased risk of disease progression and death)was observed for rs1883112(NCF4 gene)and rs1800871(IL10 gene).When patients were grouped according to the revised International Prognostic Index(R-IPI),both these SNPs further discriminated progression-free survival(PFS)and overall survival(OS)of the R-IPI-1-2 subgroup.Overall,patients harboring the rare allele showed shorter PFS and OS compared with wild-type patients.Conclusions:Two out of the 20 study SNPs were validated.Thus,these results support the role of previously identified rs1883112 and rs1800871 in predicting DLBCL resistance to R-CHOP and highlight their ability to further discriminate the prognosis of R-IPI-1-2 patients.These data point to the need to also focus on host genetics for a more comprehensive assessment of DLBCL patient outcomes in future prospective trials.展开更多
文摘T-cell lymphomas(TCLs)represent a group of lymphoid neoplasms characterized by an aggressive clinical course,even after an anthracycline-containing regimen.Novel agents for patients with relapsed/refractory TCL are urgently needed.Lenalidomide is an oral drug with immunomodulatory,antiangiogenic and direct antineoplastic effects.These peculiar mechanisms of action make TCL an attractive target for lenalidomide.We have identified five clinical trials in which lenalidomide monotherapy was investigated to treat TCL,including cutaneous TCL(CTCL)and adult T-cell lymphoma/leukemia(ATLL).In the ATLL-002 study,the overall response rate(ORR)was 42%and median progression-free survival(PFS)and overall survival were 3.8 mo and 20.3 mo,respectively.In a phase II trial for CTCL,ORR was 28%and median PFS and overall survival were 8 mo and 43 mo,respectively.For nodal peripheral TCL,ORR was between 10%and 43%in three clinical trials,with a median PFS of about 4 mo,even if some patients had a durable response.Overall toxicity is manageable and grade 3-4 events are mainly hematological and reversible.Combination strategies did not improve PFS.In conclusion,lenalidomide could represent a suitable treatment option for relapsed/refractory TCL,especially for neoplasms with a T-follicular helper origin,such as angioimmunoblastic TCL.
文摘Novel drug availability has increased the depth of response and revolutionised the outcomes of multiple myeloma patients.Minimal residual disease evaluation is a surrogate for progression-free survival and overall survival and has become widely used not-only in clinical trials but also in daily patient management.Bone marrow aspiration is the gold standard for response evaluation,but due to the patchy nature of myeloma,false negatives are possible.Liquid biopsy and blood-based minimal residual disease evaluation consider circulating plasma cells,mass spectrometry or circulating tumour DNA.This approach is less invasive,can provide a more comprehensive picture of the disease and could become the future of response evaluation in multiple myeloma patients.
文摘Great progress has been made in improving survival in multiple myeloma(MM)patients over the last 30 years.New drugs have been introduced and complete responses are frequently seen.However,the majority of MM patients do experience a relapse at a variable time after treatment,and ultimately the disease becomes drug-resistant following therapies.Recently,minimal residual disease(MRD)detection has been introduced in clinical trials utilizing novel therapeutic agents to measure the depth of response.MRD can be considered as a surrogate for both progression-free and overall survival.In this perspective,the persistence of a residual therapy-resistant myeloma plasma cell clone can be associated with inferior survivals.The present review gives an overview of drug resistance in MM,i.e.,mutation ofβ5 subunit of the proteasome;upregulation of pumps of efflux;heat shock protein induction for proteasome inhibitors;downregulation of CRBN expression;deregulation of IRF4 expression;mutation of CRBN,IKZF1,and IKZF3 for immunomodulatory drugs and decreased target expression;complement protein increase;sBCMA increase;and BCMA down expression for monoclonal antibodies.Multicolor flow cytometry,or next-generation flow,and next-generation sequencing are currently the techniques available to measure MRD with sensitivity at 10-5.Sustained MRD negativity is related to prolonged survival,and it is evaluated in all recent clinical trials as a surrogate of drug efficacy.
文摘Recent advances in multiple myeloma therapy have increased the depth of response and ultimately survivals;however,the prognosis remains poor.The BCMA antigen is highly expressed in myeloma cells,thus representing a target for novel therapies.Several agents that target BCMA through different mechanisms,including bispecific T cell engagers drug conjugated to antibody and CAR-T cells,are now available or under development.Immunotherapies targeting BCMA have shown good results in efficacy and safety in multiple myeloma patients previously treated with several lines of therapy.This review will discuss the recent development of anti-BCMA targeted treatments in myeloma,with a special focus on currently available agents.
基金funded by the Associazione Giacomo Onlus 2012-2020(Castiglioncello,Italy)(to Mini E)Fondazione Cassa di Risparmio di Firenze-ref.no.2013.0842 and ref.no.2014.0969(Firenze,Italy)(to Nobili S).
文摘Aim:Diffuse large B-cell lymphoma(DLBCL)is the most common B-cell non-Hodgkin lymphoma(NHL).Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis,in up to 30%-40%of patients,intrinsic or acquired drug resistance occurs.Constitutional genetics may help to predict R-CHOP resistance.This study aimed to validate previously identified single nucleotide polymorphisms(SNPs)in the literature as potential predictors of R-CHOP resistance in DLBCL patients,SNPs.Methods:Twenty SNPs,involved in R-CHOP pharmacokinetics/pharmacodynamics or other pathobiological processes,were investigated in 185 stage Ⅰ-Ⅳ DLBCL patients included in a multi-institution pharmacogenetic study to validate their previously identified correlations with resistance to R-CHOP.Results:Correlations between rs2010963(VEGFA gene)and sex(P=0.046),and rs1625895(TP53 gene)and stage(P=0.003)were shown.After multivariate analyses,a concordant effect(i.e.,increased risk of disease progression and death)was observed for rs1883112(NCF4 gene)and rs1800871(IL10 gene).When patients were grouped according to the revised International Prognostic Index(R-IPI),both these SNPs further discriminated progression-free survival(PFS)and overall survival(OS)of the R-IPI-1-2 subgroup.Overall,patients harboring the rare allele showed shorter PFS and OS compared with wild-type patients.Conclusions:Two out of the 20 study SNPs were validated.Thus,these results support the role of previously identified rs1883112 and rs1800871 in predicting DLBCL resistance to R-CHOP and highlight their ability to further discriminate the prognosis of R-IPI-1-2 patients.These data point to the need to also focus on host genetics for a more comprehensive assessment of DLBCL patient outcomes in future prospective trials.
