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ABSTRACT: Metabolic tumor volume (MTV) assessed using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography, a measure of tumor burden, is a promising prognostic indicator in large B-cell lymphoma (LBCL). This exploratory analysis evaluated relationships between baseline MTV (categorized as low [median or less] vs high [greater than median]) and clinical outcomes in the phase 3 ZUMA-7 study (NCT03391466). Patients with LBCL relapsed within 12 months of or refractory to first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel (axi-cel; autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (2-3 cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem cell transplantation in patients who had a response). All P values are descriptive. Within high- and low-MTV subgroups, event-free survival (EFS) and progression-free survival (PFS) were superior with axi-cel vs standard care. EFS in patients with high MTV (vs low MTV) was numerically shorter with axi-cel and was significantly shorter with standard care. PFS was shorter in patients with high MTV vs low MTV in both the axi-cel and standard-care arms, and median MTV was lower in patients in ongoing response at data cutoff vs others. Median MTV was higher in patients treated with axi-cel who experienced grade ≥3 neurologic events or cytokine release syndrome (CRS) than in patients with grade 1/2 or no neurologic events or CRS, respectively. Baseline MTV less than or equal to median was associated with better clinical outcomes in patients receiving axi-cel or standard care for second-line LBCL. The trial was registered at www.clinicaltrials.gov as #NCT03391466.
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Produtos Biológicos , Linfoma Difuso de Grandes Células B , Padrão de Cuidado , Humanos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Produtos Biológicos/uso terapêutico , Produtos Biológicos/administração & dosagem , Idoso , Adulto , Carga Tumoral , Imunoterapia Adotiva/métodos , Resultado do Tratamento , Antígenos CD19/uso terapêuticoRESUMO
ABSTRACT: Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma associated with immunodeficiency, characterized by uncertain treatment approaches and an unfavorable prognosis. We conducted a multicenter, international, retrospective cohort study, aiming to characterize the clinical features, risk factors, and outcomes of patients with PBL. Data were collected from 22 institutions across 4 countries regarding patients diagnosed with PBL between 1 January 1999 and 31 December 2020. Survival risk factors were analyzed using both univariate and multivariate regression models. Overall survival (OS) was calculated using Kaplan-Meier statistics. First-line treatment regimens were stratified into standard- and higher-intensity regimens, and based on whether they incorporated a proteasome inhibitor (PI). A total of 281 patients (median age, 55 years) were included. Immunodeficiency of any kind was identified in 144 patients (51%), and 99 patients (35%) had HIV-positive results. The 5-year OS for the entire cohort was 36% (95% confidence interval, 30%-42%). In multivariate analysis, inferior OS was associated with Epstein-Barr virus-negative lymphoma, poor performance status, advanced stage, and bone marrow involvement. In an independent univariate analysis, the international prognostic index was associated with OS outcomes. Neither immunosuppression nor HIV infection, specifically, influenced OS. Among patients treated with curative intent (n = 234), the overall response rate was 72%. Neither the intensity of the treatment regimen nor the inclusion of PIs in first-line therapy was associated with OS. In this large retrospective study of patients with PBL, we identified novel risk factors for survival. PBL remains a challenging disease with poor long-term outcomes.
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Infecções por Vírus Epstein-Barr , Infecções por HIV , Linfoma Plasmablástico , Humanos , Pessoa de Meia-Idade , Linfoma Plasmablástico/patologia , Estudos Retrospectivos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , PrognósticoRESUMO
The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.
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Radiotherapy is routinely used for management of limited-stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69-gene panel in 117 limited-stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression-free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight.
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Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted.
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Aciltransferases , Linfoma de Células B , Dose Máxima Tolerável , Humanos , Pessoa de Meia-Idade , Feminino , Masculino , Idoso , Adulto , Administração Oral , Linfoma de Células B/tratamento farmacológico , Aciltransferases/antagonistas & inibidores , Antineoplásicos/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
BACKGROUND: Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies. METHODS: We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing. FINDINGS: Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred. INTERPRETATION: Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies. FUNDING: F Hoffmann-La Roche and Genentech.
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Anticorpos Biespecíficos , Antineoplásicos , Linfoma Folicular , Recidiva Local de Neoplasia , Anticorpos Biespecíficos/efeitos adversos , Antineoplásicos/efeitos adversos , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do TratamentoRESUMO
Pretransplant Deauville score (DS) is an imaging biomarker used for risk stratification in relapsed/refractory classical Hodgkin lymphoma (cHL). However, the prognostic value of residual metabolic tumor volume (rMTV) in patients with DS 4-5 has been less well characterized. We retrospectively assessed 106 patients with relapsed/refractory cHL who underwent autologous stem cell transplantation. Pretransplant DS was determined as 1-3 (59%) and 4-5 (41%), with a markedly inferior event-free survival (EFS) in patients with DS 4-5 (hazard ratio [HR], 3.14; p = .002). High rMTV41% (rMTVhigh , ≥4.4 cm3 ) predicted significantly poorer EFS in patients with DS 4-5 (HR, 3.70; p = .014). In a multivariable analysis, we identified two independent factors predicting treatment failure: pretransplant DS combined with rMTV41% and disease status (primary refractory vs. relapsed). These two factors allow to stratify patients into three groups with divergent 2-year EFS: 89% for low-risk (51%; relapsed disease and either pretransplant DS 1-3 or DS 4-5/rMTVlow ; HR 1), 65% for intermediate-risk (28%; refractory disease and either DS 1-3 or DS 4-5/rMTVlow ; HR 3.26), and 45% for high-risk (21%; DS 4-5/rMTVhigh irrespective of disease status; HR 7.61) groups. Pretransplant DS/rMTV41% combination and disease status predict the risk of post-transplant treatment failure and will guide risk-stratified approaches in relapsed/refractory cHL.
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Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/patologia , Humanos , Recidiva Local de Neoplasia , Estudos Retrospectivos , Medição de Risco , Transplante Autólogo , Carga TumoralRESUMO
Autologous stem cell transplantation (ASCT) remains a key therapeutic strategy for treating patients with relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Clonal hematopoiesis (CH) has been proposed as a major contributor not only to the development of therapy-related myeloid neoplasms but also to inferior overall survival (OS) in patients who had undergone ASCT. Herein, we aimed to investigate the prognostic implications of CH after ASCT in a cohort of 420 lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. CH was identified in the stem cell product samples of 181 patients (43.1%) and was most common in those with T-cell lymphoma (72.2%). The presence of CH was associated with a longer time to neutrophil and platelet recovery. Moreover, patients with evidence of CH had inferior 5-year OS from the time of first relapse (39.4% vs. 45.8%, p = .043) and from the time of ASCT (51.8% vs. 59.3%, p = .018). The adverse prognostic impact of CH was not due to therapy-related myeloid neoplasms, the incidence of which was low in our cohort (10-year cumulative incidence of 3.3% vs. 3.0% in those with and without CH, p = .445). In terms of specific-gene mutations, adverse OS was mostly associated with PPM1D mutations (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.13-2.67, p = .011). In summary, we found that CH is associated with an increased risk of non-lymphoma-related death after ASCT, which suggests that lymphoma survivors with CH may need intensified surveillance strategies to prevent and treat late complications.
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Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Linfoma , Segunda Neoplasia Primária , Humanos , Transplante Autólogo/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hematopoiese Clonal , Linfoma/terapia , Linfoma/complicações , Doença de Hodgkin/complicações , Segunda Neoplasia Primária/terapia , Segunda Neoplasia Primária/genética , Transplante de Células-Tronco/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. METHODS: In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. FINDINGS: Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4-33·0), median progression-free survival was 13·2 months (95% CI 10·9-19·4) for pembrolizumab versus 8·3 months (5·7-8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48-0·88]; p=0·0027). The most common grade 3-5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. INTERPRETATION: Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. FUNDING: Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA).
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Anticorpos Monoclonais Humanizados/administração & dosagem , Brentuximab Vedotin/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Brentuximab Vedotin/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/patologia , Humanos , Imunoconjugados/administração & dosagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto JovemRESUMO
Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel-related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.
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Corticosteroides/uso terapêutico , Produtos Biológicos/efeitos adversos , Síndrome da Liberação de Citocina/prevenção & controle , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Doenças do Sistema Nervoso/prevenção & controle , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/uso terapêutico , Biomarcadores , Ciclofosfamida/uso terapêutico , Síndrome da Liberação de Citocina/induzido quimicamente , Quimioterapia Combinada , Feminino , Humanos , Leucaférese , Levetiracetam/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamente , Neutropenia/induzido quimicamente , Pontuação de Propensão , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto JovemRESUMO
Aim: Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Functional Assessment of Cancer Therapy (FACT) - Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Results: Treatment responders maintained higher FACT - Lymphoma (p ≤ 0.05), FACT - General (p < 0.05) and EuroQoL five-dimensions five-levels index scores (p < 0.001) beginning in cycle 3. The estimated difference in health state utilities for treatment response and progressive disease was both statistically significant and clinically meaningful (mean difference: 0.07; p = 0.001). Conclusion: In patients with relapsed/refractory diffuse large B-cell lymphoma, objective response to selinexor was associated with HRQoL maintenance, reduction in disease-related HRQoL decrements and higher health utilities.
Lay abstract This work examined quality of life (QoL) among patients with relapsed/refractory diffuse large B-cell lymphoma with two to five prior therapies who received single-agent selinexor in the SADAL clinical trial. Analysis of patient-reported Functional Assessment of Cancer Therapy Lymphoma and EuroQoL five-dimensions five-levels data showed that patients who had objective clinical response to selinexor maintained their QoL over the course of treatment. Grade ≥3 adverse events and serious adverse events were not associated with clinically meaningful negative QoL impacts. Clinical trial registration: NCT02227251 (ClinicalTrials.gov).
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Hidrazinas/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Triazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , RecidivaRESUMO
Despite continuing improvements in the management of classical Hodgkin lymphoma (cHL), relapse remains associated with a risk of lymphoma-related mortality. The biological composition of relapse tumour biopsies shows interpatient variability, which can be leveraged to design prognostic biomarkers. Here, we validated the RHL30 assay, a previously reported gene expression model in an independent cohort of 41 patients with relapsed cHL. Patients classified as high-risk by the RHL30 assay had inferior failure-free survival (FFS) after autologous stem cell transplantation (2-year FFS 41% vs. 92%, P = 0·035). The RHL30 model is a robust biomarker that risk-stratifies patients considered for autologous stem cell transplantation.
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Biomarcadores Tumorais/biossíntese , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Adulto , Autoenxertos , Feminino , Doença de Hodgkin/metabolismo , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Post-transplant lymphoproliferative disorder (PTLD) may arise after solid organ transplantation, and the most common subtype resembles diffuse large B cell lymphoma (DLBCL). In DLBCL-type PTLD, the anti-CD20 antibody rituximab (R) may be combined with chemotherapy (R-CHOP) or use a strategy (R-primary; similar to the PTLD-1 clinical trial) consisting of induction with four weekly doses of R-alone, without any chemotherapy or sequential R-CHOP follow-up. Here we report on a multicentre retrospective cohort of solid organ transplant patients with DLBCL-type PTLD that were treated with R. In 168 adults, two-year overall survival (OS) was 63·7% [95% CI (confidence interval) 56·6-71·7%]. No difference in OS was observed, whether patients were treated with R-CHOP versus the R-primary strategy. In the 109 patients treated with R-primary, multivariate analysis found that baseline IPI score and the response to R-induction predicted OS. Patients who responded to R-induction had durable remissions without the addition of chemotherapy. Conversely, of the 46 patients who had stable or progressive disease after R-induction (R-failure), those who received R-CHOP had an only marginally improved outcome, with a two-year OS of 45% (23·1-65·3%) vs. no R-CHOP at 32% (14·7-49·8%). In real-world patients, R-failure and high IPI scores predict a poor outcome in DLBCL-type PTLD.
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Linfoma Difuso de Grandes Células B , Transplante de Órgãos/efeitos adversos , Complicações Pós-Operatórias , Rituximab , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Retrospectivos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Taxa de Sobrevida , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Most patients with follicular lymphoma (FL) experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of several B-cell malignancies, showed promising activity in FL in a phase 1 study. We report the results of a phase 2 trial evaluating ibrutinib in recurrent FL. Forty patients with recurrent FL were treated with ibrutinib 560 mg/d until progression or intolerance. The primary end point was overall response rate (ORR). Exploratory analyses included correlations of outcome with recurrent mutations identified in a cancer gene panel that used next-generation sequencing in pretreatment biopsies from 31 patients and results of early interim positron emission tomography/computed tomography scans in 20 patients. ORR was 37.5% with a complete response rate of 12.5%, median progression-free survival (PFS) of 14 months, and 2-year PFS of 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared with those who were rituximab refractory (16.7%) (P = .04). CARD11 mutations were present in 16% of patients (5 of 31) and predicted resistance to ibrutinib with only wild-type patients responding (P = .002). Maximum standardized uptake value at cycle 1 day 8 correlated with response and PFS. Ibrutinib was well-tolerated with a toxicity profile similar to labeled indications. Ibrutinib is a well-tolerated treatment with modest activity in relapsed FL. Evaluation of BTK inhibitors in earlier lines of therapy may be warranted on the basis of improved response rates in rituximab-sensitive disease. Somatic mutations such as CARD11 may have an impact on response to ibrutinib, may inform clinical decisions, and should be evaluated in larger data sets. This trial was registered at www.clinicaltrials.gov as #NCT01849263.
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Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Linfoma Folicular/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Proteínas Adaptadoras de Sinalização CARD/genética , Progressão da Doença , Feminino , Guanilato Ciclase/genética , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piperidinas , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Resultado do TratamentoRESUMO
Mantle cell lymphoma (MCL) is a B-cell malignancy, comprising between 3% and 10% of all adult-onset non-Hodgkin lymphomas. MCL is considered incurable with current treatment modalities and most patients require multiple lines of treatment during their lifetime. MCL is very sensitive to radiotherapy (RT), even when delivered in low doses. In limited-stage MCL, RT can enable the de-escalation of systemic therapy. RT monotherapy is a valid option for frail patients. In advanced-stage disease, RT is very potent mode of palliation, even in heavily pretreated and chemo-resistant patients. Furthermore, it can provide a respite during which systemic treatment is unnecessary. In general, RT has a favorable toxicity profile and can be repeated as necessary for local relapse or distant disease. This effective, safe, and relatively inexpensive modality of therapy has been underutilized for patients with MCL. In this review, we will outline the use of RT for limited and advanced-stage disease and its potential application in combination with novel drugs.
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Linfoma de Célula do Manto/radioterapia , Radioterapia/métodos , Humanos , Linfoma de Célula do Manto/patologia , PrognósticoRESUMO
Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myelogenous leukemia (AML); however, a major cause of treatment failure is disease relapse. The purpose of this single-center Phase I study was to determine the safety and tolerability of administration of the CXCR4 inhibitor plerixafor (Mozobil; Sanofi Genzyme) along with myeloablative conditioning in patients with AML undergoing allogeneic HCT. The rationale was that plerixafor may mobilize leukemic stem cells, making them more susceptible to the conditioning chemotherapy (registered at ClinicalTrials.gov; identifier NCT01141543). Three patients were enrolled into each of 4 sequential cohorts (12 patients total). Patients in the first cohort received 1 dose of plerixafor (240 µg/kg s.c.) before the first dose of fludarabine and busulfan, and subsequent cohorts received injections before 2, 3, and 4 days of conditioning chemotherapy. The median age at HCT was 49 years (range, 38 to 58 years). All patients engrafted following HCT, with an absolute neutrophil count ≥.5â¯×â¯109/L observed at a median of 14 days (range, 11 to 18 days). Adverse events possibly related to plerixafor were transient and not severe. Main adverse events following the injection were nausea and dizziness in 4 patients (33%) and fatigue in 4 patients (33%). Among the 12 patients, 2 patients (17%) relapsed post-HCT and 6 (50%) were alive at the last follow-up. The median follow-up of survivors was 67 months (range, 53 to 82 months). In conclusion, plerixafor administration is safe and well tolerated when included in a myeloablative conditioning regimen for allogeneic HCT for AML. Further study in a larger cohort is warranted for the investigation of the impact of plerixafor on post-allogeneic HCT outcomes.
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Fármacos Anti-HIV/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/cirurgia , Transplante Homólogo/métodos , Adulto , Fármacos Anti-HIV/farmacologia , Benzilaminas , Ciclamos , Feminino , Compostos Heterocíclicos/farmacologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Treatment options for relapsed/refractory primary mediastinal large B-cell lymphoma (rrPMBCL) are limited, and prognosis is generally poor (overall response rate [ORR] 0% to 25%; 2-year overall survival 15%). PMBCL frequently involves PD-1 ligand overexpression, potentially making PMBCL particularly susceptible to PD-1 blockade. We evaluated safety and antitumor activity of pembrolizumab, an anti-PD-1 antibody, in rrPMBCL as part of the KEYNOTE-013 multicohort phase 1b trial. At time of data cutoff, 18 patients (median age 30 years; median 3 prior lines of therapy) had been enrolled and treated, of whom 17 were included in the efficacy analyses. Eleven patients (61%) experienced drug-related adverse events (mostly grade 1-2); none discontinued treatment due to adverse events. ORR was 41% (7/17); 6 additional patients (35%) had stable disease. Of patients evaluable by imaging, 13 out of 16 (81%) had decreases in target lesions. With a median follow-up of 11.3 months, median duration of response was not reached. Two patients reached the maximum 2-year treatment duration and remain in remission. Median overall survival was not reached for treated patients overall; all responders were still alive at data cutoff. These results in heavily pretreated rrPMBCL patients demonstrate that PD-1 blockade with pembrolizumab has a manageable safety profile and promising antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01953692.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Esquema de Medicação , Feminino , Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/mortalidade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Segurança do Paciente , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter's transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m2 The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m2 (60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m2 is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892.
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Núcleo Celular/metabolismo , Hidrazinas/administração & dosagem , Hidrazinas/farmacocinética , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/metabolismo , Triazóis/administração & dosagem , Triazóis/farmacocinética , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Anemia/metabolismo , Anemia/patologia , Apoptose/efeitos dos fármacos , Núcleo Celular/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Hidrazinas/efeitos adversos , Hiponatremia/induzido quimicamente , Hiponatremia/metabolismo , Hiponatremia/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Neutropenia/induzido quimicamente , Neutropenia/metabolismo , Neutropenia/patologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Triazóis/efeitos adversosRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Although 5-year survival rates in the first-line setting range from 60% to 70%, up to 50% of patients become refractory to or relapse after treatment. Published analyses of large-scale outcome data from patients with refractory DLBCL are limited. SCHOLAR-1, an international, multicohort retrospective non-Hodgkin lymphoma research study, retrospectively evaluated outcomes in patients with refractory DLBCL which, for this study, was defined as progressive disease or stable disease as best response at any point during chemotherapy (>4 cycles of first-line or 2 cycles of later-line therapy) or relapsed at ≤12 months from autologous stem cell transplantation. SCHOLAR-1 pooled data from 2 phase 3 clinical trials (Lymphoma Academic Research Organization-CORAL and Canadian Cancer Trials Group LY.12) and 2 observational cohorts (MD Anderson Cancer Center and University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence). Response rates and overall survival were estimated from the time of initiation of salvage therapy for refractory disease. Among 861 patients, 636 were included on the basis of refractory disease inclusion criteria. For patients with refractory DLBCL, the objective response rate was 26% (complete response rate, 7%) to the next line of therapy, and the median overall survival was 6.3 months. Twenty percent of patients were alive at 2 years. Outcomes were consistently poor across patient subgroups and study cohorts. SCHOLAR-1 is the largest patient-level pooled retrospective analysis to characterize response rates and survival for a population of patients with refractory DLBCL.