RESUMEN
Reinduction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second-line standard of care for transplant-eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high-dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant-eligible patients aged 18-60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase-I-part) was administered on day 0-13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end-point of computed tomography (CT)-based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT-based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end-point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Citarabina/administración & dosificación , Dexametasona/administración & dosificación , Resistencia a Antineoplásicos , Everolimus/administración & dosificación , Femenino , Alemania , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/etiología , Enfermedad de Hodgkin/mortalidad , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Pronóstico , Recurrencia , Inducción de Remisión , Retratamiento , Adulto JovenRESUMEN
High programmed cell death 1 ligand 1 (PD-L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin- and Reed-Sternberg cells (HRSC) have been shown to be associated with favourable response to anti-PD-1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD-L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti-PD-1-based first-line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced-stage or r/r cHL. All but two cases (97%) showed PD-L1 expression by the tumour cells in variable amounts. While MHC-I was rarely expressed in >50% of HRSC, MHC-II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD-L1 and MHC-I/II expression on early response to the highly effective anti-PD-1-based NIVAHL first-line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti-PD-1 first-line cHL treatment.
Asunto(s)
Antígeno B7-H1/genética , Cromosomas Humanos Par 9 , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/etiología , Translocación Genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Terapia Combinada , Variaciones en el Número de Copia de ADN , Manejo de la Enfermedad , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Alemania , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/terapia , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Pronóstico , Resultado del TratamientoRESUMEN
Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to antibodies targeting programmed cell death protein 1 (PD1) and is characterized by scarce Hodgkin and Reed-Sternberg cells (HRSCs), perpetuating a unique tumor microenvironment (TME). Although anti-PD1 effects appear to be largely mediated by cytotoxic CD8+ T cells in solid tumors, HRSCs frequently lack major histocompatibility complex expression, and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical responses and high interim complete response rates to anti-PD1 based first-line treatment were recently reported for patients with early-stage unfavorable cHL treated in the German Hodgkin Study Group phase 2 NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained from NIVAHL patients before and during the first days of nivolumab first-line cHL therapy. Mirroring the rapid clinical response, HRSCs had disappeared from the tissue within days after the first nivolumab application. The TME already shows a reduction in type 1 regulatory T cells and PD-L1+ tumor-associated macrophages at this early time point of treatment. Interestingly, a cytotoxic immune response and a clonal T-cell expansion were not observed in the tumors or peripheral blood. These early changes in the TME were distinct from alterations found in a separate set of cHL biopsies at relapse during anti-PD1 therapy. We identify a unique very early histologic response pattern to anti-PD1 therapy in cHL that is suggestive of withdrawal of prosurvival factors, rather than induction of an adaptive antitumor immune response, as the main mechanism of action.
Asunto(s)
Antineoplásicos Inmunológicos/administración & dosificación , Enfermedad de Hodgkin , Activación de Linfocitos/efectos de los fármacos , Nivolumab/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral , Femenino , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/patología , Humanos , Masculino , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T Citotóxicos/patología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/patologíaRESUMEN
The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. This multicenter, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumor load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias, anaemia, infusion-related reactions, and diarrhoea. This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an overall response rate of 92%. Ongoing maintenance treatment aims at deeper responses with minimal residual disease negativity. However, ibrutinib should still be used as a single agent outside clinical trials. Clinicaltrials.gov number: NCT02689141.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Adenina/análogos & derivados , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Piperidinas , Resultado del TratamientoRESUMEN
Although common sense suggests that we are motivated to pursue positive and avoid negative experiences, previous research shows that people regularly seek out negative experiences. In the current study, we characterized this tendency from childhood to young adulthood. Due to the known increases in risky behavior and sensation seeking in adolescence, we hypothesized that adolescents would show an increased engagement with negatively valenced stimuli compared to children and adults. Participants aged 4-25 (N = 192) completed a behavioral task assessing motivation to engage with negative, positive, and neutral images. On each trial, participants viewed two small images and selected one to view at a larger size for up to 10s. Trials were organized into three valence conditions: negative versus positive images (matched on arousal), negative versus neutral images, and positive versus neutral images. Although participants chose positive images more than neutral or negative images, participants selected negative images frequently, even when given a positive (28% of trials) or neutral (42% of trials) alternative. Contrary to expectations, the tendency to choose negative images was highest in early childhood and decreased linearly with increasing age, and the tendency to choose positive images increased linearly with age. These results provide insight into how motivation to engage with emotional stimuli varies across age. It is possible that the novelty and rarity of negative experiences drives children to pursue these stimuli. Alternatively, children may find negative images less aversive, which would caution against assuming that these stimuli elicit the same motivational states in individuals of all ages.
Asunto(s)
Emociones , Motivación , Adolescente , Adulto , Afecto , Niño , Preescolar , Humanos , Asunción de Riesgos , Adulto JovenRESUMEN
With defined chemotherapy and radiotherapy (RT) and risk-adapted treatment, early-stage classical Hodgkin lymphoma (HL) has become curable in a majority of patients. Hence, a major current goal is to reduce treatment-related toxicity while maintaining long-term disease control. Patients with early-stage favorable disease (ie, limited stage without risk factors [RFs]) are frequently treated with 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (2×ABVD) followed by 20-Gy involved-field or involved-site RT (IF/ISRT). In patients with early-stage unfavorable disease (ie, limited stage with RFs), 4 cycles of chemotherapy are usually consolidated with 30-Gy IF/ISRT. Compared with 4×ABVD, 2 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (2×BEACOPPescalated) followed by 2×ABVD improved 5-year progression-free survival (PFS), with similar 5-year overall survival. Recently, treatment strategies based on [18F]fluorodeoxyglucose positron emission tomography (PET) response were evaluated. In early-stage unfavorable HL, a majority of patients achieved a negative interim PET after 2×ABVD and an excellent outcome after 4×ABVD, whereas in those with a positive interim PET, 2×BEACOPPescalated improved 5-year PFS. Furthermore, a PET-guided RT approach was evaluated to decrease long-term toxicity. Although both the RAPID and H10 trials reported poorer disease control without RT, PET-guided omission of RT can constitute a valid therapeutic option in patients with an increased risk of RT-associated toxicity (eg, because of sex, age, or disease localization). Implementation of drugs such as the anti-CD30 antibody-drug conjugate brentuximab vedotin or the anti-programmed death 1 antibodies nivolumab or pembrolizumab might allow further reduction of overall mortality and improve quality of life in affected patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Tomografía de Emisión de Positrones , Factores de Edad , Bleomicina/administración & dosificación , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Estadificación de Neoplasias , Prednisona/administración & dosificación , Procarbazina/administración & dosificación , Medición de Riesgo , Factores Sexuales , Tasa de Supervivencia , Vinblastina/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
This study evaluated the aspects of complex decisions influenced by peers, and components of peer involvement influential to adolescents' risky decisions. Participants (N = 140) aged 13-25 completed the Columbia Card Task (CCT), a risky choice task, isolating deliberation-reliant and affect-reliant decisions while alone, while a friend monitors choices, and while a friend is merely present. There is no condition in which a nonfriend peer is present. Results demonstrated the risk-increasing peer effect occurred in the youngest participants in the cold CCT and middle-late adolescents in the hot CCT, whereas other ages and contexts showed a risk-decreasing peer effect. Mere presence was not sufficient to influence risky behavior. These boundaries in age, decision, and peer involvement constrain prevailing models of adolescent peer influence.
Asunto(s)
Conducta del Adolescente/fisiología , Conducta de Elección/fisiología , Desarrollo Humano/fisiología , Influencia de los Compañeros , Asunción de Riesgos , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
People differ in how specifically they separate affective experiences into different emotion types-a skill called emotion differentiation or emotional granularity. Although increased emotion differentiation has been associated with positive mental health outcomes, little is known about its development. Participants ( N = 143) between the ages of 5 and 25 years completed a laboratory measure of negative emotion differentiation in which they rated how much a series of aversive images made them feel angry, disgusted, sad, scared, and upset. Emotion-differentiation scores were computed using intraclass correlations. Emotion differentiation followed a nonlinear developmental trajectory: It fell from childhood to adolescence and rose from adolescence to adulthood. Mediation analyses suggested that an increased tendency to report feeling emotions one at a time explained elevated emotion differentiation in childhood. Importantly, two other mediators (intensity of emotional experiences and scale use) did not explain this developmental trend. Hence, low emotion differentiation in adolescence may arise because adolescents have little experience conceptualizing co-occurring emotions.
Asunto(s)
Desarrollo del Adolescente , Concienciación , Emociones , Adolescente , Adulto , Síntomas Afectivos , Factores de Edad , Teorema de Bayes , Niño , Preescolar , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
AFM13 is a bispecific, tetravalent chimeric antibody construct (TandAb) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase 1 dose-escalation study, 28 patients with heavily pretreated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7 mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, antitumor activity, and pharmacodynamics. Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. Pharmacokinetics assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%), with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin-refractory patients. In 13 patients who received doses of ≥1.5 mg/kg AFM13, the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and a decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a well-tolerated, safe, and active targeted immunotherapy of Hodgkin lymphoma. A phase 2 study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. This phase 1 study was registered at www.clinicaltrials.gov as #NCT01221571.
Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Enfermedad de Hodgkin/tratamiento farmacológico , Inmunoterapia/métodos , Adulto , Anciano , Anticuerpos Biespecíficos/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Antígeno Ki-1/inmunología , Masculino , Persona de Mediana Edad , Receptores de IgG/inmunología , Recurrencia , Adulto JovenRESUMEN
To evade elimination by the host immune system, tumor cells commonly exploit physiological immune checkpoint pathways, restraining efficient anti-tumor immune cell function. Growing understanding of the complex dialog between tumor cells and their microenvironment contributed to the development of immune checkpoint inhibitors. This innovative strategy has demonstrated paradigm-shifting clinical activity in various malignancies. Antibodies targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein-4 are also being investigated in lymphoid malignancies with varying levels of activity and a favorable toxicity profile. To date, evaluated only in the setting of relapsed or refractory disease, anti-programmed death 1 antibodies such as nivolumab and pembrolizumab show encouraging response rates particularly in classical Hodgkin lymphoma but also in follicular lymphoma and diffuse-large B-cell lymphoma. As the first immune checkpoint inhibitor in lymphoma, nivolumab was approved for the treatment of relapsed or refractory classical Hodgkin lymphoma by the Food and Drug Administration in May 2016. In this review, we assess the role of the pathways involved and potential rationale of checkpoint inhibition in various lymphoid malignancies. In addition to data from current clinical trials, immune-related side effects, potential limitations and future perspectives including promising combinatory approaches with immune checkpoint inhibition are discussed.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Inmunomodulación/efectos de los fármacos , Linfoma/tratamiento farmacológico , Terapia Molecular Dirigida , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/metabolismo , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Humanos , Linfoma/diagnóstico , Linfoma/inmunología , Linfoma/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma. METHODS: In this open-label, randomised, multicentre trial (HD13) we compared two cycles of ABVD with two cycles of the reduced-intensity regimen variants ABV (doxorubicin, bleomycin, and vinblastine), AVD (doxorubicin, vinblastine, and dacarbazine), and AV (doxorubicin and vinblastine), in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte predominant Hodgkin's lymphoma. In each treatment group, 30 Gy involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. From Jan 28, 2003, patients were centrally randomly assigned (1:1:1:1) with a minimisation method to the four groups. Because of high event rates, assignment to the AV and ABV groups stopped early, on Sept 30, 2005, and Feb 10, 2006; assignment to ABVD and AVD continued (1:1) until Sept 30, 2009. Our primary objective was to show non-inferiority of the experimental variants compared with ABVD in terms of freedom from treatment failure (FFTF), by excluding a difference of 6% after 5 years corresponding to a hazard ratio (HR) of 1.72, via a 95% CI. Analyses reported here include qualified patients only, and between-group comparisons include only patients recruited during the same period. The trial was registered, number ISRCTN63474366. FINDINGS: Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. 5 year FFTF was 93.1%, 81.4%, 89.2%, and 77.1% with ABVD, ABV, AVD, and AV, respectively. Compared with ABVD, inferiority of the dacarbazine-deleted variants was detected with 5 year differences of -11.5% (95% CI -18.3 to -4.7; HR 2.06 [1.21 to 3.52]) for ABV and -15.2% (-23.0 to -7.4; HR 2.57 [1.51 to 4.40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference -3.9%, -7.7 to -0·1; HR 1.50, 1.00 to 2.26). 178 (33%) of 544 patients given ABVD had WHO grade III or IV toxicity, compared with 53 (28%) of 187 given ABV, 142 (26%) of 539 given AVD, and 40 (26%) of 151 given AV. Leucopenia was the most common event, and highest in the groups given bleomycin. INTERPRETATION: Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin's lymphoma should remain ABVD followed by IFRT. FUNDING: Deutsche Krebshilfe and Swiss State Secretariat for Education and Research.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/administración & dosificación , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Enfermedad de Hodgkin/tratamiento farmacológico , Vinblastina/administración & dosificación , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) represent severe late effects in patients treated for Hodgkin lymphoma (HL). Because more recent data are scarce, we retrospectively analyzed incidence, outcome, and risk factors for the development of t-AML/MDS after HL. A total of 11,952 patients treated for newly diagnosed HL within German Hodgkin Study Group trials between 1993 and 2009 were considered. At a median follow-up of 72 months, t-AML/MDS was diagnosed in 106/11,952 patients (0.9%). Median time from HL treatment to t-AML/MDS was 31 months. The median age of patients with t-AML/MDS was higher than in the whole patient group (43 vs 34 years, P < .0001). Patients who received 4 or more cycles of BEACOPP(escalated) had an increased risk to develop t-AML/MDS when compared with patients treated with less than 4 cycles of BEACOPP(escalated) or no BEACOPP chemotherapy (1.7% vs 0.7% vs 0.3%, P < .0001). The median overall survival (OS) for all t-AML/MDS patients was 7.2 months. However, t-AML/MDS patients proceeding to allogeneic stem cell transplantation had a significantly better outcome with a median OS not reached after a median follow-up of 41 months (P < .001).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/tratamiento farmacológico , Leucemia Mieloide Aguda/inducido químicamente , Síndromes Mielodisplásicos/inducido químicamente , Neoplasias Primarias Secundarias , Adolescente , Adulto , Anciano , Bleomicina/efectos adversos , Ciclofosfamida/efectos adversos , Doxorrubicina/efectos adversos , Etopósido/efectos adversos , Femenino , Estudios de Seguimiento , Alemania , Enfermedad de Hodgkin/patología , Humanos , Incidencia , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Prednisona/efectos adversos , Procarbazina/efectos adversos , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Vincristina/efectos adversos , Adulto JovenRESUMEN
The CD30-targeting Ab-drug conjugate brentuximab vedotin (SGN-35) was recently approved for the treatment of relapsed Hodgkin lymphoma and anaplastic large-cell lymphoma by the Food and Drug Administration. In the present study, we report the experience of the German Hodgkin Study Group with brentuximab vedotin as single agent in 45 patients with refractory or relapsed CD30(+) Hodgkin lymphoma who were treated either in a named patient program (n = 34) or in the context of a safety study associated with the registration program of this drug. In these very heavily pretreated patients, an objective response rate of 60%, including 22% complete remissions, could be documented. The median duration of response was 8 months. This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in heavily pretreated CD30(+) malignancies.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Enfermedad de Hodgkin/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Antígeno Ki-1/metabolismo , Estudios Retrospectivos , Adulto , Brentuximab Vedotina , Ensayos Clínicos Fase I como Asunto , Supervivencia sin Enfermedad , Femenino , Alemania , Humanos , Estimación de Kaplan-Meier , Masculino , RecurrenciaAsunto(s)
Antineoplásicos/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Enfermedad de Hodgkin , Receptor de Muerte Celular Programada 1 , Microambiente Tumoral/efectos de los fármacos , Adulto , Anciano , Femenino , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/biosíntesis , RecurrenciaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Linfocítica Crónica de Células B/terapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/patología , Pronóstico , Rituximab/administración & dosificación , Sulfonamidas/administración & dosificaciónAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Nivolumab/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Autoinjertos , Supervivencia sin Enfermedad , Eosinófilos , Femenino , Enfermedad de Hodgkin/sangre , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/terapia , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
While classical Hodgkin lymphoma (HL) is highly susceptible to anti-programmed death protein 1 (PD1) antibodies, the exact modes of action remain controversial. To elucidate the circulating lymphocyte phenotype and systemic effects during anti-PD1 1st-line HL treatment we applied multicolor flow cytometry, FluoroSpot and NanoString to sequential samples of 81 HL patients from the NIVAHL trial (NCT03004833) compared to healthy controls. HL patients showed a decreased CD4 T-cell fraction, a higher percentage of effector-memory T cells and higher expression of activation markers at baseline. Strikingly, and in contrast to solid cancers, expression for 10 out of 16 analyzed co-inhibitory molecules on T cells (e.g., PD1, LAG3, Tim3) was higher in HL. Overall, we observed a sustained decrease of the exhausted T-cell phenotype during anti-PD1 treatment. FluoroSpot of 42.3% of patients revealed T-cell responses against ≥1 of five analyzed tumor-associated antigens. Importantly, these responses were more frequently observed in samples from patients with early excellent response to anti-PD1 therapy. In summary, an initially exhausted lymphocyte phenotype rapidly reverted during anti-PD1 1st-line treatment. The frequently observed IFN-y responses against shared tumor-associated antigens indicate T-cell-mediated cytotoxicity and could represent an important resource for immune monitoring and cellular therapy of HL.
Asunto(s)
Enfermedad de Hodgkin/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Nivolumab/uso terapéutico , Linfocitos T/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Femenino , Enfermedad de Hodgkin/inmunología , Humanos , Inmunidad/efectos de los fármacos , Masculino , Linfocitos T/inmunologíaRESUMEN
In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. To assess the efficacy of the bispecific anti-CD30/CD16A, NK-cell engaging antibody AFM13 and to select the optimal treatment schedule (arm A-C), we initiated a randomized two-stage phase II trial (NCT02321592). Due to slow recruitment, the trial was terminated after treatment of 25 patients. Treatment with AFM13 was well tolerated: only two treatment-associated serious adverse events (SAEs) were reported; all SAEs resolved completely. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2-28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life.
Asunto(s)
Antineoplásicos , Enfermedad de Hodgkin , Inmunoconjugados , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Brentuximab Vedotina , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Humanos , Inmunoconjugados/uso terapéutico , Antígeno Ki-1 , Recurrencia Local de NeoplasiaRESUMEN
Hodgkin lymphoma (HL) is a rare malignancy accounting for roughly 15% of all lymphomas and mostly affecting young patients. A second peak is seen in patients above 60 years of age. The history of HL treatment represents a remarkable success story in which HL has turned from an incurable disease to a neoplasm with an excellent prognosis. First-line treatment with stage-adapted treatment consisting of chemotherapy and/or radiotherapy results in cure rates of approximately 80%. Second-line treatment mostly consists of intensive salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Novel approaches such as antibody drug conjugates and immunomodulatory drugs have shown impressive results in clinical trials in refractory and relapsed HL and are now increasingly implemented in earlier treatment lines. This review gives a comprehensive overview on HL addressing epidemiology, pathophysiology and current treatment options as well as recent developments and perspectives.