RESUMEN
In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.
Asunto(s)
Histiocitosis de Células de Langerhans , Neoplasias Primarias Secundarias , Humanos , Adulto , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/genética , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Incidencia , Histiocitosis de Células de Langerhans/epidemiología , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , MutaciónRESUMEN
Chronic lymphocytic leukemia (CLL)-related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients' HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043.
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Leucemia Linfocítica Crónica de Células B , Humanos , Anciano , Leucemia Linfocítica Crónica de Células B/diagnóstico , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Fatiga/inducido químicamenteRESUMEN
Immune checkpoint blockade (ICB) has revolutionized cancer therapy, but varying response rates illustrate the need for biomarkers of response. Studies in mice have identified a subset of CD8 T cells that is essential for response to PD-1 ICB. These CD8 T cells co-express CXCR5, PD-1 and Tcf1, and provide effector T cells upon PD-1 ICB. It is unknown whether similar T cells play a role in PD-1 ICB in humans. We studied human peripheral blood and lymph nodes (LNs) for the frequency, phenotype, and functionality of CXCR5+ PD-1+ CD8 T cells. We find that CXCR5+ PD-1+ CD8 T cells are memory-like cells, express Tcf1, and lack expression of effector molecules. CXCR5+ PD-1+ CD8 T cells produce cytokines upon stimulation, but have limited proliferative capacity. We studied patients with hematologic malignancies with varying response rates to PD-1 ICB. Specifically in chronic lymphocytic leukemia, in which PD-1 ICB does not induce clinical responses, CXCR5+ PD-1+ CD8 T cells show loss of the memory phenotype and increased effector differentiation. In conclusion, we identified CXCR5+ PD-1+ CD8 T cells in human peripheral blood and LN, which could play a similar role during PD-1 ICB. Future studies should analyze CXCR5+ PD-1+ CD8 T cells during PD-1 ICB and their importance for therapeutic response.
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Linfocitos T CD8-positivos/inmunología , Neoplasias Hematológicas/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptores CXCR5/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Diferenciación Celular/inmunología , Femenino , Humanos , Memoria Inmunológica , Leucemia Linfocítica Crónica de Células B/inmunología , Ganglios Linfáticos/inmunología , Masculino , Persona de Mediana EdadRESUMEN
In chronic lymphocytic leukemia (CLL), acquired T-cell dysfunction impedes development of effective immunotherapeutic strategies, through as-yet unresolved mechanisms. We have previously shown that CD8+ T cells in CLL exhibit impaired activation and reduced glucose uptake after stimulation. CD8+ T cells in CLL patients are chronically exposed to leukemic B cells, which potentially impacts metabolic homeostasis resulting in aberrant metabolic reprogramming upon stimulation. Here, we report that resting CD8+ T cells in CLL have reduced intracellular glucose transporter 1 (GLUT1) reserves, and have an altered mitochondrial metabolic profile as displayed by increased mitochondrial respiration, membrane potential, and levels of reactive oxygen species. This coincided with decreased levels of peroxisome proliferator-activated receptor γ coactivator 1-α, and in line with that, CLL-derived CD8+ T cells showed impaired mitochondrial biogenesis upon stimulation. In search of a therapeutic correlate of these findings, we analyzed mitochondrial biogenesis in CD19-directed chimeric antigen receptor (CAR) CD8+ T cells prior to infusion in CLL patients (who were enrolled in NCT01747486 and NCT01029366 [https://clinicaltrials.gov]). Interestingly, in cases with a subsequent complete response, the infused CD8+ CAR T cells had increased mitochondrial mass compared with nonresponders, which positively correlated with the expansion and persistence of CAR T cells. Our findings demonstrate that GLUT1 reserves and mitochondrial fitness of CD8+ T cells are impaired in CLL. Therefore, boosting mitochondrial biogenesis in CAR T cells might improve the efficacy of CAR T-cell therapy and other emerging cellular immunotherapies.
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Linfocitos T CD8-positivos/metabolismo , Inmunoterapia Adoptiva , Leucemia Linfocítica Crónica de Células B/metabolismo , Mitocondrias/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Persona de Mediana Edad , Biogénesis de Organelos , Receptores Quiméricos de AntígenosRESUMEN
Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem-cell transplant (auto-PBSCT) predicts progression free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP to improve the mCR rate. In a Phase I dose-escalation part in 12 patients, we showed that BV-DHAP is feasible. This Phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT review, 42 of 52 evaluable patients (81% [95% CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2) and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2) and all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. ClinicalTrials.gov identifier: NCT02280993.
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Enfermedad de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brentuximab Vedotina , Cisplatino , Citarabina/uso terapéutico , Dexametasona/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Recurrencia Local de Neoplasia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Recurrencia , Terapia Recuperativa , Resultado del TratamientoRESUMEN
Despite the emergence of small molecule inhibitors, current treatment strategies for chronic lymphocytic leukemia (CLL) are not curative, and the search for new therapeutic modalities continues. Prosurvival signaling derived from the microenvironment is often mediated via JAK signaling. However, whether JAK inhibitors are useful in CLL therapy has not been studied extensively. JAK inhibitors are valuable therapeutic agents in myelofibrosis and show promising results in graft-versus-host-disease. However, JAK inhibition is associated with an increased infection risk, presumably because of the effect on other immune cells, a feature shared with other kinase inhibitors used for CLL treatment, such as the BTK inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We compared functional effects of the JAK1/2 inhibitors momelotinib and ruxolitinib, the BTK inhibitors ibrutinib and tirabrutinib, and PI3Kδ inhibitor idelalisib on malignant CLL cells but also on healthy human T, B, and NK lymphocytes. We found several interesting differences among the inhibitors, apart from expected and well-known effects. Momelotinib but not ruxolitinib blocked cytokine-induced proliferation of CLL cells. Momelotinib also reduced BCR signaling, in contrast to ruxolitinib, indicating that these JAK inhibitors in fact have a distinct target spectrum. In contrast to tirabrutinib, ibrutinib had inhibitory effects on T cell activation, probably because of ITK inhibition. Remarkably, both BTK inhibitors stimulated IFN-γ production in a mixed lymphocyte reaction. Collectively, our results demonstrate that kinase inhibitors directed at identical targets may have differential effects on lymphocyte function. Their unique profile could be strategically employed to balance desired versus unwanted lymphocyte inhibition.
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Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/farmacología , Quinasas Janus/antagonistas & inhibidores , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfocitos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa/metabolismo , Animales , Benzamidas/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Imidazoles/farmacología , Quinasas Janus/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Linfocitos/metabolismo , Linfocitos/patología , Ratones , Células 3T3 NIH , Nitrilos , Piperidinas , Purinas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Quinazolinonas/farmacologíaRESUMEN
The efficacy of autologous (αß) T-cell-based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex-independent mechanism. We studied whether Vγ9Vδ2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2-T cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2-T-cell function in CLL patients. Dysfunction of Vγ9Vδ2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2-T cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell-based therapy with ibrutinib.
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Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Linfocitos T Citotóxicos/inmunología , Adenina/análogos & derivados , Anciano , Anciano de 80 o más Años , Células Cultivadas , Técnicas de Cocultivo , Citocinas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/patología , Femenino , Humanos , Inmunoterapia Adoptiva/métodos , Leucemia Linfocítica Crónica de Células B/patología , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Piperidinas , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/patología , Células Tumorales CultivadasRESUMEN
BACKGROUND: Invasive fungal diseases (IFD) are life-threatening infections most commonly diagnosed in acute leukaemia patients with prolonged neutropenia and are uncommonly diagnosed in patients with lymphoproliferative diseases. OBJECTIVES: Following the initial report of aspergillosis diagnosed shortly after beginning ibrutinib for chronic lymphocytic leukaemia, a survey was developed to seek additional cases of IFD during ibrutinib treatment. METHODS: Local and international physicians and groups were approached for relevant cases. Patients were included if they met the following criteria: diagnosis of chronic lymphocytic leukaemia/non-Hodgkin lymphoma; proven or probable IFD; and ibrutinib treatment on the date IFD were diagnosed. Clinical and laboratory data were captured using REDCap software. RESULT: Thirty-five patients with IFD were reported from 22 centres in eight countries: 26 (74%) had chronic lymphocytic leukaemia. The median duration of ibrutinib treatment before the onset of IFD was 45 days (range 1-540). Aspergillus species were identified in 22 (63%) of the patients and Cryptococcus species in 9 (26%). Pulmonary involvement occurred in 69% of patients, cranial in 60% and disseminated disease in 60%. A definite diagnosis was made in 21 patients (69%), and the mortality rate was 69%. Data from Israel regarding ibrutinib treated patients were used to evaluate a prevalence of 2.4% IFD. CONCLUSIONS: The prevalence of IFD among chronic lymphocytic leukaemia/non-Hodgkin lymphoma patients treated with ibrutinib appears to be higher than expected. These patients often present with unusual clinical features. Mortality from IFD in this study was high, indicating that additional studies are urgently needed to identify patients at risk for ibrutinib-associated IFD.
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Infecciones Fúngicas Invasoras/etiología , Leucemia Linfocítica Crónica de Células B/microbiología , Linfoma no Hodgkin/microbiología , Neutropenia/complicaciones , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/mortalidad , Israel , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neutropenia/virología , Piperidinas , Estudios RetrospectivosRESUMEN
Chronic lymphocytic leukemia (CLL) is characterized by an acquired immune dysfunction. CLL cells affect the phenotype and function of the entire spectrum of innate and adaptive immune cells, including monocytes, T cells, and natural killer (NK) cells, leading to a tumor-supportive environment and reduced immunosurveillance. Novel immunotherapies like immune checkpoint blockade, bi- and tri-specific antibodies, and chimeric antigen receptor (CAR) T cells use the patients' immune system to induce therapeutic responses. Although these novel immunotherapies showed impressive results in several B cell lymphomas, responses in CLL were often disappointing. The strong immunomodulatory effect of CLL is believed to play a pivotal role in the low response rates to these immunotherapeutic strategies. In this review, we summarize how CLL influences the function of non-malignant lymphocytes, with a special focus on T and NK cells, two important cellular mediators for immunotherapy. Secondly, we provide a short overview of the activity of several immunotherapeutics in CLL, and discuss how novel strategies may overcome the disappointing response rates in CLL.
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Inmunoterapia/métodos , Leucemia Linfocítica Crónica de Células B/terapia , Linfocitos T Citotóxicos/fisiología , Linfocitos T/fisiología , Animales , Humanos , Linfocitos T/citología , Linfocitos T Citotóxicos/citologíaRESUMEN
Immunotherapy has emerged as a viable clinical strategy to harness endogenous antitumor T-cell immunity. Lenalidomide is an oral immunomodulatory drug that repairs antitumor T-cell function and is showing efficacy in ongoing chronic lymphocytic leukemia (CLL) and lymphoma clinical trials. This article focuses on advances in our understanding of its mechanism of action in the tumor microenvironment and provides a clinical update in CLL. Challenges associated with this drug and its potential use in the targeted drug treatment era are discussed.
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Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Talidomida/análogos & derivados , Linfocitos B/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Ensayos Clínicos como Asunto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Factores Inmunológicos/farmacología , Lenalidomida , Purinas/administración & dosificación , Quinazolinonas/administración & dosificación , Linfocitos T/efectos de los fármacos , Talidomida/farmacologíaRESUMEN
In chronic lymphocytic leukemia (CLL), CD8(+) T cells exhibit features of exhaustion and impaired functionality. Yet, reactivations of latent viruses such as cytomegalovirus (CMV) are uncommon in untreated CLL, suggesting that antiviral responses are uncompromised. We analyzed phenotypical and functional characteristics of CMV-specific CD8(+) T cells in CLL patients in comparison with age-matched healthy controls (HCs). Despite increased expression of the inhibitory receptors PD1, CD160, and CD244 on total CD8(+) T cells in CLL, expression levels of these markers were decreased on CMV-tetramer(+)CD8(+) T cells. Second, cytokine production upon stimulation with both phorbol 12-myristate 13-acetate/ionomycin and CMV-peptide-loaded antigen-presenting cells was intact in CMV-tetramer(+)CD8(+) T cells. Third, CMV-tetramer(+)CD8(+) T cells of CLL patients and HCs were equally effective in killing CMV-peptide-loaded target cells. Finally, quantitative imaging flow cytometry revealed that the proportion of CD8(+) T cells forming immunologic synapses with CMV-peptide-loaded B cells was intact. In conclusion, despite evidence for global T-cell dysfunction in CLL, we show here that CLL-derived CMV-specific CD8(+) T cells display lower expression of exhaustion markers and are functionally intact. These data indicate that the changes in the T-cell compartment in CLL may be more heterogeneous than presently assumed.
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Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Citomegalovirus/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/virología , Citocinas/inmunología , Humanos , Sinapsis Inmunológicas/inmunología , Sinapsis Inmunológicas/virologíaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Terapia Recuperativa , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brentuximab Vedotina/administración & dosificación , Brentuximab Vedotina/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Supervivencia sin Enfermedad , Femenino , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Tasa de SupervivenciaRESUMEN
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; P value for noninferiority = .9735; difference test P < .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; P value for noninferiority = .8577; difference test P = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; P = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.
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Enfermedad de Hodgkin , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina , Dacarbazina , Supervivencia sin Enfermedad , Doxorrubicina , Estudios de Seguimiento , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Prednisona , Procarbazina/efectos adversos , Vinblastina , VincristinaRESUMEN
Histological transformation of marginal zone lymphoma (tMZL) into diffuse large B-cell lymphoma is associated with poor outcomes. Clinical characteristics associated with transformation risk and outcome after transformation are largely unknown due to scarcity of data. In this population-based study, competing risk analyses were performed to elucidate clinical characteristics associated with developing transformation among 1793 MZL patients using the Netherlands Cancer Registry. Cox regression analyses were performed to elucidate clinical characteristics associated with risk of relapse and mortality after transformation. Transformation occurred in 75 (4%) out of 1793 MZL patients. Elevated LDH and nodal MZL subtype at MZL diagnosis were associated with an increased risk, and radiotherapy with a reduced risk of developing tMZL. Most tMZL patients received R-(mini)CHOP (n = 53, 71%). Age >60 years and (immuno)chemotherapy before transformation were associated with an increased risk of relapse and mortality after transformation. Two-year progression-free survival (PFS) and overall survival (OS) were 66% (95% CI 52-77%) and 75% (95% CI 62-85%) for R-(mini)CHOP-treated tMZL patients, as compared to a PFS and OS both of 41% (95% CI 19-63%) for patients treated otherwise. Our study offers comprehensive insights into characteristics associated with transformation and survival after transformation, thereby optimizing guidelines and patient counseling.
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Linfoma de Células B de la Zona Marginal , Linfoma de Células B Grandes Difuso , Humanos , Persona de Mediana Edad , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/epidemiología , Linfoma de Células B de la Zona Marginal/terapia , Inmunoterapia , Países Bajos/epidemiología , Supervivencia sin ProgresiónRESUMEN
Risk-stratified treatment strategies have the potential to increase survival and lower toxicity in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) patients. This study investigated the prognostic value of serum (s)TARC, vitamin D and lactate dehydrogenase (LDH), TARC immunohistochemistry and quantitative PET parameters in 65 R/R cHL patients who were treated with brentuximab vedotin (BV) and DHAP followed by autologous stem-cell transplantation (ASCT) within the Transplant BRaVE study (NCT02280993). At a median follow-up of 40 months, the 3-year progression free survival (PFS) was 77% (95% CI: 67-88%) and the overall survival was 95% (90-100%). Significant adverse prognostic markers for progression were weak/negative TARC staining of Hodgkin Reed-Sternberg cells in the baseline biopsy, and a high standard uptake value (SUV)mean or SUVpeak on the baseline PET scan. After one cycle of BV-DHAP, sTARC levels were strongly associated with the risk of progression using a cutoff of 500 pg/ml. On the pre-ASCT PET scan, SUVpeak was highly prognostic for progression post-ASCT. Vitamin D, LDH and metabolic tumor volume had low prognostic value. In conclusion, we established the prognostic impact of sTARC, TARC staining, and quantitative PET parameters for R/R cHL, allowing the use of these parameters in prospective risk-stratified clinical trials. Trial registration: NCT02280993.
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Enfermedad de Hodgkin , Inmunoconjugados , Humanos , Brentuximab Vedotina , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Pronóstico , Estudios Prospectivos , Trasplante de Células Madre , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Tomografía de Emisión de Positrones , Vitamina D/uso terapéuticoRESUMEN
BACKGROUND: Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status. METHODS: We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27). FINDINGS: Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35·2 months (IQR 31·5-41·3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths. INTERPRETATION: Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. FUNDING: F Hoffmann-La Roche.
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Leucemia Linfocítica Crónica de Células B , Adolescente , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , SulfonamidasRESUMEN
Approximately 10% to 30% of patients with classical Hodgkin lymphoma (cHL) develop relapsed or refractory (R/R) disease. Of those patients, 50% to 60% show long-term progression-free survival after standard salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). In the past decade, novel therapies have been developed, such as the CD30-directed antibody-drug conjugate brentuximab vedotin and immune checkpoint inhibitors, which have greatly extended the treatment possibilities for patients with R/R cHL. Several phase 1/2 clinical trials have shown promising results of these new drugs as monotherapy or in combination with chemotherapy, but unfortunately, very few randomized phase 3 trials have been performed in this setting, making it difficult to give evidence-based recommendations for optimal treatment sequencing. Two important goals for the improvement in the treatment of R/R cHL can be identified: (1) increasing long-term progression-free and overall survival by optimizing risk-adapted treatment and (2) decreasing toxicity in patients with a low risk of relapse of disease by evaluating the need for HDCT/ASCT in these patients. In this review, we discuss treatment options for patients with R/R cHL in different settings: patients with a first relapse, primary refractory disease, and in patients who are ineligible or unfit for ASCT. Results of clinical trials investigating novel therapies or strategies published over the past 5 years are summarized.
Asunto(s)
Enfermedad de Hodgkin/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/radioterapia , Humanos , Recurrencia Local de Neoplasia/terapia , Terapia Recuperativa/métodos , Trasplante Autólogo/métodosRESUMEN
In the original article [...].
RESUMEN
We assessed stage-specific trends in primary therapy and relative survival among adult follicular lymphoma (FL) patients diagnosed in the Netherlands between 1989-2016 (N = 12,372; median age, 62 years; and 21% stage I disease). Patients were stratified by disease stage and subsequently categorized into four calendar periods (1989-1995, 1996-2002, 2003-2008, and 2009-2016) and three age groups (18-60, 61-70, and >70 years). The use of radiotherapy in stage I FL remained relatively stable over time and across the three age groups (i.e., 66%, 54%, and 49% in 2009-2016, respectively). In stage II-IV FL, the start of chemotherapy within 12 months post-diagnosis decreased over time, indicating a broader application of a watch-and-wait approach. Relative survival improved considerably over time, especially since 2003 when rituximab was introduced in the Netherlands, and for stage III-IV FL patients and older age groups. Five-year relative survival for patients with stage I-II versus stage III-IV FL in the period 2009-2016 was 96% versus 90%, 93% versus 83%, and 92% versus 68% across the three age groups, respectively. Collectively, the improvement in survival since 2003 is accounted for by advances in FL management, particularly the implementation of rituximab. There remains, however, room for improvement among elderly stage III-IV FL patients.