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BACKGROUND: Chimeric antigen-receptor T-cell and bispecific antibody therapies will likely necessitate a reconsideration of the role of autologous stem-cell transplantation (ASCT) in lymphoma. Patients who are likely to profit from ASCT need to be better identified. METHODS: Here, we investigated the value of positron emission tomography/computerized tomography (PET/CT) before ASCT. All 521 patients transplanted for lymphoma 1994-2019 at Karolinska (497 conditioned with BEAM) were included. RESULTS: Outcome improved over three calendar periods 1994-2004, 2005-2014, 2015-2019 (2-year overall survival [OS]: 66, 73, 83%; P = 0.018). Non-relapse mortality (NRM) at 100 days over the three periods were 9.8, 3.9, 2.9%, respectively. The OS improvement between 1994 and 2004 and 2005-2014 was due to lower NRM (P = 0.027), but the large OS advance from 2015 was not accompanied by a significant reduction in NRM (P = 0.6). The fraction of PET/CT as pre-ASCT assessment also increased over time: 1994-2004, 2%; 2005-2014, 24%; 2015-2019, 60% (P < 0.00005). Complete responses (PET/CT-CR) were observed in 77% and metabolically active partial responses (PET/CT-PR) in 23%. PET/CT-CR was a predictor for survival in the entire population (P = 0.0003), also in the subpopulations of aggressive B-cell (P = 0.004) and peripheral T-cell (P = 0.024) lymphomas. Two-year OS and progression-free survival (OS/PFS) for patients in PET/CT-CR were in relapsed/refractory aggressive B-cell lymphoma 87%/75% and peripheral T-cell lymphoma 91%/78%. The corresponding figures in PET/CT-PR were 43%/44 and 33%/33%. Patients with solitary PET/CT-positive lesions showed acceptable outcome with ASCT followed by local irradiation (2-year OS/PFS 80%/60%). CT was less discriminative: 2-year OS/PFS: CT-CR, 76%/66%; CT-PR, 62%/51%. Outcome was inferior after BEAC compared with BEAM conditioning. CONCLUSIONS: We conclude that the improved outcome reflects better, PET/CT-informed, identification of patients who should proceed to ASCT. The excellent survival of patients in PET/CT-CR indicates that ASCT should remain part of standard therapy for lymphoma.
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Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Linfoma/diagnóstico por imagem , Linfoma/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Linfoma/mortalidade , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/mortalidade , Linfoma de Células B/terapia , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Linfoma de Células T/diagnóstico por imagem , Linfoma de Células T/mortalidade , Linfoma de Células T/terapia , Linfoma de Células T Periférico/diagnóstico por imagem , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/terapia , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/estatística & dados numéricos , Intervalo Livre de Progressão , Recidiva , Indução de Remissão , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
Rituximab monotherapy is widely used for follicular lymphoma. However, there are no established predictors for response or response duration. We analyzed the long-term prognostic relevance of pre-treatment absolute blood counts of lymphocytes with subsets and monocytes in 265 follicular lymphoma patients, uniformly treated with rituximab without chemotherapy, in two Nordic Lymphoma Group trials. There were 265 previously untreated, stage II-IV follicular lymphoma patients with a median follow-up of over 10 years. Absolute B cell counts ≥ median (0.09 × 109/L) were an independent predictor for shorter time to next treatment or death (multivariable analysis P = 0.010). In univariate analysis, absolute monocyte counts ≥ median (0.5 × 109/L) did not correlate with time to next treatment or death, but with inferior overall survival (P = 0.034). Absolute T cell or T cell subset counts were not predictive for outcome. High absolute B cell counts, possibly reflecting circulating lymphoma cells, have an unfavorable impact on time to next treatment or death in patients treated with rituximab without chemotherapy.
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Antineoplásicos/uso terapêutico , Linfócitos B , Imunossupressores/uso terapêutico , Contagem de Linfócitos , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Humanos , Interferon alfa-2/administração & dosagem , Estimativa de Kaplan-Meier , Subpopulações de Linfócitos , Linfoma Folicular/sangue , Masculino , Pessoa de Meia-Idade , Monócitos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Rituximab/administração & dosagem , Adulto JovemRESUMO
Mobilized PBSC are the main source for allogeneic HSCT. We aimed to evaluate factors that affect CD34+ cell yield including the donor's age, gender, BSA, processed blood volume and the method of G-CSF dose calculation. Data from 170 healthy donors were analyzed. The concentration of CD34+ cells in the peripheral blood (PB) and the processed volume of blood were significantly correlated to CD34+ cells yield (P < .00005 and P < .001, respectively). The G-CSF dose per m2 was significantly correlated to the concentration of CD34+ cells in the PB (P = .0003) and in the product (P = .01). Smaller BSA and less processed volume were found among female donors, who were given lesser G-CSF dose per m2 , and showed lower yield compared to men. However, multivariate analysis of the yield showed that only the concentration of CD34+ cells in the PB and the processed volume remained independent significant.
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Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco de Sangue Periférico/métodos , Adolescente , Adulto , Fatores Etários , Idoso , Antígenos CD34/análise , Antígenos CD34/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco de Sangue Periférico , Fatores Sexuais , Transplante Homólogo , Adulto JovemRESUMO
Young patients with diffuse large B-cell lymphoma (DLBCL) are variably treated with rituximab combined with cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP), CHOP-etoposide (R-CHOEP), and anthracycline-based regimens with the addition of high-dose cytarabine/methotrexate (R-HDA/M). Using the nationwide, population-based Swedish Lymphoma Registry, we evaluated outcome, by treatment and Healthcare Region, in all 751 DLBCL patients aged ≤60 years without central nervous involvement, diagnosed in Sweden between 2007 and 2012. Overall survival was estimated using multivariate Cox analysis. In patients with age-adjusted international prognostic index (aaIPI) ≥ 2, the 5-year overall survival (OS) was 70%, 76% and 85% after R-CHOP, R-CHOEP and R-HDA/M, respectively (P = 0·002); the corresponding estimates were 40%, 55%, and 92% in aaIPI = 3 (P = 0·014). There were large therapeutic differences between Sweden's six Healthcare Regions for aaIPI ≥ 2: three were "Moderate" (more R-CHOP) and three "Intensive" (more R-CHOEP and R-HDA/M). Patients with aaIPI ≥ 2 who were treated in the Intensive Regions, showed better OS (P < 0·00005), particularly those with aaIPI = 3 (5-year OS, 62% vs. 30%; P < 0·00005). There were no regional differences in therapy or survival in patients with aaIPI < 2. We conclude that in younger high-risk patients, survival appears superior after more intensive therapy than R-CHOP.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Adolescente , Adulto , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sistema de Registros , Fatores de Risco , Análise de Sobrevida , Suécia/epidemiologia , Resultado do Tratamento , Adulto JovemRESUMO
The tumour microenvironment influences outcome in patients with follicular lymphoma (FL), but its impact on transformation is less studied. We investigated the prognostic significance of the tumour microenvironment on transformation and survival in FL patients treated in the rituximab era. We examined diagnostic and transformed biopsies from 52 FL patients using antibodies against CD3, CD4, CD8, CD21 (CR2), CD57 (B3GAT1), CD68, FOXP3, TIA1, PD-1 (PDCD1), PD-L1 (CD274) and PAX5. Results were compared with a second cohort of 40 FL patients without signs of transformation during a minimum of five years observation time. Cell numbers and localization were semi-quantitatively assessed. Better developed CD21+ follicular dendritic cell (FDC) meshworks at diagnosis was a negative prognostic factor for overall survival (OS), progression-free survival (PFS) and time to transformation (TTT) in patients with subsequently transformed FL. Remnants of FDC meshworks at transformation were associated with shorter OS and PFS from transformation. High degrees of intrafollicular CD68+ and PD-L1+ macrophage infiltration, high total area scores and an extrafollicular/diffuse pattern of FOXP3+ T cells and high intrafollicular scores of CD4+ T cells at diagnosis were associated with shorter TTT. Scores of several T-cell subset markers from the combined patient cohorts were predictive for transformation, especially CD4 and CD57.
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Transformação Celular Neoplásica , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Microambiente Tumoral , Adulto , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores , Biópsia , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , Rituximab/uso terapêutico , Fatores de Tempo , Microambiente Tumoral/imunologia , Adulto JovemRESUMO
Despite the improvements in clinical outcomes for DLBCL, a significant proportion of patients still face challenges with refractory/relapsed (R/R) disease after receiving first-line R-CHOP treatment. To further elucidate the underlying mechanism of R/R disease and to develop methods for identifying patients at risk of early disease progression, we integrated clinical, genetic and transcriptomic data derived from 2805 R-CHOP-treated patients from seven independent cohorts. Among these, 887 patients exhibited R/R disease within two years (poor outcome), and 1918 patients remained in remission at two years (good outcome). Our analysis identified four preferentially mutated genes (TP53, MYD88, SPEN, MYC) in the untreated (diagnostic) tumor samples from patients with poor outcomes. Furthermore, transcriptomic analysis revealed a distinct gene expression pattern linked to poor outcomes, affecting pathways involved in cell adhesion/migration, T-cell activation/regulation, PI3K, and NF-κB signaling. Moreover, we developed and validated a 24-gene expression score as an independent prognostic predictor for treatment outcomes. This score also demonstrated efficacy in further stratifying high-risk patients when integrated with existing genetic or cell-of-origin subtypes, including the unclassified cases in these models. Finally, based on these findings, we developed an online analysis tool ( https://lymphprog.serve.scilifelab.se/app/lymphprog ) that can be used for prognostic prediction for DLBCL patients.
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Doxorrubicina , Linfoma Difuso de Grandes Células B , Humanos , Rituximab/uso terapêutico , Ciclofosfamida/uso terapêutico , Vincristina/uso terapêutico , Doxorrubicina/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Prognóstico , Perfilação da Expressão Gênica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prednisona/uso terapêuticoRESUMO
Background: Detecting the presence of Δ9-THC and CBD is mainly done through venous blood sampling, but other methods are becoming available. Oromucosal administration of Δ9-THC and CBD is less studied than inhalation, but this mode of administration is growing. In this study, we analyze samples obtained through invasive and noninvasive methods in a cohort of patients given oromucosally administered Δ9-THC and CBD to gain understanding in the strengths and weaknesses of the various detection methods. Materials and Methods: Blood, oral fluid (OF), exhaled breath, and urine were collected at several time points from 23 cannabis-naive patients after receiving a single dose of Sativex®; dose ranges: Δ9-THC, 2.7-18.9 mg; CBD 2.5-17.5 mg. Detection of Δ9-THC and CBD was done using liquid chromatography-mass spectrometry methods. Results: Δ9-THC and CBD were present in plasma, OF, and exhaled breath in all 23 patients. The detection time of Δ9-THC and CBD in OF and exhaled breath was longer than in blood. Urine analysis detected the Δ9-THC carboxy metabolite (THC-COOH) up to 7 days after administration, also in a patient who received 8.1/7.5 mg Δ9-THC/CBD. Conclusion: Time to detection of cannabinoids in blood samples was shorter than in exhaled breath and OF. Relative ease of sample collection combined with high sensitivity makes OF and exhaled breath specimens a valuable addition when samples are handled correctly. Δ9-THC metabolites were detected for an unexpected long period of time in urine. EudraCT Number: 2014-005553-39. Date of registration, December 29, 2015.
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The treatment of splenic marginal zone lymphoma is debated: splenectomy (the old standard-of-care) is better than chemotherapy but maybe not better than rituximab-containing treatment. We examined all 358 patients diagnosed with splenic marginal zone lymphoma in Sweden 2000-2020. The median overall survival was 11.0 years. The median age was 73 years; 61% were women. Age was the only independently prognostic clinical characteristic. Eighty-six patients were started on wait-and-watch, 90 rituximab monotherapy, 47 rituximab-chemotherapy, 88 splenectomy, 37 chemotherapy, and 10 both systemic therapy and splenectomy. Overall survival was inferior in patients treated with chemotherapy, but equal in patients treated with rituximab, rituximab-chemotherapy and splenectomy. Patients treated with both systemic therapy and splenectomy showed good outcome, suggesting that surgery can be safely reserved for nonresponders. After adjustment for age, survival did not differ between patients started on wait-and-watch and those treated with splenectomy or rituximab-containing therapy. Over time, rituximab use and survival increased in patients ≥73 years. This is, to our knowledge, the largest population-based study of splenic marginal zone lymphoma patients treated with upfront rituximab. We conclude that wait-and-watch remains the most reasonable option in asymptomatic splenic marginal zone lymphoma patients. Symptomatic patients should be offered single-agent rituximab in first line.
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In follicular lymphoma (FL), progression of disease ≤24 months (POD24) has emerged as an important prognostic marker for overall survival (OS). We aimed to investigate survival more broadly by timing of progression and treatment in a national population-based setting. We identified 948 stage II-IV indolent FL patients in the Swedish Lymphoma Register diagnosed 2007-2014 who received first-line systemic therapy, followed through 2020. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by first POD at any time during follow-up using Cox regression. OS was predicted by POD using an illness-death model. During a median follow-up of 6.1 years (IQR: 3.5-8.4), 414 patients experienced POD (44%), of which 270 (65%) occurred ≤24 months. POD was represented by a transformation in 15% of cases. Compared to progression-free patients, POD increased all-cause mortality across treatments, but less so among patients treated with rituximab(R)-single (HR = 4.54, 95% CI: 2.76-7.47) than R-chemotherapy (HR = 8.17, 95% CI: 6.09-10.94). The effect of POD was similar following R-CHOP (HR = 8.97, 95% CI: 6.14-13.10) and BR (HR = 10.29, 95% CI: 5.60-18.91). The negative impact of POD on survival remained for progressions up to 5 years after R-chemotherapy, but was restricted to 2 years after R-single. After R-chemotherapy, the 5-year OS conditional on POD occurring at 12, 24, and 60 months was 34%, 46%, and 57% respectively, versus 78%, 82%, and 83% if progression-free. To conclude, POD before but also beyond 24 months is associated with worse survival, illustrating the need for individualized management for optimal care of FL patients.
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Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancies. Here, we explore the contribution of RNA editing to DLBCL pathogenesis. We observed that DNA mutations and RNA editing events are often mutually exclusive, suggesting that tumors can modulate pathway outcomes by altering sequences at either the genomic or the transcriptomic level. RNA editing targets transcripts within known disease-driving pathways such as apoptosis, p53 and NF-κB signaling, as well as the RIG-I-like pathway. In this context, we show that ADAR1-mediated editing within MAVS transcript positively correlates with MAVS protein expression levels, associating with increased interferon/NF-κB signaling and T cell exhaustion. Finally, using targeted RNA base editing tools to restore editing within MAVS 3'UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling in the absence of activation by canonical nucleic acid receptor sensing.
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This phase II clinical trial investigates a one-time oromucosal dose of tetrahydrocannabinol/cannabidiol (THC/CBD) in 23 patients with indolent leukemic B cell lymphomas. Primary endpoint was a significant reduction in leukemic B cells. Grade 1 - 2 adverse events were seen in 91% of the patients; most common were dry mouth (78%), vertigo (70%), and somnolence (43%). After THC/CBD a significant reduction in leukemic B cells (median, 11%) occurred within two hours (p = .014), and remained for 6 h without induction of apoptosis or proliferation. Normal B cells and T cells were also reduced. CXCR4 expression increased on leukemic cells and T cells. All effects were gone by 24 h. Our results show that a single dose of THC/CBD affects a wide variety of leukocytes and only transiently reduce malignant cells in blood. Based on this study, THC/CBD shows no therapeutic potential for indolent B cell lymphomas (EudraCT trial no. 2014-005553-39).
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Canabinoides , Leucemia Linfocítica Crônica de Células B , Canabidiol/efeitos adversos , Canabinoides/efeitos adversos , Dronabinol/efeitos adversos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológicoRESUMO
Patients with high-risk aggressive B-cell lymphoma exhibit poor survival after R-CHOP. More intensive regimens yield higher rates of remission but also of complication. We investigated all 401 patients < 70 years with high-risk (age-adjusted [aa] international prognostic index [IPI] ≥2, extranodal, or bulky) aggressive B-cell lymphoma hospitalized at Karolinska for urgent start of immunochemotherapy (129 R-Hyper-CVAD; 261 R-CHOP/R-CHOEP). Patients showed IPI 3-5 (70%), WHO PS ≥2 (49%), bulky disease (70%), extranodal (75%) and CNS (8%) involvement. Five-year overall/progression-free survival (OS/PFS) was better in patients who started R-Hyper-CVAD (84%/77%) compared with R-CHOP/R-CHOEP (66%/55%). Differences were independent in multivariable analysis, seen in all patient categories, and accentuated in extreme high-risk disease: R-Hyper-CVAD vs. R-CHOP/R-CHOEP showed 5-year PFS 69% vs.40% in aaIPI 3 and 88% vs. 38% in CNS involvement. For validation, survival was compared between the two Karolinska sites and calendar periods. Survival was superior 2006-2010 at the site that introduced R-Hyper-CVAD/R-MA 2006, identical at both sites 2011-2017 after the other site adopted R-Hyper-CVAD/R-MA 2011, and excellent 2018-2020 when R-Hyper-CVAD/R-MA use increased to 75% of patients. Despite considerable toxicity, also patients aged 61-69 years showed better survival with R-Hyper-CVAD/R-MA. This is the largest single-centre series of patients treated with R-Hyper-CVAD/R-MA, showing favourable outcome in high-risk aggressive B-cell lymphoma.
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Treatment for patients > 60 years with classical Hodgkin lymphoma (cHL) is problematic; there is no gold standard, and outcome is poor. Using the Swedish Lymphoma Registry, we analysed all Swedish patients diagnosed with cHL between 2000 and 2014 (N = 2345; median age 42 years; 691 patients were >60 years). The median follow-up time was 6.7 years. Treatment for elderly patients consisted mainly of ABVD or CHOP, and the younger patients were treated with ABVD or BEACOPP (with no survival difference). In multivariable analysis of patients > 60 years, ABVD correlated with better survival than CHOP (p = 0.027), and ABVD became more common over time among patients aged 61-70 years (p = 0.0206). Coinciding with the implementation of FDG-PET/CT, the fraction of advanced-stage disease increased in later calendar periods, also in the older patient group. Survival has improved in cHL patients > 60 years (p = 0.027), for whom ABVD seems superior to CHOP.
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Purpose: We sought to refine the clinical picture of primary adrenal lymphoma (PAL), a rare lymphoid malignancy with predominant adrenal manifestation and risk of adrenal insufficiency. Methods: Ninety-seven patients from 14 centers in Europe, Canada and the United States were included in this retrospective analysis between 1994 and 2017. Results: Of the 81 patients with imaging data, 19 (23%) had isolated adrenal involvement (iPAL), while 62 (77%) had additional extra-adrenal involvement (PAL+). Among patients who had both CT and PET scans, 18FDG-PET revealed extra-adrenal involvement not detected by CT scan in 9/18 cases (50%). The most common clinical manifestations were B symptoms (55%), fatigue (45%), and abdominal pain (35%). Endocrinological assessment was often inadequate. With a median follow-up of 41.6 months, 3-year progression-free (PFS) and overall (OS) survival rates in the entire cohort were 35.5% and 39.4%, respectively. The hazard ratios of iPAL for PFS and OS were 40.1 (95% CI: 2.63-613.7, P = 0.008) and 2.69 (95% CI: 0.61-11.89, P = 0.191), respectively. PFS was much shorter in iPAL vs PAL+ (median 4 months vs not reached, P = 0.006), and OS also appeared to be shorter (median 16 months vs not reached), but the difference did not reach statistical significance (P = 0.16). Isolated PAL was more frequent in females (OR = 3.81; P = 0.01) and less frequently associated with B symptoms (OR = 0.159; P = 0.004). Conclusion: We found unexpected heterogeneity in the clinical spectrum of PAL. Further studies are needed to clarify whether clinical distinction between iPAL and PAL+ is corroborated by differences in molecular biology.
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Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Linfoma/diagnóstico , Linfoma/epidemiologia , Neoplasias das Glândulas Suprarrenais/complicações , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/epidemiologia , Insuficiência Adrenal/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Estudos de Coortes , Diagnóstico Diferencial , Europa (Continente)/epidemiologia , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Linfoma/complicações , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Fenótipo , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X , Estados Unidos/epidemiologiaRESUMO
Monotherapy with the anti-CD20 monoclonal antibody rituximab can induce complete responses (CR) in patients with follicular lymphoma (FL). Resting FcRγIII+ (CD16+) natural killer (NK) cells respond strongly to rituximab-coated target cells in vitro. Yet, the contribution of NK cells in the therapeutic effect in vivo remains unknown. Here, we followed the NK cell repertoire dynamics in the lymph node and systemically during rituximab monotherapy in patients with FL. At baseline, NK cells in the tumor lymph node had a naïve phenotype albeit they were more differentiated than NK cells derived from control tonsils as determined by the frequency of CD56dim NK cells and the expression of killer cell immunoglobulin-like receptors (KIR), CD57 and CD16. Rituximab therapy induced a rapid drop in NK cell numbers coinciding with a relative increase in the frequency of Ki67+ NK cells both in the lymph node and peripheral blood. The Ki67+ NK cells had slightly increased expression of CD16, CD57 and higher levels of granzyme A and perforin. The in vivo activation of NK cells was paralleled by a temporary loss of in vitro functionality, primarily manifested as decreased IFNγ production in response to rituximab-coated targets. However, patients with pre-existing NKG2C+ adaptive NK cell subsets showed less Ki67 upregulation and were refractory to the loss of functionality. These data reveal variable imprints of rituximab monotherapy on the NK cell repertoire, which may depend on pre-existing repertoire diversity.
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Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/imunologia , Rituximab/imunologia , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Antígenos CD57/imunologia , Granzimas/imunologia , Humanos , Interferon gama/imunologia , Antígeno Ki-67/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Perforina/imunologia , Receptores de IgG/imunologia , Receptores KIR/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Autologous stem-cell transplantation (ASCT) is a common treatment for lymphoma but it has some mortality. METHODS: All 433 lymphoma patients who underwent ASCT for lymphoma at Karolinska Huddinge 1994-2016 were investigated, including CD34+ cell amounts, medications, infectious and other complications, intensive care, longitudinal laboratory values, and secondary myeloid neoplasia. RESULTS: The 100-day non-relapse and overall mortalities were 5.6% and 7.2%. Stem-cell harvests < 5 million CD34+ cells/kg correlated with inferior 100-day and long-term survival. Prior to conditioning (93% BEAM), elevated (both 3-9 and ≥ 10 mg/L) C-reactive protein (CRP) and creatinine, and low albumin (but not higher age) predicted inferior higher 100-day survival. Intravenous antibiotics were given to 97% (22% positive blood cultures) and parenteral nutrition to 89%. After 1 year, 86% had normalized hemoglobin. The 5-year risk for secondary myeloid neoplasia was 4.1%, associated with smaller harvests. CONCLUSIONS: Before starting conditioning, patients should have preferably harvested ≥ 5 million CD34+ cells/kg and normal CRP, albumin, and creatinine. It appears safe to transplant patients ≥ 66 years.
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PURPOSE: Follicular lymphoma is a heterogeneous disease with variable prognosis and clinical course. We hypothesized that the presence of nonmalignant T cells in the microenvironment of the tumor may affect the outcome. EXPERIMENTAL DESIGN: Using flow cytometry, we evaluated the T-cell subsets in the lymph node microenvironment of follicular lymphoma. All patients in South Stockholm County with indolent follicular lymphoma and with flow cytometry done on a diagnostic lymph node between 1994 and 2004 were included (N = 139). Diagnosis and grade (1, 2, and 3a) were confirmed by re-review. Flow cytometry results were reanalyzed. Lymphocyte subsets, the Follicular Lymphoma International Prognostic Index, grade, and clinical characteristics were evaluated in univariable and multivariable Cox analysis with respect to overall survival (OS) and disease-specific survival (DSS). RESULTS: Higher CD8+ T-cell levels correlated with longer OS and DSS, independently of the Follicular Lymphoma International Prognostic Index (OS, P = 0.017; DSS, P = 0.020) and independently of all other prognostic factors (OS, P = 0.001; DSS, P = 0.004). Median OS was not reached for patients in the upper quarter of CD8+ T-cell levels (>8.6%), 10.4 years for patients in the middle half (4.2-8.6%), and 6.0 years for patients in the lower quarter (<4.2%). Furthermore, patients who had not required treatment within 6 months from diagnosis had more CD8+ T cells (P = 0.011). CONCLUSIONS: Higher levels of CD8+ T cells predict a better prognosis, and these data support an important role for nonmalignant immune cells in the biology of follicular lymphoma. Evaluating the CD8+ T cells by flow cytometry at diagnosis may provide prognostic information.
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Linfócitos T CD8-Positivos/metabolismo , Citometria de Fluxo/métodos , Linfonodos/patologia , Linfoma Folicular/metabolismo , Linfoma Folicular/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: For indolent lymphoma, the optimal timing, sequence, and choice of therapeutic regimens remain a matter of debate. In two Nordic Lymphoma Group randomized trials, symptomatic or clearly progressing patients were treated first line with a rituximab-containing regimen without chemotherapy. The purpose of this study was to assess long-term survival, risk of transformation, and need of new therapies. METHODS: Data were collected at cross-sectional follow-up for 321 patients with indolent lymphoma (84% with follicular lymphomas [FL]) included in one of two Nordic Lymphoma Group trials (accrual 1998 to 1999 and 2002 to 2008). All patients received first-line therapy with one or two cycles of four weekly infusions of rituximab 375 mg/m2, and 148 were randomly allocated to the addition of interferon alfa-2a. Follow-up data were retrieved from initial trial databases and medical records on repeated clinical evaluations. RESULTS: At the end of follow-up, 73% of patients were alive, with a median follow-up after random assignment of 10.6 years. Among all, 36% (38% with FL) had never needed chemotherapy. For patients with FL who required new therapy within 24 months because of early disease progression, the 10-year survival rate was 59% versus 81% for those with longer remission. Interferon was not shown to improve long-term outcome. Transformation was diagnosed in 20% of all patients (2.4% per person-year) and in 18% with FL. An additional malignancy was found in 12%. CONCLUSION: Approximately one third of patients with symptomatic indolent lymphoma (30% with FL, 23% without FL) did not need new therapy in the long term after first-line rituximab without chemotherapy. In the entire cohort, 10-year survival was excellent with no major safety issues, which suggests that chemotherapy can be delayed safely in the majority of patients.
RESUMO
Purpose: To evaluate the safety, efficacy, and immunobiological correlates of allogeneic NK-cell-based therapy in primary chemotherapy-refractory or relapsed high-risk myelodysplastic syndrome (MDS), secondary AML (MDS/AML), and de novo AML patients.Experimental Design: Sixteen patients received fludarabine/cyclophosphamide conditioning combined with total lymphoid irradiation followed by adoptive immunotherapy with IL2-activated haploidentical NK cells.Results: NK-cell infusions were well-tolerated, with only transient adverse events observed in the 16 patients. Six patients achieved objective responses with complete remission (CR), marrow CR, or partial remission (PR). Five patients proceeded to allogeneic hematopoietic stem cell transplantation (HSCT). Three patients are still free from disease >3 years after treatment. All evaluable patients with objective responses (5/5 evaluable) had detectable donor NK cells at days 7/14 following infusion and displayed reduction of tumor cell clones, some of which carried poor prognosis mutations. Residual lin-CD34+CD123+CD45RA+ blast cells in responders had increased total HLA class I and HLA-E expression. Responding patients displayed less pronounced activation of CD8+ T cells and lower levels of inflammatory cytokines following NK-cell infusion. Intriguingly, despite omission of systemic IL2, all patients displayed increased frequencies of activated Ki-67+CD127-FoxP3+CD25hiCD4+ Treg cells of recipient origin following NK-cell therapy.Conclusions: Overall, this study suggests that high-risk MDS is responsive to NK-cell therapy and supports the use of haploidentical NK-cell infusions as a bridge to HSCT in refractory patients. Objective clinical responses and reduction of high-risk clones were associated with detectable donor-derived NK cells, immunoediting of residual blast cells, and less pronounced host immune activation. Clin Cancer Res; 24(8); 1834-44. ©2018 AACR.
Assuntos
Transferência Adotiva , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/terapia , Transplante Haploidêntico , Transferência Adotiva/efeitos adversos , Transferência Adotiva/métodos , Adulto , Idoso , Biomarcadores , Evolução Clonal/imunologia , Terapia Combinada , Citocinas/biossíntese , Feminino , Sobrevivência de Enxerto , Humanos , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Indução de Remissão , Quimeras de Transplante , Transplante Haploidêntico/métodos , Resultado do TratamentoRESUMO
The diagnosis of gastrointestinal graft versus host disease (GI-GVHD) is based on clinical symptoms and histological findings. In clinical practice, it is often difficult to decide whether abdominal symptoms in an allogeneic transplant recipient are caused by GVHD or other disorders. Endoscopic biopsies are helpful in establishing the diagnosis, but endoscopy is not always possible to perform due to poor general condition of the patients. No biomarkers are routinely used to predict GVHD. The aim of fecal calprotectin and alpha-1 antitrypsin testing in our study was to find out whether determination of the concentrations of these proteins may be used as a screening method for enteric GVHD. We studied prospectively 51 patients, 8 of whom developed GI-GVHD. Our data demonstrate that elevated fecal calprotectin levels were significantly associated with presence of GI-GVHD. We found a positive association between high F-calprotectin and severe gastrointestinal GVHD. In bivariate analysis, only calprotectin but not alpha-1 antitrypsin was independently associated with GI-GVHD. Testing for fecal calprotectin after allogeneic stem cell transplantation may be a useful screening tool.