RESUMEN

This study investigates COVID-19 outcomes and immune response in chronic myeloid leukemia (CML) patients post-SARS-CoV-2 vaccination, comparing effectiveness of various vaccine options. Data from 118 CML patients (85 in Brazil, 33 in the US) showed similar infection rates prior (14% Brazil, 9.1% US) and post-vaccination (24.7% vs. 27.3%, respectively). In Brazil, AstraZeneca and CoronaVac were the most commonly used vaccine brands, while in the US, Moderna and Pfizer-BioNTech vaccines dominated. Despite lower seroconversion in the Brazilian cohort, all five vaccine brands analyzed prevented severe COVID-19. Patients who received mRNA and recombinant viral vector vaccines (HR: 2.20; 95%CI 1.07-4.51; p < .031) and those that had achieved at least major molecular response (HR: 1.51; 95% CI 1.01-3.31; p < .0001) showed higher seroconversion rates. Our findings suggest that CML patients can generate antibody responses regardless of the vaccine brand, thereby mitigating severe COVID-19. This effect is more pronounced in patients with well-controlled disease.

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype and dependent on angiogenesis (AG), whose main effectors are VEGFA and VEGFR2. Functional single nucleotide variants (SNVs) are described in VEGFA and KDR genes. However, it still unknown whether VEGFA - 2578C/A, -2489C/T, -1154G/A, -634G/C, -460C/T and KDR-604T/C, -271G/A, +1192G/A and +1719A/T SNVs act on DLBCL risk and angiogenic features. Genomic DNA from 168 DLBCL patients and 205 controls was used for SNV genotyping. Angiogenesis was immunohistochemically assessed in tumor biopsies, with reactions for VEGFA, VEGFR2, and CD34. VEGFA -1154GG genotype were associated with 1.6-fold higher DLBCL risk. KDR + 1192GG plus KDR + 1719 TT and KDR + 1192GG plus VEGFA - 2578CC combined genotypes are associated with 2.19- and 2.04-fold higher risks of DLBCL, respectively. VEGFA - 634GG or GC genotypes are associated with increased microvessel density and VEGFA levels. No relationship was observed between SNVs and cell-of-origin classification of DLBCL, but higher VEGFA and VEGFR2 were seen in non-germinal center tumors.

Asunto(s)

Predisposición Genética a la Enfermedad , Linfoma de Células B Grandes Difuso , Humanos , Polimorfismo de Nucleótido Simple , Genotipo , Linfoma de Células B Grandes Difuso/genética , Nucleótidos , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética

RESUMEN

Killer cell immunoglobulin-like receptors (KIR) exhibit extensive diversity, giving rise to different KIR profiles in populations worldwide. This study aimed to investigate the distribution of KIR genes and HLA ligands in a population from Campinas, southeastern Brazil (n = 292), and to compare their results with other populations. A comprehensive analysis of population-specific genes, genotype, and haplotype frequencies of KIR may facilitate a better understanding of their evolution and role in immunity. The genotyping of 16 KIR genes and HLA class I alleles was performed by the reverse sequence-specific oligonucleotide methodology using the Luminex platform (One Lambda, Inc., Canoga Park, CA). The framework genes were present in all individuals, with the most common non-framework KIR genes detected being KIR2DP1(96.6%), KIR2DL1(95.5%), KIR3DL1(94.5%), KIR2DS4(93.8%) and KIR2DL3(87.3%). KIR2DS1, KIR2DS3, KIR2DS5, and KIR3DS1 presented frequencies below 40%. KIR2DL2, KIR2DL5, and KIR2DS2 showed intermediate frequencies (between53% and 58%). The activating gene KIR2DS5 was the least common in this population (30.8%). Forty-five KIR profiles were found with the commonest being the homozygous A haplotype (27.4%). The distribution of KIR genes in the Brazilian population is similar to Caucasian European and Euro-descendant populations.

Asunto(s)

Receptores KIR , Humanos , Brasil , Frecuencia de los Genes , Ligandos , Receptores KIR/genética , Genotipo

RESUMEN

Multiple myeloma (MM) accounts for 10-15% of all hematologic malignancies, as well as 20% of deaths related to hematologic malignant tumors, predominantly affecting bone and bone marrow. Positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (FDG-PET/CT) is an important method to assess the tumor burden of these patients. It is often challenging to classify the extent of disease involvement in the PET scans for many of these patients because both focal and diffuse bone lesions may coexist, with varying degrees of FDG uptake. Different metrics involving volumetric parameters and texture features have been proposed to objectively assess these images. Here, we review some metabolic parameters that can be extracted from FDG-PET/CT images of MM patients, including technical aspects and predicting MM outcome impact. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are volumetric parameters known to be independent predictors of MM outcome. However, they have not been adopted in clinical practice due to the lack of measuring standards. CT-based segmentation allows automated, and therefore reproducible, calculation of bone metabolic metrics in patients with MM, such as maximum, mean and standard deviation of the standardized uptake values (SUV) for the entire skeleton. Intensity of bone involvement (IBI) is a new parameter that also takes advantage of this approach with promising results. Other indirect parameters obtained from FDG-PET/CT images, such as visceral adipose tissue glucose uptake and subcutaneous adipose tissue radiodensity, may also be useful to evaluate the prognosis of MM patients. Furthermore, the use and quantification of new radiotracers can address different metabolic aspects of MM and may have important prognostic implications.

RESUMEN

OBJECTIVES: Single nucleotide variants (SNVs) in vascular endothelial growth factor A (VEGFA) and VEGFA receptor (KDR) genes confer different inherited abilities in angiogenesis (AG) pathway. We aimed in the present study to evaluate influence of six VEGFA and four KDR SNVs in clinical features and survival of diffuse large B-cell lymphoma (DLBCL) patients. METHODS: One hundred and sixty-eight DLBCL patients diagnosed between June 2009-September 2014 were enrolled in the study. Patients were homogeneously treated with R-CHOP. Genotypes were identified in genomic DNA by real-time polymerase chain reaction. RESULTS: Patients with VEGFA -634CC and +936CT or TT genotypes were at increased risk of showing grade III / IV toxicities and not achieving complete remission with treatment, and shorter event-free and overall survival were seen in patients with VEGFA -1154GA or AA genotype and VEGFA ATAGCC haplotype. CONCLUSION: Our data suggest that inherited abnormalities in AG's gene modulate clinical features and prognosis of DLBCL patients homogeneously treated with R-CHOP.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Linfoma de Células B Grandes Difuso/patología , Neovascularización Patológica/patología , Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Anciano de 80 o más Años , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Masculino , Persona de Mediana Edad , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Prednisona/administración & dosificación , Pronóstico , Estudios Prospectivos , Rituximab/administración & dosificación , Tasa de Supervivencia , Vincristina/administración & dosificación

RESUMEN

This observational, multicenter study aimed to report the clinical evolution of COVID-19 in patients with chronic myeloid leukemia in Latin America. A total of 92 patients presented with COVID-19 between March and December 2020, 26% of whom were severe or critical. The median age at COVID-19 diagnosis was 48 years (22-79 years), 32% were 60 years or older, and 61% were male. Thirty-nine patients presented with at least one comorbidity (42.3%). Eighty-one patients recovered (88%), and 11 (11.9%) died from COVID-19. There was one case of reinfection. Patients with a major molecular response presented superior overall survival compared to patients with no major molecular response (91 vs. 61%, respectively; p = 0.004). Patients in treatment-free remission and receiving tyrosine kinase inhibitors showed higher survival rates than patients who underwent hematopoietic stem cell transplantation and those who did not receive tyrosine kinase inhibitors (100, 89, 50, and 33%, respectively; p < 0.001).

Asunto(s)

COVID-19 , Leucemia Mielógena Crónica BCR-ABL Positiva , Prueba de COVID-19 , Humanos , América Latina/epidemiología , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , SARS-CoV-2

RESUMEN

BACKGROUND: There is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients' samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL. METHODS: We assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models. RESULTS: High FOXP3/CD3 ratios (p = 0.001), high IL17A levels (p = 0.003) and low IL2 levels (p = 0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p = 0.02). In the SNV model, the CC haplotype of IL10 (p < 0.01), the GG genotype of IL2 rs2069762 (p = 0.02) and the AA+AG genotypes of TGFBR2 rs3087465 (p < 0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1 rs6957 associated with lower tumor TGFß levels (p = 0.03) and less CD163+ macrophages (p = 0.01), but did not modulate patients' survival. CONCLUSIONS: Our results indicate that the TME composition has relevant biological roles in MCL. In this setting, immunohistochemical detection of T-reg cells, IL17A and IL2, coupled with SNV genotyping in IL10, TGFBR2 and IL2, may represent novel prognostic factors in this disease, following future validations.

Asunto(s)

Inmunidad/genética , Linfoma de Células del Manto/genética , Polimorfismo de Nucleótido Simple , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Terapia Combinada , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Estudios de Asociación Genética , Genotipo , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunosupresores/uso terapéutico , Interleucinas/genética , Estimación de Kaplan-Meier , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/terapia , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Análisis de Componente Principal , Pronóstico , Modelos de Riesgos Proporcionales , Receptores de Factores de Crecimiento Transformadores beta/genética , Rituximab/uso terapéutico , Factores de Transcripción SOXC/análisis , Factor de Crecimiento Transformador beta1/genética

Asunto(s)

Predisposición Genética a la Enfermedad , Interleucina-17/genética , Linfoma Folicular/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta1/genética , Adulto , Anciano , Femenino , Humanos , Interleucina-17/inmunología , Linfoma Folicular/inmunología , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/inmunología , Receptor Tipo II de Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta1/inmunología

RESUMEN

The study of the tumor microenvironment (TME) in follicular lymphoma (FL) has produced conflicting results due to assessment of limited TME subpopulations, and because of heterogeneous treatments among different cohorts. Also, important genetic determinants of immune response, such as single-nucleotide polymorphisms (SNPs), remain underexplored in this disease. We performed a detailed study of the TME in 169 FL biopsies using immunohistochemistry, encompassing lymphocytes, macrophages, and cytokines. We also genotyped 16 SNPs within key immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, and IL17F) in 159 patients. We tested associations between SNPs, clinicopathological features and TME composition, and proposed survival models in R-CHOP/R-CVP-treated patients. Presence of the IL12A rs568408 "A" allele associated with the follicular pattern of FOXP3+ cells. The IL12A AA haplotype included rs583911 and rs568408 and was an independent predictor of worse survival, together with the follicular patterns of T-cells (FOXP3+ and CD8+) and high IL-17F tumor levels. The patterns of CD3+, CD4+ and CD8+ cells, displayed as a principal component, also associated with survival. Hierarchical clustering of the TME proteins demonstrated a cluster that was associated with worse prognosis (tumors enriched in IL-17A, IL-17F, CD8, PD1, and Ki-67). The survival of FL patients who were treated in the rituximab era shows a strong dependence on TME signals, especially the T-cell infiltration patterns and IL-17F tumor levels. The presence of the AA haplotype of IL12A in the genome of FL patients is an additional prognostic factor that may modulate the composition of T-reg cells in this disease.

RESUMEN

ABSTRACT: The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

Asunto(s)

Leucemia Linfoide , Coronavirus , COVID-19 , Linfoma , Enfermedad de Hodgkin , Leucemia Linfocítica Crónica de Células B , Linfoma de Células B , Linfoma de Células T Periférico , Linfoma de Células del Manto

RESUMEN

The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

RESUMEN

Abstract Introduction Ruxolitinib has been approved for the treatment of myelofibrosis (MF). In this study, we present safety and efficacy findings from an analysis of 104 patients with intermediate- and high-risk MF in a Brazilian cohort of the JUMP study who received treatment with ruxolitinib. Methods JUMP is a single-arm, open-label, phase IIIb, expanded-access study. The primary endpoint was to evaluate the safety and tolerability (frequency, duration, and severity of adverse events [AEs]) of ruxolitinib. Results All of the 104 patients received the treatment. Median duration of exposure was 35.8 months. The most common hematologic AEs were anemia (57.7), thrombocytopenia (38.5%), neutropenia (11.5%), and leukopenia (9.6%). Second malignancies (all grades) occurred in 19.2% of patients (n = 20). Serious AEs were reported in 62.5% of patients (n = 65). The proportions of patients with ≥50% reduction from baseline in palpable spleen length at weeks 24 and 48 were 62.7% and 69.2%, respectively. The mean change from the baseline in the Functional Assessment of Cancer Therapy (FACT)-Lymphoma total score was 10.8 [15.6%] at week 4, 12.6 [14.1%] at week 24, and 12.2 [14.3%] at week 48. The mean change from the baseline for the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale was 3.9 [42.8%] at week 4, 4.9 [29.9%] at week 24, and 4.7 [28%] at week 48. At week 48, the estimated progression-free survival, leukemia-free survival, and overall survival probabilities were 91%, 91% and 93%, respectively Overall, 21 deaths were observed in the present study. Conclusion Findings from this study suggest that ruxolitinib could be evaluated as a standard-of-care treatment for the MF population in need of a viable treatment option. NCT01493414

Asunto(s)

Humanos , Masculino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Quimioterapia , Mielofibrosis Primaria/terapia , Policitemia , Esplenomegalia , Trombocitosis , Brasil

RESUMEN

INTRODUCTION: Ruxolitinib has been approved for the treatment of myelofibrosis (MF). In this study, we present safety and efficacy findings from an analysis of 104 patients with intermediate- and high-risk MF in a Brazilian cohort of the JUMP study who received treatment with ruxolitinib. METHODS: JUMP is a single-arm, open-label, phase IIIb, expanded-access study. The primary endpoint was to evaluate the safety and tolerability (frequency, duration, and severity of adverse events [AEs]) of ruxolitinib. RESULTS: All of the 104 patients received the treatment. Median duration of exposure was 35.8 months. The most common hematologic AEs were anemia (57.7), thrombocytopenia (38.5%), neutropenia (11.5%), and leukopenia (9.6%). Second malignancies (all grades) occurred in 19.2% of patients (n=20). Serious AEs were reported in 62.5% of patients (n=65). The proportions of patients with ≥50% reduction from baseline in palpable spleen length at weeks 24 and 48 were 62.7% and 69.2%, respectively. The mean change from the baseline in the Functional Assessment of Cancer Therapy (FACT)-Lymphoma total score was 10.8 [15.6%] at week 4, 12.6 [14.1%] at week 24, and 12.2 [14.3%] at week 48. The mean change from the baseline for the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale was 3.9 [42.8%] at week 4, 4.9 [29.9%] at week 24, and 4.7 [28%] at week 48. At week 48, the estimated progression-free survival, leukemia-free survival, and overall survival probabilities were 91%, 91% and 93%, respectively Overall, 21 deaths were observed in the present study. CONCLUSION: Findings from this study suggest that ruxolitinib could be evaluated as a standard-of-care treatment for the MF population in need of a viable treatment option. NCT01493414.

RESUMEN

The purpose of this study was to assess the influence of single-nucleotide polymorphisms (SNPs) on cytokine genes in the development of diffuse large B-cell lymphoma (DLBCL). One hundred and twelve patients and 221 controls were investigated. Among them, 97 patients treated with R-CHOP were subdivided into two groups: (i) complete remission of the disease and (ii) patients who progressed to death, relapsed, or had disease progression. The SNPs investigated by PCR-SSP were TNF -308G>A (rs1800629), IFNG +874A>T (rs2430561), IL6 -174G>C (rs1800795), IL10 -1082A>G (rs1800896), IL10 -819C>T (rs1800871), IL10 -592C>A (rs1800872), and TGFB1 codon10T>C (rs1982073) and codon25G>C (rs1800471). In general, the genotypes that have been associated in the literature with lower production or intermediate production of IL-10 and higher production of IFN-γ were associated with the protection of the development of the disease, possibly favoring the Th1 immune response and diminishing the capacity of cell proliferation. However, patients receiving R-CHOP treatment presented unfavorable prognoses in the presence of genotypes related to the intermediate production of IL-10 and high production of TGF-ß1, indicating that cytokines may be related to the response to treatment and action mechanisms of Rituximab.

Asunto(s)

Predisposición Genética a la Enfermedad , Haplotipos , Interferón gamma/genética , Interleucina-10/genética , Linfoma de Células B Grandes Difuso/genética , Polimorfismo de Nucleótido Simple , Anciano , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica , Estudios de Casos y Controles , Ciclofosfamida , Doxorrubicina , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Oportunidad Relativa , Prednisona , Pronóstico , Rituximab , Resultado del Tratamiento , Vincristina

RESUMEN

ABSTRACT Introduction: The incidence of grade 3-4 anemia was reported to be 3% with imatinib therapy for newly diagnosed chronic myeloid leukemia (CML) in the chronic phase (CP). However, there are few data regarding the causes and the development of anemia after long-term treatment. This study aimed to evaluate the incidence of anemia after at least two years of imatinib treatment of CML patients in the CP and to identify other contributing causes of anemia in this population. Patients and methods: We performed a retrospective analysis of 97 CML patients in the CP treated with imatinib for at least two years. We analyzed the hemoglobin (Hb) levels of CML patients at diagnosis, upon initiation of treatment with imatinib and after two years of imatinib treatment, and investigated other causes of anemia in this population. Results: Most of the patients presented Hb levels below the normal range (80.4%) after the second year of treatment, 17.9% grade 2 and 1.3% grade 3. In 13 cases (16.7%), anemia was attributed to resistance and in 13 cases (16.7%) the following causes were identified: iron deficiency (n = 5), hypothyroidism (n = 2), vitamin B12 deficiency (n = 3), acquired immune deficiency syndrome (AIDS) (n = 1), pulmonary tuberculosis (n = 1) and renal toxicity (n = 1). In 52 patients (66.6%), there were no other factors contributing to anemia, except imatinib treatment. Conclusion: Regular follow-up is required to identify the causes of anemia not related to CML or imatinib toxicity. The importance of investigating secondary causes of anemia should be emphasized, especially in patients with good adherence to treatment and satisfactory therapeutic response.

Asunto(s)

Humanos , Masculino , Femenino , Leucemia Mielógena Crónica BCR-ABL Positiva , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/uso terapéutico , Anemia

RESUMEN

INTRODUCTION: The incidence of grade 3-4 anemia was reported to be 3% with imatinib therapy for newly diagnosed chronic myeloid leukemia (CML) in the chronic phase (CP). However, there are few data regarding the causes and the development of anemia after long-term treatment. This study aimed to evaluate the incidence of anemia after at least two years of imatinib treatment of CML patients in the CP and to identify other contributing causes of anemia in this population. PATIENTS AND METHODS: We performed a retrospective analysis of 97 CML patients in the CP treated with imatinib for at least two years. We analyzed the hemoglobin (Hb) levels of CML patients at diagnosis, upon initiation of treatment with imatinib and after two years of imatinib treatment, and investigated other causes of anemia in this population. RESULTS: Most of the patients presented Hb levels below the normal range (80.4%) after the second year of treatment, 17.9% grade 2 and 1.3% grade 3. In 13 cases (16.7%), anemia was attributed to resistance and in 13 cases (16.7%) the following causes were identified: iron deficiency (n=5), hypothyroidism (n=2), vitamin B12 deficiency (n=3), acquired immune deficiency syndrome (AIDS) (n=1), pulmonary tuberculosis (n=1) and renal toxicity (n=1). In 52 patients (66.6%), there were no other factors contributing to anemia, except imatinib treatment. CONCLUSION: Regular follow-up is required to identify the causes of anemia not related to CML or imatinib toxicity. The importance of investigating secondary causes of anemia should be emphasized, especially in patients with good adherence to treatment and satisfactory therapeutic response.

Asunto(s)

Enfermedad de Hodgkin/etiología , Receptor de Muerte Celular Programada 1/deficiencia , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Adulto , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Enfermedad de Hodgkin/patología , Humanos , Masculino , Pronóstico , Receptor de Muerte Celular Programada 1/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Factores de Riesgo , Factores Sexuales