RESUMEN
The clinical impact of therapy-related acute leukemias is increasing with the extension of cancer-related survival; however, the origins remain largely unknown. Acute erythroleukemia (AEL), a rare unfavorable type of myeloid neoplasia, may also develop secondary to cytotoxic therapy. The disorder is featured by specific genetic alterations, most importantly multi-allelic mutations of the TP53 gene. While AEL might appear as a part of the therapy-related MDS/AML, spectrum information regarding the genetic complexity and progression is largely missing. We present two AEL cases arising after cytotoxic therapy and melphalan-based myeloablation/autologous peripheral stem cell transplantation due to multiple myeloma (MM). As stated, multiple pathogenic TP53 variants were present unrelated to preexisting MM, in parallel with uninvolved/wild-type hemopoiesis. Potential mechanisms of leukemic transformation are discussed, which include (1) preexisting preneoplastic hemopoietic stem cells (HSC) serving as the common origin for both MM and AEL, (2) the generation and intramedullary survival of p53-deficient post-chemotherapy HSCs, (3) reinoculation of mobilized autologous TP53 mutated HSCs, and (4) melphalan treatment-related late-onset myelodysplasia/leukemia with newly acquired TP53 mutations.
Asunto(s)
Leucemia Eritroblástica Aguda , Mieloma Múltiple , Trasplante Autólogo , Mieloma Múltiple/terapia , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Humanos , Persona de Mediana Edad , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patología , Leucemia Eritroblástica Aguda/terapia , Masculino , Proteína p53 Supresora de Tumor/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Transformación Celular Neoplásica/genética , Mutación , Femenino , Melfalán/uso terapéutico , Melfalán/administración & dosificación , Anciano , Quimioradioterapia/métodos , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/terapia , Neoplasias Primarias Secundarias/genéticaRESUMEN
Objective Non-Hodgkin lymphoma (NHL) arising as a secondary malignancy in patients treated for classical Hodgkin lymphoma (cHL) is an infrequent and challenging clinical scenario. NHL can be presented synchronously with cHL or may develop later, sequentially, up to years after treatment for cHL. The relationship between the two lymphomas is unclear, and there are no clear guidelines for the management of these patients. We would like to find a better clinical understanding of this issue so this study investigates the occurrence and clinical characteristics of secondary NHL. Materials and methods In this retrospective cohort examination, we collected cHL cases when NHL occurred during or after the course of treating cHL. We performed the histopathologic revisions of the samples, and in every case where the quality of the sample was lower, we performed molecular examinations to find the association between cHL and NHL. We performed next-generation genome sequencing (NGS) and immunoglobulin heavy-chain variable region gene (IgHV) clonality testing. Results In a cohort of 164 cHL patients diagnosed between 2011 and 2020, six patients were identified with NHL during rebiopsy prompted by lymphoma relapse or progression. Among these, five patients were diagnosed with post-germinal center-originated diffuse large B-cell lymphoma (post-GC DLBCL), and one patient presented high-grade B-cell lymphoma (HG-BCL). The NHL manifestation differed in its timing: three cases emerged after successful cHL treatment, with at least 18 months of complete remission, while the other three patients faced primary refractory cHL. Notably, the primary refractory cases did not exhibit a confirmed clonal relationship between cHL and NHL, but NGS data raised the possibility of synchronous NHL in one case. In contrast, among the patients with sequentially occurring NHL, polymerase chain reaction (PCR) testing of the IgHV gene affirmed a clonal connection between cHL and secondary DLBCL in one case, while the high morphological similarity suggested a potential clonality between the two lymphomas in another case. Conclusion This study reveals that secondary NHL may manifest both synchronously and sequentially following cHL. Our results suggest that synchronous NHL has a worse prognosis compared to sequential cases when the different lymphomas are not recognized at the time of diagnosis. As our data showed, in some cases, mutations that accompany the tumor cells throughout their clonal evolution can be identified, with additional mutations later on. In the future, next-generation sequencing (NGS)-based processing of liquid biopsy samples can overcome the limitations resulting from the spatial heterogeneity of lymphoid malignancies. Over the long term, this identification could lead to early patient selection and alternative treatment strategies, ultimately leading to improved prospects for cure.
RESUMEN
AIMS: TP53 alterations have a significant prognostic effect in myeloid neoplasms. Our objective was to investigate the TP53 gene mutation status, p53 protein expression and their relationship in dysplasia-related myeloid neoplasms with varying levels of myeloblast counts. METHODS AND RESULTS: A total of 76 bone marrow biopsy samples with different blast counts were analysed. Total and strong (3+) p53 expression was determined. Dual immunohistochemical staining was performed to determine the cell population associated with p53 expression. NGS analysis was performed using the Accel-Amplicon Comprehensive TP53 panel. Both p53 expression and TP53 VAF showed a significant correlation with the myeloblast ratio (P < 0.0001); however, p53 expression was also present in other cell lineages. The VAF value exhibited a significant correlation with p53 expression. A high specificity (0.9800) was observed for TP53 mutation using the ≥ 10% strong (3+) p53 cut-off value, although the sensitivity (0.4231) was low. CONCLUSIONS: Strong (3+) p53 expression using a ≥ 10% cut-off value accurately predicts TP53 mutation but does not reveal the allelic state. The p53 expression is significantly influenced by myeloblast count, and histological interpretation should consider the presence of intermixed non-neoplastic marrow cells with varying physiological p53 expression.
Asunto(s)
Mutación , Síndromes Mielodisplásicos , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/metabolismo , Masculino , Persona de Mediana Edad , Femenino , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Médula Ósea/metabolismo , Adulto JovenRESUMEN
Autologous stem cell transplantation (ASCT) is the standard treatment of primary refractory or relapsed Hodgkin-lymphoma, which can provide a cure rate of about 50%. The aim of our study was to analyze the data of 126 HL patients undergoing AHSCT in Hungary between 01/01/2016 and 31/12/2020. We assessed the progression-free and overall survival, the prognostic role of PET/CT performed before transplantation and effect of brentuximab vedotin (BV) treatment on survival outcomes. The median follow-up time from AHSCT was 39 (1-76) months. The 5-year OS comparing PET- and PET + patients was 90% v. 74% (p = 0.039), and 5-year PFS was 74% v. 40% (p = 0.001). There was no difference in either OS or PFS compared to those who did not receive BV before AHSCT. We compared BV treatments based on their indication (BV only after AHSCT as maintenance therapy, BV before and after AHSCT as maintenance treatment, BV only before AHSCT, no BV treatment). There was statistically significant difference in the 5-year PFS based on the inication of BV therapy. Recovery rates of our R/R HL patient population, who underwent AHSCT, improved significantly. Our positive results can be attributed to the PET/CT directed, response-adapted treatment approach, and the widespread use of BV.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Inmunoconjugados , Humanos , Brentuximab Vedotina , Enfermedad de Hodgkin/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Hungría , Inmunoconjugados/uso terapéutico , Resultado del Tratamiento , Trasplante Autólogo , Recurrencia Local de Neoplasia/terapia , Trasplante de Células MadreRESUMEN
Overall and disease-free survival of Hodgkin lymphoma patients has improved significantly since the 2000s. This is due to the use of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) polychemotherapy and modern radiotherapy. In recent years, further diagnostic and therapeutic changes have been made, which further improve patients' survival. The most significant role in this is the improvement of diagnostics, such as the 18FDG-PET/CT, which is now routinely used repeatedly during treatment, and the response-adapted treatment(s) based on it. The main role of ABVD treatment in first-line treatment is still clear, but the combination of anti-CD30 monoclonal antibody (brentuximab vedotin) and AVD (adriamycin, vinblastine, dacarbazine) is already available as a targeted treatment for patients at higher risk. The role of autologous hematopoietic stem cell transplantation in the treatment of high-risk, relapsing/refractory patients is still clear, but the new, targeted innovative drugs (brentuximab vedotin, pembrolizumab) can already be used in the previous salvage treatments. New therapeutic options have new side effects, which must be taken into account during treatment (and after it). In our summary, we present these new diagnostic and therapeutic approaches, based on our own practice and experience. Orv Hetil. 2023; 164(11): 403-410.
Asunto(s)
Enfermedad de Hodgkin , Inmunoconjugados , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/uso terapéutico , Brentuximab Vedotina/uso terapéutico , Dacarbazina/uso terapéutico , Doxorrubicina/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Inmunoconjugados/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Vinblastina/uso terapéuticoRESUMEN
BACKGROUND: Mutation of the TP53 gene is one of the major drivers of myelodysplastic neoplasias (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MR). TP53 mutations present in these hematopoietic malignancies form a distinct molecular genetic cluster with a worse prognosis than without the alteration. However, besides well-characterized hot-spot variants, a significant proportion of TP53 alterations are of uncertain clinical significance. METHODS: To enlighten so far unknown aspects, bone-marrow samples from altogether 77 patients are analyzed retrospectively with the diagnosis of AML-MR (26 cases), MDS-IB (12 cases), and MDS-LB (39 cases) according to WHO 2022 guidelines. Next-generation sequencing results are correlated with histological, cytogenetic, and survival data. RESULTS: Twenty out of the 30 TP53 mutation types detected by NGS are not categorized in current public databases; thus, their clinical significance remained mysterious. Because of the interpretation difficulties and the absence of clinical correlations, pathogenicity is established based on in silico approaches. The 12 pathogenicity classification systems, as well as protein stability, protein-DNA, protein-protein interaction, and post-translational modification analyses are applied. We found statistically significant differences between AML/MDS groups considering p53 pathogenicity, protein structural changes, and overall survival. The largest number of abnormalities with the most severe consequences are found in AML-MR cases. CONCLUSIONS: These molecular and in silico protein data further support that MDS with increased-blast (MDS-IB) is an intermediate group between AML-MR and MDS with low-blast (MDS-LB) patients, which frequently progresses to AML and is therefore considered a pre-leukemic condition.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Genes p53 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
OBJECTIVE: Although the majority of patients with Hodgkin lymphoma (HL) has recently become long-term survivors, 20%-30% of HL patients have primary refractory disease or relapse. It is essential to identify patients at risk of treatment failure during first-line therapy. To objective of the present study was to investigate the combined prognostic role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging and thymus and activation-regulated chemokine (TARC) levels in Hodgkin lymphoma. SUBJECTS AND METHODS: Between 01/01/2013 and 01/03/2019 77 HL patients were enrolled in this study where serum TARC levels were measured by an immunoassay and 18F-FDG PET/CT scans were performed at baseline, after the second cycle of ABVD treatment (interim) and at the end of first-line therapy. RESULTS: Twenty-six patients (34%) had early-stage HL, while 51 patients presented with advanced-stage disease. Fifteen patients had primary refractory HL, while 1 patient relapsed after first-line therapy. Optimal TARC cut-off value for progression-free survival (PFS) was 700pg/mL based on receiver operating characteristic (ROC) curve analysis. With Cox regression analysis, 18F-FDG PET/CT with Deauville scores of 3, 4, or 5 and TARC levels above 700pg/mL predicted treatment failure at interim assessment. Inclusion of HL patients with a Deauville score of 3 to the high-risk population resulted in a 7-fold increase in the estimated risk of relapse compared to patients with Deauville score 4-5 with TARC levels above 700pg/mL. Patients with interim 18F-FDG PET/CT Deauville scores 3-5 had a significant survival benefit if their TARC levels were 700pg/mL. Positive predictive value (PPV) of interim 18F-FDG PET/CT scans with a Deauville score 3-5 was 47.8%, while combined PPV of a similar 18F-FDGPET/CT assessment and elevated TARC levels was 88.8%. CONCLUSION: Interim 18F-FDG PET/CT and TARC analyzed together accurately identify HL patients who do not respond sufficiently to treatment and who need an early change of therapy.
Asunto(s)
Quimiocina CCL17/metabolismo , Fluorodesoxiglucosa F18 , Enfermedad de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Dacarbazina , Doxorrubicina , Humanos , Recurrencia Local de Neoplasia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , Pronóstico , VinblastinaRESUMEN
INTRODUCTION: Nowadays, more than 80% of newly diagnosed classical Hodgkin lymphoma (HL) patients can be cured and become long-term survivors due to risk and response-adapted treatment strategies. A well-known side effect is cognitive dysfunction that appears in HL patients after chemotherapy. In the present study, we aimed to measure cognitive dysfunction in our HL patients in this study and to find potential correlations between patient-related factors, the signs and symptoms of their diseases, or therapeutic factors. METHODS: We carried out a computer-assisted assessment (CANTAB) of cognitive dysfunction in 118 patients. We examined the domains of visual memory, attention, working memory, and planning. RESULTS: The median age of 64 females and 54 males at diagnosis was 29 (13-74) and 41 (21-81) years at the completion of CANTAB. Fifty-two percent of all patients showed cognitive impairment. Attention was impaired in 35% of patients, the working memory and planning were impaired in 25%, while visual memory was affected in 22%. All the three functions showed a significant association with inactive employments status. A close correlation was found between visual memory/working memory and planning, higher age at HL diagnosis or the completion of CANTAB test, and disability pensioner status. DISCUSSION: Our investigation suggests that patients with inactive employment status and older age require enhanced attention. Their cognitive function and quality of life can be improved if they return to work or, if it is not possible, they receive a cognitive training.
Asunto(s)
Disfunción Cognitiva , Enfermedad de Hodgkin , Cognición , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Femenino , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/psicología , Humanos , Hungría , Masculino , Memoria a Corto Plazo , Pruebas Neuropsicológicas , Calidad de Vida , Sobrevivientes/psicologíaRESUMEN
Even though information about the pathophysiology and clinical features of grey-zone lymphoma, an entity intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma, is growing, there are still a number of unanswered questions. The disease has no easily reproducible diagnostic criteria, which makes identification challenging. Uncommon, mixed histological picture and unusual clinical presentation should raise suspicion for grey-zone lymphoma. In this retrospective analysis we present 9 gray zone lymphoma patients, who were diagnosed in our institute between 2008 and 2018. The histological diagnoses was oftentime challenging, we asked for a revision in three cases due to the unusual clinical behavior and in other three cases only the relapse of the disease proved to be grey-zone lymphoma. Based on the initial histopathological diagnoses we applied adriablastine-bleomycine-vinblastine and procarbasine or cyclophosphamide-vincristine-adriablastine and prednisolon as first line chemotherapy regime with additional rituximab in six cases and brentuximab-vedotine in one patient. In six of the nine patients due to the primary refractory disease we used rituximab plus cisplatine, cytosine-arabinoside, prednisolone salvage treatment and five of these patients responded well enough to become eligible for autologous stem cell transplantation. One young male patient was refractory for various treatments and died due to the progression of his lymphoma. As a rare disease grey-zone lymphoma has no existing diagnostic criteria or guiedlines for its standard of care, which makes the everyday practice rather challenging for the clinicians, and emphasize the importance of unique decision making in every case and the repeated consultation between the pathologist and hematologist.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/patología , Linfoma de Células B Grandes Difuso/patología , Recurrencia Local de Neoplasia/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pronóstico , Estudios Retrospectivos , Terapia Recuperativa , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Standard bleomycin-containing first-line therapy and/or irradiation may cause pulmonary toxicity in Hodgkin lymphoma (HL) patients. Our aim was to prospectively assess effects of chest irradiation, bleomycin administration, and other factors on lung function in the treatment of patients with HL. METHODS: Pulmonary function of newly diagnosed HL patients was assessed via a St. George Respiratory Questionnaire, dynamic inhalation lung scintigraphy, spirometry, and an assessment of the diffusion capacity of the lung for carbon monoxide (DLCO) before, during, and after treatment. RESULTS: This prospective study was conducted at the University of Debrecen. The study included 84 patients with classical HL. Most patients received standard doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy. Both intramuscular and intravenous administrations of bleomycin were used. Brentuximab vedotin combination chemotherapy was administered to 12 patients. Mediastinal involved-field irradiation therapy (IFRT) was used to treat 16 patients. Lung scintigraphy revealed pulmonary toxicity more sensitively than DLCO. Intravenous bleomycin administration decreased diethylenetriamine pentaacetic acid clearance. Intramuscular bleomycin had the lowest level of pulmonary toxicity among considered treatments. Currently used, mediastinal IFRT had a lower level of pulmonary toxicity than bleomycin. The current prospective evaluation confirmed previous results that determined that cumulative bleomycin dose and administration are major risk factors for pulmonary toxicity, while the currently used treatment method, mediastinal irradiation, was determined to be relatively safe for treating for HL patients. CONCLUSION: We agree with decreasing bleomycin dosage and number of cycles administered and we do not recommend avoiding mediastinal IFRT, unless multiple pulmonary risk factors are present.
RESUMEN
The characteristics of autoimmune cytopenias (AICP) associated with Hodgkin lymphoma (HL) are not thoroughly defined. We retrospectively assessed the clinical features of HL-associated AICPs in 563 HL patients diagnosed over a period of 28 years. We identified 8 cases of autoimmune hemolytic anemia (AIHA) and 8 cases of autoimmune thrombocytopenia among 14 patients altogether. Four (26%) AICPs were present at lymphoma diagnosis, while 11 (74%) cytopenias occurred during follow-up after first-line therapy. The overall incidence of HL-associated AICPs was 2.8%. Nine (75%) cytopenias responded to intravenous steroids. Seven (46%) AICPs led to the diagnosis of HL, indicated a relapse, or revealed secondary malignancies. AIHAs and AICPs altogether were more likely to develop in patients with advanced-stage HL (p = 0.010 and p < 0.004, respectively). HL patients experiencing AICPs had an increased short-term (1-year) mortality compared to the general HL population (p < 0.022). The 5-year OS of HL patients with concurrent AICPs at diagnosis was inferior compared to HL patients developing AICPs during follow-up (p = 0.005), and to HL patients without AICPs (p < 0.001). Patients with HL-associated AICPs appear to have a particular disease-related profile. The association of HL and AICPs may increase short-term mortality, while patients with concurrent AICPs at HL diagnosis have a dismal prognosis.
Asunto(s)
Anemia Hemolítica Autoinmune/complicaciones , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/mortalidad , Púrpura Trombocitopénica Idiopática/complicaciones , Adulto , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/terapia , Biomarcadores , Biopsia , Terapia Combinada , Comorbilidad , Manejo de la Enfermedad , Femenino , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/terapia , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/terapia , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
Up to 30% of patients with classical Hodgkin lymphoma (cHL) are not responsive to frontline therapy or relapse after primary treatment. In these cases, autologous hematopoietic stem cell transplantation (AHSCT) is the standard of care. The combination of brentuximab vedotin and bendamustine (BV + B) is an effective salvage regimen in this challenging subpopulation. This nationwide multicenter study investigated the real-world efficacy and safety of the BV + B regimen as a bridge to AHSCT in patients with primary refractory or relapsed cHL. A total of 41 cHL patients underwent AHSCT after receiving at least 1 cycle of BV + B (with brentuximab vedotin given at 1.8 mg/kg on day 1 and bendamustine at 90 mg/m2 on days 1-2 every 4 weeks). After a median of 3 (1-6) cycles of BV + B, the objective response rate was 78%, with 29 (70.7%) patients achieving complete remission. Twelve (29.3%) patients relapsed after AHSCT, 2 (4.9%) of them died, while 2 (4.9%) patients are lost to follow-up. After a median of 17 months of follow-up, the estimated 2-year overall- and progression-free survival after AHSCT was 93 and 62%, respectively. Features of advanced disease at recurrence (p = 0.038) and the presence of stage IV cHL at relapse (p = 0.024) are strong predictor markers of unfavorable outcomes. Twenty-four (58.5%) patients experienced adverse events of any grade, while no grade IV toxicities were reported. BV + B is an effective salvage option with a manageable toxicity profile in cHL. The real-world safety and efficacy of this combination are similar to the observations made on the study population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Brentuximab Vedotina/administración & dosificación , Brentuximab Vedotina/efectos adversos , Terapia Combinada , Evaluación de Medicamentos , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/terapia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Neutropenia/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Tomografía de Emisión de Positrones , Supervivencia sin Progresión , Estudios Retrospectivos , Trasplante Autólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: The present study evaluates the impact of hypoxia-related carbonic anhydrase IX and XII isoenzyme expression as a basic adaptive mechanism to neutralise intracellular acidosis in classical Hodgkin's lymphoma (cHL). METHODS AND RESULTS: Eighty-one primary biopsies and 15 relapsed tissue samples diagnosed with cHL were analysed for necrosis, CAIX and CAXII expression and cell proliferation to compare hypoxia-related histological and functional data with survival characteristics. Variable, but highly selective cell membrane CAIX expression could be demonstrated in Hodgkin-Reed-Sternberg (HRS) cells in 39 of 81 samples (48.1%), while virtually no staining presented in their microenvironment. In contrast, CAXII expression in HRS cells could be demonstrated in only 18 of 77 samples (23.4%), with significant stromal positivity (50 of 77, 64.9%). The CAIX+ positive phenotype was strongly associated with lymphocyte depletion (four of four, 100%) and nodular sclerosis (29 of 51, 56.9%) subtypes. CAIX/Ki-67 dual immunohistochemistry demonstrated suppressed cell proliferation in CAIX+ positive compared to CAIX- negative HRS cells (P < 0.001). Seventy-two months' progression-free survival (PFS) was significantly lower for the CAIX positive group (0.192) compared with the CAIX negative group (0.771) (P < 0.001), while the overall survival (OS) did not differ (P = 0.097). CONCLUSION: Hypoxic stress-related adaptation - highlighted by CAIX expression - results in cellular quiescence in HRS cells, potentially contributing to the short-term failure of the standard chemotherapy in cHL.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Anhidrasa Carbónica IX/metabolismo , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/enzimología , Acidosis/enzimología , Biopsia , Hipoxia de la Célula , Proliferación Celular , Estudios de Cohortes , Estudios de Seguimiento , Enfermedad de Hodgkin/patología , Humanos , Inmunohistoquímica , Isoenzimas , Estimación de Kaplan-Meier , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/enzimología , Ganglios Linfáticos/patología , Necrosis/diagnóstico por imagen , Recurrencia Local de Neoplasia/enzimología , Recurrencia Local de Neoplasia/patología , Supervivencia sin ProgresiónRESUMEN
INTRODUCTION: A growing body of evidence supports the usefulness of dysplastic signs detected by flow cytometry in the diagnosis of myelodysplastic syndromes (MDS). Our aim was to assess the impact of pre-analytical variables (delayed sample handling, type of anticoagulant, and different clones of antibody) in the interpretation of flow cytometric results. MATERIAL AND METHODS: Bone marrow samples were labelled and analysed immediately after aspiration and on two consecutive days. The effect of anticoagulant type was evaluated in 16 bone marrow samples. Thirty-seven different immunophenotypic variables were recorded after eight-colour staining. Furthermore, 8 normal peripheral blood samples collected in K3-EDTA and Na-heparin were examined with different clones of CD11b antibodies and four parameters were recorded with both anticoagulants on two consecutive days. RESULTS: Fourteen significant differences were detected in the initial immunophenotype of fresh samples collected in K3-EDTA and Na-heparin. Regardless of the anticoagulant type, eleven parameters remained stable despite delayed sample handling. Due to delayed sample processing, more alterations were detected in the samples collected in K3-EDTA than in the samples collected in Na-heparin. The type of CD11b clone influenced the reduction of fluorescence intensity only in samples collected in K3-EDTA, where the alterations were contrary to the changes observed in Na-heparin. CONCLUSIONS: Delayed sample processing causes considerable immunohenotypic alterations, which can lead to false interpretation of the results. If delayed sample evaluation is unavoidable, markers that remain more stable over time should be considered with more weight in the diagnosis of MDS.
Asunto(s)
Células de la Médula Ósea/patología , Citometría de Flujo/normas , Inmunofenotipificación/normas , Síndromes Mielodisplásicos/diagnóstico , Manejo de Especímenes/normas , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/análisis , Anticoagulantes/química , Biomarcadores/análisis , Células de la Médula Ósea/inmunología , Antígeno CD11b/inmunología , Errores Diagnósticos/prevención & control , Ácido Edético/química , Femenino , Heparina/química , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/patología , Estudios Prospectivos , Factores de TiempoRESUMEN
PURPOSE: Majority of relapses in Hodgkin lymphoma (HL) occur within 3 years after initial treatment, late relapses (LR), happening 5 or more years after first diagnosis is rare events. Neither clinical characteristics, risk factors, nor optimal treatment is well described for LR patients. Our aim was to provide a comprehensive analysis on the LR of HL to outline a patient population at risk of relapsing late. PATIENTS AND METHODS: 637 HL patients were treated at the University of Debrecen between 1981 and 2010. Patient data was evaluated retrospectively. Survival analysis was performed using the Kaplan-Meier method and odds ratios (OR) were identified by binary logistic regression models. RESULTS: With a median observational time of 9.08 years 584 (91%) HL patients achieved complete remission (CR) after first line treatment. Relapse occurred in 176 (28%) patients, 26 (4%) of them 5 or more years after first diagnosis. With multivariable analysis, initial diagnosis before the age of 24 (p < 0.001), initial presentation between 1981 and 1990 or 1991-2000 (p = 0.025 and p = 0.023, respectively) and first line treatment with radiotherapy only (p = 0.034) were identified as independent risk factors for LR. We observed a significantly impaired OS for patients with early relapse HL compared to those in long-term remission or experiencing LR (p < 0.001). CONCLUSION: Late relapse of HL presents with clinical characteristics very similar to primary disease and appears to have a good prognosis. First diagnosis in childhood or young adulthood and first line treatment before the ABVD era increases the risk of relapsing late.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/terapia , Radioterapia/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Terapia Combinada , Femenino , Enfermedad de Hodgkin/patología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Inducción de Remisión , Estudios Retrospectivos , Trasplante Autólogo , Adulto JovenRESUMEN
INTRODUCTION: The treatment of relapsed or refractory Hodgkin lymphoma is still a major therapeutic challenge. The use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, represents a promising approach for these patients, however clinical outcomes have not yet been evaluated in Hungary. AIM: Our aim was to assess the efficacy, safety and outcome of brentuximab vedotin treatment in Hungarian Hodgkin lymphoma patients. METHOD: In this retrospective case note review we enrolled patients at 6 clinical sites countrywide who were diagnosed with Hodgkin lymphoma and received brentuximab vedotin between 1 January 2013 and 31 December 2016. RESULTS: A total of 86 patients were treated with brentuximab vedotin during the examined period. Before therapy initiation 66% of our patients had advanced-stage disease. Overall response rate to brentuximab vedotin, administered before autologous hematopoietic stem cell transplantation (n = 54) was 66.6%, complete remission rate was 42.6%. Thirty patients received brentuximab vedotin after AHSCT, 46.67% responded to treatment, 30% achieved complete remission. Thirty-six patients received the drug as a single-agent therapy, 50 patients were given brentuximab vedotin in combination, 39 of them with bendamustin. Toxicity was observed only in 13.95% of our patients, most common symptom was skin rash. Based on our analysis the estimated 5-year overall survival rate was 78.7%, the estimated progression free survival rate was 23.59 months (95% CI: 19.50-27.68). CONCLUSION: Brentuximab vedotin carries a substantial improvement in the treatment of relapsed or refractory Hodgkin lymphoma. Our results underline prior observations published in the literature. The use of brentuximab vedotin in combination can be beneficial, however further investigation is needed on the subject. Orv Hetil. 2017; 158(41): 1630-1634.
Asunto(s)
Antineoplásicos/administración & dosificación , Enfermedad de Hodgkin/terapia , Inmunoconjugados/administración & dosificación , Trasplante de Células Madre , Brentuximab Vedotina , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Hungría , Inducción de Remisión , Trasplante AutólogoRESUMEN
INTRODUCTION: Extranodal natural killer/T (NK/T) cell lymphoma, nasal type (ENKTL) represents a rare subtype of T-cell lymphomas with aggressive clinical behavior according to WHO 2016 classification. AIM: ENKTL has distinctive geographic distribution with higher incidence in Asia and Latin America (10% of all non-Hodgkin lymphoma cases), than in Europe and North America (<1%). ENKTL tipically origins from nasopharynx and upper aerodigestive tract. Anthracycline-based chemotherapy regimens are largely ineffective in the treatment of ENKTL. METHOD: Our aims were to evaluate the incidence and treatment strategies of ENKTL patients in Hungarian Haematological Centres between 2003 and 2015. Altogether 20 patients with ENKTL were treated in the 4 haematological hospitals (male:female ratio 12:8, with median 49.5 years of age). RESULTS: Ten patients had localized (stage I-II) disease at the time of the diagnosis. Seventeen patients were treated with chemotherapy (11/CHOP, CHOP-like, 2/HyperCVAD, 1/ProMACECytaBom, 1/SMILE, 2/others), which was completed with involved-field radiation therapy (IFRT) (40-46 Gy) in 6 cases were used. After first-line therapy 9 patients achieved complete remission (CR), 3 patients had partial remission (PR), 3 patients had progressive disease (PD), and 2 patients had stable disease (SD). Median follow-up was 32 (3-113) months. Five patients received second-line therapy for progressive or recurrent disease [2/DHAP, 1/VIM, 1/HyperCVAD, 1/ProMACECytaBom]. None of the patients achieved CR after second-line therapy. Two patients have undergone autologous hematopoietic stem cell transplantation (HSCT) after the first CR. CONCLUSION: ENKTL treatment is more effective with nonanthracycline-containing regimens. L-asparaginase containing chemotherapy and concurrent or sequential chemo-radiotherapy improves survival and CR rates. Orv Hetil. 2017; 158(41): 1635-1641.
Asunto(s)
Linfoma Extranodal de Células NK-T/terapia , Neoplasias Nasales/terapia , Adulto , Antineoplásicos/administración & dosificación , Asparaginasa/administración & dosificación , Terapia Combinada , Trasplante de Células Madre Hematopoyéticas , Humanos , Hungría , Incidencia , Linfoma Extranodal de Células NK-T/epidemiología , Linfoma Extranodal de Células NK-T/patología , Persona de Mediana Edad , Neoplasias Nasales/epidemiología , Neoplasias Nasales/patología , Adulto JovenRESUMEN
T-cell lymphoma is a poor prognostic hematological malignancy. The generally used - not sufficiently effective - induction chemotherapy should be improved with consolidative autologous hemopoetic stem cell transplantation. The authors describe the role, place and effectiveness of transplantation in this disorder. One hundred thirty three autologous stem cell transplantations were performed in the last 22 years in Hungary. Detailed results are available from the last 6 years. In this period 43 transplantations were carried out in 4 Hungarian centers. Carmustine-etoposide-cytosine arabinoside-melphalan (BEAM) conditioning regimen was used in 95%. The transplantation was done mainly in complete remission (84%), 1 year after transplantation 65% of patients were still in complete remission. Eleven patients died, 82% of them have progressive disease. Brentuximab vedotin has already proved the effectiveness, several other chemoterapeutics, monoclonal antibodies, kinase inhibitors are under investigation. In certain cases allogeneic stem cell transplantation has real indication among therapeutic options. Orv Hetil. 2017; 158(41): 1615-1619.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunoconjugados/administración & dosificación , Linfoma de Células T/terapia , Brentuximab Vedotina , Quimioterapia de Consolidación , Humanos , Hungría , Inducción de Remisión , Trasplante AutólogoRESUMEN
BACKGROUND: Due to risk and response adapted treatment strategies, more than 80% of newly diagnosed classical Hodgkin lymphoma (HL) patients can be cured, and become long-term survivors. However, a high proportion of survivors suffer from treatment-related long-term side effects such as secondary malignancy, organ failure, persistent fatigue and psychological distress. The aim of this study was to evaluate psychological distress and its risk factors among our HL survivors. METHODS: One hundred sixty-three (50% female) adult HL survivors were contacted between January 1, 2012 and march 31, 2015 in our outpatient centre. The patients were asked to complete a standardized, validated, self-administered Hungarian questionnaire with demographic questions and the following scales: Hospital anxiety and depression scale (HADS14), general health questionnaire (GHQ12), sense of coherence (SOC13) perceived stress scale (PSS4), dysfunctional attitude scale (DAS17). Disease and treatment data were acquired from hospital records. RESULTS: Majority of HL survivors are in early adulthood, our most important goal should be to return them to normal life after their lymphoma is cured. The employment status at the time of survey seemed to be crucial so patients were divided into either active (n = 93) or inactive (n = 47) group. Retired survivors (n = 19) were excluded from the subgroup analysis. Psychological distress was significantly lower in active patients. Multiple logistic regression analysis showed significant differences between the inactive and active subgroups, such as age at diagnosis (≥30 years or below, p = 0.001), education level (below college vs. college, p = 0.032) and treatment related long-term side effects (yes vs. no, p < 0.001). Predictors for treatment-related long-term side effects are female gender (p = 0.011), chemotherapy protocol (ABVD vs. other, p < 0.001). CONCLUSIONS: Our data suggest that employment status and treatment-related long-term side effects play a critical role in the health related quality of life outcome among Hungarian HL survivors.
Asunto(s)
Empleo/psicología , Enfermedad de Hodgkin/psicología , Calidad de Vida , Estrés Psicológico , Sobrevivientes/psicología , Adulto , Anciano , Empleo/estadística & datos numéricos , Femenino , Humanos , Hungría , Masculino , Persona de Mediana Edad , Estrés Psicológico/psicología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Approximately 10-30% of Hodgkin lymphoma patients relapses or experience refractory disease after first line treatment. Nowadays, autologous stem cell transplantation can successfully salvage half of these patients, median overall survival is only 2-2.5 years. Several prognostic factors determine success of autologous stem cell transplantation. Result of transplantation can be improved considering these factors and using consolidation treatment, if necessary. Patients who relapse after autologous transplantation had worse prognosis, treatment of this patient population is unmet clinical need. Several new treatment options became available in the recent years (brentuximab vedotin and immuncheckpoint inhibitors). These new treatment options offer more chance for cure in relapsed/refractory Hodgkin patients. Outcome of allogenic stem cell transplantation can be improved by using haploidentical donors. New therapeutic options will be discussed in this review. Orv Hetil. 2017; 158(34): 1338-1345.