RÉSUMÉ
Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.
Sujet(s)
Lymphome B diffus à grandes cellules , Lymphome malin non hodgkinien , Humains , Marqueurs biologiques , Lymphocytes T CD8+/anatomopathologie , Cellules tueuses naturelles/anatomopathologie , Lénalidomide/usage thérapeutique , Lymphome B diffus à grandes cellules/anatomopathologie , Récidive tumorale locale/anatomopathologie ,RÉSUMÉ
PURPOSE: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. PATIENTS AND METHODS: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1-14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1-3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1-21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). RESULTS: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3-4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.
Sujet(s)
Lymphome B diffus à grandes cellules , Lymphome malin non hodgkinien , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Marqueurs biologiques , Humains , Lénalidomide/effets indésirables , Lymphome B diffus à grandes cellules/anatomopathologie , Lymphome malin non hodgkinien/traitement médicamenteux , Récidive tumorale locale/traitement médicamenteux , Récidive tumorale locale/anatomopathologie , Rituximab/usage thérapeutique , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: The search for immunological markers with ability of predicting clinical outcome is a priority in lymphomas, and in cancer in general. It is well known that some immunomodulatory cells, such as myeloid derived suppressor cells (MDSCs) or regulatory T cells (Tregs), are recruited by tumors, jeopardizing antitumor immunosurveillance. In this work, we have studied blood levels of these immunosuppressive cells in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), prior to and along the course of the experimental rituximab, gemcitabine, dexamethasone, and cisplatin (R2-GDP) schedule, as a translational substudy of the R2-GDP-GOTEL trial (EudraCT Number: 2014-001620-29), which included lenalidomide as an immunomodulator. METHODS: Blood samples were taken before treatment, at cycle 3 and end of induction. Samples were analyzed by flow cytometry. Non-parametric tests were used. Mann-Whitney U test was used to compare basal cells distributions, and Wilcoxon test was considered to compare cells distribution at different times. Spearman test was performed to measure the degree of association between cell populations. RESULTS: In this study, MDSC and Treg circulating concentration was found increased in all patients compared with a healthy control group and decreased after treatment only in patients with longest overall survival (>24 months), reaching the levels of the healthy group. Likewise, the number of inhibited T lymphocytes expressing Programmed Death-1 (PD-1) were increased in peripheral blood from patients and decreased on the treatment, whereas activated T lymphocytes increased after therapy in those with better overall survival. CONCLUSIONS: In conclusion, blood concentration of MDSCs and Treg cells may be good prognostic markers for overall survival after 2 years in R/R DLBCL. These results point to a possible role of these elements in the immunosuppression of these patients, as assessed by the circulating activated and inhibited T lymphocytes, and therefore, they may be considered as therapeutic targets in DLBCL.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Marqueurs biologiques tumoraux/immunologie , Lymphome B diffus à grandes cellules/traitement médicamenteux , Cellules myéloïdes suppressives/métabolisme , Lymphocytes T régulateurs/métabolisme , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Études cas-témoins , Essais cliniques comme sujet , Femelle , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Humains , Lymphome B diffus à grandes cellules/sang , Lymphome B diffus à grandes cellules/immunologie , Mâle , Adulte d'âge moyen , Cellules myéloïdes suppressives/effets des médicaments et des substances chimiques , Récepteur-1 de mort cellulaire programmée/métabolisme , Analyse de survie , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Résultat thérapeutiqueRÉSUMÉ
El síndrome de anticuerpos antifosfolipídicos catastrófico (SAAFC) es una forma rara de presentación del síndrome de anticuerpos antifosfolipídicos, de mal pronóstico, por lo que son necesarios un diagnóstico y un tratamiento precoces. Presentamos un paciente que tuvo gangrena como manifestación inicial de un SAAFC (AU)
Catastrophic antiphospholipid syndrome (CAPS) is an unusual form of presentation of antiphospholipid syndrome with a poor prognosis, so early diagnosis and treatment are necessary. We report a patient who had gangrene as the initial manifestation of CAPS (AU)
Sujet(s)
Humains , Femelle , Adulte , Syndrome des anticorps antiphospholipides/complications , Gangrène/étiologie , Anticorps antiphospholipides/isolement et purification , Diagnostic précoce , Ulcère du pied/étiologie , Glucocorticoïdes/usage thérapeutique , Héparine bas poids moléculaire/usage thérapeutique , Transfusion sanguineRÉSUMÉ
Catastrophic antiphospholipid syndrome (CAPS) is an unusual form of presentation of antiphospholipid syndrome with a poor prognosis, so early diagnosis and treatment are necessary. We report a patient who had gangrene as the initial manifestation of CAPS.