RESUMEN
RCHOP is the standard of care for patients with diffuse large b-cell lymphoma (DLBCL) but failures occur in approximately 40% of them. We performed a meta-analysis of 21 randomized controlled trials (RCTs) comparing experimental regimens with RCHOP. We searched the database of PubMed with proper criteria, and data of efficacy (Progression Free Survival-PFS) in the ITT population were extracted and analyzed. Cross comparisons of RCTs were performed by using the CINEMA software. Odds ratio (OR) and 95% confidence intervals (95%, CI) are reported. The literature search yielded 21 RCTs including 5785 patients in the RCHOP arm and 5648 patients in the experimental arm. Odds ratio (OR) for PFS in the total cohort was OR (95%, CI): 0.87 (0.76-0.99), p=0.02. Among different strategies to improve RCHOP, addition of a novel agent on RCHOP improved PFS. In total 1740 patients in the RCHOP arm were compared with 1755 in the RCHOP plus a novel agent arm, and the OR (95% CI) for PFS was 0.84 (0.71-0.97), p=0.02. Indirect comparisons of nine studies adding a novel agent on RCHOP does not give prominence to any agent. Subgroup analysis according to cell of origin was performed for non-GC DLBCL patients. In this subgroup, 1546 patients treated with RCHOP were compared with 1538 patients treated with experimental regimens. The OR (95% CI) for PFS was 0.86 (0.73-1.02), p=0.34. Overall survival data extracted from 18 studies showed no superiority of experimental regimens over RCHOP. Efficacy of RCHOP backbone is marginally improved when adding a novel anti-lymphoma agent.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Linfoma de Células B Grandes Difuso , Prednisona , Rituximab , Vincristina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Doxorrubicina/uso terapéutico , Doxorrubicina/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Prednisona/uso terapéutico , Prednisona/administración & dosificación , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Rituximab/uso terapéutico , Rituximab/administración & dosificación , Vincristina/uso terapéutico , Vincristina/administración & dosificaciónRESUMEN
The regimen of 5-azacytidine for patients with myelodysplastic syndrome (MDS) has remained unchanged since its first approval. Although several modifications have since been made and delays and dose reductions are common especially during the first treatment cycles, there are minimal data on the prognostic effect of these modifications. In this study, based on data from 897 patients with MDS treated with 5-azacytidine recorded in a national registry, the effect of treatment delays and dose reductions on response, transformation to acute myeloid leukaemia, and survival (after 5-azacytidine initiation, OST ) were analysed. Delays during the first two cycles were noted in 150 patients (16·7%) and were found to adversely affect OST independently of the International Prognostic Scoring System score [hazard ratio (HR), 1·368; P = 0·033] or pre-existing neutropenia (HR, 1·42; P = 0·015). In patients achieving a response, delays before response achievement were correlated with its type (complete remission, 2·8 days/cycle; partial remission, 3·3 days/cycle; haematologic improvement, 5·6 days/cycle; P = 0·041), while delays after response achievement did not have any effect on retention of response or survival. Dose reductions were found to have no prognostic impact. Based on our results, treatment delays especially during the first cycles should be avoided, even in neutropenic patients. This strict strategy may be loosened after achieving a favourable response.
Asunto(s)
Azacitidina/administración & dosificación , Reducción Gradual de Medicamentos , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/mortalidad , Sistema de Registros , Tiempo de Tratamiento , Adulto , Anciano , Anciano de 80 o más Años , Azacitidina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Higher-risk Myelodysplastic syndromes (MDS) patients undergoing treatment with 5-azacytidine (AZA) are typically elderly with several comorbidities. However, the effect of comorbidities on the effectiveness and safety of AZA in real-world settings remains unclear. We analyzed data from 536 AZA-treated patients with higher-risk MDS, Myelodysplastic/Myeloproliferative neoplasms and low blast count Acute Myeloid Leukemia enrolled to the Hellenic National Registry of Myelodysplastic and Hypoplastic Syndromes. Multivariate analysis adjusted also for the International Prognostic Scoring System (IPSS), its revised version (IPSS-R) and the French Prognostic Scoring System (FPSS), demonstrated independent associations of overall and leukemia-free survival with estimated glomerular filtration rate (eGFR) <45 mL min-1 /1.73 m2 (P = .039, P = .023, respectively), ECOG performance status <2 (P = .015, P = .006), and presence of peripheral blood blasts (P = .008, P = .034), while secondary MDS also correlated with significantly shorter leukemia-free survival (P = .039). Addition of eGFR <45 mL min-1 /1.73 m2 , in IPSS-R and FPSS increased the predictive power of both models. Only FPSS ≤2 and eGFR <45 mL min-1 /1.73 m2 predicted worse response to AZA in multivariate analysis, whereas eGFR <45 mL min-1 /1.73 m2 correlated significantly with death from hemorrhage (P = .003) and cardiovascular complications (P = .006). In conclusion, in the second largest real-world series of AZA-treated MDS patients, we show that an eGFR <45 mL min-1 /1.73 m2 is an independent predictor of worse response and survival. This higher cut-off, instead of the commonly used serum creatinine >2 mg/dL, can be utilized as a more precise indicator of renal comorbidity during AZA therapy. Incorporation of eGFR in the prognostic assessment of AZA-treated MDS patients may prove useful not only in routine practice, but also for the appropriate patient stratification in clinical trials with AZA combinations.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Azacitidina/efectos adversos , Tasa de Filtración Glomerular , Enfermedades Renales/mortalidad , Síndromes Mielodisplásicos/mortalidad , Sistema de Registros/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND Osteoporosis affects millions of postmenopausal women worldwide. Invariant natural killer T cells (iNKT) are important cells for bone homeostasis. The sim of this study was to investigate the contribution of invariant natural killer T cells (iNKT) in the increased receptor activator of the nuclear factor-kappaB ligand (RANKL) pool and bone resorption, a characteristic of patients with osteoporosis. MATERIAL AND METHODS Whole blood was collected from 79 female patients. The dual energy x-absorptiometry scan was performed in all patients, and the T-score was calculated in order to classify our patients according to the World Human Organization (WHO) criteria for diagnosis and classification of osteoporosis. Eleven patients had a T-score -2.5 and were included in the osteoporosis group. We performed alpha-galactosylceramide activation of iNKT cells in vitro. Surface RANKL expression was detected by multicolor flow cytometry in naive and activated lymphocytes. Beta-Crosslaps (ß-CTx) levels were measured in whole blood plasma by ELISA (enzyme-linked immunosorbent assay). RESULTS Although iNKT cells were not clonally expanded in patients with osteoporosis, iNKT cells from osteoporotic patients overexpressed RANKL compared to ND and osteopenic patients. This is a distinctive feature of iNKT cells and is not seen in conventional T-lymphocytes. RANKL expression in iNKT cells was not related to ß-CTx levels in the blood. Finally, iNKT cell activation by the prototypal glycolipid ligand alpha-galactosylceramide increased by 8 times their RANKL expression. CONCLUSIONS In patients with osteoporosis, iNKT cells specifically overexpress RANKL, a cytokine that regulates osteoclast activity. It seems that iNKT cells have a long-standing effect of on the bone physiology, which plays an important role in the bone loss of patients with osteoporosis.
Asunto(s)
Células T Asesinas Naturales/metabolismo , Osteoporosis/inmunología , Ligando RANK/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Citocinas/metabolismo , Femenino , Citometría de Flujo , Glucolípidos/metabolismo , Humanos , Activación de Linfocitos , Persona de Mediana Edad , FN-kappa B/metabolismo , Ligando RANK/genéticaAsunto(s)
Transfusión de Componentes Sanguíneos , Donantes de Sangre , Seguridad de la Sangre , COVID-19/diagnóstico , Anciano de 80 o más Años , Plaquetas/virología , COVID-19/transmisión , Selección de Donante , Femenino , Humanos , Masculino , Persona de Mediana Edad , Transfusión de Plaquetas , SARS-CoV-2/aislamiento & purificaciónRESUMEN
Multiple myeloma (MM) is an incurable B-cell malignancy. The immunotherapeutic approach for MM therapy is evolving. The Cd1d/invariant natural killer T-cell/glycolipid immune axis belongs to the innate immunity, and we have highlighted role in myeloma pathogenesis in the present study. The recent development of the chimeric antigen receptor (CAR19)-invariant natural killer T-cells resulted in our renewed interest in this immune system and offer new perspectives for future anti-MM immunotherapies.
Asunto(s)
Antígenos CD1d/inmunología , Glucolípidos/inmunología , Inmunidad Innata , Inmunoterapia Adoptiva , Mieloma Múltiple , Células T Asesinas Naturales/inmunología , Humanos , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapiaRESUMEN
BACKGROUND: 5-azacytidine (5-AZA) improves survival of patients with higher-risk myelodysplastic syndromes (MDSs) and oligoblastic acute myeloid leukemia (AML); however, predictive factors for response and outcome have not been consistently studied. METHODS: This study of the Hellenic MDS Study Group included 687 consecutive patients with higher-risk MDS and oligoblastic AML treated with 5-AZA. RESULTS: The International Prognostic Scoring System (IPSS) revised version (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 or 1 versus ⩾2) and baseline serum ferritin (SF) levels > 520 ng/ml were shown to independently predict response to 5-AZA. In the survival analysis, the IPSS and IPSS-R risk classification systems along with the ECOG PS and SF levels > 520 ng/ml proved to be independent prognosticators for overall survival (OS), as well as for leukemia-free survival (LFS). Next, we built new multivariate models for OS and LFS, incorporating only ECOG PS and SF levels besides IPSS or IPSS-R risk classification systems. Thereby, the new modified IPSS and IPSS-R risk classification systems (H-PSS, H-PSS-R) could each discriminate a low, an intermediate and a high-risk patient group regarding OS and LFS. The H-PSS and H-PSS-R proved to be better predictors of OS than their previous counterparts as well as the French prognostic score, while the most powerful OS predictor was the new, H-PSS-R system. CONCLUSIONS: ECOG PS and SF levels > 520 ng/ml independently predict response to 5-AZA, OS and LFS. Their incorporation in the IPSS and IPSS-R scores enhances these scores' predictive power in 5-AZA-treated higher-risk MDS and oligoblastic AML patients.
RESUMEN
Cardiovascular disease (CVD) emerges as a major cause of death in patients with myelodysplastic syndrome (MDS), but predictors of fatal CVD and the effect of MDS-specific treatments on CVD mortality remain largely unknown. In an analysis involving 831 patients with MDS with known causes of death, we noted an independent association of lower risk MDS, age >70 years, pre-existing CVD, and treatment with erythropoiesis-stimulating agents with a higher risk of death from CVD. If externally validated, these simple risk factors could increase clinicians' awareness toward CVD complications and guide early introduction of intensive monitoring and preventive interventions in MDS patients.
RESUMEN
BACKGROUND: Hypomethylating agents have altered the prognosis of myelodysplastic syndrome (MDS) so that long-term survival is now a feasible treatment goal. PATIENTS AND METHODS: We analyzed data from patients with MDS treated with 5-azacytidine recorded in the Hellenic 5-azacytidine registry. We divided patients, on the basis of their survival after 5-azacytidine initiation (OST), in groups of long-term survivors (Q3 and P90 group with OST above the third quartile and the 90th percentile of the whole group, respectively) and short-term survivors comprising the remaining patients, and compared the characteristics between the groups. The study included 626 patients, 157 in the Q3 group and 63 in the P90 group. RESULTS: Categorization per the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), and World Health Organization-based prognostic scoring system (WPSS) was found to predict long-term survival, while multivariate analysis revealed that response to 5-azacytidine was the strongest predictor of long-term survival. Nevertheless, patients with hematologic improvement (HI) and stable disease (SD) were equally distributed in the groups of short- and long-term survival. CONCLUSION: SD should not be considered a poor treatment response and should not be grouped with failure, while HI offers similar prognosis to SD and thus should not be grouped with complete and partial remission. Patients with SD should continue treatment with 5-azacytidine.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/farmacología , Azacitidina/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Sistema de RegistrosRESUMEN
BACKGROUND: Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are characterised by abnormal epigenetic repression and differentiation of bone marrow haematopoietic stem cells (HSCs). Drugs that reverse epigenetic repression, such as 5-azacytidine (5-AZA), induce haematological improvement in half of treated patients. Although the mechanisms underlying therapy success are not yet clear, induction of endogenous retroelements (EREs) has been hypothesised. METHODS: Using RNA sequencing (RNA-seq), we compared the transcription of EREs in bone marrow HSCs from a new cohort of MDS and chronic myelomonocytic leukaemia (CMML) patients before and after 5-AZA treatment with HSCs from healthy donors and AML patients. We further examined ERE transcription using the most comprehensive annotation of ERE-overlapping transcripts expressed in HSCs, generated here by de novo transcript assembly and supported by full-length RNA-seq. RESULTS: Consistent with prior reports, we found that treatment with 5-AZA increased the representation of ERE-derived RNA-seq reads in the transcriptome. However, such increases were comparable between treatment responses and failures. The extended view of HSC transcriptional diversity offered by de novo transcript assembly argued against 5-AZA-responsive EREs as determinants of the outcome of therapy. Instead, it uncovered pre-treatment expression and alternative splicing of developmentally regulated gene transcripts as predictors of the response of MDS and CMML patients to 5-AZA treatment. CONCLUSIONS: Our study identifies the developmentally regulated transcriptional signatures of protein-coding and non-coding genes, rather than EREs, as correlates of a favourable response of MDS and CMML patients to 5-AZA treatment and offers novel candidates for further evaluation.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Retroelementos/genética , Anciano , Empalme Alternativo , Azacitidina/farmacología , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Proteínas Portadoras/genética , Diferenciación Celular , Proteínas Activadoras de GTPasa/genética , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Manosiltransferasas/genética , Persona de Mediana Edad , Inducción de Remisión , Transcriptoma/efectos de los fármacos , Insuficiencia del Tratamiento , Proteínas Supresoras de Tumor/genéticaRESUMEN
Hypomethylating agents are widely used in chronic myelomonocytic leukemia (CMML). We analyzed the characteristics of 88 patients with CMML homogeneously treated with 5-azacytidine (Hellenic 5-Azacytidine Registry). The overall response rate was 48.9% and the median overall survival (OS) 29.7 months. Out of the seven most widely used prognostic scoring systems for CMML, the Dusseldorf score (DUSS) showed the best prognostic capability (HR, 2.27; p < .001). Forty-one (48.8%) patients progressed to acute myeloid leukemia (AML) after a median time of 15.2 months following treatment initiation. High serum ferritin levels at diagnosis were independently correlated with low OS (HR, 2.84; p = .022), as were circulating blasts (HR, 3.47; p = .014), while a platelet count <100 × 109/L was marginally predictive of lower OS (HR, 1.45; p = .06). We selected these three factors to create a new risk stratification system for CMML with three risk groups. Finally, we highlighted for the first time the prognostic significance of serum ferritin levels in CMML.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mielomonocítica Crónica/mortalidad , Sistema de Registros/estadística & datos numéricos , Medición de Riesgo/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
In patients with myelodysplastic syndrome (MDS), the prognostic significance of chromosome 17 abnormalities has not yet been fully elucidated, except for isochromosome 17q that has been characterized as an intermediate risk abnormality in the Revised International Prognostic Scoring System (IPSS-R). To further characterize the prognostic significance of chromosome 17 abnormalities we analyzed the hematologic and prognostic characteristics of 548 adult patients with MDS treated with 5-azacytidine through the Hellenic 5-azacytidine registry and found 32 patients with a chromosome 17 abnormality (6 with i[17q], 15 with -17, 3 with add[17p] and the rest with other rarer abnormalities, mostly translocations). The presence of a chromosome 17 abnormality was correlated with poor prognostic features (high IPSS, IPSS-R, and WPSS scores) and a low overall survival rate (15.7 vs 36.4 months for patients without chromosome 17 abnormalities, Kaplan-Meier, Log Rank P < 0.00001), but these results were confounded by the fact that most (92.3%) of the cases with a chromosome 17 abnormality (with the exception of i(17q) that was found in all cases as an isolated abnormality) were found in the context of a complex karyotype. Nevertheless, one should not ignore the contribution of chromosome 17 abnormalities to the prognostic significance of a complex karyotype since 33.8% of complex karyotypes encompassed a chromosome 17 abnormality.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Cromosomas Humanos Par 17 , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
JAK2V617F is a gain of function point mutation that occurs in Myeloproliferative Neoplasm (MPN) patients and deranges their hemopoiesis at cellular level. We speculate that hyperfunctioning JAK2 can modify osteoclast (OCL) homeostasis in MPN patients. We studied 18 newly diagnosed MPN patients and four age-matched normal donors (ND). Osteoclast forming assays started from selected monocytes also and under titrated concentrations of the JAK2 Inhibitor AG-490 (Tyrphostin). Genomic DNA was extracted from the formed osteoclasts, and the JAK2V617F/JAK2WT genomic DNA ratio was calculated. OCLs formed from monocytes derived from heterozygous (Het) for the JAK2V617F mutation MPN patients, were three times more compared to those from JAK2 wild type (WT) MPN patients (p=0,05) and from ND as well (p=0,03). The ratio of JAK2V617F/JAK2WT genomic DNA was increased in OCLs compared to the input monocyte cells showing a survival advantage of the mutated clone. In comparison to ND and JAK2 WT MPN patients, OCLs from patients JAK2V617F (Het) were more susceptible to JAK2 inhibition. These alterations in osteoclast homeostasis, attributed to mutated JAK2, can deregulate the hemopoietic stem cell niche in MPN patients.
Asunto(s)
Síndromes Mielodisplásicos , Neoplasias , Púrpura Trombocitopénica Idiopática , Trombocitopenia , Adulto , Humanos , Síndromes Mielodisplásicos/complicaciones , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/complicaciones , Púrpura Trombocitopénica Idiopática/epidemiología , Sistema de RegistrosRESUMEN
AIM: To investigate the mode of transmission and the natural history of chronic hepatitis B virus (HBV) infection in children of different ethnicities in Greece. This study was part of the Interreg I-II EC project. PATIENTS AND METHODS: One hundred seventy-three hepatitis B surface antigen (HBsAg)(+) carriers, median age 6.9 (5-12) y, were prospectively followed-up for a mean period of 5.3 (1-12) y for serological markers of HBV infection, serum alanine aminotransferase (ALT), HBV-DNA, alpha-fetoprotein levels and ultrasonography. RESULTS: Vertical transmission predominates (61.8%) in Moslem children and horizontal (44%) in those born in Russia. At entry, 73 of 173 (42%) HBsAg(+) genotype D children were hepatitis B e antigen (HBeAg)(+), ranging from 27% to 67% among ethnic groups; 55 of 173 (32%) had ALT > 2 x upper normal limit (UNL), ranging from 21% to 39%. Of 100 anti-HBe(+) children, 85 (85%) were inactive carriers. During the follow-up period, seroconversion to anti-HBe was observed in 40 of 73 (55%) children with an annual rate of 11%; 35 of 40 (87.5%) had biochemical remission, and 28 of 35 (80%) lost HBV-DNA. In the anti-HBe(+) group, 27 of 100 (27%) lost HBV-DNA and 9 of 100 (9%) lost HBsAg. The annual seroconversion rate for HBeAg was significantly lower: in children with vertical transmission compared with horizontal (7.7% vs 14.8%, respectively, P < 0.001) and in Muslim children compared with both Christian children and those born in Russia (8.6% vs 12%, respectively, P < 0.001). No differences were found among the ethnic groups after adjusting for the mode of infection. Two of 173 children had progression of liver disease. CONCLUSIONS: The differences in HBeAg(+) status and seroconversion rate among the ethnic groups are related to the time/mode of HBV infection. The majority of children who developed anti-HBe immunity had biochemical remission, and a substantial number of the inactive carriers lost viremia during the observation period of up to 12 y.
Asunto(s)
Hepatitis B Crónica/etnología , Hepatitis B Crónica/transmisión , Niño , Preescolar , Cristianismo , Progresión de la Enfermedad , Femenino , Grecia , Humanos , Islamismo , Masculino , Estudios Prospectivos , Federación de Rusia/etnologíaRESUMEN
Myeloid neoplasms with isolated isochromosome 17q [MN i(17q)] has been described as a distinct entity with poor prognosis. However, literature reports show a considerable clinical and molecular heterogeneity. We describe a 58-year-old male patient who was diagnosed as refractory anemia with multilineage dysplasia and ringed sideroblasts with isolated i(17q). Though he initially responded well to erythropoietin, he gradually progressed to an aggressive form of MDS/MPN refractory to azacytidine and died 29 months after the first diagnosis. Notably, in contrast to disease advancement, his karyotype reverted to normal, whereas his mutational profile remained unchanged. To our knowledge, this is the first report of karyotype normalization during disease progression in patients with MN i(17q). It suggests that the i(17q) anomaly is dispensable for the leukemic transformation and highlighting the underlying clinical and molecular complexity which both has to be resolved before the establishment of MN with isolated i(17q) as a distinct entity.