RESUMO
Involvement of female genital track (FGT) by diffuse large B cell lymphoma (DLBCL) represents an extremely rare diagnosis. Especially data regarding early-stage disease (i.e., IE, IIE) is very limited. Importantly, previous studies showed controversial results about the risk of central nervous system (CNS) relapse in this entity. Herein, we describe one of the largest reported real-world series of patients with early-stage FGT DLBCL aiming to investigate the clinicopathological characteristics, response to therapy and survival outcomes in the era of immunochemotherapy. We analyzed 21 consecutive patients with biopsy proven DLBCL from uterus or ovary classified as stage IE or IIE out of 1905 newly diagnosed DLBCL patients (1.1%). Uterine and ovarian localization was observed in 14 and seven patients, respectively. Median age was 66 years (range 33-96); 9/21 (43%) were <55 years. Regarding Cell of Origin DLBCL subtype, Germinal Center B-cell subtype was found in seven patients, non-GCB in 10 and non-classified in 4 patients. Median follow-up was 57 months and 5-year overall survival, lymphoma specific survival and Freedom from Progression were 78%, 89% and 90%, respectively. There was no correlation of patients' characteristics with survival parameters. Interestingly, none of the patients experienced CNS relapse. Our results indicate that localized FGT DLBCL exhibits a good prognosis and may not increase the risk for secondary CNS involvement.
Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/diagnóstico , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Estadiamento de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Taxa de Sobrevida , Neoplasias dos Genitais Femininos/patologia , Neoplasias dos Genitais Femininos/terapia , Neoplasias dos Genitais Femininos/mortalidade , Neoplasias dos Genitais Femininos/diagnósticoRESUMO
We evaluated the efficacy and prognostic impact of bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) versus previous anti-myeloma therapies, that is, bortezomib standard combinations (BSC) or conventional chemotherapy (CT), in a large cohort of patients with primary plasma cell leukemia (pPCL), including those fulfilling the revised diagnostic criteria, that is, circulating plasma cells (cPCS): ≥5%; 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86) out of 3324 myeloma patients (3%), registered in our database between 2001 and 2021, were studied; 37% had cPCS 5%-19%; 89% received novel combinations including DBQ (21%), VRd (16%) and BSC (52%); 35% underwent autologous stem cell transplantation. 83% achieved objective responses. Treatment with VRd/DBQ strongly correlated with a higher complete response rate (41% vs. 17%; p = .008). After a median follow-up of 51 months (95% CI: 45-56), 67 patients died. Early mortality was 3.5%. Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ versus BSC/CT (25 months, 95% CI: 13.5-36.5 vs. 13 months 95% CI: 9-16.8; p = .03). Median overall survival (OS) was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ versus BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p < .001; HzR: 3.88). In the multivariate analysis VRd/DBQ therapy, del17p(+) and PLT <100.000/µL, independently predicted OS (p < .05). Our study has demonstrated that in the real-world setting, treatment with VRd/DBQ induces deep and durable responses and is a strong prognostic factor for OS representing currently the best therapeutic option for pPCL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Plasmocitária , Mieloma Múltiplo , Humanos , Idoso , Bortezomib/uso terapêutico , Leucemia Plasmocitária/terapia , Grécia , Dexametasona , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante Autólogo , Mieloma Múltiplo/tratamento farmacológicoRESUMO
We investigated incidence, characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) treated mainly with novel therapies. Based on definition (BMPCs <20% and lytic lesions/plasmacytomas, without anemia, renal insufficiency or hypercalcemia) we identified 140 patients with MFMM, among 4650 myeloma patients (3%). Twice the number of patients with typical myeloma were used as controls; 60% were <65 years and 70% had advanced bone disease. Plasmacytomas were more frequent in MFMM compared with standard myeloma (68% vs 15%, P < .05). Adverse prognostic parameters (high lactate dehydrogenase, advanced stage, high risk cytogenetics, immunoparesis) were less common in patients with MFMM compared with controls (P < .05); 90% received novel agents and 47% underwent autologous transplantation upfront; 90% achieved an objective response; 70% had at least very good partial response which was significantly higher compared with controls (P < .05). After a median follow-up of 52 months, 33 patients have died. Early death (<12 months) was infrequent in MFMM. Median progression-free survival and overall survival (OS) were 46 and 129 months respectively, both significantly longer compared with controls (P < .001). Proteasome inhibitor (PI)-based therapy was the only independent predictor for OS in the multivariate analysis (HR: 3.9; P < .001). In conclusion, MFMM is a distinct entity presented in young and elderly subjects, characterized by limited bone marrow infiltration, advanced bone disease and frequent presence of plasmacytomas; MFMM patients have less often adverse prognostic features and achieve excellent responses and prolonged OS especially when treated with PI-based therapies. Novel imaging will help in a more accurate classification of this entity.
Assuntos
Mieloma Múltiplo/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Dados , Feminino , Grécia , Humanos , Incidência , Israel , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease (EMD) and high-risk cytogenetics is not yet defined. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with EMD undergoing single autologous (nâ¯=â¯373), tandem autologous (nâ¯=â¯84), or autologous-allogeneic transplant (nâ¯=â¯31) between 2003 and 2015. At least 1 high-risk abnormality was present in 41% (nâ¯=â¯202), with del(17p) (40%) and t(4;14) (45%) the most frequent. More than 1 high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival (OS) and progression-free survival (PFS) of 54% and 29%, respectively, versus 78% and 49% for standard-risk cytogenetics (P < .001). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, OS and PFS were 70% and 43% for single autologous versus 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic (Pâ¯=â¯.06 and Pâ¯=â¯.30). In multivariate analysis high-risk cytogenetics were associated with worse survival (hazard ratio [HR], 2.00; Pâ¯=â¯.003), whereas tandem autologous significantly improved outcome versus single autologous transplant (HRs, .46 and .64; Pâ¯=â¯.02 and Pâ¯=â¯.03). Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival, but results were limited because of small population (HR, .31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with EMD and significantly worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis.
Assuntos
Aberrações Cromossômicas , Mieloma Múltiplo , Transplante de Células-Tronco , Adulto , Idoso , Autoenxertos , Intervalo Livre de Doença , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Fatores de Risco , Sociedades Médicas , Taxa de SobrevidaRESUMO
OBJECTIVES: To evaluate the prognostic impact of hypercalcemia in newly diagnosed patients with symptomatic multiple myeloma (MM), especially after the incorporation of new agents. METHODS: we analyzed the outcomes of newly diagnosed patients with symptomatic myeloma included in the database of the Greek Myeloma Study Group for the prognostic effect of the presence of hypercalcemia (defined as corrected serum calcium ≥11 mg/dL) at diagnosis. RESULTS: Among 2129 consecutive patients with symptomatic MM, 19.5% presented with hypercalcemia at the time of diagnosis. The presence of hypercalcemia was associated with anemia, thrombocytopenia, lower estimated glomerular filtration rate (eGFR), advanced ISS stage, and presence of lytic lesions. Hypercalcemia was more common in patients with high-risk cytogenetics and was associated with inferior survival across different time periods, age groups, and primary treatments. Hypercalcemia was also associated with a twofold increase in the risk of early death. In patients without available FISH, hypercalcemia could substitute for the presence of high-risk cytogenetics and identify patients with worse prognosis along with ISS stage and elevated serum LDH. CONCLUSION: Hypercalcemia remains a poor prognostic feature in the era of novel agents despite the improvement in the outcomes of patients who present with elevated calcium.
Assuntos
Hipercalcemia/etiologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Hipercalcemia/diagnóstico , Estimativa de Kaplan-Meier , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Estadiamento de Neoplasias , Osteólise , Prognóstico , Resultado do Tratamento , Adulto JovemRESUMO
Autologous hematopoietic cell transplantation (AHCT) has presented a revolutionary advance in the management of hematologic malignancies with low toxicity. However, oral mucositis (OM) remains a distressing toxic effect of AHCT and one of the major side effects of the conditioning. This prospective, observational study aimed to evaluate the severity of oral cavity pain and quality of life (QOL) and explore incidence, duration, and potential risk factors of moderate/severe OM. Thirty-nine patients receiving prophylactic palifermin post-AHCT were enrolled. QOL and severity of pain were assessed using validated questionnaires (Functional Assessment of Cancer Therapy-General (FACT-G) and mouth and throat soreness (MTS), respectively). The incidence of moderate/severe OM was 28.2 % with a median duration of 5 days and was associated with younger age and female gender. Severity of pain related to OM was generally low or moderate with only 25 % of patients reporting a score >6 on the MTS scale of 0-10 on day +7. Health-related QOL was worse on day +7 in the transplant unit compared to day 1, while on discharge day, all scores recovered and the total FACT-G score was not different from that on day 1. In our population, the incidence and duration of OM and the severity of pain related to OM appeared to be lower compared to that reported in previous studies. The impact of OM on QOL assessments seemed to be reversible with optimal supportive care despite the major transient disabilities mainly attributable to OM.
Assuntos
Antineoplásicos/administração & dosagem , Fator 7 de Crescimento de Fibroblastos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Qualidade de Vida , Estomatite/epidemiologia , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Fatores Etários , Terapia Combinada , Estudos Transversais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Profilaxia Pós-Exposição , Estudos Prospectivos , Fatores Sexuais , Estomatite/diagnóstico , Estomatite/etiologia , Transplante Autólogo/efeitos adversosRESUMO
Involvement of the central nervous system (CNS) is a rare complication of multiple myeloma (MM). Herein, we have described the incidence, characteristics, prognostic factors for post CNS-MM survival, and outcome of CNS-MM and explored the efficacy of novel agents (NA) (thalidomide, bortezomib, lenalidomide) in this setting. Between 2000 and 2013, 31 (0.9 %) out of 3408 newly diagnosed symptomatic MM patients, consecutively diagnosed and treated during the same period in 12 Greek centers, developed CNS-MM (M/F 15/16, median age 59 years, range 20-96 years; newly diagnosed/relapsed-refractory 2/29; median time to CNS-MM diagnosis 29 months). Clinical and laboratory characteristics were retrospectively recorded. Twenty-six percent of patients had circulating plasma cells (PCs) or plasma cell leukemia (PCL) at CNS-MM and 39 % had skull-derived plasmacytomas, suggesting hematological and contiguous spread. Treatment for CNS-MM was offered in 29/31 patients and 11/29 responded (NA 18/29, additional radiotherapy 9/28, intrathecal chemotherapy 13/29). The median post CNS-MM survival was 3 months (95 % CI 1.9-4.1) and did not differ between patients treated with NA and/or radiotherapy vs. others. In the multivariate analysis, prior treatment of MM with NA, extramedullary disease (EMD) during MM course (i.e., plasmacytomas, circulating PCs, or documented PCL) and abnormally high LDH at MM diagnosis were independent prognostic factors, whereas treatment of CNS-MM with NA did not predict for post CNS-MM survival. Despite the relatively limited number of patients due to the rarity of CNS-MM, our results suggest that NA do not seem to improve post CNS-MM survival. Patients with EMD display shortened post CNS-MM survival and should be followed thoroughly.
Assuntos
Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Grécia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
The combination of lenalidomide plus dexamethasone (RD) is very effective for patients with relapsed/ refractory myeloma. However, the effect of RD on bone metabolism has not been previously evaluated in these patients. To address this issue, we initially performed a retrospective study in 106 consecutive patients with relapsed or refractory myeloma who received RD. We measured the following bone indices on Cycle 1/Day 1 and then on Cycles 3 and 6/Day 28: dickkopf-1 (Dkk-1), sRANKL, osteoprotegerin (OPG), bone resorption markers (C-telopeptide of collagen type-I, CTX and TRACP-5b) and bone formation markers (bone-specific alkaline phosphatase-bALP and osteocalcin). RD produced a reduction of CTX only in responders, with no effect on bone formation. To validate these results, we then evaluated prospectively 99 patients who received either RD (n550) or VRD (bortezomib + RD, n549). RD reduced CTX, mainly in responders but showed no effect on bone formation, confirming the result of the retrospective study. However, the addition of bortezomib to RD (VRD arm) reduced Dkk-1, sRANKL/OPG, and CTX, while it increased bALP and OC after six cycles of therapy. These changes were irrespective of treatment response, which was similar between treatment arms. No skeletal-related events were observed in the VRD arm while two, nonresponding patients treated with RD developed a vertebral fracture. We conclude that RD reduces bone resorption only in responding patients with relapsed/refractory myeloma but has no effect on bone formation. Combination with bortezomib, which enhances bone formation, seems to be preferred for the management of myeloma patients with osteolytic disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Dexametasona/administração & dosagem , Feminino , Grécia , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Gradação de Tumores , Estadiamento de Neoplasias , Recidiva , Estudos Retrospectivos , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Resultado do TratamentoRESUMO
Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary plasma cell tumors. The treatment of choice is local radiotherapy (R/T) ± surgical excision. The role of adjuvant chemotherapy (C/T) or novel agents (NA) is uncertain. Data related to prognostic factors are inconclusive. Herein, we describe the clinical features, survival and prognosis of 97 consecutive patients, 65 with bone SP (SBP), and 32 with extramedullary SP (SEP), diagnosed and treated in 12 Greek Myeloma Centers. Objective response rate (≥PR) and complete response (CR) was 91.8% and 61.9%, respectively, and did not differ between the 2 groups. Overall, 38 patients relapsed or progressed to multiple myeloma (MM). After a median follow-up of 60 months, 5 and 10-year overall survival (OS) probability was 92% and 89% in SEP and 86% and 69% in SBP, respectively (P = 0.2). The 5- and 10-year MM-free survival (MMFS) probability was 90% and 70% for patients with SEP vs. 59% and 50% for patients with SBP, respectively (P = 0.054). Overall, the 5- and 10-year OS probability, plasmacytoma relapse-free survival (PRFS), progression-free survival and MMFS was 84% and 78%, 72% and 58%, 58% and 43%, and 70% and 59%, respectively. In the multivariate analysis, prolonged PRFS and young age were positive predictors of OS. Achievement of CR was the only positive predictor of PRFS. Immunoparesis was the only negative predictor of progression to MM. The addition of C/T or NA-based treatment increased toxicity without offering any survival advantage over R/T.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Plasmocitoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Ácidos Borônicos/administração & dosagem , Bortezomib , Quimioterapia Adjuvante , Dexametasona/administração & dosagem , Progressão da Doença , Feminino , Grécia , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Análise Multivariada , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Plasmocitoma/diagnóstico , Plasmocitoma/mortalidade , Plasmocitoma/patologia , Prognóstico , Pirazinas/administração & dosagem , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
International Staging System (ISS), serum free light chain ratio (sFLCR) and lactate dehydrogenase (LDH) are well known, easily assessed independent prognostic indicators of outcome in multiple myeloma (MM). The purpose of the study was to re-examine the prognostic contribution of these variables in a multicenter setting with special attention to MM patients treated with autologous stem cell transplantation (ASCT) or novel agents (NA). Three hundred and five symptomatic newly diagnosed MM patients were retrospectively studied. Twenty-seven per cent, 32% and 41% were in ISS stages 1, 2, and 3, respectively. Fifty-six per cent of them presented kappa light chain monoclonality; median sFLCR was 27.04 (0.37-1.9 × 10(5) ) and 47.97 (0.26-2.3 × 10(7) ) for kappa patients and lambda patients, respectively; patients with sFLCR above median constituted the high sFLCR group. Thirty-one per cent of patients had increased LDH. As first line treatment, 55.7% received conventional treatment and 44.3% NA. After induction, 24% underwent ASCT, whereas 76% received NA at any line, either bortezomib (82.5%), thalidomide (48%) or lenalidomide (27%). When the 305 patients were analyzed together, staging, high sFLCR and abnormal LDH were predictive of survival. The same was true for patients that never received NA, whereas neither high sFLCR nor abnormal LDH constituted adverse factors in patients that received NA frontline. In the last group of patients, no difference was observed between ISS stages 2 and 3. The median 5-year survival of patients that never received NA versus those who did frontline was 29% vs 47%, 7% vs 52% and 24% vs 40% in patients with abnormal LDH, high sFLCR and ISS stage 3, respectively (p = 0.03, p < 0.00001 and p = 0.035). In conclusion, patients gaining the most from NA are those with an aggressive disease as reflected by advanced stage, abnormal LDH and high sFLCR. In addition, the adverse impact of these three variables is obscured by NA.
Assuntos
Biomarcadores Tumorais/sangue , L-Lactato Desidrogenase/sangue , Mieloma Múltiplo/sangue , Intervalo Livre de Doença , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/terapia , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Transplante Autólogo/métodosRESUMO
OBJECTIVES: The estimation of glomerular filtration rate (eGFR) in multiple myeloma (MM) is based on equations that use serum creatinine (sCr), such as the Modification of Diet in Renal Disease (MDRD) equation. However, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) group has suggested that eGFR based on both sCr and cystatin C (CKD-EPI-sCr-CysC) is more accurate than other formulae for the estimation of kidney dysfunction. The aim of this study was to prospectively evaluate, for the first time in the literature, the CKD-EPI-sCR-CysC formula in newly diagnosed patients with symptomatic MM. METHODS: We studied 220 newly diagnosed, previously untreated, patients with symptomatic myeloma and calculated eGFR using the MDRD, the CKD-EPI-sCR, the CKD-EPI-CysC, and the CKD-EPI-sCr-CysC equations. RESULTS: CKD-EPI-sCr-CysC equation detected more myeloma patients with stage 3-5 renal impairment than the MDRD, CKD-EPI, or CKD-EPI-CysC equations: 45% vs. 39.5%, 42.2%, and 43.1%, respectively (P < 0.01). This was also observed in the elderly patients (>70 yrs), while in patients ≤70 yrs, the CKD-EPI-CysC equation managed to identify higher number of patients with stage 3-5 renal impairment (RI) than the other equations. Furthermore, 63 (28.6%) patients with eGFR values by the MDRD formula were reclassified to higher CKD stages according to CKD-EPI-CysC equation. The median overall survival for all patients was 52 months. In the multivariate analysis, that included International Staging System stage, lactate dehydrogenase (LDH) ≥300 U/L and eGFR for each different equation (as a continuous variable), only eGFR that included CysC, but not sCr had independent prognostic value (P = 0.013) along with high LDH (P = 0.029). CONCLUSIONS: Our results suggest that equations based on CysC reveal higher number of MM patients with RI compared with equations based only in sCr. Furthermore, the CKD-EPI-CysC formula independently predicted for survival. Based on these data, we suggest that CKD-EPI equations based on CysC should substitute MDRD, as it has been suggested for patients with several other renal disorders.
Assuntos
Creatinina/sangue , Cistatina C/sangue , Modelos Estatísticos , Mieloma Múltiplo/sangue , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Taxa de Filtração Glomerular , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/fisiopatologia , Análise Multivariada , Guias de Prática Clínica como Assunto , Prognóstico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
Background: Despite advances in the treatment of oncology patients, therapy-related side effects may lead to premature morbidity. Inflammatory activation that has been linked to cardiovascular disease is crucial for the pathogenesis of both Hodgkin (HL) and non-Hodgkin lymphoma (NHL). Objectives: The purpose of this study was to assess the vascular effects of chemotherapy in patients with HL and NHL by positron emission tomography/computed tomography with 18-fluorodeoxyglucose (18-FDG PET/CT) and to investigate interactions with systemic inflammation as assessed by circulating inflammatory markers. Methods: Between July 2015 and July 2019, 65 consecutive patients (mean age 56 ± 17.78 years) with confirmed diagnosis of either HL (n = 33) or NHL (n = 32) were prospectively studied. PET/CT imaging was performed at baseline, at an interim phase, and after first-line treatment. Aortic FDG uptake was assessed by measuring global aortic target-to-background ratio (GLA-TBR). Serum biomarkers interleukin (IL)-6 and IL-1b were measured at each phase. Results: Patients with HL demonstrated significant reduction in aortic TBR after first-line treatment (median GLA-TBR baseline: 1.98, median GLA-TBR third scan: 1.75, median difference = -0.20, 95% CI: -0.07 to -0.33, P = 0.006), which remained significant after adjustment for confounders (adj. R2 of model = 0.53). In contrast, patients with NHL did not demonstrate a significant aortic inflammation response (P = 0.306). Furthermore, patients with HL demonstrated a significant reduction in IL-6 (P = 0.048) and IL-1b (P = 0.045), whereas patients with NHL did not demonstrate significant reduction in IL-6 (P = 0.085) and IL-1b levels (P = 0.476). Conclusions: Aortic inflammation, as assessed by 18-FDG PET/CT, is reduced in HL patients after first-line treatment but not in NHL patients. These findings imply that different pathophysiological pathways and different therapies might affect the arterial bed in different ways for patients with lymphoma.
RESUMO
The circulating levels of several angiogenic cytokines [angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang-1/Ang-2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin-1/angiopoietin-2 ratio correlated with advanced disease features including international staging system (ISS)-3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin-2) we found that angiopoietin-2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang-1/Ang-2 ratio correlated with survival. Patients with circulating Ang-1/Ang-2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first-line therapy with novel agent-based regimens (65% of our patients). Furthermore, a subset of ISS-3 patients with serum Ang-1/Ang-2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang-1/Ang-2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50-2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.
Assuntos
Angiopoietina-1/sangue , Angiopoietina-2/sangue , Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocinas/sangue , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , PrognósticoRESUMO
Sclerostin is a Wingless and Int-1 inhibitor, which is produced by osteocytes and inhibits osteoblast-driven bone formation. Sclerostin is implicated in the pathogenesis of bone loss in metabolic bone disorders but there is no information for its effect on multiple myeloma (MM)-related osteolytic disease. We evaluated circulating sclerostin in 157 newly diagnosed patients with symptomatic myeloma, in 25 with relapsed myeloma who received bortezomib monotherapy, in 21 patients with monoclonal gammopathy of undetermined significance (MGUS), and in 21 healthy controls. Patients with active myeloma had elevated circulating sclerostin compared to MGUS patients and controls (p < 0.01). MM patients who presented with fractures at diagnosis (n = 34) had very high levels of circulating sclerostin compared with all others (p < 0.01), whereas sclerostin correlated negatively with bone specific alkaline phosphatase (a bone formation marker; r = -0.541, p < 0.0001) and positively with C-telopeptide of collagen type-1 (a bone resorption marker; r = 0.524, p < 0.0001). Patients with International Staging System (ISS)-3 disease had higher circulating sclerostin compared to ISS-1 and ISS-2 MM (p = 0.001). Furthermore, patients with high sclerostin (upper quartile, n = 40) had a median survival of 27 months versus 98 months of all others (p = 0.031). Relapsed MM patients had higher levels of circulating sclerostin even compared to newly diagnosed patients (p < 0.01). Bortezomib monotherapy resulted in a reduction of sclerostin by almost 50% in both responders and non-responders. These results suggest that patients with active myeloma have elevated circulating sclerostin, which correlated with advanced disease features including severe bone disease. Our study indicates sclerostin as a possible target for the development of novel therapies to enhance osteoblast function in myeloma.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas Morfogenéticas Ósseas/fisiologia , Remodelação Óssea , Ácidos Borônicos/uso terapêutico , Marcadores Genéticos/fisiologia , Mieloma Múltiplo/sangue , Pirazinas/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Morfogenéticas Ósseas/sangue , Bortezomib , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/fisiopatologiaRESUMO
Monocytopenia is a common finding in patients with myelodysplastic syndrome (MDS), but although monocytes may exhibit prognostic significance in MDS due to their role in innate immunity, they have not been incorporated in any prognostic scoring system for MDS. In this study, we analyzed national registry data from 1719 adults with MDS. Monocytopenia was present in 29.5% of the patients and was correlated with the presence of excess blasts and higher revised international prognostic scoring system categories. Univariate analysis showed that monocytopenia was prognostic of a lower overall survival [(OS), 32.0 versus 65.0 months, p < 0.001], while it retained its prognostic significance in a multivariate model comprising anemia, neutropenia and thrombocytopenia [hazard ratio (HR) for OS, 1.320, p < 0.001]. Moreover, it was prognostic of a lower leukemia free survival (LFS) both in univariate analysis and in a multivariate model comprising cytopenias, bone marrow blasts, and cytogenetic risk (HR for LFS 1.27, p = 0.031). The findings regarding OS and LFR were exclusive or more pronounced in lower risk patients, respectively. Moreover, monocytopenia could divide the low and intermediate risk groups of IPSS-R in prognostically distinct subgroups. Our results redefine the prognostic role of monocytes in MDS and set the basis for further studies to validate our results and expand our knowledge on the prognostic significance of monocytopenia in MDS.
Assuntos
Síndromes Mielodisplásicas , Neutropenia , Trombocitopenia , Adulto , Humanos , Prognóstico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Medula Óssea , Modelos de Riscos Proporcionais , Trombocitopenia/complicaçõesRESUMO
Autologous hematopoietic cell transplantation (auto-HCT) may be performed in multiple myeloma (MM) patients relapsing after a previous auto-HCT. For those without an adequate dose of stored stem cells, remobilization is necessary. This retrospective study included patients who, following disease relapse after the first auto-HCT(s), underwent stem cell remobilization and auto-HCT performed using these cells. There were 305 patients, 68% male, median age at salvage auto-HCT was 59 years. The median time to relapse after the first-line penultimate auto-HCT(s) was 30.6 months, the median follow-up after salvage auto-HCT 31 months. The 2- and 4-year non-relapse mortality (NRM) after the salvage auto-HCT was 5 and 9%, the relapse incidence 56 and 76%, respectively. Overall survival (OS) after 2 and 4 years was 76 and 52%, progression-free survival (PFS) 39 and 15%. In multivariable analysis an increasing interval between the penultimate auto-HCT and relapse was associated with better OS and PFS, later calendar year of salvage auto-HCT with better OS. In conclusion, salvage auto-HCT performed with cells remobilized after a previous auto-HCT was associated with acceptable NRM. The leading cause of failure was disease progression of MM, which correlated with a shorter interval from the penultimate auto-HCT to the first relapse.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Feminino , Humanos , Masculino , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia , Estudos Retrospectivos , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: Multiple myeloma (MM) patients presenting with anaemia as their sole clinical manifestation are rare and not fully defined. METHODS: Retrospective multi-site study comparing the characteristics and outcome of MM patients with anaemia only with matched patients, presenting with multi-organ disease. RESULTS: Anaemia-only patients had a higher percentage of bone marrow monoclonal plasma cells group (median 60% [IQR 42-80%] vs. 37% [IQR 17-65%], respectively; p < 0.001), and a lower responsiveness to treatment (≥VGPR rates were 54% vs 74%, p = 0.049). Median survival in anaemia only patients was 65.9 ± 6.9 vs 83.4 ± 8.8 months in matched control patients (P = n.s). CONCLUSIONS: MM patients presenting with anaemia only represents a unique, potentially less favorable population.
Assuntos
Anemia , Bortezomib/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/mortalidade , Anemia/terapia , Autoenxertos , Bortezomib/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Estudos RetrospectivosRESUMO
The "POWERFUL" multicenter, retrospective, and prospective study investigated the effectiveness of pomalidomide plus low-dose dexamethasone (POM/LoDex) therapy in relapsed/refractory multiple myeloma in routine care in Greece. Ninety-nine eligible adult patients treated with POM/LoDex according to the approved label after having received ≥2 prior therapies, including lenalidomide and bortezomib, were consecutively enrolled between 16 November 2017 and 21 February 2019 in 18 hematology departments. Fifty patients (50.5%) started POM/LoDex as third-line treatment. During the treatment period (median: 8.3 months; range: 0.3-47.6 months), the median POM dose was 4 mg/day, and 31.3% of the patients received additional antimyeloma agents. The overall response rate was 32.3%. During a median follow-up period of 13.8 months (Kaplan-Meier estimate), the median progression-free survival (PFS) was 10.5 months (95% CI: 7.4-14.4). The PFS was not significantly different between patients receiving POM/LoDex in the third versus later line of therapy, nor between patients receiving concomitant antimyeloma therapy versus POM/LoDEx doublet. During the prospective safety data collection period (median: 7.6 months) among patients with prospective follow-up (N = 75), POM-related adverse event incidence rate was 42.7% (serious: 18.7%; grade ≥ 3 hematological POM-related adverse events: 8.0%). Only neutropenia (13.3%) was reported at a frequency ≥10%. In conclusion, in this real-world study, POM/LoDex displayed a long PFS with no new safety signals emerging.
RESUMO
OBJECTIVES: High serum lactate dehydrogenase (LDH) is associated with features of advanced disease and inferior survival in multiple myeloma. It is however unclear whether LDH adds to the prognostic value of International Staging System (ISS) and whether it retains its prognostic significance in patients who are exposed to novel agent-based therapies. PATIENTS/METHODS: To address these issues we analyzed 996 consecutive symptomatic patients who were included in the database of the Greek Myeloma Study Group and received frontline treatment between January 1, 1995 and December 31, 2008. RESULTS: The median overall survival (OS) of all patients was 40 months with a clear improvement in those who started treatment after January 1, 2000 (49 vs. 31 months; P < 0.01). A multivariate model showed that LDH, ISS, performance status, age and platelet counts had an independent prognostic value for OS (P < 0.001 for all parameters). The median OS of patients with high (11% of patients) and normal LDH was 15 vs. 44 months (P < 0.001). High LDH was associated with inferior OS within all ISS groups: 22 vs. 76 months for high and normal LDH groups, respectively, in ISS-1 (P < 0.01); 11 vs. 40 months in ISS-2 (P < 0.001) and 17 vs. 27 months in ISS-3 (P < 0.01). The median OS of high and normal LDH groups among patients who received novel agents was 21 vs. 51 months, respectively (P < 0.001). CONCLUSIONS: Lactate dehydrogenase is a readily available and inexpensive variable, which has a major impact on the survival of myeloma patients even when they belong to a low or intermediate ISS subgroup and even when they receive novel agent-based therapies.
Assuntos
L-Lactato Desidrogenase/sangue , Mieloma Múltiplo/diagnóstico , Fatores Etários , Antineoplásicos/uso terapêutico , Feminino , Grécia , Humanos , Masculino , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Contagem de Plaquetas , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: There is evidence that metabolic disease burden in lymphoma influences patient outcome. However, the impact of disease severity on the cardiovascular system is unknown. OBJECTIVES: The aim of this study was to examine whether lymphoma is associated with arterial inflammation by investigating the relationship between disease metabolic burden and arterial fluorodeoxyglucose (FDG) uptake. METHODS: Sixty-two chemotherapy-naïve patients with active Hodgkin's or non-Hodgkin's lymphoma were matched (2:1) to individual control groups of lymphoma patients previously treated and free of active disease. All groups underwent 18F-FDG position emission tomography-computed tomography imaging. Disease severity was quantified by metabolic tumor volume (MTV) and total lesion glycolysis corresponding to standardized uptake values (SUVs) ≥41% or ≥2.5 of the maximum SUV within lymphoma regions, and aortic FDG uptake was quantified through the target-to-background ratio (TBR). Inflammatory and disease severity biomarkers were also measured. RESULTS: MTV and total lesion glycolysis measurements were significantly correlated with inflammatory and disease biomarkers. Aortic TBR was higher in patients with active non-Hodgkin's lymphoma compared with control subjects (median difference 0.51; 95% confidence interval [CI]: 0.28 to 0.78; p < 0.001). Similarly, patients with active Hodgkin's lymphoma had higher values of aortic TBR compared with control subjects (median difference 0.31; 95% CI: 0.15 to 0.49; p < 0.001). In addition, aortic TBR was modestly increased in patients with stage III to IV disease compared with those with stage I to II disease (median aortic TBR: 2.23 [interquartile range: 2.01 to 2.54] vs. 2.06 [interquartile range: 1.83 to 2.27; p = 0.050). In multivariable analysis, aortic FDG uptake and MTV≥2.5 values were independently associated (ß = 0.425; 95% CI: 0.189 to 0.662; p = 0.001; R2 = 0.208), as were aortic FDG uptake and MTV≥41% (ß = 0.407; 95% CI: 0.167 to 0.649, p = 0.001; R2 = 0.191). CONCLUSIONS: Aortic wall FDG uptake is related with disease severity indicative of a possible vascular effect of lymphoma. This work highlights a new potential role of molecular imaging in cardio-oncology for evaluating disease severity and its consequences on the vasculature.