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1.
Sci Rep ; 11(1): 20239, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642385

RESUMO

Accurate risk stratification in COVID-19 patients consists a major clinical need to guide therapeutic strategies. We sought to evaluate the prognostic role of estimated pulse wave velocity (ePWV), a marker of arterial stiffness which reflects overall arterial integrity and aging, in risk stratification of hospitalized patients with COVID-19. This retrospective, longitudinal cohort study, analyzed a total population of 1671 subjects consisting of 737 hospitalized COVID-19 patients consecutively recruited from two tertiary centers (Newcastle cohort: n = 471 and Pisa cohort: n = 266) and a non-COVID control cohort (n = 934). Arterial stiffness was calculated using validated formulae for ePWV. ePWV progressively increased across the control group, COVID-19 survivors and deceased patients (adjusted mean increase per group 1.89 m/s, P < 0.001). Using a machine learning approach, ePWV provided incremental prognostic value and improved reclassification for mortality over the core model including age, sex and comorbidities [AUC (core model + ePWV vs. core model) = 0.864 vs. 0.755]. ePWV provided similar prognostic value when pulse pressure or hs-Troponin were added to the core model or over its components including age and mean blood pressure (p < 0.05 for all). The optimal prognostic ePWV value was 13.0 m/s. ePWV conferred additive discrimination (AUC: 0.817 versus 0.779, P < 0.001) and reclassification value (NRI = 0.381, P < 0.001) over the 4C Mortality score, a validated score for predicting mortality in COVID-19 and the Charlson comorbidity index. We suggest that calculation of ePWV, a readily applicable estimation of arterial stiffness, may serve as an additional clinical tool to refine risk stratification of hospitalized patients with COVID-19 beyond established risk factors and scores.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34642126

RESUMO

INTRODUCTION: Tumor necrosis factor alpha (TNF-α) is a cytokine with a key role in proinflammation and multiple diseases, including cancer. The gene encoding TNF-α is located within a highly polymorphic region on chromosome 6p21.3; two polymorphisms -308G/A (rs1800629) and -238G/A (rs361525) have been associated with occurrence of human diseases. There is a debate in recent meta-analyses that reached discrepant conclusions regarding the potential role of TNF-α polymorphisms in multiple myeloma (MM) risk. The aim of this systematic review and meta-analysis is to investigate the association between the aforementioned two polymorphisms with the risk and survival of MM. MATERIALS AND METHODS: Eligible articles were identified through an extensive search in PubMed database (end of search: June 18, 2020). The pooled effect estimates were calculated following the random-effects models by Der Simonian and Laird. Separate analyses were conducted by ethnicity. Between-study heterogeneity was quantified, and the deviation of genotype frequencies in controls from the Hardy-Weinberg equilibrium was evaluated. RESULTS: Eighteen studies (2934 cases, 4291 controls) have been included in the quantitative synthesis examining risk and 5 studies for survival (557 cases). No association was found between -308G/A and -238G/A TNF-α polymorphisms and MM susceptibility in all genetic models for both Caucasian and East Asian populations. There was no association between -308G/A and -238G/A TNF-α polymorphisms and survival (overall or progression-free) of MM. CONCLUSION: This systematic review and meta-analysis did not reveal a significant effect of -308G/A and -238G/A TNF-α polymorphisms upon risk or survival of MM.

3.
J Clin Oncol ; : JCO2100838, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34606378

RESUMO

PURPOSE: The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE. METHODS: Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety. RESULTS: With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade ≥ 3 adverse events of clinical interest generally decreased over time. CONCLUSION: In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.

4.
J Clin Oncol ; : JCO2101045, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34520219

RESUMO

PURPOSE: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively (P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without (P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

5.
Future Oncol ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34521277

RESUMO

In the Phase III ICARIA-MM study (NCT02990338), the addition of the anti-CD38 monoclonal antibody isatuximab to pomalidomide and dexamethasone led to increased progression-free survival and improved response rates in patients with relapsed/refractory multiple myeloma. There is an unmet treatment need, particularly among patients with poor prognoses, including those with high-risk cytogenetics, those who have renal impairment, those who are elderly and those who are refractory to prior lines of treatment. In this review, the subgroup analyses from the ICARIA-MM study, representing subpopulations with poor prognostic factors, are discussed. Overall, the addition of isatuximab to pomalidomide and dexamethasone improved progression-free survival and disease response rates across different subgroups, regardless of prognostic factor.

6.
Blood Adv ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34529762

RESUMO

The urgency of the COVID-19 pandemic has led to accelerated vaccine development within less than a year. Immunocompromised patients with hematological malignancies are more susceptible to COVID-19 and at higher risk of severe complications and worse outcomes compared with general population. In this context, we evaluated the humoral response by determining the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenstrom Macroglobulinemia (WM) after vaccination with the BNT162b2 or AZD1222 vaccine. An FDA-approved, ELISA-based methodology was implemented to evaluate NAbs on the day of the first vaccine shot, as well as on day 22 and 50 afterwards. 106 patients with WM (43% males, median age 73 years) and 212 healthy controls (46% males, median age 66 years) who were vaccinated during the same period, at the same center were enrolled in the study (which is registered at www.clinicaltrials.gov as NCT04743388). Our data indicate that vaccination with either 2 doses of the BNT162b2 or 1 dose of the AZD1222 vaccine leads to lower production of NAbs against SARS-CoV-2 in patients with WM compared with controls both on day 22 and on day 50 (P<0.001 for all comparisons). Disease-related immune dysregulation and therapy-related immunosuppression are involved in the low humoral response. Importantly, active treatment with either Rituximab or Bruton's Tyrosine Kinase inhibitors was proven as an independent prognostic factor for suboptimal antibody response following vaccination. In conclusion, patients with WM have low humoral response following COVID-19 vaccination, which underlines the need for timely vaccination ideally during a treatment-free period and for continuous vigilance on infection control measures.

7.
Amyloid ; : 1-8, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34468250

RESUMO

Daratumumab has major and rapid activity in AL amyloidosis with favourable toxicity. We used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain deposition disease (LCDD), who had not achieved a haematologic complete response (hemCR) after standard therapy with bortezomib, cyclophosphamide and dexamethasone (VCD). We evaluated minimal residual disease (MRD) and changes in the bone marrow (BM) microenvironment before and after consolidation using next generation flow cytometry (NGF). At the time of consolidation, 21 patients were in very good partial response (VGPR) and four in partial response (PR); all had detectable MRD. One month after consolidation completion, 8 patients (32%) achieved a hemCR, of whom 5 (20%) became also MRD negative. In the BM, we observed significant changes in B-cell precursors, naïve B-cells, T-cells, CD27+ NK & NKT cells, mast cells and erythroblasts. After a median follow-up of 25 months, none of the patients in hemCR has relapsed and all have achieved an organ response; a haematologic relapse occurred in 6/17 patients that did not achieve hemCR. In conclusion, consolidation with a short course of daratumumab can improve depth of response in patients with AL amyloidosis or LCDD and significantly affects BM environment.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34344638

RESUMO

BACKGROUND: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status. PATIENTS AND METHODS: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients. RESULTS: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10-5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%). CONCLUSION: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.

9.
Clin Cancer Res ; 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380643

RESUMO

PURPOSE: The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia. Results from the final analysis are now reported. PATIENTS AND METHODS: Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed. RESULTS: After a median follow-up of 58 months (range: 9-61), median PFS was 39 months [95% confidence interval (CI): 25-not evaluable]; 60-month PFS rate was 40%. In MYD88L265P/CXCR4WHIM and MYD88L265P/CXCR4WT subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (≥ partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin ≤11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of -37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation. CONCLUSIONS: In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia.

10.
Cell Rep ; 36(6): 109504, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34352226

RESUMO

Early responses to vaccination are important for shaping both humoral and cellular protective immunity. Dissecting innate vaccine signatures may predict immunogenicity to help optimize the efficacy of mRNA and other vaccine strategies. Here, we characterize the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (IFN-γ) levels early after boost correlate with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We identify a systemic signature including increases in IL-15, IFN-γ, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (TNF-α) and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination results in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Quimiocina CXCL10/imunologia , Interferon gama/imunologia , Interleucina-15/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , COVID-19/metabolismo , Vacinas contra COVID-19/administração & dosagem , Feminino , Humanos , Imunidade/imunologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/imunologia
11.
Vaccines (Basel) ; 9(7)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34358129

RESUMO

It is unclear whether the ChAdOx1 nCov-19 vaccine can induce the development of anti-PF4 antibodies in vaccinated individuals who have not developed thrombosis. The aim of this prospective study was to evaluate the presence of antibodies against heparin/PF4 in adults who received a first dose of the ChAdOx1 nCov-19 vaccine, and correlate them with clinical data and antibody responses to the vaccine. We detected non-platelet activating anti-PF4 antibodies in 67% (29/43) of the vaccinated individuals on day 22 following the first dose of the ChAdOx1 nCov-19 vaccine, though these were detected in low titers. Furthermore, there was no correlation between the presence of anti-PF4 IgG antibodies and the baseline clinical characteristics of the patients. Our findings suggest that the ChAdOx1 nCov-19 vaccine can elicit anti-PF4 antibody production even in recipients without a clinical manifestation of thrombosis. The presence of anti-PF4 antibodies was not sufficient to provoke clinically evident thrombosis. Our results offer an important insight into the ongoing investigations regarding the underlying multifactorial pathophysiology of thrombotic events induced by the ChAdOx1 nCov-19 vaccine.

12.
J Clin Oncol ; : JCO2100105, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34388022

RESUMO

PURPOSE: Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS: We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS: A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction (P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION: Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.

13.
Blood Cancer J ; 11(8): 138, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341335

RESUMO

Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Neutralizing antibodies (NAbs) against SARS-CoV-2 were evaluated in 276 patients with plasma cell neoplasms after vaccination with either the BNT162b2 or the AZD1222 vaccine, on days 1 (before the first vaccine shot), 22, and 50. Patients with MM (n = 213), SMM (n = 38), and MGUS (n = 25) and 226 healthy controls were enrolled in the study (NCT04743388). Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs in patients with MM compared with controls both on day 22 and on day 50 (p < 0.001 for all comparisons). Furthermore, MM patients showed an inferior NAb response compared with MGUS on day 22 (p = 0.009) and on day 50 (p = 0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies (Mabs) or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination. In conclusion, MM patients have low humoral response following SARS-CoV-2 vaccination, especially under treatment with anti-CD38 or belamaf. This underlines the need for timely vaccination, possibly during a treatment-free period, and for continuous vigilance on infection control measures in non-responders.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Mieloma Múltiplo , SARS-CoV-2 , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/imunologia , Estudos Prospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo
14.
Cells ; 10(8)2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34440710

RESUMO

The aim of this study was to investigate the kinetics of neutralizing antibodies (NAbs) and anti-SARS-CoV-2 anti-S-RBD IgGs up to three months after the second vaccination dose with the BNT162b2 mRNA vaccine. NAbs and anti-S-RBD levels were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and three months after the second vaccination (D111) (NCT04743388). 283 health workers were included in this study. NAbs showed a rapid increase from D8 to D36 at a constant rate of about 3% per day and reached a median (SD) of 97.2% (4.7) at D36. From D36 to D50, a slight decrease in NAbs values was detected and it became more prominent between D50 and D111 when the rate of decline was determined at -0.11 per day. The median (SD) NAbs value at D111 was 92.7% (11.8). A similar pattern was also observed for anti-S-RBD antibodies. Anti-S-RBDs showed a steeper increase during D22-D36 and a lower decline rate during D36-D111. Prior COVID-19 infection and younger age were associated with superior antibody responses over time. In conclusion, we found a persistent but declining anti-SARS-CoV-2 humoral immunity at 3 months following full vaccination with BNT162b2 in healthy individuals.


Assuntos
Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/metabolismo , Formação de Anticorpos , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
BMC Med ; 19(1): 208, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34420521

RESUMO

BACKGROUND: Coronavirus SARS-CoV-2, the causative agent of COVID-19, has caused a still evolving global pandemic. Given the worldwide vaccination campaign, the understanding of the vaccine-induced versus COVID-19-induced immunity will contribute to adjusting vaccine dosing strategies and speeding-up vaccination efforts. METHODS: Anti-spike-RBD IgGs and neutralizing antibodies (NAbs) titers were measured in BNT162b2 mRNA vaccinated participants (n = 250); we also investigated humoral and cellular immune responses in vaccinated individuals (n = 21) of this cohort 5 months post-vaccination and assayed NAbs levels in COVID-19 hospitalized patients (n = 60) with moderate or severe disease, as well as in COVID-19 recovered patients (n = 34). RESULTS: We found that one (boosting) dose of the BNT162b2 vaccine triggers robust immune (i.e., anti-spike-RBD IgGs and NAbs) responses in COVID-19 convalescent healthy recipients, while naïve recipients require both priming and boosting shots to acquire high antibody titers. Severe COVID-19 triggers an earlier and more intense (versus moderate disease) immune response in hospitalized patients; in all cases, however, antibody titers remain at high levels in COVID-19 recovered patients. Although virus infection promotes an earlier and more intense, versus priming vaccination, immune response, boosting vaccination induces antibody titers significantly higher and likely more durable versus COVID-19. In support, high anti-spike-RBD IgGs/NAbs titers along with spike (vaccine encoded antigen) specific T cell clones were found in the serum and peripheral blood mononuclear cells, respectively, of vaccinated individuals 5 months post-vaccination. CONCLUSIONS: These findings support vaccination efficacy, also suggesting that vaccination likely offers more protection than natural infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/uso terapêutico , COVID-19 , Glicoproteína da Espícula de Coronavírus/imunologia , COVID-19/prevenção & controle , COVID-19/terapia , Humanos , Cinética , Leucócitos Mononucleares , RNA Mensageiro , SARS-CoV-2
16.
Clin Exp Med ; 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34283338

RESUMO

Vaccination against SARS-CoV-2 is considered as the most important preventive strategy against COVID-19, but its efficacy in patients with hematological malignancies is largely unknown. We investigated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenstrom Macroglobulinemia (WM), Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). After the first dose of the vaccine, on D22, WM/CLL/NHL patients had lower NAb titers compared to controls: the median NAb inhibition titer was 17% (range 0-91%, IQR 8-27%) for WM/CLL/NHL patients versus 32% (range 2-98%, IQR 19-48%) for controls (P < 0.001). Only 8 (14%) patients versus 114 (54%) controls developed NAb titers ≥ 30% on D22 (p < 0.001). Our data indicate that the first dose of both BNT162b2 and AZD1222 leads to lower production of NAbs against SARS-CoV-2 in patients with WM/CLL/NHL compared to controls of similar age and gender and without malignant disease. Even though the response rates were not optimal, vaccination is still considered essential and if possible should be performed before treatment initiation. These patients with suboptimal responses should be considered to be prioritized for booster doses.

17.
Blood ; 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34269818

RESUMO

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone; D-Rd) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone; D-VMP). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better, and after ≥CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving ≥CR. In MAIA, (D-Rd, n=368; Rd, n=369), and ALCYONE (D-VMP, n=350; VMP, n=356), the median duration of follow-up was 36.4 months and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS versus control groups. In a pooled analysis, patients who were MRD negative had improved PFS versus patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. ClinicalTrials.gov identifier NCT02252172 (MAIA); NCT02195479 (ALCYONE).

18.
Blood ; 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34289038

RESUMO

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM) using data from four phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD-negativity rates and reduced the risk of disease progression or death by approximately half versus standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response (CR) or better with MRD-negative status, and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10‒5 threshold). Patient-level data were pooled from all four studies, and for patients with TIE NDMM plus patients with RRMM who received ≤2 prior lines of therapy (≤2PL). PFS was evaluated by response and MRD status. Median follow-up (months) was: POLLUX, 54.8; CASTOR, 50.2; ALCYONE, 40.1; and MAIA, 36.4. Patients who achieved ≥CR and MRD negativity had improved PFS versus those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.ClinicalTrials.gov: NCT02076009/NCT02136134/NCT02195479/NCT02252172.

19.
Expert Rev Hematol ; 14(7): 621-632, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34170207

RESUMO

Introduction: Waldenström's macroglobulinemia (WM) is a rare lymphoma characterized by the accumulation of IgM-secreting lymphoplasmacytic cells in the bone marrow and other organs. Clinical sequelae relate to direct tissue infiltration by malignant cells but also to the physicochemical and immunological properties of the monoclonal IgM, resulting in a variety of disease-related complications.Areas covered: This narrative review, following a thorough Pubmed search of pertinent published literature, discusses complications secondary to WM, related to direct tumor infiltration, monoclonal IgM circulation, and deposition, as well as other less common ones. The description and pathophysiology of these complications were described together with their specific management strategies and in the context of available treatment options for WM (anti-CD20 monoclonal antibody-based combinations, proteasome inhibitors, BTK inhibitors, and other emerging ones).Expert opinion: The availability of many novel, active and less toxic regimens for the treatment of WM allows the management of the disease with strategies that depend on clinical presentation and disease-related complications, age, toxicity considerations, and presence of comorbidities.

20.
N Engl J Med ; 385(1): 46-58, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192431

RESUMO

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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