To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.
Patients with immunoglobulin light chain (AL) amyloidosis and stage IIIb cardiac involvement have a dismal outcome despite the introduction of novel treatments. However, a rapid hematologic response translates in better survival. We evaluated the impact of early cardiac response and its depth on outcome in 249 patients with newly-diagnosed stage IIIb cardiac AL amyloidosis. Hematologic and cardiac responses were evaluated by intent to treat. After a median follow-up of 52 months, 219 (84%) patients died, and median survival was 4.2 months. The 30- and 90-day hematologic response rates were 22% (at least very good partial response [VGPR] in 9%) and 24% (at last VGPR in 15%), respectively. Early hematologic response resulted in better survival. At 90 days, 21 (8%) patients achieved a cardiac response (cardiac very good partial response [cardiac VGPR] in 12 cases and cardiac partial response [cardiac PR] in 9). At 90-day landmark analysis, cardiac response resulted in longer survival (median 54 months), also in patients with at least VGPR (median 62 vs. 26 months, P=0.011). Patients with cardiac VGPR had a longer survival than those with cardiac PR (median 92 vs. 24 months; P=0.027), while patients without cardiac response had a poor survival (median 6 months). A baseline difference of involved/uninvolved free light chains (dFLC) >50 mg/L (OR 0.21, P=0.024) and a bone marrow plasma cell infiltrate >10% (OR 0.23, P=0.040) were negative predictors of 90-day cardiac response. Early cardiac responses are rare but possible in stage IIIb AL amyloidosis and translate in longer survival.
In both monoclonal gammopathy of uncertain significance (MGUS) and multiple myeloma (MM) patients, immune functions are variably impaired, and there is a high risk of bacterial infections. Neutrophils are the most abundant circulating leukocytes and constitute the first line of host defense. Since little is known about the contribution of autophagy in the neutrophil function of MGUS and MM patients, we investigated the basal autophagy flux in freshly sorted neutrophils of patients and tested the plastic response of healthy neutrophils to soluble factors of MM. In freshly sorted high-density neutrophils obtained from patients with MGUS and MM or healthy subjects, we found a progressive autophagy trigger associated with soluble factors circulating in both peripheral blood and bone marrow, associated with increased IFNγ and pSTAT3S727. In normal high-density neutrophils, the formation of acidic vesicular organelles, a morphological characteristic of autophagy, could be induced after exposure for three hours with myeloma conditioned media or MM sera, an effect associated with increased phosphorylation of STAT3-pS727 and reverted by treatment with pan-JAK2 inhibitor ruxolitinib. Taken together, our data suggest that soluble factors in MM can trigger contemporary JAK2 signaling and autophagy in neutrophils, targetable with ruxolitinib.
Endothelial dysfunction (ED) is frequently encountered in transplant medicine. ED is an argument of high complexity, and its understanding requires a wide spectrum of knowledge based on many fields of basic sciences such as molecular biology, immunology, and pathology. After hematopoietic stem cell transplantation (HSCT), ED participates in the pathogenesis of various complications such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy (TA-TMA), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), and engraftment syndrome (ES). In the first part of the present manuscript, we briefly review some biological aspects of factors involved in ED: adhesion molecules, cytokines, Toll-like receptors, complement, angiopoietin-1, angiopoietin-2, thrombomodulin, high-mobility group B-1 protein, nitric oxide, glycocalyx, coagulation cascade. In the second part, we review the abnormalities of these factors found in the ED complications associated with HSCT. In the third part, a review of agents used in the treatment of ED after HSCT is presented.
Allogeneic hematopoietic stem cell transplantation (HSCT) for high-risk acute myeloid leukemia (AML) represents the only curative option. Progress has been made in the last two decades in the pre-transplant induction therapies, supportive care, selection of donors and conditioning regimens that allowed to extend the HSCT to a larger number of patients, including those aged over 65 years and/or lacking an HLA-identical donor. Furthermore, improvements in the prophylaxis of the graft-versus-host disease and of infection have dramatically reduced transplant-related mortality. The relapse of AML remains the major reason for transplant failure affecting almost 40–50% of the patients. From 10 to 15 years ago to date, treatment options for AML relapsing after HSCT were limited to conventional cytotoxic chemotherapy and donor leukocyte infusions (DLI). Nowadays, novel agents and targeted therapies have enriched the therapeutic landscape. Moreover, very recently, the therapeutic landscape has been enriched by manipulated cellular products (CAR-T, CAR-CIK, CAR-NK). In light of these new perspectives, careful monitoring of minimal-residual disease (MRD) and prompt application of pre-emptive strategies in the post-transplant setting have become imperative. Herein, we review the current state of the art on monitoring, prevention and treatment of relapse of AML after HSCT with particular attention on novel agents and future directions.
BackgroundThe anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who received at least three prior lines of therapy, including proteasome inhibitor and immunomodulatory agent. A retrospective multicentric study was designed to evaluate feasibility, tolerability, and efficacy of daratumumab in monotherapy in RRMM.MethodsThis study included 44 consecutive RRMM patients that underwent daratumumab monotherapy after a median number of four prior therapies (range 2–9). Patients were treated in seven Sicilian centers, as part of Sicilian Myeloma Network and three Calabrian centers outside of controlled clinical trials from August 2016 through July 2020.ResultsThe regimen was well tolerated with few grade 3–4 haematological and rare non-haematological adverse events, such as pneumonia. Definitive discontinuation was due to disease progression in 25 (57%) patients. Since three patients did not complete at least one full cycle, a total of 41 patients was evaluated for response. Overall response rate was 37%, and the disease control rate (stable disease or better) was high (73%). The best achieved responses within 6 months were very good partial remission or better (27%), partial remission (10%), minimal response (14%) and stable disease (22%). After a median follow up of 7.8 months, median progression free survival (PFS) was 7.2 months and overall survival (OS) 7.8 months. Univariate analysis showed that patients with PR or better after 6 months of therapy had longer median PFS and OS (respectively 29.5 vs 3.6 months, p=0.0001 and 30.6 vs 3.9 months p=0.0001), confirmed by multivariate analysis. Furthermore, standard cytogenetic risk and biochemical relapse type had prolonged median PFS, but not OS (respectively unreached vs 2.6, p=0.03 and 23.9 vs 6.2, p=0.05) in both univariate and multivariate analysis. Additionally, univariate analysis showed that patients treated with carfilzomib-lenalidomide-dexamethasone prior to daratumumab had significantly shorter PFS compared to pomalidomide-dexamethasone (3.4 months vs 9.3 months, p=0.03), that multivariate analysis failed to confirm.ConclusionsOur findings indicate that daratumumab as single agent is safe and well-tolerated regimen in real-life, associated to prolonged PFS and OS in responding patients. No new safety signals were identified.
INTRODUCTION. Myeloid suppressor cells are a heterogeneous group of myeloid cells that are increased in most cancer patients. Recently, we and another group demonstrated that MDSC play an important role of immune escape in chronic myeloid leukemia (CML) patients inducing T cell tolerance. The aim of this study was to investigate the effect of the tyrosine kinase inhibitors (TKI) therapy on MDSC and possible correlation with clinical response. METHODS. MDSCs were analyzed in peripheral blood of 20 healthy donors (HD) and 30 CML patients at diagnosis. MDSCs were also measured during TKI treatment (18 patients treated with imatinib and 10 patients with dasatinib). Granulocytic MDSCs (G-MDSCs) were identified as CD11b+CD33+CD14-HLADR- cells, while the monocytic MDSCs (M-MDSCs) as CD14+HLADR by cytofluorimetric analysis. Immuno-suppressive activity was tested through incubation of MDSCs with autologous CFSE-labeled T cells and stimulation with phytohaemagglutinin (PHA). Controls included a positive T cell proliferation control (T cells plus PHA) and a negative one (T cells only). After three days, T cell proliferation was analyzed by flow cytometry. Exosomes were isolated from CML serum at diagnosis (n=5) by sequential ultracentrifugation. RESULTS. G-MDSCs and M-MDSCs percentages in CML patients were greater than HD (respectively 82.5±9.6% vs 56.2±5.4% and 33.6±19% vs 5.9±4%, p<0.0001). Both isolated subpopulations showed expression of BCR/ABL and were able to inhibit T cells proliferation in comparison to positive control (from 48±7.6% to 25±5% for G-MDSC, p=0.0057 and 16.7±0.6% for M-MDSC, p<0.0001). No suppressive effect was observed in co-cultures with G-MDSC and M-MDSC obtained from HD. In addition, M-MDSC percentage correlated with BCR-ABLABL transcript levels in patients at diagnosis (r=0.5816, p=0.0006). Evaluating the effect of TKI therapy on MDSC levels, we found that both imatinib (IM) and dasatinib (DAS) induced a significant reduction of G-MDSC percentage at 6 months (from 82.5±9.6% to 55±17.3% after IM and 48.7±13% after DAS, p<0.0001) and 12 months (61.2±9.7% after IM and 33.4±14% after DAS, p<0.0001) of treatment. The levels of M-MDSCs significantly decreased only after DAS therapy (from 33.6±19% to 6.8±12.6% at 6 months, p=0.014 and 11.4±12.3% at 12 months, p=0.008); while there was a mild reduction after IM treatment (22.2±24.5% and 22.3±21.7% respectively at 6 and 12 months) although a great variability was observed among patients. Subsequently, correlation of MDSC reduction and clinical response to TKI therapy was investigated. We found that in DAS, but not in IM treated patients, a correlation between percentage of Major Molecular Response (MMR) and number of persistent M-MDSCs was found.. In fact, a significant difference was recorded by comparing M-MDSC levels in the MMR group (n=6) versus no MMR (n=4) at 6 or 12 months (p=0.0034). In addition, to evaluate if leukemic cells are able to expand MDSC by releasing soluble factors or exosomes, we incubated monocytes obtained from HD with sera or exosomes from CML patients at diagnosis or healthy subjects. M-MDSCs percentage significantly increased only in conditions with CML serum ( 29±13%; p=0.0006) or exosomes (8 ±2,8%; p=0.01) while no effect was observed on G-MDSC percentage. CONCLUSION: Therapy with TKI reduces the percentage of MDSCs and levels of the monocytic subset correlates with MMR in patients treated with dasatinib, suggesting their importance in clinical investigation as prognostic factor. Moreover, our data suggest the possible development in CML patients of a circuit primed by tumor cells that, through the release of soluble factors and exosomes, are able to expand M-MDSCs, creating an immunotolerant environment that results in T cell anergy and facilitates tumor growth. Disclosures No relevant conflicts of interest to declare.
Background: In the era of novel drugs a growing number of multiple myeloma (MM) patients are treated until disease progression. Serum free light chain (sFLC) assay is recommended for disease monitoring in oligo-secretory and micromolecular MM. Methods: In this real-life survey, a total of 130 relapsed/refractory MM patients treated at our center with at least three lines were investigated as a retrospective cohort. Results: The median age at diagnosis was 64 years and more than half of patients were male. A total of 24 patients (18%) had oligo-secretory/micromolecular disease at diagnosis. More than 20% of 106 normo-secretory patients had oligo-secretory/micromolecular escape. In order to evaluate potential role of sFLC assay before (“pre”) and after (“post”) every treatment line, involved serum free light chain values (iFLC) less than 138 mg/mL and serum free light chain ratios (FLCr) <25 were identified by using ROC curve analysis. The analysis of the entire cohort throughout four treatment lines demonstrated a statistically significant negative impact on progression-free survival (PFS) for both involved pre-sFLC and its ratio (respectively p = 0.0086 and p = 0.0065). Furthermore, both post-iFLC and post-FLCr greater than the pre-established values had a negative impact on PFS of the study cohort; respectively, p = 0.014 and p = 0.0079. Odds ratio analysis evidenced that patients with both involved post-sFLC greater than 138 mg/mL and post-FLCr above 25 at disease relapse had a higher probability of having clinical relapse (respectively p = 0.026 and p = 0.006). Conclusions: Alterations of sFLC values, namely iFLC and FLCr, both prior to treatment initiation and in the course of therapy at every treatment line, could be of aid in relapse evaluation and treatment outcome. We therefore suggest close periodical monitoring of sFLC assay, independently from secretory status.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.