•Narsoplimab down-modulates SARS-CoV-2-induced activation of the lectin pathway and endothelial cell damage.•Narsoplimab can reduce the thrombotic risk of Covid-19 patients.•All patients treated with ...narsoplimab improved and survived without any drug-related adverse events.
In COVID-19, acute respiratory distress syndrome (ARDS) and thrombotic events are frequent, life-threatening complications. Autopsies commonly show arterial thrombosis and severe endothelial damage. Endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis, activates the lectin pathway of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2), the lectin pathway’s effector enzyme, binds the nucleocapsid protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), resulting in complement activation and lung injury. Narsoplimab, a fully human immunoglobulin gamma 4 (IgG4) monoclonal antibody against MASP-2, inhibits lectin pathway activation and has anticoagulant effects. In this study, the first time a lectin-pathway inhibitor was used to treat COVID-19, six COVID-19 patients with ARDS requiring continuous positive airway pressure (CPAP) or intubation received narsoplimab under compassionate use. At baseline and during treatment, circulating endothelial cell (CEC) counts and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were assessed. Narsoplimab treatment was associated with rapid and sustained reduction of CEC and concurrent reduction of serum IL-6, IL-8, CRP and LDH. Narsoplimab was well tolerated; no adverse drug reactions were reported. Two control groups were used for retrospective comparison, both showing significantly higher mortality than the narsoplimab-treated group. All narsoplimab-treated patients recovered and survived. Narsoplimab may be an effective treatment for COVID-19 by reducing COVID-19-related endothelial cell damage and the resultant inflammation and thrombotic risk.
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Regression of hepatitis C virus (HCV)–associated lymphoma with interferon (IFN)-based antiviral treatment supports an etiological link between lymphoma and HCV infection. In addition, a favorable ...impact of antiviral treatment on overall survival of patients with HCV-related lymphoma has been reported. Data on IFN-free regimens combining direct-acting antivirals (DAAs) in HCV-associated lymphoproliferative disorders are scanty. We analyzed the virological and lymphoproliferative disease response (LDR) of 46 patients with indolent B-cell non-Hodgkin lymphomas (NHLs) or chronic lymphocytic leukemia (CLL) and chronic HCV infection treated with DAAs. The histological distribution was 37 marginal zone lymphomas (MZLs), 2 lymphoplasmacytic lymphomas, 2 follicular lymphomas, 4 CLL/small lymphocytic lymphomas (CLL/SLLs), and 1 low-grade NHL not otherwise specified. Thirty-nine patients received a sofosbuvir-based regimen and 7 patients received other DAAs. The median duration of DAA therapy was 12 weeks (range, 6-24 weeks). A sustained virological response at week 12 after finishing DAAs was obtained in 45 patients (98%); the overall LDR rate was 67%, including 12 patients (26%) who achieved a complete response. The LDR rate was 73% among patients with MZL, whereas no response was observed in CLL/SLL patients. Seven patients cleared cryoglobulins out of 15 who were initially positive. After a median follow-up of 8 months, 1-year progression-free and overall survival rates were 75% (95% confidence interval CI, 51-88 and 98% 95% CI, 86-100, respectively. DAA therapy induces a high LDR rate in HCV-associated indolent lymphomas. These data provide a strong rationale for prospective trials with DAAs in this setting.
•Direct-acting antiviral agents are able to induce lymphoma response in patients with HCV-associated indolent non-Hodgkin lymphoma.•The highest rate of lymphoma response (73%) was observed in patients with marginal zone lymphoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The association between B-cell non-Hodgkin lymphoma (NHL) and hepatitis B virus (HBV) is well demonstrated by epidemiological studies. Most studies concerning this association have been conducted in ...endemic areas. Thus, little is known concerning the clinical characteristics of HBV-related lymphomas in non-endemic areas.
Here, we report the characteristics and outcomes of 39 patients with active HBV infection and B-cell NHL collected retrospectively in France and Italy. We also compared their characteristics with those of HCV-positive patients with NHL.
The gender ratio (M/F) was 3.3 and the median age at NHL diagnosis, 59 years. The pathological distribution was 24 (62%) diffuse large B-cell lymphomas (DLBCLs) and 15 (38%) other lymphomas subtypes: marginal zone lymphoma (n = 6), follicular lymphoma (n = 3), mantle cell lymphoma (n = 2), Burkitt's lymphoma (n = 1), and not otherwise specified low-grade B-NHL (n = 3). Treatment included antiviral therapy for 35 patients (90%). Twenty-two (92%) DLBCL patients received an R-CHOP or R-CHOP-like regimen, leading to complete remission for 18 (75%).At one year, 21 DLBCL patients (88%) were alive, and 13 other B-cell lymphoma patients (87%) were alive.
This European study underscores the predominance of DLBCL among patients with active HBV infection and their similar outcomes to non-HBV infected patients with DLBCL when treated with R-CHOP and antivirals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Marginal zone lymphomas (MZLs) are indolent nonfollicular B-cell lymphomas (INFLs) and have heterogeneous clinical behavior. Recently, time to progression of disease at 24 months (POD24) was ...identified to stratify overall survival (OS) in follicular non-Hodgkin lymphoma and in INFL. Here, we examined the ability of POD24 to predict subsequent OS in a large, international cohort of MZL as part of the NF10 prospective international registry headed by Fondazione Italiana Linfomi (FIL). POD24 was only calculated for MZL patients requiring immediate therapy and was defined as experiencing lymphoma progression within 24 months from diagnosis. Among the 1325 patients enrolled in the NF10 study, we identified 321 patients with MZL for whom immediate therapy was planned right after lymphoma diagnosis. Overall, POD24 was confirmed in 59 patients (18%). Three-year OS for patients with POD24 was 53% with a hazard ratio of 19.5 (95% confidence interval, 8.4-45) compared with patients without POD24 (3-year OS, 95%). Association of POD24 with OS was confirmed for the subgroup of splenic and extranodal MZLs. Assessment of POD24 stratifies subsequent outcome in MZL and identifies a high-risk population. This trial was registered at www.clinicaltrials.gov as #NCT02904577.
•Patients with MZL who experience POD24 from initial systemic therapy have a significantly increased risk of death.•Association of POD24 with survival is confirmed for the main MZL subtypes.
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Background: Despite significant advancements in treatment efficacy of acute promyelocytic leukemia (APL), early death (ED) - mainly related to major hemorrhagic and thrombotic events occurring within ...30 days from diagnosis - remains a prominent hurdle to therapeutic success. In this regard, Österroos et al. very recently developed a score which stratifies the risk of ED of patients (pts) with APL in three categories (low score 0-2, high score 3-4, very high score 5-7) according to age (<50 years, 50-59 years, 60-69 years and ≥70 years), white blood cell count (<3.0x10 9/L, 3.0-5.0x10 9/L and >5.0x10 9/L), and platelet count (≥30x10 9/L and <30x10 9/L), all of which are readily available, real-world variables. However, the presence of specific comorbidities, or diseases characteristics, such as the presence of FLT3-ITD mutation, CD2 expression and bcr3 PML::RARA transcript were not evaluated, even if they could potentially further improve the risk stratification ( Österroos et al. Haematologica 2022;107(7):1528-1537). Aims: The aims of this study were to integrate the score proposed by Österroos et al. and evaluate the role of pts comorbidities and disease biological data in modifying risk stratification. Methods: Data were retrospectively collected from 127 consecutive pts diagnosed at our Center from January 2000 to May 2023. Patients had been treated according to the AIDA protocol (n = 76, 60%) or with the combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) (n = 39, 31%) ( Lo-Coco et al. N Engl J Med 2013;369:111-121); 10 pts received ATRA; only 2 pts did not receive any treatment. Results: Table 1 summarizes the main clinical characteristics of the 127 pts included in this study. Overall, ED rate was 11% (n = 14, 12 died within 7 days from diagnosis); the cause of death was a hemorrhagic event in 11 pts. The score identified low- (n = 79, 64%), high- (n = 39, 31%) and very high-risk (n = 6, 5%) categories; ED rates for each category were 3.8%, 20.5% and 0%, respectively. Despite no ED events were registered in our small very-high risk cohort (n = 6), a third of these pts (n = 2) experienced cerebral hemorrhage at disease onset and eventually survived. We confirmed that the score proposed by Österroos et al. was better at predicting ED risk than the Sanz score, with the Area Under the Receiver Operating Characteristic (AUROC) curve of 0.73 (95% CI 0.60-0.87) vs 0.66 (95% CI 0.51-0.81). The AUROC of the reference study cohort was 0.77 (95% CI 0.72-0.83). The presence of specific biological characteristics of the disease, such as FLT3-ITD mutation, bcr3 PML::RARA transcript or CD2 expression were not associated with an increased risk of ED (Table 2). Similarly, the presence of comorbidities (i.e. cardiovascular diseases, hypertension, chronic kidney disease, diabetes mellitus, dyslipidemia, and smoking) were not associated with an increased risk of ED (data not shown). By univariate analysis the presence of fever at diagnosis and male sex showed a trend toward an increased risk of ED (OR 3.77, 95% CI 0.88-19.26, P = 0.08 and OR 3.13, 95% CI 0.92-14.36, P = 0.09, respectively). Conclusions: Our data support the use of the score developed by Ö sterroos et al. to better predict the risk of ED in APL and to select the pts who may benefit from more aggressive supportive care. The presence of fever at diagnosis and male sex seems to be associated with a further increase in the risk of ED but this association needs to be confirmed in a larger study. The integration of biological characteristics of disease and comorbidities does not improve the risk stratification of ED.
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Background. The only curative treatment of Myelodysplastic syndromes (MDS) is represented by allogeneic hematopoietic cell transplantation (HCT). The risk scoring system conventionally used in ...clinical practice for transplant decision-making is IPSS-R (Greenberg PL et al, 2012), which has been shown to predict the HCT outcome(Della Porta MG et al, 2014). The recent broader application of next generation sequencing (NGS) in clinical practice provides an abundance of molecular data and poses the challenge of better prognostic stratification in MDS patients. Recently, Bernard et al(Elsa Bernard et al, 2022) developed a molecular prognostic score called IPSS-Molecular (IPSS-M) which defines six risk categories based on the patient's molecular profile combined with clinical and cytogenetic data. In the original study, only 9% of patients underwent HSCT, therefore the utility of this score in the transplant decision making needs to be explored. Aim.The aim of this study is to evaluate the impact of IPSS-M on the outcome of HCT in patients with MDS. Methods and Results. This is a single center study including 60 consecutive MDS patients who received allogeneic HCT from 2004 to 2023 at Papa Giovanni XXIII Hospital, Bergamo. The median age at transplantation was 57 years and 70% were males. HCT related parameters are listed in Table 1. Of note, 53 out of 60 patients (88%) received an upfront HCT. According to IPSS-RA (age-adjusted IPSS-R), patients clustered in Very Low (4/60), Low (11/60), Intermediate (24/60), High (16/60) and Very High (5/60) risk groups. We retrospectively performed a NGS study before HCT by using a panel of 30 genes for all patients who had available DNA and calculated IPSS-M score for each patient. According to IPSS-M, patients clustered in Very Low (2/60), Low (12/60), Moderate Low (15/60), Moderate High (9/60), High (12/60) and Very High (10/60). Re-stratification occurred in 59% of patients (35/60), of which 22% (13/60) were down-staged and 37% (22/60) were upstaged. With a median follow-up time of 7 years after HSCT, the 5-year overall (OS) and relapse-free survival (RFS) was 67% and 64% respectively. In order to evaluate the utility of IPSS-M in estimating OS and RFS in HCT setting compared to IPSS-R, a concordance test was performed. In terms of OS and RFS, IPSS-M resulted respectively in a C-index of 0.772 and 0.729 compared to 0.567 and 0.607 of IPSS-R (table 2). Conclusions. Despite the limitations due to the small sample and the retrospective design of the study, we conclude that IPSS-M performed better compared to the conventional score in predicting RFS and OS of our MDS patients undergoing HSCT, providing data supporting the integration of clinical and molecular information in this setting. Further improvements may be achieved by integrating the molecular data with clinical information regarding HSCT-related parameters such as performance status, donor and conditioning regimen.
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Introduction
Hepatitis B virus (HBV) is a hepatotropic virus accounting for chronic hepatitis and cirrhosis. HBV is also known as oncogenic, leading to increased risks of not only hepatocellular ...carcinoma but also other cancers including B-cell non-Hodgkin lymphoma (NHL) (Odd-ratio: 1.9-2.0). According to the World Health Organization, 257 million people in the world have an active HBV infection, areas of high prevalence being in Africa, Western Pacific, and Southeast Asia. While some studies were performed in endemic area, little is known concerning the characteristics of HBV-related NHL in Occident. Moreover, although the need for antivirals to prevent HBV reactivation is well known in patients with HBV receiving chemo or immunotherapy, their impact on their prognosis is unknown. Our aim is to describe the characteristics and outcomes of patients with NHL and active HBV in non-endemic areas.
Methods
Thirty-nine consecutive patients diagnosed with active HBV infection and B-cell NHL between 2002 and 2017 were enrolled retrospectively in France and Italy. Active HBV infection was defined by positive antigen HbS (AgHbs) and/or positive HBV-DNA in serum. HCV or HIV positive patients were excluded. Their characteristics and outcomes were analyzed and, for Diffuse Large B-cell Lymphoma (DLBCL), compared with those of HBV-negative patients enrolled in R-CHOP arms of LYSA trials.
Results
Most patients were men (29/39), and median age at NHL diagnosis was 59 years ranging from 29 to 88 years. Twenty-two patients (57%) were born in Europe, 13 in Africa (33%), 4 in Asia (10%). Thirty-three patients had positive AgHbs and 28, positive viral load. The histological subtype distribution was: 23 (59%) DLBCL; 13 low-grade NHL (LG-NHL) including 4 follicular lymphoma (FL), 3 spleen marginal zone lymphoma (SMZL), 3 mucosa associated lymphoid tissue lymphoma and 3 not otherwise specified LG-NHL; 2 mantle cell and one Burkitt lymphoma. Of note, none of the primary DLBCL had a low-grade component but 2 FL and one LG-NHL transformed to DLBCL during follow-up. Five patients had a monoclonal immunoglobulin component. Overall, 26 patients (67%) had an extra-nodal involvement (bone marrow (10), liver (8), digestive (6), and bone (5)).
All but one DLBCL patients were treated with R-CHOP/R-CHOP-like regimen leading to complete remission in 19 out of 22 (84%). Treatment of LG-NHL patients was diverse: Rituximab monotherapy, immuno-chemotherapy (R-CHOP, R-Chlorambucil, R-Bendamustine), corticosteroids alone or with radiotherapy, Helicobacter pylori treatment or wait and watch. After front-line therapy, 20 DLBCL patients (87%) and 9 LG-NHL (69%) patients achieved complete remission (CR). Thirty-six patients received antiviral treatment following NHL diagnosis while 3 did not (one DLBCL, 2 LG-NHL). Seven patients (18%) died during follow-up: 4 due to progression of lymphoma (3 DLBCL and one LG-NHL), 2 to hepatocellular carcinoma, one to infection. Median overall survival was 81 months without difference between DLBCL and LG-NHL patients. Lastly, the comparison of the outcomes of the 23 DLBCL patients with those of HBV-negative patients did not show significant difference.
Conclusions
To our knowledge, this is the first study exploring HBV-related NHL in non-endemic areas. Interestingly, more than 40% of patients were born in high-endemic areas. The strong predominance of DLBCL (59%) is concordant with studies performed in high-incidence areas. Strikingly, it contrasts with the peculiar distribution of HCV-related NHL supporting that some different pathophysiological mechanisms contribute to NHL in HBV. However, as in HCV-related NHL, frequent hepatic or digestive involvement raises the hypothesis of home privileged lymphomagenesis favored by viral induced inflammation or by infection of B-cells. No difference was detected when comparing HBV DLBCL outcomes with non HBV patients. Remarkably, all patients, except one, received antiviral therapy combined with chemotherapy. In endemic areas, while some studies reported that patients with HBV NHL had a poorer prognostic, others suggested that antivirals could overcome this pejorative impact.
This study, performed in Western Europe, area of low HBV prevalence, underlines the predominance of DLBCL among patients with active HBV infection and the similar outcomes of DLBCL patients to non-HBV patients when treated with a combination of R-CHOP and antivirals.
No relevant conflicts of interest to declare.
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IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with Myelodysplastic syndromes (MDS). For many years, the selection of patients to allogeneic ...HSCT has been largely based on use of the International Prognostic Scoring System-Revised (IPSS-R). However, the recent broader application of next generation sequencing in clinical practice provided an abundance of molecular data and led to the introduction of molecular prognostic scores as IPSS-Molecular (IPSS-M). In this paper, we retrospectively analyzed the outcomes of 57 consecutive MDS patients treated with allogeneic HSCT in our center. Re-stratification from IPSS-R to IPSS-M occurred in almost half of patients. The application of IPSS-M to our cohort demonstrated a stronger prognostic separation compared to IPSS-R and improved the C-index. Very high-risk IPSS-M patients showed worse outcomes following HSCT compared to high-risk patients. This study provides data supporting the need of integrating molecular information in the transplant decision making of patients with MDS. This allows an earlier and better identification of patients to whom the transplant should be advised.
•IPSS-R is commonly used to allocate MDS patients to HSCT.•Novel scores as IPSS-M taking into account the molecular data have been introduced.•This is a retrospective single-center study on MDS patients treated with HSCT.•Re-stratification from IPSS-R to IPSS-M occurred in almost half of patients.•IPSS-M demonstrated a stronger prognostic separation compared to IPSS-R.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Acute myeloid leukemia (AML) poses significant challenges, especially in intermediate and high-risk cases due to modest rates of complete remission (CR) of 50-60% yelding a 2-year ...survival probability of about 30-40%. Preliminary results from the AML1718 part 1 trial have demonstrated remarkable improvements, with a composite complete remission (CCR) rate reaching an impressive 82%, and a 1-year survival probability of 72%. These findings represent a substantial advancement compared to historical data. Hereby, we present the comprehensive results of the AML1718 study, with a primary focus on the CCR as the primary endpoint. Methods: The safety and efficacy of venetoclax (VEN) in combination with FLAI (fludarabine, cytarabine, and idarubicin as a first-line treatment for newly diagnosed adult patients with ELN 2017 intermediate- or high-risk AML) was investigated in the GIMEMA AML1718 phase 1/2 multicenter trial (NCT03455504). The study followed a modified two-stage Simon's design, including safety run-in cohorts (SRI-C1 and SRI-C2), an extension phase (Part 1 with P1-C1 and P1-C2 cohorts), and a confirmatory cohort (P2). VEN was administered at a daily dose of 400 mg in combination with FLAI (V-FLAI 400) in SRI-C1 and P1-C1, while in SRI-C2 and P1-C2, the VEN dose was escalated to 600 mg/day (V-FLAI 600). In P2 we used the lower effective dosage of V-FLAI 400, with centralized measurable residual disease (MRD) assessment with flow cytometry following ELN guidelines. After V-FLAI induction, consolidation therapy with cytarabine-based regimens and consideration for allogeneic stem cell transplant (HSCT) were conducted. Adjustments to the VEN dose were made for patients concurrently receiving posaconazole. VEN administration was discontinued until recovery for patients achieving remission by day 21 and during consolidation courses. Results: Since February 2019, a total of 124 patients were treated in this study, 6 in SRI-C1, 6 in SRI-C2, 22 in P1-C1, 23 in P1-C2, and 67 in P2. Among them, 95 patients received V-FLAI 400 and 29 patients received V-FLAI 600. Posaconazole was administered to 115 patients (93%) as antifungal prophylaxis during the first course. The patient population had a median age of 55 years (ranging from 18 to 66), with 70 patients (56%) being male. According to ELN 2017 risk, 67 patients (54%) were classified as intermediate- and 57 patients (46%) as high-risk. Sixteen (13%) patients had a seconday AML. Genetic mutation analysis showed that 4/56 tested patients (7.1%) had IDH1, 11/55 (20%) IDH2, 16/108 (14.7%) FLT3 ITD, 3/112 ( 2.8%) NPM1 mutation; TP53 data are not yet available. The primary endpoint, the CCR, was achieved in 93 out of 124 patients (75%) after the 1 st course (table 1). One patient initially in partial remission (PR) achieved CR after the second V-FLAI induction. In P2, 47/67 patients achieved CCR (70.0%, with 9 patients not yet tested). Central MRD analysis showed that that 31 out of 48 tested patients obtained MRD negativity at day 28 of course 1 (64.5%, treshold 0.1% by flow). With a median follow-up of 10 months, 60 patients (49%) underwent hematopoietic stem cell transplant (HSCT) in CR, and 1 patient underwent HSCT in partial remission. The median overall survival (OS) was 22.4 months (95% confidence interval C.I. 13.4 months - not reached, Figure 1), with a 12-month OS probability of 64% (95% C.I. 54% - 76%). The median disease-free survival (DFS) was 20.7 months (95% C.I. 12.1 months - not reached), and the 12-month DFS probability was 64% (95% C.I. 50% - 76%). The treatment was found to be safe, with only 4 deaths recorded during induction (3.2%), and a 60-day mortality rate of 6% including disease progression-related deaths. Infections were the most commonly reported grade 3+ adverse events. Overall, the safety profile of the treatment regimen was consistent with any intensified AML induction regimen. Among transplanted patients, no instances of graft failure or higher-than-expected incidence of graft-versus-host disease (GVHD) were observed. No significant differences were observed between the 400 mg and 600 mg arms. Conclusions: V-FLAI demonstrated remarkable efficacy without any safety concerns. Impressive CCR rate and MRD-negativity qualify the combination for randomized comparisons . A virtual-randomized phase 3 trial is currently being prepared.
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