Highlights • The in-depth CV evaluation before ANA was prospectively investigated in 55 ET pts. • The in-depth CV evaluation was not necessary to define patients fit for ANA therapy. • The in-depth ...CV evaluation before and during ANA did not predict CV adverse events. • The CV adverse events during ANA were easily managed by the hematologists. • The CV adverse events were cause of ANA withdrawal in only one of 38 patients (edema).
Background. HPgV (previously called GBV-C) is a single-stranded RNA virus belonging to the Flaviviridae, and is the most closely related human virus to the Hepatitis C virus. HPgV is transmitted ...through parenteral, sexual and perinatal routes and replicates in vitro in T and B-lymphocytes. Active infection lasts months to years and viremia can be detected in plasma by real time (RT)-PCR methods. HPgV viremia has been linked to risk of non-Hodgkin lymphoma in some previous studies, but these have had a limited number of cases. In the largest study conducted to date, we evaluated the association of HPgV viremia and viremic load (VL) with risk of developing lymphoma, overall and by major subtypes, in the Mayo Clinic Case-Control Study of Lymphoma. Because the virus has also been associated with better prognosis in the setting of co-infection with HIV in many studies, we further assessed the association of HPgV with prognosis. Finally, to better understand the association of HPgV with lymphoma risk we correlated the HPgV status with circulating levels of selected cytokines in a subset of our controls.
Methods. To assess the role of HPgV in lymphoma risk (etiology), we used risk factor data and banked plasma samples (stored at -80°C) from 2094 lymphoma cases newly diagnosed from 2002-2009 and 1572 frequency matched controls. Plasma samples (blind to case/control status) were tested for HPgV RNA by RT-PCR, and those with RNA concentrations < 5,000 genome equivalents/ml were confirmed using nested RT-PCR methods. We used unconditional logistic regression model to estimate odds ratio (ORs) and 95% confidence intervals (CI) for the association of HPgV status (negative/positive) and VL (tertiles among positive controls) with lymphoma risk, adjusted for age and sex. To assess the role of HPgV in lymphoma outcome (prognosis), we used 2948 cases from the Iowa/Mayo Molecular Epidemiology Resource, a prospective cohort study of newly diagnosed lymphoma patients (included all cases from the case-control study). We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% CI for the association of HPgV viremia status and VL with event-free (EFS) and overall (OS) survival, adjusted for clinical and treatment variables. Circulating serum cytokines in 379 controls with HPgV data were analyzed using the Luminex-100 system Version 1.7. Data were acquired using STar Station software and analysis was performed using the MasterPlex QT 1.0 system.
Results. The mean age of cases was 61 years, and 58.2% were male, while the mean age of controls was 63 years, and 51.1% were male; 78 (5.0%) controls and 211 (10.1%) cases were HPgV positive. There was a positive association of HPgV viremia with risk of lymphoma overall (OR = 2.14; 95% CI 1.63-2.80; p <0.0001), and for all major subtypes except HL and CLL/SLL (Table). Further adjustment for history of hepatitis, transfusion, autoimmune disease, atopy, family history of lymphoma, farming, obesity, smoking, alcohol use, or sun exposure did not confound these results, and results were consistent when excluding plasma samples (38%) collected after initiation of treatment. There was no dose-response association of VL with overall lymphoma risk: compared to HPgV negative, OR = 1.8 for lowest tertile (95% CI 0.58-5.97), OR = 4.3 for middle tertile (95% CI 0.97-19.6), and OR = 2.5 for highest tertile (95% CI 0.95-6.97). In the control group, median levels of serum sIL2-R (p=0.04), MIP1α (p=0.03) and MIG (p=0.02) were significantly higher in HPgV viremia positive compared to HPgV negative controls. In contrast to the analysis for risk, there was no association of HPgV viremia with EFS (HR = 1.00; 95% CI 0.85-1.18) or OS (HR = 0.97; 95% CI 0.79-1.20) for lymphoma overall, nor for any of the subtypes (Table). Likewise, there was no association of EFS or OS with viremic load.
Conclusion. HPgV infection was associated with the overall risk of lymphoma, as well as most of the major NHL subtypes except CLL/SLL and HL, and this was not confounded by other lymphoma risk factors. However, there was no association of HPgV status with prognosis. Among controls, HPgV viremia was associated with higher levels of IL-2R, MIP1α and MIG, which were previously associated with risk of DLBCL and FL in a case-control analysis, and suggests potential mechanistic pathways for further exploration. These data support the hypothesis for a role for this virus in the etiology of multiple lymphoma subtypes.
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Nowakowski:Nanostring: Research Funding; Bayer: Consultancy, Research Funding; Abbvie: Consultancy; Genetech: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; celgene: Consultancy, Research Funding; pharmacyclics: Consultancy. Ansell:Affimed: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Celldex: Research Funding. Cerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering .
INTRODUCTION: Mantle Cell Lymphoma (MCL) is considered an aggressive B-cell lymphoma, but with a heterogeneous outcome and a median overall survival ranging from 3 to 5 years (yrs). Two different ...subsets are recognized, known as “classical” and “leukemic non-nodal” subtypes. Unfrequently MCL presents with isolated extranodal localization mimicking mucosa-associated lymphoid tissue (MALT) lymphomas; a large series of European Mantle Cell Network has been recently reported (Morello et al, ICML 2017). On the other side, pathological features of this peculiar presentation are not yet clarified.
METHODS: We collected data on 34 patients (pts) with extranodal mantle cell lymphoma (EMCL) of MALT site, diagnosed between 2001 and 2016 in 10 Italian Centers of Fondazione Italiana Linfomi (FIL) network. The diagnosis of MCL was confirmed through detection of CyclinD1 overexpression and/or t(11;14). All pts were >18 yrs and HIV negative. Only minimal locoregional nodal involvement, with CT longest axis <2 cm, and bone marrow involvement with only extranodal disease were allowed. Pts with splenomegaly and leukemic disease were excluded. We performed a central pathological review of 21/34 cases (62%) in the Section of Anatomic Pathology of University of Pavia and compared their features with a cohort of nodal MCL.
RESULTS: Clinical features and treatments are summarised in Table 1.
Biopsied extranodal sites were as follows: 11 pts (32%) Waldeyer's ring, 11 (32%) gastrointestinal tract, 3 (9%) ocular adnexa, 3 (9%) oral cavity, 3 (9%) salivary glands, 2 (6%) thyroid and 1 (3%) liver. Detailed morphology was assessed in 28 pts: classical in 22 pts (78%), pleomorphic in 3 (11%) and blastoid in 3 (11%). CD5 expression was performed in 31 cases: 21 (68%) positive, 6 (19%) partially positive and 4 (13%) negative. Median Mib1/Ki67 was low (15%, range: 2-70%), <30% in 83% and ≥30% in 17% cases. CyclinD1 was available in 33 pts (88% positive, 3% negative, 9% partially positive) and t(11:14) in 13 pts (92% positive). SOX11 staining was performed in 21 cases: 17 (81%) resulted positive, 3 (14%) partially positive and only 1 (5%) negative. Overall, no statistically significant difference with nodal MCL series was observed, particularly regarding cytological features, CD5 and SOX11 expression and Mib1/Ki67. MIPI score was calculated in 33 pts: 15 (46%) low, 13 (39%) intermediate and 5 (15%) high; biologic-MIPI score was available in 29 pts: 7 (24%) low, 14 (48%) intermediate and 8 (28%) high.
After a median follow-up of 5.1 yrs (0.5-15), overall survival (OS) was 93% at 5 yrs and 75% at 10 yrs with 4 deaths (2 for lymphoma, 2 for unknown cause). All the 12 pts treated with autologous stem cell transplantation was still alive at last follow-up. Progression-free survival (PFS) was 74% after 5 yrs and 64% after 10 yrs of follow-up. Univariate analysis results are overlapping with European series: pts with age <65 yrs (p=0.002), ECOG 0 (p=0.012), low MIPI score (p=0.005) and low biologic MIPI score (p=0.008) had a longer OS. In univariate analysis, a longer PFS was observed in pts with age <65 yrs (p=0.016), ECOG 0 (p=0.002), low MIPI score (p<0.001) and low biologic MIPI score (p=0.011). In multivariate analysis, age (p=0.022) confirmed its impact on PFS, after adjusting for biologic MIPI score.
CONCLUSIONS: According to our preliminary data, we define EMCL as a subset with preferential involvement of Waldeyer's ring and gastrointestinal tract, mimicking the clinic-pathologic features of marginal zone lymphoma of extranodal sites, from which it should be differentiated via a thorough histologic characterization, and featuring the indolent course of the indolent variant of MCL. On the other hand, our cases harbored the morphologic and phenotypic features of the nodal form of MCL. On the basis, the true nature of this putative MCL subset should be deepened upon biologic characterization, including mutational and IGVH status analysis.
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Loseto:gilead: Membership on an entity's Board of Directors or advisory committees; janssen: Consultancy; italfarmaco: Membership on an entity's Board of Directors or advisory committees. Arcaini:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; Gilead: Research Funding. Zaja:Novartis: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Gilead: Honoraria; Janssem: Honoraria; Celgene: Honoraria, Research Funding.
Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoma characterized by splenomegaly, frequent moderate lymphocytosis with or without villous morphology and possible involvement of ...various organs, especially the bone marrow (BM). Diagnosis is classically based on the spleen histology, but it can be made on the BM biopsy, based on the typical intrasinusoidal cell infiltration pattern and immunohistochemistry. Different therapeutic options are available, but to date there are no conclusive comparative data.
We retrospectively analyzed 83 consecutive patients with a diagnosis of SMZL observed at our Institution between 1999 and 2013. The diagnosis was based on the BM biopsy in 79 patients; the BM was negative in 4 patients. Diagnosis was histologically confirmed on the spleen in 27 patients who underwent splenectomy. Patients presented a median age of 72.5 years (range 38-84); 43 were males. The median spleen size at diagnosis was 145 mm, ranging from 100 to 300 mm. The majority of patients were stage IV at diagnosis for BM infiltration (95%); B symptoms were present in 4 of them (4.8%). Forty-two patients (50.6%) had a lymphocytosis at diagnosis and 13 (15.6%) presented an IPI score higher than 3. Thirty-five of them (42%) had a MZL BM infiltration superior to 30% of the total bone cellularity. Forty-two patients (50.6%) underwent a watch and wait policy (WW), while 41 (49.4%) were treated within 6 months from diagnosis, mainly because of symptomatic splenomegaly; in these patients, treatment consisted of splenectomy, chemotherapy or chemotherapy plus immunotherapy with Rituximab. The features of patients submitted to WW with respect to patients treated at diagnosis were comparable for the various parameters mentioned above, except for spleen size (higher in patients treated at presentation) and lymphocyte count (higher in patients who were observed). After a median follow-up of 64 months, the overall median survival was 96%. Among the 42 WW patients, 18 (42.8%) are still untreated after a median follow-up of 57.5 months, while 24 (57.2%) have required therapy; the median treatment-free interval in these patients was 25.5 months. Concerning the 41 patients who underwent treatment at diagnosis, after a median follow-up of 50 months, 13 (31.7%) have required a subsequent second-line treatment. The interval between first-line approach and re-treatment in patients treated at diagnosis was 30 months. Overall, 27 patients were treated with splenectomy only (either at diagnosis or after a WW period): only 6 of them (22%) had a subsequent progression after a median latency of 42 months; 26 were treated with chemotherapy alone (alkylating agents in the majority of them, combination therapy in a minority): 15 of them (60%) had a subsequent relapse or progression after a median of 9 months; 12 patients received a Rituximab-containing regimen: of these, only 2 (16%) have so far required a second-line therapy after 10 and 26 months respectively.
The WW policy is a valid option for asymptomatic patients: in these patients, after 4.5 years from diagnosis more than 40% is still untreated. In patients requiring treatment, splenectomy alone is followed in the majority of patients by a long period of good disease control: only 22% required a second-line therapy after 3.5 years. The addiction of Rituximab to chemotherapy seems to reduce the probability of relapse and to prolong the response duration. However, these preliminary data need to be confirmed by larger studies.
No relevant conflicts of interest to declare.
Background: Comorbidities and body mass index (BMI) are significantly associated with outcome in patients (pts) who receive continue treatment with tyrosine kinase inhibitors (TKIs), such as in Ph+ ...leukemias. Ruxolitinib (RUX) is the first JAK1/2 inhibitor that may induce spleen/symptom responses and improve quality of life in pts with myelofibrosis (MF). Up-to-date, no data are available on the impact of comorbidities and BMI on pts treated with RUX.
Aims: To evaluate the impact of comorbidities and BMI on responses, overall survival (OS) and maintenance of RUX dose in a large cohort of pts.
Methods: Data were extracted from an electronic database that included retrospective data on pts treated before January 2015 in 16 Italian Hematology centers. Response to RUX was evaluated according to IWG-MRT criteria. BMI was calculated at the time of start of RUX and classified according to WHO criteria. Comorbidities were recorded at the time of start of RUX and classified according to the Charlson Comorbidity Index (CCI). Overall survival (OS) was calculated from the date of RUX start to the time of death or to last follow-up, whichever came first.
Results: Between June 2011 and Apr 2016, 289 pts with PMF (52.6%), or PET-MF (17%) or PPV-MF (30.4%) were treated with RUX in participating Centers. At RUX start, median age was 68.4 years (range 39-89) with a male prevalence (56.4%); International Prognostic Score System (IPSS) was intermediate (intm)-1 (15.6%), intm-2 (45.3%), high (39.1%). Transfusion dependence and spleen enlargement were present in 26.6% and 96.9% of pts, respectively (69.6% with spleen≥ 10 cm). Median total symptom score (TSS) was 20 (range 0-70). JAK2V617F was present in 80.3% of 234 evaluable pts. Median follow-up from MF diagnosis was 3.8 yr (range 0.3-29.6) and median RUX exposure was 20 months (3-56.2).
Overall, comorbidities were evaluable in 275 pts. CCI stratification showed the absence of comorbidities in 100 pts (36.4%), one comorbidity in 63 pts (22.9%) and two or more in 112 pts (40.7%). Compared to pts with CCI <2, pts with CCI ≥2 were more frequently: male (66.1% vs 49.1%, p=0.005), ≥65y (74.1% vs 54%, p=0.001), at intm2/high IPSS risk (90.2% vs 81%, p=0.03) and transfusion-dependent (36.6% vs 20.2%, p=0.003). Notably, the percentage of pts starting RUX >2y from MF diagnosis was lower if CCI≥2 (33.9% vs 54%, p=0.001).
Higher CCI did not correlate with lower spleen response (achieved by 45.2% vs 34.7%, p=0.09), TSS response (90.1% vs 83.2%, p=0.11), and higher incidence of RUX-induced anemia (Hb <10 g/dl in pts with baseline Hb ≥10 g/dl) (48% vs 41%, p=0.33). RUX starting and titrated doses at 12-wks were similar in the two groups (p=0.44 and p=0.81, respectively).
OS was significantly higher in pts with CCI<2 (96.7% vs 87.8% at 2 yr, p<0.001). After stratification according to CCI (below or above 2) and the achievement of a spleen response, both factors remained significantly associated with survival. Indeed, in pts with CCI<2 OS at 2 yr was 92.7% and 79.1%, depending on the achievement of a spleen response (SR) or not (NR), respectively (p=0.034). Analogously, in pts with CCI≥2 the achievement of a spleen response significantly increased survival (79.2% vs 55.3% in pts without spleen response, p=0.011). Notably, OS was comparable in pts with lower CCI /no spleen response and in pts with higher CCI/spleen response (79.1% vs 79.2%) (Figure 1).
BMI was evaluable in 269 pts: 169 pts (62.8%) were classified as under-weight/normal for a BMI <25, whereas 100 pts were overweight/obese (BMI ≥25). Pts with BMI≥25 were more frequently male (71% vs 47.3%, p<0.001) and with a lower incidence of anemia (30% vs 42%, p=0.049). BMI stratification did not correlate with differences in spleen response (p=0.83) and TSS (p=0.18) or onset of anemia/infections during treatment (p=0.49 and p=0.28). Starting and median doses, as well as percentage of pts reducing RUX dose over time, were similar in the two groups.
Summary: In MF pts treated with RUX, BMI and comorbidities did not influence the achievement of spleen/symptom responses, maintenance of RUX dose or onset of drug-related anemia. Although CCI stratification correlated with survival, as in Ph+ leukemias treated with TKIs, the achievement of a spleen response was able to counterbalance the negative prognostic effect of a higher CCI. Consequently, higher BMI and CCI should not be regarded as contraindication to RUX therapy.
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Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding. Cimino:Bristol-Mayer: Honoraria; Celgene: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.
From November 2012 to July 2014, brentuximab vedotin (BV) was available in Italy for patients with relapsed Hodgkin’s lymphoma (HL) outside a clinical trial context based on a local disposition of ...the Italian Drug Agency (AIFA) issued according to a national law (Law 648/96: "medicinal products that are provided free of charge on the national health service"). A large Italian observational retrospective study was conducted on the use of BV in the everyday clinical practice to check if clinical trial results are confirmed even in a real life context. Primary endpoint was the best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and the safety profile. BV was infused intravenously at the dose of 1.8 mg/kg every 3 weeks. A total of 234 HL patients were treated in 40. All patients had histologically documented CD30+ HL; 49% had relapsed and 51% had refractory disease. Patients were heavily pretreated with a median of 3 previous therapies (including autologous stem cell transplant SCT in the 69% of cases). Best response was observed after a median of 4 cycles in 140 patients (59.8%): 74 (31.6%) patients obtained a complete response (CR) and 66 (28.2%) achieved a partial response (PR); overall response rate at the end of the treatment was 48.3% (62 CR and 51 PR). The best response rate was higher in the elderly subset (>60 years): 14 (50%) CR and 5 (17.8%) PR. Disease free survival was 26.3% at 29 months and progression free survival 31.9% at 55 months. We identified 30 long term responders (patients with a response ≥ 12 months) of whom 18 are still in CR, 7 with a consolidative SCT and 11 without any consolidative procedure. Duration of response did not differ who achieved at least PR and then either did or did not undergo consolidative SCT. All patients were included in the safety profile for the analysis; in general, the treatment was well tolerated in everyday clinical practice and the toxicity profile was closely similar to the previously published data; no death has been linked to BV-induced toxicity. This preliminary analysis could indicate that BV displays a number of features favoring its use as a bridge to transplant in patients with active disease who achieve a suboptimal response to salvage treatment. Even in a real life context, BV induces clinical responses quite rapidly, i.e. within the first 4 cycles in most responders, thus permitting the timely application of the transplantation phase. BV displays a favorable toxicity profile, without overlapping toxicities with most of the agents employed in high-dose conditioning regimens. Furthermore, for HL patients ineligible for transplant or for who transplant failed, may represent a feasible effective therapeutic option.
Rusconi:Janssen: Consultancy, Other: Congress attendance; Teva: Consultancy, Other: Congress attendance; Takeda: Consultancy. Spina:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.
From November 2012 to July 2014, brentuximab vedotin (BV) was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma (ALCL) outside a clinical trial context based on a ...local disposition of the Italian Drug Agency (AIFA) issued according to a national law (Law 648/96: "medicinal products that are provided free of charge on the national health service"). A large Italian observational retrospective study was conducted on the use of BV in the everyday clinical practice to check if clinical trial results are confirmed even in a real life context. Primary endpoint was the best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and the safety profile. BV was infused intravenously at the dose of 1.8 mg/kg every 3 weeks for a maximum of 16 cycles. A total of 40 ALCL (18 anaplastic lymphoma kinase ALK negative and 22 ALK-positive status) patients were treated with BV in 40 Hematology Centers. All patients had histologically documented CD30+ ALCL; 16 (40%) had relapsed and 24 (60%) had refractory disease. Patients were heavily pretreated with a median of 2 previous therapies (including autologous transplant in the 32.5% of cases). Best response was observed after a median of 4 cycles in 31 patients (77.5%): 19 (47.5%) patients obtained a complete response (CR) and 12 (30%) achieved a partial response (PR); overall response rate at the end of the treatment was 62.5% (18 CR and 7 PR). The best response rate was higher in the elderly subset (>60 years): 9 (64.2%) CR and 3 (21.4%) PR, achieving a total of 85.6%. At the latest follow up 15/18 patients are still in CR (3 with consolidative procedure). Global progression free survival was 39.1% at 29 months and disease free survival 54% at 23.9 months (median not reached). Median duration of response was 12 months (range 9-24 months). We identified 5 long term responders (patients with a response ≥ 12 months), all were still in CR at the latest follow up (1 underwent allogeneic transplant). Particularly, all the long term responders were aged <30 years at first BV infusion.
All patients were included in the safety profile for the analysis; in general, the treatment was well tolerated even in this real life context and the toxicity profile was closely similar to the previously published data; no death has been linked to BV toxicity. Toxicity was primarily neurological and rarely so serious as to require treatment reduction or interruption; furthermore, neurological toxicity always reversed completely after end of treatment. No long-term toxicity was assessed during the follow-up period, even in patients later subjected to transplant consolidation.
BV induces clinical responses quite rapidly, i.e. within the first 4 cycles in most responders, thus permitting the timely application of the transplantation phase. Furthermore, BV displays a favorable toxicity profile, without overlapping toxicities with most of the agents employed in high-dose conditioning regimens. For patients ineligible for transplant or for who transplant failed, BV may represent a feasible effective therapeutic option in everyday clinical practice.
Rusconi:Takeda: Consultancy; Teva: Consultancy, Other: Congress attendance; Janssen: Consultancy, Other: Congress attendance. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.
This paper explores financial networks of cryptocurrency prices in both time and frequency domains. We complement the generalized forecast error variance decomposition method based on a large VAR ...model with network theory to analyze the dynamic network structure and the shock propagation mechanisms across a set of 40 cryptocurrency prices. Results show that the evolving network topology of spillovers in both time and frequency domains helps towards a more comprehensive understanding of the interactions among cryptocurrencies, and that overall spillovers in the cryptocurrency market have significantly increased in the aftermath of COVID-19. Our findings indicate that a significant portion of these spillovers dissipate in the short-run (1–5 days), highlighting the need to consider the frequency persistence of shocks in the network for effective risk management at different target horizons.
Patients (pts) with relapsed DLBCL who can not be managed with consolidative autologous or allogeneic transplantation exhibit a poor prognosis. Despite a high response rate to induction ...chemo(immuno)therapy, these pts invariably experience early relapse and die of lymphoma progression. Single-drug maintenance may be a good alternative to intensified consolidation to prolong response duration in these pts. Lenalidomide is an oral immunomodulator, active against DLBCL, which can be taken for several years with an excellent safety profile. Accordingly, we designed a multicenter phase II trial addressing safety and efficacy of lenalidomide maintenance in pts with chemosensitive relapse of DLBCL who are not suitable for intensified consolidation or experienced a failure after autologous transplant (NCT00799513). Herein, we report the interim analysis on the first 17 enrolled pts.
Selection criteria were: 1) adult HIV-negative pts; 2) histologically-proven de novo or transformed DLBCL; 3) relapsed disease responsive (partial or complete response) to conventional salvage therapy; 4) ECOG PS ≤3; 5) time to progression from the previous line ≥3 months. Pts with CNS involvement, HBV-DNA or HCV-RNA positivity or active infections were excluded. After confirmation of objective response to salvage therapy, pts were registered and treated with lenalidomide 25 mg/day once daily for 21 days out of 28, for two years or until lymphoma failure or unacceptable toxicity. Primary endpoint was the 1-year PFS. With the null hypothesis (P0) of 1-year PFS of 30%, this study will consider a satisfactory efficacy of lenalidomide a P1 corresponding to a 1-yr PFS of 50%, 47 pts will be needed (α: 0,05; β: 80%).
17 pts were enrolled (median age 73, range 52-86; M:F ratio: 1.1). Eleven pts had a de novo DLBCL, 6 had a transformed DLBCL. Fifteen pts were enrolled after the first relapse, two pts after the 3rd and 4th relapse. All pts experienced a relapse after anthracycline- and rituximab-based chemotherapy, with a median time to progression after the previous line of 16 months (range 6-88). Only one patient was previously managed with autologous transplant. Most pts had unfavourable features: IPI ≥2 in 15 cases, advanced stage in 14, extranodal disease in 13, high LDH in 7. Two pts had bone marrow infiltration; one had HCV and HBc seropositivity. Salvage chemotherapy consisted of high-dose-cytarabine-based combinations in 12 pts, high-dose-ifosfamide-based regimens in 3 and anthracycline-based regimens in 2; all pts received rituximab as part of salvage therapy. Response to salvage therapy was complete in 12 pts and partial in 5.
Three pts completed the planned maintenance, treatment is ongoing in 4; 3 pts interrupted maintenance due to lymphoma relapse, treatment was interrupted due to toxicity in 7 pts (diarrhoea in 3, rash in 2, prolonged neutropenia, anorexia) after 3, 10, 14, 6, 8, 12, and 1 course, respectively. Eight pts needed a transient dose reduction to 10 or 15 mg/d due to rash (n=5), neutropenia (n=2) and neuropathy. There were 4 SAEs (febrile neutropenia and diarrhoea) in 3 pts. Grade 3-4 haematological toxicity consisted of neutropenia in 7 pts and thrombocytopenia in 2. Grade 3-4 non-haematological toxicity consisted of diarrhoea in 3 pts and rash in 5.
Four of the 5 pts in partial response after induction chemoimmunotherapy achieved a complete remission during maintenance. At the last delivered lenalidomide course, 14 (82%; 95%CI: 64-100%) pts were in complete remission, and 3 pts experienced progressive disease, with a median response duration of 26+ months. At a median follow-up of 23 months, 12 (71%) pts remained in complete remission, two responders experienced relapse (27 & 34 months). The 1-year (primary endpoint) PFS was 79% for the whole series. Pts who received at least six lenalidomide courses had a 2-year PFS of 90%. Dose reductions were non influential on PFS (1-year: 75% vs. 83%). All pts are alive (NED in 14).
Lenalidomide maintenance is feasible and well tolerated in pts with relapsed DLBCL. As expected, diarrhoea and rash remain frequent dose-limiting side effects in this elderly population. With obvious limitations, this interim analysis shows encouraging PFS figures, with long-lasting remission in most pts who received at least six lenalidomide courses. Accrual completion is warranted.
No relevant conflicts of interest to declare.
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare diseases, characterized by an aggressive behavior and a poor clinical outcome. High-dose therapy followed by autologous stem cell ...transplantation (ASCT) has been used as salvage and upfront treatment with conflicting results. However, no standard therapy has so far been established due to the lack of randomized studies.
The records of 54 untreated patients with a confirmed diagnosis of PTCL managed at our Institute between 2001 and 2011 were reviewed. The histologic subtypes were: 37 (68%) peripheral T-cell lymphomas unspecified (PTCL-U), 13 (24%) anaplastic large cell lymphomas (ALCL), of which 4 (30%) ALK-positive, 2 (4%) angio-immunoblastic lymphomas (AITL) and 2 (4%) enteropathy-associated T-cell lymphomas (EATL). The clinical characteristics were: median age 56 years (range 18-79); 40 men and 14 women; 13 (24%) and 41 (76%) patients were, respectively, in Ann Arbor stages I-II and III-IV. An elevated serum LDH was present in 33% of patients, 48% had B symptoms and 24% had a bone marrow involvement. The ECOG performance status was 2-3 in 28% of patients. According to the International Prognostic Index (IPI) and the prognostic index for T-cell lymphomas (PIT), 11% and 22% were classified as low risk, 30% and 33% as low-intermediate risk, 12% and 33% as high-intermediate risk and 29% and 12% as high risk, respectively. CHOP-like regimens were given to 32 (59%) patients, 14 of whom received the CHOEP regimen. The remaining 22 (41%) patients were treated with more intensive third generation regimens (MACOP-B like). ASCT was planned as upfront consolidation therapy for 16/54 (30%) patients.
A complete response (CR) was obtained in 30/54 (55.5%) patients, a partial response in 7 (13%), while 17 (31.5%) patients showed a lymphoma progression during induction therapy. No difference in terms of CR rate was observed between the CHOP-like and MACOP-B-like regimens. At a median follow-up of 19 months (range 3-138), the 5-years OS and 5-years PFS were 32% (95% CI 25.3-38.5) and 27% (95% CI 20.2-34.5), respectively. At univariate analysis, bone marrow involvement (p=0.003), PIT high risk group (p<0.001) and lymphocytopenia (p=0.06) predicted a shorter PFS. Five of 16 (31%) patients did not receive the planned ASCT consolidation due to early progression. Patients who received an ASCT as consolidation therapy presented a slightly better 5-year PFS than patients treated with chemotherapy alone (95% CI 37.7% vs 25%; p=0.08).
The prognosis of PTCLs remains poor despite the use of intensive chemotherapy regimen including upfront ASCT. More active induction chemotherapy regimens, including novel agents, should be designed in an attempt to increase the quality of response before ASCT consolidation therapy.
No relevant conflicts of interest to declare.
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