Valorization of clinical trials from the Italian National Health Service perspective: definition and first application of a model to estimate avoided costs

Introduction: From the perspective of healthcare organizations and public health care systems, the value of a clinical trial can be assessed from a clinical and economical perspective. However, to date, there is no standardized model for systematically capturing the economic value of clinical trials at organizational and system levels. The aim of this study was to develop and test a methodology for estimating the avoided costs deriving from the management of patients as part of a clinical trial. Methods: Our methodology is based on the assumption that the economic value of a clinical trial derives from 1) the funding received by the experimental site from a trial's sponsor, and from 2) the cost avoided by the experimental site with the treatment of patients within a study and not according to standard care by the experimental site. Results: By applying the methodology to onco-hematological clinical trials conducted in two academic hospitals from 2011 to 2016, we demonstrate that savings between 2 million and 4 million euros were achieved over a five-year period. Thus, for every 1,000 euros invested by the pharmaceutical company into the clinical studies conducted at these hospitals, the hospitals saved on average 2,200 euros due to costs not incurred as a result of the trials. Conclusions: The study has proposed and tested a methodology for estimating the economic value of clinical trials by taking into account avoided costs deriving from the treatment of patients enrolled in sponsored trials. The study has proposed a management tool for healthcare institutions to govern clinical trials

Safety and Efficacy of Subcutaneous Rituximab in Previously Untreated Patients with CD20+ Diffuse Large B-Cell Lymphoma or Follicular Lymphoma: Results from an Italian Phase IIIb Study

Subcutaneous (SC) rituximab may be beneficial in terms of convenience and tolerability, with potentially fewer and less severe administration-related reactions (ARRs) compared to the intravenous (IV) form. This report presents the results of a phase IIIb study conducted in Italy. The study included adult patients with CD20+ DLBCL or FL having received at least one full dose of IV RTX 375 mg/m2 during induction or maintenance. Patients on induction received ≥4 cycles of RTX SC 1400 mg plus standard chemotherapy and FL patients on maintenance received ≥6 cycles of RTX SC. Overall, 159 patients (73 DLBCL, 86 FL) were enrolled: 103 (54 DLBCL, 49 FL) completed induction and 42 patients with FL completed 12 maintenance cycles. ARRs were reported in 10 patients (6.3%), 3 (4.2%) with DLBCL and 7 (8.1%) with FL, all of mild severity, and resolved without dose delay/discontinuation. Treatment-emergent adverse events (TEAEs) and serious adverse events occurred in 41 (25.9%) and 14 patients (8.9%), respectively. Two patients with DLBCL had fatal events: Klebsiella infection (related to rituximab) and septic shock (related to chemotherapy). Neutropenia (14 patients, 8.9%) was the most common treatment-related TEAE. Two patients with DLBCL (2.8%) and 6 with FL (7.0%) discontinued rituximab due to TEAEs. 65.2% and 69.7% of patients with DLBCL and 67.9% and 73.6% of patients with FL had complete response (CR) and CR unconfirmed, respectively. The median time to events (EFS, PFS, and OS) was not estimable due to the low rate of events. At a median follow-up of 29.5 and 47.8 months in patients with DLBCL and FL, respectively, EFS, PFS, and OS were 70.8%, 70.8%, and 80.6% in patients with DLBCL and 77.9%, 77.9%, and 95.3% in patients with FL, respectively. The switch from IV to SC rituximab in patients with DLBCL and FL was associated with low risk of ARRs and satisfactory response in both groups. This trial was registered with NCT01987505

Primary Cutaneous B-Cell Lymphoma: An Update on Pathologic and Molecular Features

Primary cutaneous B-cell lymphomas (PCBCLs) account for 25% of all primary cutaneous lymphomas. Three major types are currently recognized by the WHO classification: primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL) (both considered indolent lymphomas) and primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT), which is, instead, a very aggressive disease. Nowadays, the PCBCL’s category also includes some rare entities such as intravascular B-cell lymphoma (IVBL) and the EBV+ mucocutaneous ulcer (EBVMCU). Furthermore, controversies still exist concerning the category of primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), because some cases may present with clinical and histological features between PCFCL and PCDLBCL-LT. Therefore, some authors proposed introducing another category called PCDLBCL, not otherwise specified (NOS). Regardless, PCBCLs exhibit distinct features and differ in prognosis and treatment from their nodal/systemic counterparts. Therefore, clinicopathologic analysis is a key diagnostic element in the work-up of these lymphomas

Primary Cutaneous B-Cell Lymphoma: An Update on Pathologic and Molecular Features

Primary cutaneous B-cell lymphomas (PCBCLs) account for 25% of all primary cutaneous lymphomas. Three major types are currently recognized by the WHO classification: primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL) (both considered indolent lymphomas) and primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT), which is, instead, a very aggressive disease. Nowadays, the PCBCL’s category also includes some rare entities such as intravascular B-cell lymphoma (IVBL) and the EBV+ mucocutaneous ulcer (EBVMCU). Furthermore, controversies still exist concerning the category of primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), because some cases may present with clinical and histological features between PCFCL and PCDLBCL-LT. Therefore, some authors proposed introducing another category called PCDLBCL, not otherwise specified (NOS). Regardless, PCBCLs exhibit distinct features and differ in prognosis and treatment from their nodal/systemic counterparts. Therefore, clinicopathologic analysis is a key diagnostic element in the work-up of these lymphomas

Double expressor and double/triple hit status among primary cutaneous diffuse large B cell lymphoma: A comparison between leg type and NOS Subtypes

none13Primary cutaneous diffuse large B-cell lymphomas (pcDLBCL) are rare hematological neoplasms. pcDLBCL category includes primary cutaneous large B-cell lymphoma "leg type" (pcDLBCL-LT), characterized by a particularly unfavorable outcome, and primary cutaneous large B-cell lymphoma "not otherwise specified" (pcDLBCL-NOS), a widely debated sub-entity with a more indolent course. The negative prognostic impact of double expressor status (DE status, given by coexpression of MYC and BCL2) and double/triple hit status (DH/TH status, given by translocations of MYC and BCL2 and/or BCL6) in nodal DLBCL is well-known; however, no unanimous conclusions regarding relevance of DE and DH/TH status have been reached in pcDLBCL. Therefore, our purpose has been to investigate the presence and prognostic relevance of DE and DH/TH status among a retrospective multicentric cohort of 16 pcDLBCL-LT and 17 pcDLBCL-NOS. All cases were thoroughly re-evaluated, both on a morphological and immunoistochemical level, and tested by means of fluorescence hybridization in situ for MYC, BCL2 and BCL6 rearrangements. DE status was observed in 69% of pcDLBCL-LT and in 24% of pcDLBCL-NOS; however, it did not impact on prognosis in any of the groups examined. Combining molecular results, we highlighted a relevant fraction of DH pcDLBCL (three pcDLBCL-LT and one pcDLBCL-NOS) and the very first case of TH pcDLBCL-LT reported to date. All DH cases were characterized by MYC and BCL6 rearrangements. Overall, DH/TH cases represented 15% (5/33) of all pcDLBCLs and were mostly pcDLBCL-LTs. DH/TH status and DH status alone were associated with poorer OS and DSS (both p<0,05) among all pcDLBCLs, without reaching statistical significance in pcDLBCL-LT and pcDLBCL-NOS groups. In conclusion, MYC, BCL2 and BCL6 cytogenetical testing could be useful in identifying a putative subset of more aggressive pcDLBCLs, although this observation has to be confirmed by further studies.noneLucioni, Marco; Pescia, Carlo; Bonometti, Arturo; Fraticelli, Sara; Moltrasio, Chiara; Ramponi, Antonio; Riboni, Roberta; Roccio, Stefano; Ferrario, Giuseppina; Arcaini, Luca; Goteri, Gaia; Berti, Emilio; Paulli, MarcoLucioni, Marco; Pescia, Carlo; Bonometti, Arturo; Fraticelli, Sara; Moltrasio, Chiara; Ramponi, Antonio; Riboni, Roberta; Roccio, Stefano; Ferrario, Giuseppina; Arcaini, Luca; Goteri, Gaia; Berti, Emilio; Paulli, Marc

Double expressor and double/triple hit status among primary cutaneous diffuse large B cell lymphoma: A comparison between leg type and NOS Subtypes

Primary cutaneous diffuse large B-cell lymphomas (pcDLBCL) are rare hematological neoplasms. pcDLBCL category includes primary cutaneous large B-cell lymphoma "leg type" (pcDLBCL-LT), characterized by a particularly unfavorable outcome, and primary cutaneous large B-cell lymphoma "not otherwise specified" (pcDLBCL-NOS), a widely debated sub-entity with a more indolent course. The negative prognostic impact of double expressor status (DE status, given by coexpression of MYC and BCL2) and double/triple hit status (DH/TH status, given by translocations of MYC and BCL2 and/or BCL6) in nodal DLBCL is well-known; however, no unanimous conclusions regarding relevance of DE and DH/TH status have been reached in pcDLBCL. Therefore, our purpose has been to investigate the presence and prognostic relevance of DE and DH/TH status among a retrospective multicentric cohort of 16 pcDLBCL-LT and 17 pcDLBCL-NOS. All cases were thoroughly re-evaluated, both on a morphological and immunoistochemical level, and tested by means of fluorescence hybridization in situ for MYC, BCL2 and BCL6 rearrangements. DE status was observed in 69% of pcDLBCL-LT and in 24% of pcDLBCL-NOS; however, it did not impact on prognosis in any of the groups examined. Combining molecular results, we highlighted a relevant fraction of DH pcDLBCL (three pcDLBCL-LT and one pcDLBCL-NOS) and the very first case of TH pcDLBCL-LT reported to date. All DH cases were characterized by MYC and BCL6 rearrangements. Overall, DH/TH cases represented 15% (5/33) of all pcDLBCLs and were mostly pcDLBCL-LTs. DH/TH status and DH status alone were associated with poorer OS and DSS (both p<0,05) among all pcDLBCLs, without reaching statistical significance in pcDLBCL-LT and pcDLBCL-NOS groups. In conclusion, MYC, BCL2 and BCL6 cytogenetical testing could be useful in identifying a putative subset of more aggressive pcDLBCLs, although this observation has to be confirmed by further studies

COVID-19 vaccination rate and safety profile in a multicentre Italian population affected by mixed cryoglobulinaemic vasculitis

Mixed cryoglobulinaemic vasculitis (MCV) is an immune-complex-mediated systemic vasculitis characterised by heterogeneous clinical manifestations mainly involving lymphatic system, skin, kidney and peripheral nervous system. Although MCV patients have been included in priority programs for vaccination against SARS-CoV-2 in Italy, limited information is available for these patients. Aims of this multicentre Italian study were to investigate SARS-CoV-2 vaccination rate in MCV patients and its safety profile