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Chimeric Antigen Receptor-T cells (CAR-T) are considered novel biological agents, designed to selectively attack cancer cells expressing specific antigens, with demonstrated clinical activity in patients affected with relapsed/refractory B-cell malignancies. In consideration of their complexity, the use of CAR-T requires dedicated clinical setting and health care practitioners with expertise in the selection, treatment, and management of toxicities and side effects. Such issue appears particularly important when contextualized in the rapid progress of CAR-T cell treatment, translating into a constant need of updating and evolution. Moreover, the clinical grade manufacturing of CAR-T cells is complex and implies articulated regulatory and organizational aspects. The main goal of this review is to summarize and provide an accurate analysis of the clinical, logistic, and regulatory requirements of CAR-T cell centers. Finally, we describe a new occupational figure called \"CAR-T specialist\" devoted to the establishment and coordination of the required facilities and regulatory landscape in the context of cancer centers.

Background Castleman disease (CD) encompasses a range of heterogeneous non‐clonal lymphoproliferative disorders, including unicentric (UCD), and multicentric (MCD) forms. The latter is subdivided into HHV‐8+ MCD, POEMS‐MCD, and idiopathic‐MCD, not otherwise specified (iMCD‐NOS). Methods Here we report the clinical characteristics and outcomes of 28 consecutive CD patients, diagnosed in two centers of northern Italy according to recently published diagnostic criteria. Results UCD was reported in 12 cases (43%) and MCD in 16 (57%). Among these, 6 (21%) were HHV‐8 positive (1 HIV‐positive and 5 HIV‐negative), and 10 (36%) had iMCD‐NOS. Treatment of UCD consisted of surgical excision in 10/12 cases, resulting in ongoing complete remission in all cases. Single nodal localization favorably affected overall survival (OS) and progression‐free survival (PFS) (p < 0.05). Out of 16 MCD patients, 10 had iMCD‐NOS and 6 had HHV‐8+MCD. Anti‐IL‐6 monoclonal antibody was used as first‐line treatment in 5/10 iMCD‐NOS patients, 3 of whom relapsed, although none died. Two out of 6 patients with HHV‐8+ MCD were treated with single‐agent rituximab and one with rituximab plus chemotherapy. UCD patients had significantly better OS and PFS compared to iMCD and HHV‐8+MCD groups (p < 0.001). Conclusions Our report confirms that UCD, iMCD‐NOS, and HHV‐8+MCD represent distinct clinical entities with different outcomes requiring specific treatment approaches. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.

The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin's lymphomas (NHL) has been demonstrated by epidemiological studies, in particular in highly endemic geographical areas such as Italy, Japan, and southern parts of United States. In these countries, together with diffuse large B-cell lymphomas, marginal zone lymphomas are the histotypes most frequently associated with HCV infection; in Italy around 20-30% cases of marginal zone lymphomas are HCV positive. Recently, antiviral treatment with interferon with or without ribavirin has been proved to be effective in the treatment of HCV-positive patients affected by indolent lymphoma, prevalently of marginal zone origin. An increasing number of experiences confirmed the validity of this approach in marginal zone lymphomas and in other indolent NHL subtypes like lymphoplasmacytic lymphoma. Across different studies, overall response rate was approximately 75%. Hematological responses resulted significantly associated with the eradication of the virus. This is the strongest evidence of a causative link between HCV and lymphomas. The aim of this paper is to illustrate the relationship between HCV infection and different subtypes of indolent B-cell lymphomas and to systematically summarize the data from the therapeutic studies that reported the use of antiviral treatment as hematological therapy in patients with HCV-associated indolent lymphomas.

Follicular lymphoma (FL) is an indolent lymphoma with long median survival. Many studies have been performed to build up prognostic scores potentially useful to identify patients with poorer outcome. In 2004, an international consortium coordinated by the International Follicular Lymphoma Prognostic Factor project was established and a new prognostic study was launched (FLIPI2) using progression-free survival (PFS) as main endpoint and integrating all the modern parameters prospectively collected. Low-grade non-Hodgkin lymphomas were once considered as a heterogenous group of lymphomas characterized by an indolent clinical course. Each entity is characterized by unique clinicobiologic features. Some studies have been focused on prognostic factors in single lymphoma subtypes, with the development of specific-entity scores based on retrospective series, for instance splenic marginal zone lymphoma (SMZL). A widely accepted prognostic tool for clinical usage for indolent non-follicular B-cell lymphomas is largely awaited. In this paper we summarized the current evidence regarding prognostic assessment of indolent follicular and non-follicular lymphomas.

The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients. We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18–65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2–3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 on day 1, plus oral prednisone 100 mg on days 1–5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m2 and doxorubicin 70 mg/m2) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m2 on day 1 or 4 plus intravenous cytarabine 2000 mg/m2 and dexamethasone 4 mg/m2 every 12 h on days 1–3 plus intravenous mitoxantrone 8 mg/m2 on days 1–3) plus BEAM (intravenous carmustine 300 mg/m2 on day −7, intravenous cytarabine 200 mg/m2 twice a day on days −6 to −3, intravenous etoposide 100 mg/m2 twice a day on days −6 to −3, plus intravenous melphalan 140 mg/m2 on day −2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018. Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57–88), 2-year failure-free survival was 71% (95% CI 64–77) in the transplantation group versus 62% (95% CI 55–68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47–0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71–83] versus 77% [71–83]; HR 0·98 [0·65–1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group. Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis. Fondazione Italiana Linfomi.

BEACOPP combination chemotherapy was compared with ABVD chemotherapy in advanced Hodgkin's disease. BEACOPP therapy was associated with higher initial rates of complete response and freedom from relapse but also with more short-term and long-term toxic effects. The regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was introduced in the mid-1970s as treatment for advanced Hodgkin's lymphoma 1 and became the standard of treatment for this disease after trials showed that ABVD was as effective as, or more effective than, the regimen of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), with fewer toxic effects. 2 More recently, the German Hodgkin Lymphoma Study Group (GHSG) has developed a front-line intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP regimen, which includes higher-than-standard doses of etoposide, doxorubicin, and cyclophosphamide). This regimen, as compared with COPP-ABVD, has been . . .

Early therapies to prevent severe COVID-19 have an unclear impact on patients with hematological malignancies. The aim of this study was to assess their efficacy in this group of high-risk patients with COVID-19 in preventing hospitalizations and reducing the SARS-CoV-2 shedding. This was a single-center, retrospective, observational study conducted in the Fondazione IRCSS Policlinico San Matteo of Pavia, Northern Italy. We extracted the data of patients with hematologic malignancies and COVID-19 who received and did not receive early COVID-19 treatment between 23 December 2021, and May 2022. We used a Cox proportional hazard model to assess whether receiving any early treatment was associated with lower rates of hospitalization and reduced viral shedding. Data from 88 patients with hematologic malignancies were extracted. Among the patients, 55 (62%) received any early treatment, whereas 33 (38%) did not. Receiving any early therapy did not significantly reduce the hospitalization rate in patients with hematologic malignancies (HR 0.51; SE 0.63; p-value = 0.28), except in the vaccinated non-responders subgroup of patients with negative anti SARS-CoV-2 antibodies at the time of infection, who benefited from early therapies against SARS-CoV-2 (HR 0.07; SE 1.04; p-value = 0.001). Moreover, no difference on viral load decay was observed. In our cohort of patients with hematologic malignancies infected with SARS-CoV-2, early treatment were not effective in reducing the hospitalization rate due to COVID-19, neither in reducing its viral shedding.

FDG-positron emission tomography (PET) performed early during therapy in advanced Hodgkin lymphoma patients has been confirmed as being important for progression-free survival. A group of patients with a negative interim-PET (i-PET) showed a positive end induction PET (e-PET). The aim of this study was to evaluate the clinical characteristics of patients with a positive e-PET as a secondary end point of the HD0801 study. A total of 519 patients with advanced-stage de novo Hodgkin lymphoma received initial treatment and underwent an i-PET. Patients with negative results continued the standard treatment. i-PET negative patients were then evaluated for response with an e-PET and those patients found to have a positive one were also then given a salvage therapy. Among 409 i-PET negative, 16 interrupted the therapy, 393 patients were evaluated with an e-PET, and 39 were positive. Sixteen out of 39 underwent a diagnostic biopsy and 15 were confirmed as HD. Seventeen out of 39 e-PET were reviewed according to the Deauville Score and, in sixteen, it was confirmed positive (10 DS 5, 6 DS 4). With the exception of high LDH value at diagnosis (p = 0.01; HR 95% CI 1.18–4.89), no clinical characteristics were significantly different in comparison with e-PET negative patients. Positive e-PET after a negative i-PET has a worse outcome when compared with i-PET positive patients salvaged with therapy intensification. It was not possible to identify clinical characteristics associated with a positive e-PET.