Primary mediastinal lymphoma: diagnosis and treatment options.

Primary mediastinal large B-cell lymphoma (PMBCL) is a unique B-cell lymphoma variant that arises from a putative thymic medulla B cell. It constitutes 2-4% of non-Hodgkin lymphomas and occurs most frequently in young females. PMBCL is characterized by a diffuse proliferation of medium-to-large B cells associated with sclerosis. Molecular analysis shows that PMBCL is a distinct entity compared to other types of diffuse large B-cell lymphomas. PMBCL is characterized by a locally invasive anterior mediastinal bulky mass. The combination of rituximab with CHOP/CHOP-like regimens followed by mediastinal radiation therapy (RT) is associated with a 5-year progression-free survival of 75-85%. However, the role of consolidation RT still remains uncertain. More intensive regimens, such as DA-EPOCH-R without mediastinal RT, have shown very promising results. The conclusive role of PET-CT scan requires prospective studies and there is hope that this may allow to de-escalate RT and accordingly yield reliable prognostic information

Is now the time for molecular driven therapy for diffuse large B-cell lymphoma?

INTRODUCTION: Recent genetic and molecular discoveries regarding alterations in diffuse large B-cell lymphoma (DLBCL) deeply changed the approach to this lymphoproliferative disorder. Novel additional predictors of outcomes and new therapeutic strategies are being introduced to improve outcomes. Areas covered: This review aims to analyse the recent molecular discoveries in DLBCL, the rationale of novel molecular driven treatments and their impact on DLBCL prognosis, especially in ABC-DLBCL and High Grade B Cell Lymphoma. Pre-clinical and clinical evidences are reviewed to critically evaluate the novel DLBCL management strategies. Expert commentary: New insights in DLBCL molecular characteristics should guide the therapeutic approach; the results of the current studies which are investigating safety and efficacy of novel 'X-RCHOP' will probably lead, in future, to a cell of origin (COO) based upfront therapy. Moreover, it is necessary to identify early patients with DLBCL who carried MYC, BCL2 and/or BCL6 rearrangements double hit lymphomas (DHL) because they should not receive standard R-CHOP but high intensity treatment as reported in many retrospective studies. New prospective trials are needed to investigate the more appropriate treatment of DHL

Repeated successful use of eltrombopag in chronic primary immune thrombocytopenia: description of an intriguing case.

Thrombopoietin receptor agonists (TPO-RAs) are used as effective alternative treatments in ITP patients unresponsive to first-/second-line therapies. TPO- RAs can also be used to normalize platelet count to safely perform invasive pro- cedures and chemotherapy, in case of malignancies. In few responsive patients, TPO-RAs can be suspended maintaining a sustained respons

Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) Patients: A Retrospective Analysis of Eligibility Criteria for CAR-T Cell Therapy

Patients (pts) with diffuse large B-cell lymphoma (DLBCL) refractory to second-line therapy or relapsed after an autologous stem cell transplant (ASCT) have a very poor clinical outcome with a median overall survival (OS) of 5 and 8-10 months, respectively. Autologous anti-CD19 chimeric antigen receptor (CD19 CAR) T cells have been associated with sustained complete remissions and long-term survivals in a large proportion of pts with R/R DLBCL by the two pivotal clinical trials Zuma1 and Juliet. This has led to the rapid approval by FDA and then by EMA of CAR-T cells for the third-line treatment of R/R DLBCL. Despite being a potentially revolutionary treatment for pts with advanced disease, the costs are much greater than any previously approved cancer therapy and this may become a substantial economic challenge for the health care system. The definition of inclusion and exclusion criteria capable of identifying more precisely pts who can successfully undergo CAR-T cell therapy, minimizing the severity of the toxicity, still remains a matter of discussion. Moreover, some eligible pts run the risk of becoming ineligible because of poor disease control. Indeed, one of the major obstacles to the successful use of CAR-T cells is the 4-5 week period so far required for the manufacturing and transfer of CAR-T cells. To address this issue, we have examined data of R/R DLBCL pts managed between 2010 and 2018 at our Center in order to: 1) better identify the characteristics and outcome of a cohort of R/R DLBCL pts potentially eligible, according to the approval criteria, for CAR-T cell therapy; 2) define factors influencing CAR-T cell eligibility; 3) make a realistic estimate of pts eligible for CAR-T cells. In this retrospective real-life cohort of R/R DLBCLs, 82/480 pts (17%) were R/R tosecond-line treatment including ASCT. Considering Juliet's inclusion/exclusion criteria for CAR-T cell therapy, only 50 pts (10.4%) would be eligible for CAR-T cells. Our analysis suggests that elevated LDH plus ECOG ≥2 have to be considered the two most significant features of very rapid disease progression. These variables should be taken in account in order to better select DLBCL pts potentially eligible to CAR-T therapy

Management of patients with lymphoma and COVID-19: Narrative review and evidence-based practical recommendations

Patients with hematologic malignancies can be immunocompromized because of their disease, anti-cancer therapy, and concomitant immunosuppressive treatment. Furthermore, these patients are usually older than 60 years and have comorbidities. For all these reasons they are highly vulnerable to infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and have an increased risk of developing severe/critical Coronavirus disease 2019 (COVID-19) compared to the general population. Although COVID-19 vaccination has proven effective in reducing the incidence of severe/critical disease, vaccinated patients with lymphoma may not be protected as they often fail to develop a sufficient antiviral immune response. There is therefore an urgent need to address the management of patients with lymphoma and COVID-19 in the setting of the ongoing pandemic. Passive immunization with monoclonal antibodies against SARS-CoV-2 is a currently available complementary drug strategy to active vaccination for lymphoma patients, while monoclonal antibodies and antiviral drugs (remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir) have proven effective in preventing the progression to severe/critical COVID-19. In this narrative review we present the most recent data documenting the characteristics and outcomes of patients with concomitant lymphoma and COVID-19. Our ultimate goal is to provide practice-oriented guidance in the management of these vulnerable patients from diagnosis to treatment and follow-up of lymphoma. To this purpose, we will first provide an overview of the main data concerning prognostic factors and fatality rate of lymphoma patients who develop COVID-19; the outcomes of COVID-19 vaccination will also be addressed. We will then discuss current COVID-19 prophylaxis and treatment options for lymphoma patients. Finally, based on the literature and our multidisciplinary experience, we will summarize a set of indications on how to manage patients with lymphoma according to COVID-19 exposure, level of disease severity and former history of infection, as typically encountered in clinical practice

Efficacy of residual site radiation therapy (ISRT) in patients with primary mediastinal lymphoma with Deauville Score 4 following R-CHT: results of a retrospective mono institutional study

Background: In order to evaluate the efficacy of residual site radiation therapy (RSRT) in terms of progression-free survival (PFS) and overall survival (OS) in patients with primary mediastinal lymphoma (PMBCL) with Deauville Score 4 (DS 4) following rituximab and chemotherapy treatment (R-ICHT). Methods: Thirty-one patients with PMBCL were recruited. After completion of R-ICHT, patients were staged with 18F-fluorodeoxyglucose positron-emission tomography, showing DS 4, and were treated with adjuvant RSRT. The chosen techniques for RT delivery were intensity-modulated radiation therapy (IMRT) or three-dimensional conformal RT (3D-CRT). Most patients underwent the first one using cone-beam computed tomography (CBCT). All patients were evaluated every 3 months for the first 2 years and every 6 months afterwards for a period of at least 5 years, with clinical and radiological procedures as required. Results: All patients received RSRT with a dose of 30 Gy in 15 fractions. The median follow-up time of 52.7 months (IQR: 26–64.1 months). The 5-year OS rate was 100%. The 2-year and 5-year PFS rates were 96.7% and 92.5%, respectively. Patients with relapsed disease had been treated with high-dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT). Conclusion: RSRT in patients with PMBCL treated with ICHT and DS 4 did not impact unfavorably on patient survival

Whole body MRI with diffusion weighted imaging versus 18F‑fuorodeoxyglucose‑PET/CT in the staging of lymphomas

Purpose To assess the diagnostic performance of Whole Body (WB)-MRI in comparison with 18F-Fluorodeoxyglucose-PET/CT (18F-FDG-PET/CT) in lymphoma staging and to assess whether quantitative metabolic parameters from 18F-FDG-PET/CT and Apparent Diffusion Coefficient (ADC) values are related. Materials and methods We prospectively enrolled patients with a histologically proven primary nodal lymphoma to undergo 18F-FDG-PET/CT and WB-MRI, both performed within 15 days one from the other, either before starting treatment (baseline) or during treatment (interim). Positive and negative predictive values of WB-MRI for the identification of nodal and extra-nodal disease were measured. The agreement between WB-MRI and 18F-FDG-PET/CT for the identification of lesions and staging was assessed through Cohen's coefficient k and observed agreement. Quantitative parameters of nodal lesions derived from 18F-FDG-PET/CT and WB-MRI (ADC) were measured and the Pearson or Spearman correlation coefficient was used to assess the correlation between them. The specified level of significance was p ≤ 0.05. Results Among the 91 identified patients, 8 refused to participate and 22 met exclusion criteria, thus images from 61 patients (37 men, mean age 30.7 years) were evaluated. The agreement between 18F-FDG-PET/CT and WB-MRI for the identification of nodal and extra-nodal lesions was 0.95 (95% CI 0.92 to 0.98) and 1.00 (95% CI NA), respectively; for staging it was 1.00 (95% CI NA). A strong negative correlation was found between ADCmean and SUVmean of nodal lesions in patients evaluated at baseline (Spearman coefficient rs = − 0.61, p = 0.001). Conclusion WB-MRI has a good diagnostic performance for staging of patients with lymphoma in comparison with 18F-FDG-PET/CT and is a promising technique for the quantitative assessment of disease burden in these patients

Residual Site Radiotherapy After Immunochemotherapy in Primary Mediastinal B-Cell Lymphoma: A Monoinstitutional Retrospective Study

Aim: To evaluate the efficacy of residual site radiation therapy (RSRT) on local control (LC), progressionfree (PFS) and overall (OS) survival in patients with primary mediastinal lymphoma (PMBCL), following rituximab and chemotherapy treatment (ICHT). Patients and Methods: The study included 34 patients with PMBCL treated between 2006 and 2014 with ICHT with/without autologous stem cell transplantation and RSRT. Between the end of ICHT/stem cell transplantation and RSRT, patients were evaluated with F-18-fluorodeoxyglucose positron-emission tomography. The gross tumor volume included morphological mediastinal residual disease after ICHT/SCT. The percentage of LC, PFS and OS were assessed. Results: All patients received RSRT with a median dose of 30 Gy. Median follow-up was 82 months. One patient out of 34 (3%) showed progressive disease 9 months from diagnosis. The 10-year PFS and OS were 97% and 97% respectively. Conclusion: RSRT in patients with PMBCL treated with ICHT did not impact unfavorably on LC and patient survival

Mantle Cell Lymphoma of Mucosa-Associated Lymphoid Tissue:A European Mantle Cell Lymphoma Network Study

While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6–182), 5-year progression-free survival (PFS) was 45% (95% CI: 35–54) and 5-year overall survival (OS) was 71% (95% CI: 62–79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p = 0.001) and median OS of 9.8 years vs 6.9 years (p = 0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment

Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the FIL MCL0208 trial

In the FIL MCL0208 phase III trial, lenalidomide maintenance (LEN) after transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell surface receptors might predict drug efficacy. Genotypes were obtained by real-time polymerase chain reaction (RT-PCR) in peripheral blood (PB) germ line DNA. Polymorphisms of either ABCB1 or VEGF were found in 69% and 79% of 278 patients and predicted favorable PFS vs homozygous wild type (WT) in the LEN arm: 3-year PFS 85% vs 70% (p < 0.05) and 85% vs 60% (p < 0.01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (OS, 76%): in fact, in these patients LEN did not improve PFS vs OBS (3-year PFS 44% vs 60%, p = 0.62). Moreover, CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, while ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL. This trial is registered at eudract.ema.europa.eu as 2009-012807-25