Summary Background Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. Methods This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18–70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m 2 , intravenous infusion, day 0; methotrexate 3·5 g/m 2 , the first 0·5 g/m 2 in 15 min followed by 3 g/m 2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m 2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m 2 , 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m 2 , day 1; etoposide 100 mg/m 2 per day in 500–1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m 2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine–thiotepa and autologous HSCT (carmustine 400 mg/m 2 in 500 mL glucose 5% solution in a 1–2 h infusion, day −6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days −5 and −4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov , NCT02329080 . The trial ended after accrual completion; the database lock was Dec 31, 2019. Findings Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55–61). 49 patients (65%; 95% CI 54–76) had an objective response after MATRix–RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51–71) had an objective response, with a median duration of objective response of 26 months (IQR 16–37). At a median follow-up of 29 months (IQR 20...
An important unmet need in the management of primary mediastinal B-cell lymphoma (PMBCL) is to identify the patients for whom first-line therapy will fail to intervene before the lymphoma becomes refractory. High heterogeneity of intratumoral F-fluorodeoxyglucose (18FDG) uptake distribution on positron emission tomography/computed tomography (PET/CT) scans has been suggested as a possible marker of chemoresistance in solid tumors. In the present study, we investigated the prognostic value of metabolic heterogeneity (MH) in 103 patients with PMBCL prospectively enrolled in the International Extranodal Lymphoma Study Group (IELSG) 26 study, aimed at clarifying the role of PET in this lymphoma subtype. MH was estimated using the area under curve of cumulative standardized uptake value-volume histogram (AUC-CSH) method. Progression-free survival at 5 years was 94% vs 73% in low- and high-MH groups, respectively ( = .0001). In a Cox model of progression-free survival including dichotomized MH, metabolic tumor volume, total lesion glycolysis (TLG), international prognostic index, and tumor bulk (mediastinal mass > 10 cm), as well as age as a continuous variable, only TLG ( < .001) and MH ( < .001) retained statistical significance. Using these 2 features to construct a simple prognostic model resulted in early and accurate (positive predictive value, 89%; negative predictive value, ≥90%) identification of patients at high risk for progression at a point that would allow the use of risk-adapted treatments. This may provide an important opportunity for the design of future trials aimed at helping the minority of patients who harbor chemorefractory PMBCL. The study is registered at ClinicalTrials.gov as NCT00944567.
BackgroundMesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited.MethodsThe addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and for other time-to-event endpoints).DiscussionThe outcome of this trial will provide evidence of the potential benefit of the use of nivolumab in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely to become the new standard of care in the UK.Trial registrationEudraCT Number: 2016–003111-35 (entered on 21 July 2016); ClinicalTrials.gov, ID: NCT03063450. Registered on 24 February 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2602-y) contains supplementary material, which is available to authorized users.
Treatment consisted of 6 cycles of the standard R-CHOP21 regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone every 21 days); 4 doses of intrathecal liposomal cytarabine; 2 courses of intravenous (iv) intermediate-dose methotrexate (1.5 gr/m2) and to the contralateral testis.The study was designed to demonstrate (80% power, a = .05) a PFS improvement from 67% to 82% at 10 years (primary endpoint). Results: Fifty-four patients (median age: 66 years, range: 37-79 years) with untreated stage I (n = 32) or II (n = 22) PTL were treated with R-CHOP21, 53 received at least 3 doses of intrathecal CNS prophylaxis, 48 received at least one dose of iv methotrexate and 50 received prophylactic RT. No unexpected side effects were observed. At a median follow-up of 5 years, 7patients progressed and 7 died, with 5-year PFS of 88% (95%CI, 74-94%) and 5-year OS of 92% (95%CI, 79%-97%). No CNS relapses occurred. In 4 cases, both nodal and extranodal relapses were reported, the latter including the gastrointestinal tract and the pleurae in the same patient, as well as, 1 patient each, the kidneys, the spinal canal (extra-axial) and the contralateral testis (9 years after RT). Two patients relapsed only at extranodal sites (skin, adrenal gland), 1 had nodal relapse. Notably, 4 of 7 failures were late relapses occurring after 6 to 10 years from treatment.Causes of death were lymphoma (n = 4), second cancer (n = 1), cerebral vasculopathy (n = 1), unknown (n = 1).Conclusions: Definitive assessment of the primary endpoint will need longer follow-up. Thus far, comparison of these results with those of the IELSG10 trial (5-yr PFS, 88 vs 74%; 5-yr OS, 92 vs 85%; 5-yr CNS relapse rate, 0 vs 6%) suggests that combined treatment of PTL with R-CHOP21 plus intensive CNS prophylaxis and loco-regional RT is feasible, may abrogate CNS relapses and lead to very promising outcomes. Nevertheless, late relapses, mainly at extranodal sites, still represent a clinical challenge.The research was funded by: Mundipharma provided the drug depocyte free of charge
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