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T.A. Eyre et al.
Table 1. Key eligibility criteria.
Inclusion
•Studies of DLBCL as the dominant lymphoma subtype assessing the risk of CNS relapse
Exclusion
• Case series with <100 patients treated with rituximab- chemotherapy
•CNS involvement at diagnosis
•Non-rituximab or non-obinutuzumab exposed cohorts •Cohorts where no patients received CNS prophylaxis •Early phase clinical trials
•Pharmacokinetic studies •Narrative reviews •Opinion papers •Education papers •Commentaries •Editorials
•Conference abstracts •Case-reports •Animal studies
IT chemotherapy agent was not defined in all studies, although methotrexate and ara-C were the only employed agents used when described.
CNS relapse outcomes
The cumulative incidence rate of CNS relapse was reported in 10 studies and a crude rate of CNS relapse (number of CNS events/total number of patients) was reported in four studies. The cumulative incidence CNS relapse rate from eight studies reporting rates in anti- CD20 monoclonal antibody-specific cohorts ranged between 1.9% at a median of 6.5 years follow-up27 and 8.4% at 5 years.28 Across the nine studies specifically reporting a median time to CNS relapse in anti-CD20 monoclonal antibody-exposed (sub)populations, the median of those median times reported was 10 months.
In 10 studies reporting details regarding the nature of the CNS relapses in rituximab or obinutuzumab exposed patients, there were 73% (128 of 175) isolated CNS relaps- es, 24% (42 of 175) CNS relapses concurrent at the time of systemic relapse, and 3% (5 of 175) cases of CNS relapse occurring at a later time point following documented sys- temic relapse.
Ten studies provided a detailed breakdown of the anatomical site of CNS relapse in rituximab or obinu- tuzumab-exposed patients. In total there were 191 CNS relapses, of which 111 (58%) were parenchymal, 52 (27%) were leptomeningeal, 23 (12%) were both parenchymal and leptomeningeal, one was intraocular (1%) and four (2%) were either not known or not specifically defined. Therefore, a total of 70% (134 of 191) of patients had demonstrable parenchymal involvement at CNS relapse.
Intrathecal prophylaxis efficacy
Efficacy analyses were performed in all 14 studies and these are presented Tables 3A-C. Patients receiving IT pro- phylaxis typically had demonstrable risk factors for CNS relapse, although the recommendations for IT prophylaxis varied considerably across studies (Table 4). As such, these
•Studies of DLBCL in the rituximab era: rituximab or obinutuzumab
exposed patients represented ≥100 patients and the majority
of the patients within the individual study.
•Studies of DLBCL treated with anthracycline-based chemotherapy
•Studies analysing the relative influence of stand-alone IT prophylaxis on outcome •Meta-analysis
•Late phase clinical trials •Cohort studies •Cross-sectional studies •Retrospective studies •Observational studies •Case-control studies
DLBCL: diffuse large B cell lymphoma; CNS: central nervous system; IT: intrathecal.
Results
Search results
Of 804 search results, 12 studies were eligible for inclu- sion. One study was later excluded because of the authors concerns over quality of the reported study.23 Following the search expansion phase, three additional studies were included.6,24,25 In total, 14 studies met eligibility criteria for this review. Full details of the PRISMA inclusion/exclusion process are presented in Figure 1. Three studies were post hoc analyses from prospective randomised controlled clinical trials, one was an analysis of a multicentre, nation- al, prospective database and all others were retrospective data series (seven single centre; three multicentre). Three studies were conducted in Japan, two in the USA and Canada, and one each in Germany, the UK, China, Singapore, South Korea and Thailand respectively.
A cumulative total of 7,357 (74.7%) anti-CD20 mono- clonal antibody-exposed patients were assessed across the 14 series which included a cumulative total of 9,842 patients overall. All studies used rituximab or obinu- tuzumab24 plus CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) or CHOP-like regimens as the chemotherapy backbone given at between 14-28 day intervals apart from a single study which analysed a cohort treated with DA-EPOCH (dose adjusted etoposide, prednisolone, vincristine, cyclophosphamide and doxoru- bicin).26 Five studies included patients ≥18 years, two stud- ies included patients ≥16 years, one study included patients ≥15 years and one included patients 60-80 years. Five studies did not define age criteria. Three studies included patients with transformed indolent B-cell non- Hodgkin lymphoma (iNHL), and four studies included a relatively small number of patients with primary mediasti- nal B-cell lymphoma (PMBCL). The median percentage of patients receiving some form of IT prophylaxis across each individual study was 11.9% (range: 4.0-38.9%). The dosing frequency, total number of IT injections adminis- tered and chemotherapy agent used varied (Table 2). The
Key Eligibility Criteria
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