European Association of Neuro-Oncology (EANO) guidelines for treatment of primary central nervous system lymphoma (PCNSL)
Khê Hoang‐XuanMartina DeckertAndrés J.M. FerreriJulia FurtnerJaime Gállego Pérez‐LarrayaRoger HenrikssonAndreas F. HottingerBenjamin KasendaFlorence LefrancAlexander LossosCatherine McBainMatthias PreusserPatrick RothRoberta RudàUwe SchlegelRiccardo SoffiettiCarole SoussainMartin TaphoornValérie TouitouMichael WellerJacoline E. C. Bromberg
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Abstract:
The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and the publication of practice-changing randomized trials, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to update the previously published evidence-based guidelines for immunocompetent adult patients with PCNSL and added a section on immunosuppressed patients. The guideline provides consensus considerations and recommendations for the treatment of PCNSL, including intraocular manifestations and specific management of the elderly. The main changes from the previous guideline include strengthened evidence for the consolidation with ASCT in first-line treatment, prospectively assessed chemotherapy combinations for both young and elderly patients, clarification of the role of rituximab even though the data remain inconclusive, of the role of new agents, and the incorporation of immunosuppressed patients and primary ocular lymphoma. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field.Keywords:
Guideline
In the Rituximab for Relapse Prevention in Nephrotic Syndrome (RITURNS) trial, we demonstrated superior efficacy of single-course rituximab over maintenance tacrolimus in preventing relapses in children with steroid dependent nephrotic syndrome (SDNS) during a 1-year observation. Here we present the long-term outcomes of all 117 trial completers, who were followed up for another 2 years.Relapsing patients in the rituximab arm received a second course of rituximab, either with (n = 44) or without mycophenolate mofetil (MMF) cotreatment (n = 15). In the tacrolimus arm, second line rituximab monotherapy was initiated after relapses (n = 32) or electively (n = 24).All 12-month relapse-free patients in the rituximab arm relapsed in the second postexposure year, resulting in similar median relapse-free survival times in the 2 trial arms (62 vs. 59 weeks). Second line rituximab in the tacrolimus arm was less effective than first-line therapy in patients switched to rituximab following a relapse (relapse-free survival 55 vs. 63 weeks, P < 0.01). B-cell counts 6 months post-rituximab predicted relapse risk both for first and second line therapy. MMF cotreatment yielded much improved 2-year relapse-free survival as compared to rituximab monotherapy (67% vs. 9%, P < 0.0001). Higher grade 2 adverse event rates were observed post-rituximab versus on tacrolimus (0.87 vs. 0.53 per year).The superior therapeutic effect of rituximab in SDNS vanishes during the second year post-exposure. Rituximab appears to yield longer remission when applied as first line as compared to second line therapy. Maintenance MMF following rituximab induces long-term disease remission.
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This study investigated responses to retreatment with rituximab in chronic immune thrombocytopenic purpura (ITP) patients. Treatment with rituximab in chronic ITP patients induces long-lasting responses in approximately 30% of patients but even these patients may relapse. Twenty patients who had achieved a response to rituximab and relapsed were retreated with rituximab (375 mg/m(2)x 4); this data was analyzed retrospectively. Subsequently, 16 patients were prospectively randomized to receive rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) or double dose rituximab (DDR). Retreatment with standard dose rituximab demonstrated responses similar to initial rituximab treatment in 15 of 20 patients. Neither of the two more intensive regimens (R-CVP, DDR) induced responses in any patient who had previously failed to respond to rituximab nor induced substantially longer-lasting responses among previous responders. No additional toxicity was noted with the DDR regimen, whereas R-CVP was not well tolerated. These results suggest that retreatment with standard dose rituximab induces similar responses in 75% of previously responding patients and is well tolerated. Neither combining rituximab with CVP nor doubling the dose of rituximab increased the response rate.
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Rituximab, an anti-CD2O monoclonal antibody, is an emerging and effective option for the treatment of patients with refractory steroid-dependent nephrotic syndrome (SDNS), but few studies have assessed the long-term prognosis in these patients. We therefore evaluated the efficacy of rituximab in 35 patients, aged 4-21 years, who experienced SDNS while being treated with immunosuppressants. Patients were monitored for 24-63 months. After the first infusion of rituximab, the number of relapses and the dose of prednisolone were significantly reduced, and the steroid withdrawal period was significantly increased. However, 22 patients (63%) required retreatment with rituximab owing to relapses. At the last observation, only three patients (9%) could discontinue immunosuppressants completely and only three continued to show remission during the observation period. Although rituximab could not induce a complete cure of refractory SDNS, it resulted in longer remission times when immunosuppressants were continued after rituximab therapy, indicating the effectiveness of rituximab followed by immunosuppressants. We also found that patients who experienced more relapses before rituximab therapy were more likely to relapse earlier after rituximab therapy.
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Refractory (planetary science)
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Experience with rituximab in patients with new ANCA-associated vasculitis (AAV) is still very limited, especially in patients with severe (organ- or life-threatening) AAV. Rituximab may be more effective in anti-PR3 AAV, but potentially less effective in some granulomatous manifestations of AAV. We do not know what the response is to rituximab on the tissue level. Rituximab induction needs to be followed by maintenance treatment, and potentially very long rituximab maintenance may result in higher risk of rituximab-related complications (e.g. decrease in IgG levels). Long-term experience with rituximab in AAV is insufficient. Treatment with rituximab is more expensive than the standard treatment with cyclophosphamide and corticosteroids and seems to be cost-effective only in patients primarily treated with cyclophosphamide. Rituximab can be used in some newly diagnosed patients with AAV (e.g. women with child-bearing potential, or patients with active vasculitis and severe infection), but with the available information, it may be too early to use it as a first-line treatment in all new AAV patients.
ANCA-Associated Vasculitis
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Background: PP and rituximab are two major therapies commonly used in transplantation. They are often used in combination to prevent or treat AMR. Since PP can remove antibodies while rituximab is a B-cell depleting monoclonal antibody. The right sequence of using rituximab and PP is critical to achieve the best treatment efficacy. This meta-analysis analyzed the commonly used PP/rituximab protocols and pointed out a common error in current clinic practice. Methods: We did a PubMed title search for recent 5 years literature in major transplant journals and investigated treatment protocols with rituximab and PP. We tried to address the question whether rituximab treatment followed by multiple sessions of PP will compromise B-cell depleting effects of rituximab. Results: Among a total of 12 papers in which rituximab was used with concomitant PP, three papers did not describe detailed treatment sequence. Rituximab was given after multiple sessions of PP in three studies. In the rest 6 studies, one or two doses of rituximab were administered followed by multiple sessions of PP. The half-life of rituximab is approximately 2-4 weeks with a wide variability between subjects. The clearance rate of rituximab after one session of PP/PE is 47-54%. Multiple (4-5) sessions of PP/PE can clear it to undetectable level. Apparently, the B cell depletion effect of rituximab will be significantly compromised if PP treatment is performed right after the rituximab is given. Significantly, a single dose of rituximab without PP usually completely removed peripheral B cells within 1-2 days and sustained profound B cell suppression up to 2-3 years of observation period. However, when multiple cycles of PP were performed right after rituximab therapy, peripheral B cells were detectable within 1st week in 60-71% of patients. B cell counts started to increase from month 5-6, and recovered to baseline levels with 1-2 years. Conclusion: A combined treatment with rituximab therapy followed by multiple cycles of PP is a very common error in current clinic practice. These treatment protocols significantly diminished treatment efficacy of rituximab. People may argue that the maximum effect of rituximab in depleting circulating B cells was observed within 2 days with more than 90% depletion rate. However, this argument ignores the long-term effect of rituximab on CD20+ B cells in lymphoid tissues. Similar mistaken treatment sequence is commonly found in other protocols which also need to be paid attention to. Authors suggest that PP should be used either before or after 1-2 half-life of any given immune-suppressants, which will help maintain or maximize their effects. Certainly, it is a different issue if PP is used to remove rituximab or other drugs from peripheral blood in order to minimize their severe side effects.
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About 20% of TTP are resistant to plasma exchange. As reported in a few case reports and small case series, rituximab has been used in the treatment of TTP with some benefit. However, the optimal dosing, frequency, and timing of rituximab remain to be determined. We treated three cases of refractory TTP with rituximab. Case 1 exhibited brain sequelae probably due to the late administration of rituximab, case 2 died before the expected effect of rituximab could occur, and case 3 recovered completely because of the early administration of rituximab. These results suggest that rituximab should be given as early as possible in TTP, but large clinical studies are required to determine the optimal use of rituximab in TTP.
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Thrombocytopenic purpura
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Among new treatments for ANCA-associated vasculitis, rituximab is the most promising. It has already been demonstrated that rituximab is not inferior to cyclophosphamide in inducing remission. This drug is therefore an alternative to cyclophosphamide for induction treatment. In the long term, it has been shown that patients who have received 4 infusions of rituximab to induce remission, not followed by a maintenance treatment, have the same relapse rate as patients who have been treated with azathioprine for maintenance. This high relapse rate supports a maintenance treatment which could also be rituximab. The results obtained with rituximab vs. azathioprine are encouraging and could favour rituximab use, but long-term results are still needed. Rituximab is safe and side effect frequency and severity are comparable to the side effects observed in patients treated with cyclophosphamide for induction, and azathioprine or methotrexate for maintenance. New studies are needed to evaluate the long-term side effects of this biotherapy.
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