A Multicentric Prospective Phase 2 Study of Intravenous Rituximab and Intrathecal Liposomal Cytarabine in Combination with C5R Protocol Followed by Brain Radiotherapy for Immunocompetent Patients with Primary CNS Lymphoma: A Lymphoma Study Association (LYSA) Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 796-796 ◽  
Author(s):  
Herve Ghesquieres ◽  
Herve Tilly ◽  
Anne Sonet ◽  
Jehan Dupuis ◽  
Alexia Schwartzmann ◽  
...  
Keyword(s):  
Mmse Score ◽  
Primary Cns Lymphoma ◽  
Complete Response ◽  
Cns Lymphoma ◽  
Liposomal Cytarabine ◽  
Lymphomatous Meningitis ◽  
Off Label ◽  
Brain Radiotherapy ◽  
Immunocompetent Patients

Abstract Abstract 796 Background: The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favourable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years: the complete response (CR) rate was 33%, the 5-year progression-free survival (PFS) and overall survival (OS) rates were 31% and 42%, respectively with however 9% of toxic death. Rituximab improves outcome of systemic Diffuse Large B-Cell Lymphoma (DLBCL) but it is unclear if its addition is useful in PCNSL with DLBCL histology. Intrathecal (IT) liposomal cytarabine (Depocyt) which shows a long-CSF half-life and better efficacy compared to IT methotrexate and free cytarabine in lymphomatous meningitis is also an attractive treatment for PCNSL. Methods: In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and IT liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL. The primary objective of this study is the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT, according to International Primary CNS Lymphoma Collaborative Group response criteria. The number of patients was calculated in order to improve the 30% CR/CRu rate of LNHCP93 study up to 50%. The secondary objectives were side effect profile including acute and late neurological toxicities, PFS and OS. Patients received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients. A new response assessment was performed after RT. Patients were followed every 4 months for the first two years and then every 6 months. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test. Results: Fifty-three PCNSL patients with a confirmed diagnosis of CD20 positive DLBCL were included between August 2007 and September 2011: median age was 55 years (range, 36–60), 57% were male, 42% had a performance status >1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Median MMSE score assessed for 42 patients at baseline was 26 (range 3–30). After immuno-CT, 22 patients achieved a CR and 13 a CRu (CR + CRu, 66%), 7 a partial response (13%), 6 had a stable or progressive disease (11%) and 5 (10%) were not evaluated due to early death (n=2) or toxicities (n=3). For 45 patients who completed the fourth cycles, CR/CRu rate was 75.6%. Thirty-one patients (58%) presented at least one serious adverse event, mainly infections (25 patients, 47%). At least one red blood cell and platelet transfusions were given in 94% and 68% of patients, respectively and 57% of patients experienced a febrile neutropenia. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 22 months, 15 patients progressed or relapsed (28.3%) and 13 patients died (24.5%), 3 (5.7%) of them from acute toxicity. The 2-year PFS and OS rates are 67% (95%CI, 50.0% to 79.4%) and 82% (95%CI, 67.0% to 90.7%), respectively. Median MMSE score was 27 (range, 26–30) for the 7 patients evaluated between 12 and 18 months after the beginning of treatment. Conclusions: With the addition of intravenous rituximab and intrathecal liposomal cytarabine, C5R protocol provided higher CR/CRu rate and promising outcome results with a 2-year PFS of 67% as compared to historical controls. No additional severe toxicities were observed compared to C5R protocol and with short follow-up no neurocognitive decline was observed. Disclosures: Off Label Use: Depocyt (intrathecal liposomal cytarabine) is off-label used in first line therapy of Primary CNS Lymphoma but approval for treatment of lymphomatous meningitis. Morschhauser:Roche: Honoraria. Blay:Roche: Honoraria, Research Funding.

scholarly journals RTHP-34. IMPROVED SURVIVAL IN CNS LYMPHOMA WITH SALVAGE LOW-DOSE WHOLE-BRAIN RADIOTHERAPY WITH FOCAL BOOST AND CONCURRENT TEMOZOLOMIDE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi217-vi217
Author(s):  
Katherine Selwa ◽  
Anna Laucis ◽  
Theodore Lawrence ◽  
Larry Junck ◽  
Kyle Cuneo ◽  
...  
Keyword(s):  
Low Dose ◽  
Radiation Treatment ◽  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Complete Response ◽  
Concurrent Chemotherapy ◽  
Cns Lymphoma ◽  
Whole Brain ◽  
Brain Radiotherapy ◽  
Kaplan Meier

Abstract OBJECTIVE There is no standard salvage radiotherapy (RT) regimen, nor a consensus on the concurrent chemotherapy use in CNS lymphoma. We assessed the efficacy of low-dose whole-brain radiotherapy (WBRT) with focal-boost to the area of disease and concurrent temozolomide for the salvage treatment of CNS lymphoma. METHODS A single center retrospective study of CNS lymphoma patients seen between 01/2004 and 02/2019. The inclusion criteria were: diagnosis of CNS lymphoma, age > 18 years at diagnosis, radiation treatment to the brain, and formulation of plan at University of Michigan with at least one follow-up. Overall survival (OS) was determined by Kaplan Meier method. RESULTS Out of 93 patients (median age 58, 45% female), 73% were diagnosed with primary CNS lymphoma (n=68), and the remainder with secondary CNS lymphoma. Radiation modalities were WBRT alone (n=52), low-dose WBRT + focal boost (n=33) and focal RT alone (n=8). Twenty-six patients (28%) received concurrent temozolomide with radiation. Those who received WBRT+boost achieved complete response at a significantly higher rate than those who received WBRT alone (36% vs 17% respectively, p=0.047). The median OS among all groups was 45 months. There was a significant improvement in OS in patients receiving low-dose WBRT+boost compared to WBRT alone (median 65 vs 14 months respectively, p=0.016). OS was significantly longer in patients who received concurrent temozolomide than in those who did not (median 86 vs 23 months respectively, p=0.0287). CONCLUSIONS In CNS lymphoma salvage RT, a longer survival was observed with low-dose WBRT with focal-boost compared to WBRT alone, as well as with concurrent temozolomide. This result is limited by the selection bias to each of the treatment groups; however, the low-dose WBRT with focal-boost and concurrent temozolomide is a useful salvage alternative to standard WBRT as it may reduce long-term neurocognitive toxicity.

scholarly journals Rituximab, Methotrexate, Procarbazine, and Vincristine Followed by Consolidation Reduced-Dose Whole-Brain Radiotherapy and Cytarabine in Newly Diagnosed Primary CNS Lymphoma: Final Results and Long-Term Outcome

2013 ◽  
Vol 31 (31) ◽  
pp. 3971-3979 ◽  
Author(s):  
Patrick G. Morris ◽  
Denise D. Correa ◽  
Joachim Yahalom ◽  
Jeffrey J. Raizer ◽  
David Schiff ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Cns Lymphoma ◽  
Karnofsky Performance Score ◽  
Whole Brain ◽  
Long Term Outcome ◽  
Reduced Dose ◽  
Brain Radiotherapy

Purpose A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma. Patients and Methods Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor. Results Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33). Conclusion R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.

scholarly journals Twenty-year follow-up of a pilot/phase II trial on the Bonn protocol for primary CNS lymphoma

Neurology ◽  
2020 ◽  
Vol 95 (23) ◽  
pp. e3138-e3144
Author(s):  
Sabine Seidel ◽  
Hendrik Pels ◽  
Sabine Schlömer ◽  
Annika Kowoll ◽  
Klaus Fliessbach ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Cns Lymphoma ◽  
Karnofsky Performance Score ◽  
Class Iii ◽  
Entire Cohort ◽  
Brain Radiotherapy ◽  
Long Term Follow Up

ObjectiveTo determine whether a fraction of patients with primary CNS lymphoma (PCNSL) had been cured by systemic and intraventricular methotrexate- and cytarabine-based chemotherapy (Bonn protocol) after a very long-term follow-up of nearly 20 years.MethodsSixty-five patients (median age 62 years, range 27–75; median Karnofsky performance score 70, range 20–90) had been treated with systemic and intraventricular polychemotherapy without whole brain radiotherapy from September 1995 until December 2001. All patients still alive in 2019 were contacted and interviewed on their current life situation.ResultsMedian follow-up for surviving patients was 19.6 years (17.5–23.3 years). Out of 65 patients, 11 (17%) were still alive. Six of those never experienced any relapse. For the whole study population, median overall survival (OS) was 4.4 years (95% confidence interval [CI] 2.9–5.9); for patients ≤60 years, 11.0 years (95% CI 4.8–17.0). The 10-year OS rate for the entire cohort was 29% and the estimated 20-year OS rate was 19%. Four late relapses were observed after 9.8, 10.3, 13.3, and 21.0 years.ConclusionAt a median follow-up of 19.6 years, 17% of patients were alive and free of tumor; however, even after response for decades, an inherent risk of relapse, either systemic or cerebral, characterizes the biology of PCNSL.Classification of evidenceThis work provides Class III evidence that PCNSL treatment with methotrexate-based polychemotherapy including intraventricular therapy is associated with long-term disease control in some patients.

scholarly journals Sustained Complete Remission in Multi-Relapsed Primary CNS Lymphoma Treated with Ibrutinib Monotherapy: A Case Report

2021 ◽  
pp. 1337-1341
Author(s):  
Anna Mair ◽  
Armin Muigg ◽  
Günther Stockhammer ◽  
Stephanie Mangesius ◽  
Dominik Wolf ◽  
...  
Keyword(s):  
Complete Remission ◽  
Malignant Disease ◽  
Kinase Inhibitor ◽  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
High Recurrence Rate ◽  
Cns Lymphoma ◽  
Off Label ◽  
Brain Radiotherapy ◽  
Bruton Tyrosine Kinase

Primary CNS lymphoma (PCNSL) is a highly aggressive malignant disease with a high recurrence rate and a poor prognosis. We present the case of a 71-year-old woman diagnosed with PCNSL in June 2010. After 3 relapses and intensive treatment with multiple chemotherapy regimens and whole-brain radiotherapy, she received off-label treatment with the Bruton tyrosine kinase inhibitor ibrutinib, responded well, achieved a complete remission, and is progression-free for now &#x3e;3 years.

scholarly journals Intensive Chemotherapy and Immunotherapy in Patients With Newly Diagnosed Primary CNS Lymphoma: CALGB 50202 (Alliance 50202)

2013 ◽  
Vol 31 (25) ◽  
pp. 3061-3068 ◽  
Author(s):  
James L. Rubenstein ◽  
Eric D. Hsi ◽  
Jeffrey L. Johnson ◽  
Sin-Ho Jung ◽  
Megan O. Nakashima ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Progression Free Survival ◽  
Complete Response ◽  
Remission Induction ◽  
Cns Lymphoma ◽  
High Dose ◽  
Newly Diagnosed ◽  
Brain Radiotherapy ◽  
Myeloablative Chemotherapy

Purpose Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome. Patients and Methods Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial. Results The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age > 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival. Conclusion CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.

scholarly journals Updated Results Confirm Favorable Outcome of Immunocompetent Patients with Primary CNS Lymphoma Treated By C5R Protocol in Combination with Intravenous Rituximab and Intrathecal Liposomal Cytarabine: A Multicentric Prospective Phase 2 Study of the Lymphoma Study Association (LYSA)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3060-3060
Author(s):  
Herve Ghesquieres ◽  
Herve Tilly ◽  
Anne Sonet ◽  
Jehan Dupuis ◽  
Alexia Schwartzmann ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Prognostic Scores ◽  
Cns Lymphoma ◽  
High Dose ◽  
Liposomal Cytarabine ◽  
Whole Brain ◽  
Class 1 ◽  
Prospective Phase ◽  
Study Association ◽  
Immunocompetent Patients

Abstract Background: The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favorable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years. In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and intrathecal (IT) liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL in the R-C5R protocol. We previously presented the results of the primary objective of the R-C5R protocol, showing an improvement of the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT from 33% in the LNHCP93 to 66% in the R-C5R protocol. We also showed no additional severe toxicities as compare to C5R with the addition of intravenous rituximab and IT liposomal cytarabine. We present here the updated results of the 53 patients included in this multicentric prospective phase 2 study from the lymphoma study association (LYSA) with a median follow-up 28 months (range, 1.08-75.04). Methods: This prospective study was designed for 18 to 60 years old immunocompetent patients with confirmed CD20 positive diffuse large B-cell lymphoma PCNSL. Fifty-three patients included between August 2007 and September 2011 received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2 and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients and then patients were followed every 4 months during the first 2 years and then every 6 months for the next 3 years. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test. Results: The median age of the 53 PCNSL patients was 55 years (range, 36-60), 57% were male, 42% had a performance status (PS)>1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Clinical characteristics according to the MSKCC score was as follows: 16 patients (32%) ≤50 years (class 1); 23 patients (46%) >50 years and KPS≥70 (class 2); 11 patients (22%) >50 years and KPS<70 (class 3). Of the 39 available patients, 38% had 0-1, 38% had 2, 21% had 3 and 3% had 4 adverse IELSG prognostic scores, respectively. Median MMSE score assessed for 42 patients at baseline was 26 (range, 3-30). Forty-five patients (85%) completed the fourth cycles of immune-CT and three patients (5.7%) died of acute toxicity. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 28 months, 20 patients progressed or relapsed (37.7%). The 3-year progression free survival (PFS) rate of whole cohort was 58% (95%CI, 42.5% to 71%). The 3-year PFS rates were 64.2%, 63.5% and 53% for patients with MSKCC class 1, 2 and 3, respectively (P=0.53); the 3-year PFS rates were 86% and 39% for patients with 0-1 and 2-4 adverse IELSG prognostic scores, respectively (P=0.02). The 3-year PFS rates were 66% and 80% for patients who received a reduced whole brain RT with a boost and patients treated with whole brain RT (P=0.25), respectively. At relapse or progression, 18 patients received a salvage treatment that allowed five CR/CRu. Five patients received a high-dose CT with autologous stem cell transplantation at relapse. The 3-year overall survival (OS) rate for whole cohort was 67% (95%CI, 48.3% to 80.1%). The median MMSE score was 29 (range, 23-30) for the 11 patients evaluated between 18 and 24 months after the beginning of treatment. Conclusions: With the addition of intravenous rituximab and IT liposomal cytarabine, R-C5R protocol provided promising outcome results with a 3-year PFS and OS of 58% and 67%, respectively. These results compared favorably with historical controls included in the LNHCP93 who presented a 3-year PFS and OS of 44% and 58%, respectively. IELSG score remained a strong prognostic factor for the patients treated with this schedule and could be helpful to stratify consolidation treatment after response to primary immunochemotherapy in particular patients with 2-4 IELSG score. Disclosures Ghesquieres: Mundipharma: Honoraria. Off Label Use: Liposomal cytarabine formulation had demonstrated better efficacy compared to standard cytarabine for the treatment of lymphomatous meningitis and is off label use in first line therapy of primary CNS lymphoma. Morschhauser:Mundipharma: Honoraria.

scholarly journals High-dose methotrexate-based regimens and post-remission consolidation for treatment of newly diagnosed primary CNS lymphoma: meta-analysis of clinical trials

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Junyao Yu ◽  
Huaping Du ◽  
Xueshi Ye ◽  
Lifei Zhang ◽  
Haowen Xiao
Keyword(s):  
Meta Analysis ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
Progression Free Survival ◽  
Complete Response ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Dose Methotrexate

AbstractWith the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL). This review focused on first-line induction and consolidation treatment of PCNSL and aimed to determine the optimal combination of HD-MTX and the long-term beneficial consolidation methods. A comprehensive literature search of MEDLINE identified 1407 studies, among which 31 studies met the inclusion criteria. The meta-analysis was performed by using Stata SE version 15. Forest plots were generated to report combined outcomes like the complete response rate (CRR), overall survival, and progression-free survival. We also conducted univariate regression analyses of the baseline characteristics to identify the source of heterogeneity. Pooled analysis showed a CRR of 41% across all HD-MTX-based regimens, and three- and four-drug regimens had better CRRs than HD-MTX monotherapy. In all combinations based on HD-MTX, the HD-MTX + procarbazine + vincristine (MPV) regimen showed pooled CRRs of 63% and 58% with and without rituximab, respectively, followed by the rituximab + HD-MTX + temozolomide regimen, which showed a pooled CRR of 60%. Pooled PFS and OS showed that post-remission consolidation with autologous stem cell transplantation (ASCT) was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Next, whole-brain radiation therapy (WBRT) + chemotherapy showed a pooled 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. In HD-MTX-based therapy of newly diagnosed PCNSL, MPV with or without rituximab can be chosen as the inductive regimen, and the rituximab + HD-MTX + temozolomide regimen is also a practical choice. Based on our study, high-dose chemotherapy supported by ASCT is an efficacious approach for consolidation. Consolidation with WBRT + chemotherapy can be another feasible approach.

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