Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma

Neurology ◽  
2021 ◽  
Vol 97 (13) ◽  
pp. 628-631
Author(s):  
Caroline Houillier ◽  
Cecile Moluçon Chabrot ◽  
Marie-Pierre Moles-Moreau ◽  
Lise Willems ◽  
Guido Ahle ◽  
...  
Keyword(s):  
Karnofsky Performance Status ◽  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Complete Response ◽  
Rapid Onset ◽  
High Rate ◽  
Cns Lymphoma ◽  
T Cell Therapy ◽  
Heavily Pretreated ◽  
Rate Of Response

Background and ObjectivesTo evaluate the efficacy and tolerance of the association rituximab-lenalidomide-ibrutinib (R2I) in relapsed/refractory (R/R) primary CNS lymphoma (PCNSL).MethodsR/R PCNSL patients treated with R2I were retrospectively selected and analyzed from the French LOC database.ResultsFourteen patients (median age: 63 years, median Karnofsky Performance Status: 75%) received R2I, administered after a median of 2 previous lines of chemotherapy, including autologous stem cell transplantation (ASCT) in 5 cases. The best response was complete response in 4/14 patients and partial response in 4/14 patients, achieved in a median of 2.5 months. Three responder patients received consolidation treatment (WBRT: N = 2, ASCT: N = 1) after R2I, and R2I served as a bridge before CAR-T cell therapy for one patient. R2I was discontinued due to toxicity in 3/14 patients. There were no toxicity-related deaths.DiscussionThe R2I combination resulted in a high rate of response of rapid-onset in heavily pretreated patients with poor prognosis, with manageable toxicity, and allowed 3 patients to proceed to consolidation. Although preliminary, these results support the use of R2I for R/R PCNSL failing conventional chemotherapies.Classification of EvidenceThis study provides Class IV evidence that combination of rituximab-lenalidomide-ibrutinib induces a high rate of response in heavily pretreated R/R PCNSL.

scholarly journals Management and outcome of primary CNS lymphoma in the modern era

Neurology ◽  
2020 ◽  
Vol 94 (10) ◽  
pp. e1027-e1039 ◽  
Author(s):  
Caroline Houillier ◽  
Carole Soussain ◽  
Hervé Ghesquières ◽  
Pierre Soubeyran ◽  
Olivier Chinot ◽  
...  
Keyword(s):  
Karnofsky Performance Status ◽  
Performance Status ◽  
Real Life ◽  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Progression Free Survival ◽  
Population Based ◽  
Cns Lymphoma ◽  
High Dose ◽  
Population Based Study

ObjectiveReal-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.MethodsThe French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.ResultsWe identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients <60 years of age received consolidation treatment in 77% of cases, consisting of whole-brain radiotherapy (WBRT) (54%) or high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) (23%). Among patients >60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (<60 years: not reached [NR], 70%, and 61%; >60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.ConclusionsOur study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

Early Relapses in Primary CNS Lymphoma (PCNSL) without Intraventricular Treatment.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4440-4440
Author(s):  
Ingo G.H. Schmidt-Wolf ◽  
Hendrick Pels ◽  
Annika Jurgens ◽  
Axel Glasmacher ◽  
Holger Schulz ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Response Duration ◽  
Complete Response ◽  
High Response Rate ◽  
High Rate ◽  
Cns Lymphoma ◽  
High Dose ◽  
Median Response ◽  
Kaplan Meier ◽  
Intraventricular Treatment

Abstract Background: A systemic and intraventricular polychemotherapy regimen (“Bonn protocol”) with deferred radiotherapy had resulted in durable responses in 75% of patients < 60 years with primary CNS lymphoma (PCNSL), but had been complicated by a high rate of Ommaya reservoir infections. Purpose: Here, efficacy and toxicity of this regimen but without intraventricular treatment was evaluated in PCNSL. Patients and Methods : From 08/03 to 11/05, 18 patients with PCNSL < 60 years (median age 53 years) were treated within a phase II trial with a high-dose methotrexate (MTX; cycles 1,2,4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide. Results: Study accrual was prematurely stopped in 11/05 due to a high rate of early relapses. Seventeen/18 patients were assessable for response: Nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu), two (12%) partial response (PR), four (24%) showed progressive disease (PD); in one treatment was stopped due to toxicity. Median follow-up is 23 months; Kaplan-Meier estimates for median response duration were ten months only in responding patients and for median time to treatment failure (TTF) eight months in the whole group; median overall survival (OS) has not yet been reached. Systemic toxicity was mainly hematologic. Conclusions: In patients < 60 years with PCNSL polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with inclusion of intraventricular treatment.

Complete Response After High-Dose Methotrexate-Based Chemotherapy as a Major Prognostic Factor for Primary CNS Lymphoma: An Exploratory Analysis of the LNHCP93 Trial of the Groupe d'Etude Des Lymphomes De l'Adulte.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 101-101
Author(s):  
Hervé Ghesquières ◽  
Celine Ferlay ◽  
Agathe Bajard ◽  
Catherine Sebban ◽  
David Perol ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Complete Response ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Status Number

Abstract Abstract 101 Background: Treatment of primary CNS lymphoma (PCNSL) is based on high-dose methotrexate (HD-MTX) containing chemotherapy (CT) followed by brain radiotherapy (RT). Initial CT allowed 30% to 63% of complete response (CR) in recent large series. After CT, consolidation RT can increase the CR rate up to 80%. Despite this high rate of response after initial treatment, the outcome of patients remained poor. The impact of the quality of response on outcome is not well known as well as the outcome of PR patients who converted to CR after RT. We assessed these questions in patients with newly diagnosed PCNSL treated with HD-MTX-containing CT followed by RT in the prospective LNHCP93 GELA study. Methods: 99 patients were treated in this prospective phase II study between 1995 and 2002. Patients younger than 61 years received C5R protocol (Blay et al. Blood 1995), Patients aged 61-70 years received reduced doses of C5R protocol and patients older than 70 years received a specific schedule with MTX, vepeside and cyclophosphamide. After CT, brain RT was planned: 20 Gy whole brain and a 36 Gy boost to the tumor bed. Responses after CT and after RT were evaluated by MacDonald criteria. Evaluation of response was made at time of the beginning of RT, 21-35 days after the last course of CT, and one month after the end of RT. Results: Median age of the 99 PCNSL patients was 63 years (range, 20-82), 51% were male, 51% had performance status >1, and 58% had involvement of deep structures of brain. Forty-five patients were younger than 61 years, 36 were aged 61-70 years and 18 older than 70 years. After a median follow-up 83 months, median overall survival (OS) and progression-free survival (PFS) were 33 and 20 months, respectively. Seventeen patients (17%) died of acute toxicity during CT; 3 patients (3%) did not receive RT; 8 patients (8%) progressed or had stable disease after CT and 3 patients (3%) had no available data. Thus, 68 patients were assessable for this exploratory study with thirty-six patients (36%) in PR and 32 patients (32%) in CR after CT. Sixteen of PR patients converted to CR after RT (44% of PR patients after CT). Median OS of patients in CR and PR after CT was 80 and 34 months with a 5-year OS probability of 65% and 29%, respectively (p=0.02). Median PFS of patients in CR and PR after CT was 60 and 21 months with a 5-year PFS probability of 56% and 17%, respectively (p=0.03). In univariate and multivariate analysis, age and response were the two prognostic factors for OS but not performance status, number of tumors at diagnosis, site of tumor (involvement of deep structures). Only response to CT was predictive of PFS in multivariate analysis but not age, performance status, number of tumors, site of tumor at diagnosis. 5-year OS was 65% for CR patients before RT compared to 31% and 28% for PR patients who converted to CR after RT and for patients not in CR after RT, respectively (p=0.06). The 5-year PFS probability was 56% for CR patients before RT compared to 13% and 20% for patients who converted to CR after RT and those not in CR after RT, respectively (p=0.09). Conclusion: Despite the inherent bias of response analysis as a prognostic factor, this analysis of a prospective study of PCNSL patients showed that only patients achieving CR after CT may experience long term survival. This study also showed that PR patients who converted to CR after RT had a poor outcome, similar to patients that did not reach a CR after chemoradiotherapy. Disclosures: No relevant conflicts of interest to declare.

Importance of Radiotherapy in the Outcome of Patients With Primary CNS Lymphoma: An Analysis of the CHOD/BVAM Regimen Followed by Two Different Radiotherapy Treatments

2002 ◽  
Vol 20 (1) ◽  
pp. 231-236 ◽  
Author(s):  
E. M. Bessell ◽  
A. López-Guillermo ◽  
S. Villá ◽  
E. Verger ◽  
B. Nomdedeu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Complete Response ◽  
Cns Lymphoma ◽  
Reduced Dose ◽  
Increased Risk ◽  
Risk Of Relapse ◽  
All Treatment

PURPOSE: To assess the effect of a reduced dose of radiotherapy (RT) in patients with primary CNS lymphoma (PCNSL) responding to the cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD)/carmustine, vincristine, methotrexate, and cytarabine (BVAM) regimen. PATIENTS AND METHODS: Patients received one cycle of CHOD and two of BVAM. In the first trial, all 31 patients received 45-Gy whole-brain RT (CHOD/BVAM I). In the second, with 26 patients, RT dose was reduced to 30.6 Gy if there was a complete response (CR) after chemotherapy (CHOD/BVAM II). RESULTS: Age, performance status, and chemotherapy received were similar in both protocols. CR rate at the end of all treatment was 68% for CHOD/BVAM I and 77% and for CHOD/BVAM II. Treatment modality was the only predictor of relapse, with 3-year relapse risks of 29% and 70% for CHOD/BVAM I and II, respectively. This was specifically important in the 25 patients less than 60 years old (3-year relapse risk, 25% v 83%; P = .01). The 5-year overall survival (OS) was 36%. Age (< 60 v ≥ 60 years) was the only predictor for OS in the multivariate analysis (relative risk, 2.1; 95% confidence interval, 1.4 to 2.8). RT dose was the only predictor of OS in patients younger than 60 years old who achieved CR at the end of all treatment (3-year OS, 92% v 60% for patients receiving 45 or 30.6 Gy, respectively; P = .04). CONCLUSION: Reduction of the RT dose from 45 Gy to 30.6 Gy in patients younger than 60 years old with PCNSL who achieved CR resulted in an increased risk of relapse and lower OS.

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.

How I treat primary CNS lymphoma

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 510-522 ◽  
Author(s):  
Andrés J. M. Ferreri
Keyword(s):  
Molecular Mechanisms ◽  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Poor Performance ◽  
Cns Lymphoma ◽  
Poor Performance Status ◽  
Level Of Evidence ◽  
Therapeutic Decisions ◽  
New Ideas ◽  
Rare Malignancy

Abstract Primary CNS lymphoma (PCNSL) is a rare malignancy with peculiar clinical and biologic features, aggressive course, and unsatisfactory outcome. It represents a challenge for multidisciplinary clinicians and scientists as therapeutic progress is inhibited by several issues. Molecular and biologic knowledge is incomplete, limiting the identification of new therapeutic targets, and the particular microenvironment of this malignancy, and sanctuary sites where tumor cells grow undisturbed, strongly affects treatment efficacy. Moreover, active treatments are known to be associated with disabling neurotoxicity, posing the dilemma of whether to intensify therapy to improve the cure rate or to de-escalate treatment to avoid sequels. The execution of prospective trials is also difficult because of the rarity of the tumor and the impaired general condition and poor performance status of patients. Thus, level of evidence is low, with consequent uncertainties in therapeutic decisions and lack of consensus on primary endpoints for future trials. Despite this unfavorable background, laboratory and clinical researchers are coordinating efforts to develop new ideas, resulting in the recent publication of studies on PCNSL's biology and molecular mechanisms and of the first international randomized trials. Herein, these important contributions are analyzed to provide recommendations for everyday practice and the rationale for future trials.

Combination intraventricular chemotherapy for meningeal neoplasia.

1986 ◽  
Vol 4 (1) ◽  
pp. 68-73 ◽  
Author(s):  
L Giannone ◽  
F A Greco ◽  
J D Hainsworth
Keyword(s):  
Karnofsky Performance Status ◽  
Performance Status ◽  
Single Agent ◽  
Transitional Cell ◽  
Response Duration ◽  
Complete Response ◽  
Response To Therapy ◽  
Entire Group ◽  
Intraventricular Chemotherapy ◽  
Wbc Count

Twenty two patients with meningeal neoplasia were treated with biweekly combination intraventricular chemotherapy using methotrexate, cytosine arabinoside, and thiotepa. Patients with the following malignancies were included: breast cancer, ten patients; lung cancer, seven; non-Hodgkin's lymphoma, two; malignant melanoma, one; transitional cell carcinoma of the bladder, one; and malignant glioma, one. Eight of 22 patients (36%) had a Karnofsky performance status of less than 50%. Eleven of 22 patients received radiotherapy to symptomatic areas, and seven received systemic chemotherapy in addition to combination intraventricular therapy. Patients were evaluated for both toxicity and response to therapy. Myelosuppression was the major toxic condition and occurred in 17 of 22 patients (77%). Ten patients (45%) had a nadir WBC count of less than 1000/microL or a platelet count of less than 25,000/microL. No patient achieved a complete response (CR), although nine patients (41%) had partial responses (PRs) lasting 4 to 24 + weeks. Median survival for the entire group was 10 weeks (range, 6 to 24+ weeks). In this small group of patients, simultaneous triple-drug intraventricular chemotherapy caused unacceptable myelosuppression without increasing the response rate, response duration, or survival when compared with single-agent methotrexate and radiotherapy.

Rituximab significantly improves complete response rate in patients with primary CNS lymphoma

2012 ◽  
Vol 109 (2) ◽  
pp. 285-291 ◽  
Author(s):  
Tobias Birnbaum ◽  
Elisabeth Anne Stadler ◽  
Louisa von Baumgarten ◽  
Andreas Straube
Keyword(s):  
Response Rate ◽  
Complete Response Rate ◽  
Primary Cns Lymphoma ◽  
Complete Response ◽  
Cns Lymphoma

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 PC3 - 130 A Meta-Analysis on the use of High-Dose Methotrexate Only Versus Combination Chemotherapy for the Treatment of Newly-Diagnosed Patients with Primary CNS Lymphoma

2016 ◽  
Vol 43 (S4) ◽  
pp. S20-S21
Author(s):  
M.C. Concepcion Sales
Keyword(s):  
Side Effects ◽  
Disease Progression ◽  
Combination Chemotherapy ◽  
Primary Cns Lymphoma ◽  
Complete Response ◽  
Cns Lymphoma ◽  
High Dose ◽  
Cochrane Central Register ◽  
High Dose Methotrexate ◽  
Dose Methotrexate

Primary CNS Lymphoma (PCNSL) is an unusual extranodal form of Non-Hodgkin’s Lymphoma with a locally aggressive course but a rare tendency to disseminate systemically. There are various modalities available for the treatment of PCNSL which include chemotherapy, radiotherapy, surgery and immunotherapy. The effectiveness of adding another anti-neoplastic agent to HD-MTX have been optimized in small scale studies yet the “ perfect combination” has yet to be elucidated Objectives: This study aims to 1) compare the response to treatment of monotherapy with high-dose Methotrexate (HD-MTX) versus HD-MTX and an additional anti-neoplastic agent by evaluating complete response, partial response, stable disease and disease progression and 2) to compare the hematologic and non-hematologic side effects among patients subjected to monotherapy vs combination chemotherapy. Methodology: Journals from Medline, EMBASE, Cochrane Central Register of Control Trials (CENTRAL) and other relevant websites (www.clinicaltrials.org) without any restrictions in the year, language and status of publication were searched. Literatures cited by eligible studies and systemic reviews were also checked to identify useful articles. The following Medical Subject Headings (MeSH) were used: ‘primary CNS lymphoma’, ‘treatment’, ‘chemotherapy’ and ‘randomized control trial’. Statistical analysis was performed using the RevMan software version 5.1. Odds ratio (OR) and 95 % confidence interval (95% CI) were used as summary statistics. Results and Conclusion: The use of high-dose methotrexate and another anti-neoplastic agent showed benefit in terms of achieving complete response and delaying disease progression among patients diagnosed with PCNSL. However, the risks of hematologic toxicities such as anemia, neutropenia, thrombocytopenia and infection was higher in patients treated with the combination chemotherapy. Significant non-hematologic side effects such as mucositis was also observed in patients receiving an add-on to high dose methotrexate.

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