Relapsed Primary Central Nervous System Lymphoma Research Articles

Zanubrutinib plus Cytarabine in Patients with Refractory/Relapsed Primary Central Nervous System Lymphoma

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare subtype of aggressive extranodal non-Hodgkin lymphoma. Currently, there is no standard of care for the treatment of refractory or relapsed PCNSL (r/r PCNSL). We conducted a prospective single-arm phase II study to evaluate zanubrutinib plus cytarabine for r/r PCNSL. Methods: Using Simon’s two-stage design, we analyzed 34 patients who received high-dose cytarabine (3.0 g/m2 once daily) for 2 days and zanubrutinib (160 mg twice daily) for 21 days each cycle for up to 6 cycles. The study was registered at www.chictr.org.cn as #ChiCTR2000039229. Results: The median follow-up was 19 months. The overall response rate was 64.7% (95% confidence interval [CI], 47.9–78.5%) with a complete remission or unconfirmed complete remission rate of 47.1% (16/34) and a partial remission rate of 17.6% (6/34). The median progression-free survival was 4.5 months (95% CI, 1.5–9.4), and the median OS was 18 months (95% CI, 9.5 to not estimable). The median duration of the response was 9 months (95% CI, 3.2 to not estimable). The most common treatment-emergent adverse events were thrombocytopenia (55.9%). No treatment-related death occurred. Conclusion: Zanubrutinib and cytarabine showed efficacy in r/r PCNSL with an acceptable safety profile.

CTNI-81. REAL-WORLD TREATMENT RESULTS OF RELAPSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA TREATED BY MEDICAL THERAPIES

Abstract Recurrence of primary central nervous system lymphoma (PCNSL) is a condition which often leads to morbidity and mortality. Consensus regarding the optimal treatment regimen for relapsed PCNSL has not been achieved due to the rarity of the disease. In this study, we conducted a retrospective, single-institution study to investigate real world treatment results of relapsed PCNSL treated by several medical therapeutic regimens. Relapsed PCNSL patients treated at the authors’ institution were identified, and progression-free survival (PFS), overall survival (OS) were analyzed among patients treated by medical therapies. Patients treated by radiotherapy, treated for intraocular or systemic relapses, or best supportive care, were excluded from the survival analysis. 83 patients with first, 44 with second, 25 with third relapse were identified. Upon each relapse, number of patients who received medical therapies for CNS lesions, radiotherapy, treatment for intraocular or systemic relapse, and best supportive care were 48 (57.8%), 5(6%), 4(4.8%), 26(31.3%) (first relapse), 31(70.5%), 3(6.8%), 1(2.3%), 9(20.5%) (second relapse), 13(52.0%), 0, 1(4%), 11(44.0%) (third relapse), respectively. A total of 101 CNS relapses were treated by medical therapies, and PFS (months), OS (months) of the four groups of treatments (rituximab, methotrexate, procarbazine and vincristine [R-MPV], methotrexate [MTX], tirabrutinib, and others) were as follows. PFS: 13.0, 4.5, 2.7, 3.0, and OS: 70.0, 26.4, 51.2, 9.7 (all relapse). PFS: 12.7, 7.0, 3.0, 3.2, and OS: 58.9, 33.1, not reached(n/r), 16.1 (first relapse). PFS: 34.3, 3.9, 25.3, 1.5, and OS: n/r, 28.1, 25.5, 7.5 (second relapse). PFS: 10.1, 3.9, 2.4, 2.9, and OS: 14.9, 22.3, n/r, 8.1 (third relapse). In relapsed PCNSL, favorable PFS was observed in patients treated by R-MPV. Favorable OS was also observed in tirabrutinib, which might suggest that tirabrutinib failure were effectively salvaged by R-MPV. R-MPV might confer better prognosis in relapsed PCNSL.

Treatment Options for Recurrent Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m2) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.

Analysis of Key Factors Associated with Response to Salvage High-Dose Methotrexate Rechallenge in Primary Central Nervous System Lymphoma with First Relapse

Background: Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin’s lymphoma that occurs in the central nervous system. Although sensitive to chemotherapy, 35–60% of PCNSL patients still relapse within 2 years after the initial treatment. High-dose methotrexate (HD-MTX) rechallenge is generally used in recurrent PCNSL, especially for patients who have achieved a response after initial methotrexate (MTX) treatment. However, the overall remission rate (ORR) of HD-MTX rechallenge is about 70–80%. Additionally, the side effects of HD-MTX treatment endanger the health of patients and affect their quality of life. Methods: This is a retrospective study of patients with first relapse PCNSL at Huashan Hospital, Fudan University between January 2000 and November 2020. By comparing the clinical characteristics and radiological manifestations of first relapsed PCNSL patients with remission and non-remission after receiving HD-MTX rechallenge, we screened out the key factors associated with HD-MTX rechallenge treatment response, to provide some help for the selection of salvage treatment strategies for patients with recurrent PCNSL. Additionally, patients with remission after HD-MTX rechallenge were followed up to identify the factors related to progression-free survival of the second time (PFS2) (time from the first relapse to second relapse/last follow-up). The Kruskal–Wallis and Pearson chi-square tests were performed to examine the univariate association. Further, multivariable logistic regression analysis was used to study the simultaneous effect of different variables. Results: A total of 207 patients were enrolled in the study based on the inclusion criteria, including 114 patients in the remission group (RG) and 81 patients in the non-remission group (nRG), and 12 patients were judged as having a stable disease. In Kruskal–Wallis and Pearson chi-square tests, progression-free survival rates for first time (PFS1) and whether the initial treatment was combined with consolidated whole brain radiotherapy (WBRT) were related to the response to HD-MTX rechallenge treatment, which was further validated in regression analysis. Further, after univariate analysis and regression analysis, KPS was related to PFS2. Conclusions: For PCNSL patients in their first relapse, HD-MTX rechallenge may be an effective salvage treatment. PFS1 and whether initial treatment was combined with consolidation WBRT were associated with HD-MTX rechallenge treatment response. In addition, patients with higher KPS at the time of the first relapse had a longer PFS2 after HD-MTX rechallenge treatment.

Ibrutinib in Refractory or Relapsing Primary Central Nervous System Lymphoma: A Systematic Review.

Primary Central Nervous System Lymphoma (PCNSL) is a rare variant of Non-Hodgkin Lymphoma (NHL) representing 1–2% of all NHL cases. PCNSL is defined as a lymphoma that occurs in the brain, spinal cord, leptomeninges, or eyes. Efforts to treat PCNSL by traditional chemotherapy and radiotherapy have generally been unsuccessful as a significant proportion of patients have frequent relapses or are refractory to treatment. The prognosis of patients with Refractory or Relapsed (R/R) PCNSL is abysmal. The optimal treatment for R/R PCNSL is poorly defined as there are only a limited number of studies in this setting. Several studies have recently shown that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has promising results in the treatment of R/R PCNSL. However, these are preliminary studies with a limited sample size. In this systematic review, we explored and critically appraised the evidence about the efficacy of the novel agent ibrutinib in treating R/R PCNSL.

Selective salvage radiotherapy could provide favorable outcomes in patients with refractory or relapsed primary central nervous system lymphoma.

To date, there is no relevant data supporting the role of salvage radiotherapy (sRT) in patients with refractory or relapsed primary central nervous system lymphoma (PCNSL). Herein, we aimed to investigate the impact of sRT in patients with refractory or relapsed PCNSL following upfront HD-MTX. We retrospectively reviewed 89 patients who had refractory (n = 16) or recurrent disease after an initial favorable response (n = 73); among them, 41 were treated with sRT and 48 were treated without sRT (nRT). Event-free survival (rEFS) and overall survival (rOS) after first recurrence were considered from the date of recurrence to date of each event. Overall, the first failure was diagnosed at a median of 11.0months [interquartile range (IQR), 5.6-26.4] after first treatment. More than half of the patients had recurrent disease involving initial tumor bed (n = 47), deep structure (n = 67), and multiple lesions (n = 58). Among 19 patients who were initially treated with 23.4Gy of whole brain RT, 10 patients received sRT as a re-irradiation; other 31 patients in sRT group were RT naïve patients. There was no significant difference in tumor characteristics between sRT and nRT group. Overall and complete response after salvage treatment were 80% and 48%, respectively; sRT provided higher overall response rate than nRT (93% vs. 69%, p = 0.011). With a median follow-up of 14.3months (IQR, 7.9-31.4), 2-year rEFS and rOS rates were 27% and 57%, respectively. There were no differences in rEFS and rOS according to sRT (sRT vs. nRT, 26% vs. 28%, p = 0.730; 63% vs. 50%, p = 0.690). Poor performance, recurrence interval < 8months, and unfavorable response following salvage treatment were associated with inferior rEFS and rOS. Additionally, sRT and stem cell transplantation improved response rate independently after multivariate analysis for complete/partial response. We found favorable response rate and comparable survival outcomes following sRT compared with non-local treatments for patients with refractory/relapsed PCNSL. Further studies of patient selection could stratify patients who can benefit from sRT.

Treatment of Primary Central Nervous System Lymphoma: Standard Treatments According to the Japanese 2019 Guideline and Novel Treatments

Management of primary central nervous system lymphoma (PCNSL) includes induction and consolidation therapies in newly diagnosed patients, as well as second-line therapy in relapsed or refractory patients. The current standard-of-care induction therapy involves methotrexate (MTX)-based multi-agent immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine. Deferral or dose reduction of radiation therapy is considered in consolidation therapy, especially in elderly patients who carry a high risk of radiation-induced delayed neurotoxicity. Since elderly patients comprise the main population of PCNSL, minimally toxic treatments that are effective and feasible for them are strongly needed. For second-line therapy, rechallenge using MTX-based chemotherapy (in patients with a prior durable response to MTX-based chemotherapy) or radiation therapy is considered. Bruton's tyrosine kinase inhibitor tirabrutinib (for relapsed and refractory PCNSL) and high-dose chemotherapy with autologous stem cell transplantation support using thiotepa and busulfan (BuTT) were approved by the Japanese Ministry of Health and Welfare in March 2020 and has recently become available for clinical practice. While these novel treatments seem promising, the optimal use of these treatments along with the standard-of-care therapy of PCNSL should be defined and investigated in clinical trials.

Venetoclax and Obinutuzumab for Relapsed Primary CNS Lymphoma

Venetoclax and Obinutuzumab for Relapsed Primary CNS Lymphoma

Efficacy and Toxicity of Treatments for Primary Central System Lymphoma: Review of the Recent Literature

Primary Central Nervous system lymphoma (PCNSL) is an uncommon type of central nervous system lymphoma, most commonly presenting as hemiparesis and headache. Currently, there is a wide range of treatments for PCNSL, consisting of various permutations between chemotherapy, radiation and autologous stem cell transplant (ASCT). Although the backbone of PCNSL treatment consists of High-dose Methotrexate (HD-MTX), the role of combination versus single agent chemotherapy, combined modality (chemotherapy + radiation) versus chemotherapy or radiation alone, and the use of consolidative ASCT are contested. Surgery does not have a role in the treatment of PCNSL although stereotactic biopsies tend to help with symptomatic relief. Radiation monotherapy is generally reserved for patients with contraindications to chemotherapy or as a palliative measure. Combined chemotherapy and radiation treatment has been shown to have a great efficacy, although its increased neurotoxicity compared to chemotherapy alone is a major drawback. A growing body of research is focused on comparing the efficacy of various chemotherapeutic regimens. Currently, the MATRix regimen comprising of HD-MTX(3.5g/m2)-cytarabine/rituximab/thiotepa is widely used. The additional survival benefit of ASCT is contested although its role in the treatment of refractory or relapsed PCNSL is generally agreed upon. Finally, intrathecal HD-MTX has been shown to have added survival benefit when added to the standard therapies. Further retrospective and prospective studies are required to compare the efficacy and toxicity of various treatment options, with a focus on different chemotherapeutic agents and ASCT.

High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation As a Salvage Treatment in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma

Introduction Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma for which standard treatment has yet to be established. There are only limited treatment options for patients with refractory disease to induction chemotherapy and patients with relapsed PCNSL. In this study, we evaluate high-dose chemotherapy followed by ASCT as a salvage treatment for patients with refractory or relapsed PCNSL to induction treatment.Methods The PCNSL registry data prospectively collected from March 1993 to May 2017 at a single institute, Asan Medical Center, was retrospectively reviewed. Relapsed or refractory PCNSL patients who received high-dose chemotherapy followed by ASCT as salvage modality were included in this analyses. Overall survival (OS) was defined as the time from the day of stem cell infusion to death by any cause, and progression-free survival as the time from the day of stem cell infusion to disease progression or death by any cause.Results Total 241 patients with diagnosis of PCNSL were identified and 18 patients were included in this study. Nine patients (50%) had refractory disease, 4 patients (22.2%) relapsed without consolidation, and 5 patients (27.8%) relapsed after whole-brain radiotherapy consolidation. Median follow-up period of the survivors was 2.2 years (range, 0.1-15.0). Median age was 57 years (range, 29-64) and 12 patients were male. Sixteen patients received methotrexate (MTX) based combination chemotherapy as induction treatment and 12 patients showed complete response (CR) or partial response (PR) as the best response to induction treatment. All patients received systemic chemotherapy as second-line treatment. Ten patients received ifosfamide, carboplatin, etoposide, and dexamethasone (ICE/D), 5 patients received cytarabine and etoposide (CYVE), 2 patients received high-dose MTX, and 1 patient received etoposide, dexamethasone, cytarabine, and cisplatin (EDAP). Four patients showed CR and 12 patients showed PR as the best response to second-line treatment. Twelve patients received thiotepa, busulfan, and cyclophosphamide (TBC) as conditioning regimen for ASCT, 4 patients received BCNU, etoposide, cytarabine, and cyclophosphamide (BEAC), 1 patient received busulfan, cyclophosphamide, and etoposide (BuCyE), and 1 patient received BCNU, etoposide, cytarabine, and melphalan (BEAM). Median OS and PFS was 1.5 years (95% CI not applicable), and 0.9 years (95% CI 0.6-1.2), respectively. The 2-years OS and PFS rate was 49.5% and 36.7%, respectively. Median hospitalization duration was 19 days (range, 4-51) and median dose of CD34+ cells infused was 7.57 × 106 cells/kg (range, 4.77-70.50). Seventeen patients (94.4%) had complete recovery of granulopoiesis and 15 patients (83.3%) had complete recovery of thrombopoiesis. Ten patients (55.6%) showed grade 3-4 diarrhea and 4 patients (22.2%) showed grade 3-4 mucositis.Conclusion High-dose chemotherapy followed by ASCT could be a treatment option in patients with refractory or relapsed PCNSL to induction chemotherapy. Further prospective studies are warranted. DisclosuresNo relevant conflicts of interest to declare.

Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma

AbstractThere is an unmet need for effective biological therapies for relapsed central nervous system (CNS) lymphoma. Lenalidomide is active in activated B-cell type diffuse large B-cell lymphoma and rituximab is effective in CNS lymphoma. These observations are the basis for this first trial of an immunomodulatory drug as monotherapy in CNS lymphoma, and, in patients with inadequate responses to lenalidomide, with rituximab. In an independent cohort, we evaluated lenalidomide maintenance after salvage with high-dose methotrexate or focal irradiation in relapsed primary CNS lymphoma (PCNSL). We determined safety, efficacy, and cerebrospinal fluid (CSF) penetration of lenalidomide at 10-, 15-, and 20-mg dose levels in 14 patients with refractory CD20+ CNS lymphoma. Nine subjects with relapsed, refractory CNS lymphoma achieved better than partial response with lenalidomide monotherapy, 6 maintained response ≥9 months, and 4 maintained response ≥18 months. Median progression-free survival for lenalidomide/rituximab was 6 months. In the independent cohort, response duration with lenalidomide maintenance after complete responses 2 through 5 were significantly longer than response durations after standard therapy. The CSF/plasma partition coefficient of lenalidomide was ≥20% at 15- and 20-mg dose levels. Change in CSF interleukin-10 at 1 month correlated with clinical response and response duration to lenalidomide. Metabolomic profiling of CSF identified novel biomarkers, including lactate, and implicated indoleamine-2,3 dioxygenase activity with CNS lymphoma progression on lenalidomide. We conclude that lenalidomide penetrates ventricular CSF and is active as monotherapy in relapsed CNS lymphomas. We provide evidence that maintenance lenalidomide potentiates response duration after salvage in relapsed PCNSL and delays whole brain radiotherapy (WBRT). This trial was registered at www.clinicaltrials.gov as #NCT01542918.

Primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL), confined to the brain, eyes, spinal cord or leptomeninges without systemic involvement. Overall prognosis, diagnosis and management of PCNSL differ from other types of NHL. Prompt diagnosis and initiation of treatment are vital to improving clinical outcomes. PCNSL is responsive to radiation therapy, however whole-brain radiotherapy (WBRT) inadequately controls the disease when used alone and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined, however HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials address the role of rituximab, and of consolidative treatment using ASCT or reduced-dose WBRT. Despite high tumor response rates to initial treatment, many patients have relapsing disease with very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on age, previous treatment and response, performance status and comorbidities at the time of relapse. Novel therapeutics targeting underlying tumor biology include small molecule inhibitors of B-cell receptor, cereblon, and mammalian target of rapamycin signaling, and immunotherapy programmed cell death 1 receptor inhibitors and chimeric antigen receptor T cells.

Diagnosis and management of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole-brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced-dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314-24. © 2017 American Cancer Society.

High Dose-Chemotherapy Followed By Autologous Peripheral Blood Stem Cell Transplantation for Patients with Refractory or Recurrent Primary Central Nervous System Lymphoma –Results of a Multicenter Study By the Germany Collaborative PCNSL Study Group

Introduction: Primary central nervous system lymphoma (PCNSL) relapses in up to 60% after conventional chemotherapy. The prognosis of refractory or recurrent PCNSL is very poor with a median survival of up to 5 months. Whole brain radiotherapy may improve survival up to 10 months, but is associated with significant neurotoxicity. High-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) have demonstrated high efficacy in the treatment of newly-diagnosed primary CNS lymphoma (PCNSL) in younger patients (pts.). To evaluate the efficacy of this approach, we initiated a prospective multicenter phase II study with HDT and ASCT for relapsed PCNSL. This trial is registered at ClinicalTrials.gov (NCT 00647049)Patients and Methods: Thirty eight pts. <65 years were treated within the phase II trial, chemotherapy (CHT) consisted of 2 cycles of Rituximab (3,75mg/m²), AraC (2x 3 g/m2) plus thiotepa (TT, 40 mg/m2) followed by rG-CSF and stem-cell-mobilization after the 1st cycle. Conditioning regimen included BCNU (400 mg/m2) and TT (4x5 mg/kgBW) followed by ASCT. Patients not in complete remission after HDT and ASCT underwent WBRT.Results: From 2007 to 2012, 38 pts (18 female, 20 male) with relapsed (n=31) or refractory (n=7) PCNSL from 10 German centers were enrolled and evaluable for analysis (median age 58 years, range 37-66 years). All pts had aggressive B-cell lymphomas (DLBCL). Median Karnofsky performance status at diagnosis was 90% (range 60-100). Patients were intensively pretreated, all pts underwent HD-MTX within the first-line-treatment, 15 of 38 pts were treated within the Bonn protocol. Thirty-one of 38 pts (81,6%) received HDT and ASCT according to protocol. Three pts died before PBSCT, 4 further pts were treated off study due to PD (n=2), refusal of HDT (n=1) and insufficient stem cell harvest (n=1). Regarding the primary endpoint in the intent-to-treat population, 22 pts (57,9%) achieved complete (CR) and and 5 (13,2%) partial remission (PR) after HDT and ASCT, respectively. In patients treated per protocol, the CR and PR-rate rate was 71% and 16,1% respecticely. The overall respinse rate in the per protocol population was 86,1%. Six pts in PR after HDT and ASCT received consolidating WBRT. After a median 39-month follow-up (range 0-48 mo), 1 and 2 years OS was 63% and 57%, respectively. Median survival of the intent-to-treat population was 29 months. Further results will be presented.Conclusion: Sequential systemic application of high-dose cytostatic agents followed by HDT+ASCT is highly effective as salvage therapy for pts. with relapsed or refractory PCNSL. DisclosuresIllerhaus:Riemser: Honoraria. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Stilgenbauer:Pharmacyclics, Janssen: Honoraria, Research Funding.

Two Cases of Treatment with Intrathecal Rituximab for Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin’s lymphoma (NHL), usually composed of diffuse large B-cells. Although rituximab is known for its curative effect on B-cell NHL, data on the use of intrathecal rituximab for PCNSL are limited. In this report, we present two patients showing relapsed PCNSL with lymphomatous meningitis. Both patients were refractory to conventional methotrexate-based intrathecal chemotherapy. However, after intrathecal rituximab with or without conventional intrathecal chemotherapy, both patients showed stable disease on magnetic resonance brain imaging and cerebrospinal fluid analysis. There were no serious adverse events during each of 3 and 6 cycles with intrathecal rituximab immunotherapy. (Korean J Med 2014;87:224-228)

Salvage treatment with temozolomide in refractory or relapsed primary central nervous system lymphoma and assessment of the MGMT status

High-dose methotrexate (HD-MTX) is effective in the initial treatment of primary central nervous system lymphoma (PCNSL). Because treatment options in patients with progressive or recurrent PCNSL are limited, prognosis is poor. Temozolomide, a well-tolerated oral alkylating agent that permeates the blood brain barrier (BBB), is effective against malignant glioma and recurrent PCNSL. The gene for the deoxyribonucleic acid (DNA) repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which is closely related to cellular sensitivity to alkylating agents, is inactivated by promoter hypermethylation. We evaluated the results of temozolomide treatment and the methylation status of the promoter region of the MGMT gene in 17 patients (median age 68 years) with refractory or relapsed PCNSL. They were immunocompetent and had received initial treatment with HD-MTX (3.5 g/m(2)) with or without irradiation. All were treated with temozolomide 150-200 mg/m(2), for 5 days in the course of 28 days; treatment was continued until disease progression. We observed five complete remissions, five partial responses (PRs) with stable disease (SD), and seven with disease progression. Median overall survival after the temozolomide treatment was 6.7 months. One patient manifested grade 3 neutropenia and thrombocytopenia. Eleven tumor specimens were available for MGMT analysis. MGMT promoter methylation (mMGMT) in the tumor tissue was found in 4 (36.4%), the other seven harbored a non-methylated MGMT promoter (nmMGMT). There was no statistically significant difference in median overall survival between patients with mMGMT (11.1 months) and nmMGMT (6.7 months) (P = 0.63). Although some patients were elderly and had been heavily pre-treated, temozolomide resulted in a complete response (CR) in 29% and was well tolerated without any major toxicity.

Temozolomide plus rituximab for elderly with relapsed primary central nervous system lymphoma

The aim of our study was to analyze the long-term results of rituximab combined with temozolomide in treatment of elderly patients (> 60 years) with relapsed primary central nervous system lymphoma (PCNSL). Twelve postoperative elderly patients (> 60 years) were treated between August 2004 and October 2009. Temozolomide 100 mg/m2 to 200 mg/m2 days 1 to 7 and 15 to 21 and rituximab 375 mg/m2 days 1, 5, 8, 22. The maximum number of rituximab cycles was two. After one or two cycles of this combination, patients with an objective response and an acceptable level of toxicity continued treatment with single agent temozolomide (days 1 to 5, every 28 days). The overall survival was analyzed by using Kaplan-Meier. The overall survival was 9 months. Toxicity was very mild with no grade 3–4 neurotoxicity toxic events. Rituximab combined with temozolomide seems to yields substantial long-term survival with moderate toxicity for the treatment of elderly relapsed PCNSL.

Platine and cytarabine-based salvage treatment for primary central nervous system lymphoma

The aim of this study was to evaluate the efficacy and toxicity of two chemotherapy regimens based on platinum and cytarabine in association with etoposide and methylprednisolone (ESHAP) or with dexamethasone (DHAP) with or without Rituximab (± R) in patients with refractory or a relapsed Primary Central Nervous System Lymphoma (PCNSL). All consecutive patients from two French centers with refractory or relapsed PCNSL treated with ESHAP/DHAP ± R were included. We analyzed the overall response rate (ORR), toxicity and overall survival (OS) after salvage chemotherapy. Intensive chemotherapy and hematopoietic stem cell rescue (IC + HCR) was offered to patients less than 65 years of age and consisted of high-dose thiotepa, busulfan and cyclophosphamide. These results were compared with two previously reported series of PCNSL patients treated with the CYVE (high-dose cytarabine and etoposide) regimen at relapse. Twenty-two patients received a total of 60 DHAP/ESHAP cycles (median 3; range 1-5). The median age was 59 years. The ORR after salvage chemotherapy was 59%. Toxicity was mainly hematological, 18% of patients showing febrile neutropenia. There was no treatment-related death. ESHAP or DHAP regimens led to similar ORRs compared to the CYVE regimen in relapsed or refractory PCNSL, although they seemed less toxic. The therapeutic results of the ESHAP/DHAP regimens in relapsed or refractory PCNSL were also similar to those for relapsed systemic non-Hodgkin's lymphomas (sNHL). Both chemotherapies, CYVE regimen and ESHAP/DHAP are treatment options to be considered in relapsed or refractory PCNSL, especially when IC + HCR is planned as a consolidation treatment. More efforts are still needed to improve the ORR at relapse.

Topotecan as salvage therapy for relapsed or refractory primary central nervous system lymphoma

Treatment for patients with refractory or relapsed primary CNS lymphoma (PCNSL) remains unsatisfactory. Topotecan is an intravenous topoisomerase I inhibitor with good CSF penetration and documented efficacy in patients with relapsed systemic non-Hodgkin's lymphoma. In this study 15 patients with refractory or relapsed PCNSL were treated with intravenous topotecan (1.5 mg/m(2)) for five consecutive days during each 21-day cycle. All 15 patients had measurable, contrast-enhancing tumor on cranial MRI at the time of relapse. Three (20%) patients achieved a complete response after one, three and four cycles, respectively, while three (20%) patients achieved a partial response after two cycles each, for a total response proportion of 40%. Three patients had stable disease at the end of topotecan treatment. Six patients (40%) had progressive disease during treatment. Median overall survival was 981 days (95% CI: 275, NA) and median progression free survival was 60 days (95% CI: 46, 945). Three out of 15 patients had grade 3 thrombocytopenia. Six out of 15 patients had grade 3 neutropenia, while 5/15 patients had grade 4 neutropenia, and 13/15 patients received g-CSF at some point during treatment. There were no deaths directly related to treatment toxicity. Our study shows that topotecan, as a salvage therapy in patients with relapsed or refractory PCNSL, is associated with an overall response proportion of 40% and should be considered in patients who have failed prior methotrexate-based chemotherapy and/or whole brain irradiation. However, progression is frequent and early and most patients required growth factor support due to myelotoxicity.

Recurrent primary central nervous system lymphoma (PCNSL) treated with pemetrexed

2086 Introduction: Untreated, survival in PCNSL is approximately 2 months. However using high dose methotrexate based regimens, median survival is up to 60 months. A significant number of patients relapse. There is currently no standard therapy, but many regimens have been used with variable results. Pemetrexed is a multi-targeted anti-folate agent approved for first line treatment of malignant pleural mesothelioma and second-line for locally advanced or metastatic non-small cell lung cancer. A phase II trial was initiated for patients with recurrent gliomas, PCNSL or brain metastases. Pemetrexed, in addition to inhibiting dihydrofolate reductase, targets other sites of inhibition, giving it a broader spectrum of activty. This suggests that pemetrexed could be effective in PCNSL. Patients and Methods: The dose of pemetrexed used was 900 mg/m2 every 3 weeks; based on phase I data where the MTD was 800 mg/m2 in heavily pretreated patients and not reached in lightly pretreated patients. Patients received dexamethasone 4 mg twice daily on the day before, the day of, and the day after each infusion of pemetrexed and supplemental folic acid and B12. Eligibility criteria for PCNSL patients included failure of at least one prior chemotherapy regimen. Patients had to be &gt; 18 year of age with KPS status of &gt; 60. Adequate bone marrow, liver, and renal function were required. An MRI was done every 6 weeks and for patients who attained a CR, a maximum of six doses was given. Results: To date, five patients with recurrent PCNSL have been treated on this trial after signing IRB approved consent. Patient Characteristics Discussion: We report our experience of pemetrexed in 5 patients with recurrent PCNSL. Toxicity has been minimal except in the one patient who was heavily pretreated (including a stem cell transplant). Activity was seen in all patients but transient in two. Pemetrexed is active in relapsed PCNSL. The optimal dose and schedule need to be determined, as well as activity in a larger group of patients. We continue to enroll patients in this study. [Table: see text] No significant financial relationships to disclose.