Autologous Stem Cell Transplantation in Central Nervous System Lymphoma: A Multicenter Retrospective Series and a Review of the Literature

BackgroundCentral nervous system (CNS) lymphoma is associated with poor outcomes. Autologous stem cell transplantation (ASCT) has been reported to improve outcomes when used as a consolidation strategy in primary CNS lymphoma (PCNSL) and as a salvage strategy in patients with disease relapse limited to the CNS. Herein, we describe our experience of using ASCT in PCNSL and secondary CNS lymphoma (SCNSL).Patients and MethodsWe evaluated clinical outcomes of 18 patients from 2 major academic centers with a median age of 55 (range, 46-72) years. Thirteen patients had PCNSL and 5 patients had SCNSL. Most of the cases were in the first (CR1) or second (CR2) complete remission (CR1 = 7, CR2 = 7) at the time of ASCT. Carmustine with thiotepa (n = 12, 67%) was the most commonly prescribed preparative regimen.ResultsThe median follow-up from ASCT for surviving patients was 12 (range, 0.9-115) months. The 2-year progression-free survival (PFS) and overall survival (OS) were 74% (95% confidence interval [CI], 48%-99%) and 80% (95% CI, 55%-100%), respectively. Two-year non-relapse mortality was 0%. The 2-year cumulative incidence of relapse/progression was 27% (95% CI, 10%-72%). In subgroup analysis of PCNSL patients, 2-year PFS, OS, and relapse were 71% (95% CI, 38%-100%), 71% (95% CI, 38%-100%), and 29% (95% CI, 9%-92%), respectively.ConclusionIn this retrospective study of patients with CNS lymphoma, consolidation with ASCT after high-dose methotrexate-based chemotherapy is safe and effective in reducing disease relapse.     

奥布替尼维持治疗对老年或体弱中枢神经系统淋巴瘤患者的疗效和安全性分析

目的:探讨基于奥布替尼的维持治疗在老年或体弱中枢神经系统淋巴瘤(central nervous system lymphoma, CNSL)患者中的疗效及安全性。方法:回顾性分析2015年7月至2021年6月我院收治的18例CNSL患者,接受基于奥布替尼方案的维持治疗,观察其无进展生存期(PFS)和安全性。结果:在11例原发性中枢神经系统淋巴瘤(PCNSL)患者中,中位维持治疗5(IQR 2.3～8.5)个月后,6个月、12个月PFS率分别为63.6%、50.9%。在7例继发性中枢神经系统淋巴瘤(SCNSL)患者中,中位维持治疗7.7(IQR 5～9)个月后,6个月、12个月PFS率分别为100%、75%。在7例经诱导治疗达完全缓解的患者中,经过中位7.7(IQR 5～9.5)个月维持治疗后,6个月、12个月PFS率均为100%。有8例患者报告了3或4级不良反应。结论:基于奥布替尼方案的维持治疗在老年或体弱CNSL患者中是安全且有效的,可以有效延长其PFS,是一种新的维持治疗选择。     

Salvage therapy with bendamustine for methotrexate refractory recurrent primary CNS lymphoma: a retrospective case series

There is comparatively limited therapy for recurrent primary central nervous system lymphoma (PCNSL). Salvage therapies include re-challenge with high-dose methotrexate (HD-MTX), whole brain radiotherapy, temozolomide, topotecan and premetrexed. Bendamustine is a novel bifunctional alkylator with established activity in B cell systemic lymphomas but never previously evaluated in PCNSL. The objective of the current study was to assess response and toxicity of bendamustine in recurrent PCNSL following prior salvage therapy in a retrospective case series. Twelve adults [six males; six females: median age 59 years (range 43–74)] with HD-MTX refractory recurrent PCNSL were treated with bendamustine. All patients were treated at second recurrence following failure of prior salvage therapy. A cycle of bendamustine was defined as two consecutive days of treatment (100 mg/m²/day) administered once every 4 weeks (maximum number of cycles 6). Toxicities seen were Grade 2 (24 episodes in 10 patients) and 3 (10 episodes in 5 patients) only and included lymphopenia (8 patients), hyperglycemia (7 patients), fatigue (7 patients) and nausea (4 patients). The median number of cycles of therapy was 3.5 (range 1–6). Radiographic response was progressive disease in 5 (42 %), stable disease in 1 (8 %), partial response in 3 (25 %) and complete response in 3 (25 %). Median progression free survival (PFS) was 3.5 months (range 1–14 months) and 6-month PFS was 33 %. In this small retrospective series of select patients with recurrent PCNSL refractory to HD-MTX, bendamustine appears to have modest single agent activity with manageable toxicity. Confirmation in a larger series of similar patients is required.     

Outcomes of Autologous Stem Cell Transplantation as a Consolidative Strategy for the Treatment of Primary and Isolated Secondary Central Nervous System Diffuse Large B Cell Lymphomas

IntroductionStandard consolidation for primary diffuse large B cell lymphoma (DLBCL) of the central nervous system (CNS) (PCNSL) is not established. This single center, retrospective observational study aims to define the outcomes of consolidative high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in patients with PCNSL and isolated secondary CNS DLBCL (SCNSL) and evaluate the prognostic factors.Patients and MethodsAll consecutive patients performed an HDC/ASCT for PCNSL or isolated SCNSLs between October 2012 and February 2022 were identified. Primary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsAmong 35 patients included, 28 had PCNSL and 7 had isolated SCNSL. Median age was 51 (16-78). Males constituted 48.6%. Median follow-up after HDC/ASCT was 42.0 months. MATRIX (51.4%) and TEAM (80.0%) were the most frequent regimens of induction and conditioning, respectively. OS and PFS 1- and 2-year after HDC/ASCT were 68.0%, 57.0%, 58.0%, 48.0%, respectively. Increasing age, poor performance and comorbidities were associated with lower OS and PFS and higher non-relapse mortality (NRM). Complete response (CR) 1 at HDC/ACST was independently associated with higher OS and PFS [hazard ratio (HR): 4.67 and 6.99, respectively].ConclusionIn patients < 60 years consolidative HDC/ASCT yields promising OS and PFS. Patients ≥ 60 years may less likely benefit from consolidative HDC/ASCT and should be studied further in trials of novel agents, lower doses of consolidative radiotherapy and dose-adjusted conditioning regimens. Not only age, but also comorbidities, clinical performance and response to induction correlate with outcomes. Patients with isolated SCNSL may achieve similar outcomes.     

Durable Survival Outcomes in Primary and Secondary Central Nervous System Lymphoma After High-dose Chemotherapy and Autologous Stem Cell Transplantation Using a Thiotepa,Busulfan, and Cyclophosphamide Conditioning Regimen

BackgroundHigh-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results.Patients and MethodsA retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1).ResultsThe 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL.ConclusionHDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.     

The development of targeted chemotherapy for CNS lymphoma—a pilot study of the IDARAM regimen

Purpose We have developed and evaluated a CNS-targeted chemotherapy regimen based on the pharmacokinetic properties of the individual drugs in the combination.Patients and methods In a twin-track study, 16 patients with secondary CNS lymphoma (SCNSL) and 8 with primary CNS lymphoma (PCNSL) were treated with IDARAM which comprised idarubicin 10 mg/m² i.v., days 1 and 2; dexamethasone 100 mg, 12-h infusion, days 1, 2 and 3; cytosine arabinoside (ARA-C) 1.0 g/m², 1-h infusion, days 1 and 2; methotrexate 2.0 g/m², 6-h infusion, day 3 (with folinic acid rescue); and cytosine arabinoside 70 mg plus methotrexate 12 mg, intrathecally, days 1 and 8. Two cycles were delivered at 3-weekly intervals. After response assessment, patients received adjuvant cranial radiotherapy (40 Gy over 20 fractions).Results The series comprised 24 patients, 11 male and 13 female. Their median age was 53 years (range 21 to 73 years). Grade 4 neutropenia and thrombocytopenia occurred in the majority of patients treated. Of the eight PCNSL patients, seven achieved complete remission (CR). Four remained in CR at the time of this report with a median duration of follow-up of 25 months (range 11 to 42 months). Of the 16 SCNSL patients, 12 achieved CR. Seven patients remained in CR at the time of this report with a median duration of follow-up of 24 months (range 18 to 57 months).Conclusion This study suggests that IDARAM is an effective regimen in both PCNSL and SCNSL and is suitable for further development and evaluation.This work is presented on behalf of the Central and Southern Lymphoma Group.     

BTK抑制剂在中枢神经系统淋巴瘤中的治疗作用及安全性分析

目的：研究布鲁顿酪氨酸激酶（Bruton’s tyrosine kinase,BTK）抑制剂治疗复发/难治性中枢神经系统淋巴瘤(relapsed/refractory central nervous system lymphoma,R/R CNSL）的有效性和安全性。方法：回顾性分析郑州大学第一附属医院2018年10月至2021年10月收治的43例R/R CNSL患者,分别使用BTK抑制剂单药、BTK抑制剂联合化疗、BTK抑制剂联合免疫治疗方案,BTK抑制剂包括伊布替尼、泽布替尼、奥布替尼,初始剂量分别为（420～560）mg/d、320 mg/d、（100～150）mg/d,分析治疗后的最好疗效和不良反应。结果：BTK抑制剂单药组（A组）、BTK抑制剂联合化疗组（B组）、BTK抑制剂联合免疫治疗组（C组）的客观缓解率（objective response rate,ORR）分别为44.4%、85.7%和76.9%,B组的ORR高于A、C组,原发中枢神经系统淋巴瘤（primary CNSL,PCNSL）患者的ORR(78.6%vs. 66.7%)高于继发中枢神经系统淋巴瘤（second...     

Pemetrexed for primary central nervous system lymphoma in the elderly

Objective

The aim of this study was to evaluate the efficacy and safety of a consecutive series of elderly patients with primary central nervous system lymphoma (PCNSL) treated with single-agent pemetrexed without radiotherapy or intrathecal chemotherapy.

Methods

Twelve histologically confirmed newly diagnosed PCNSL patients older than 65 years were studied between 2008 and 2013. An induction chemotherapy was initially given (pemetrexed 600 mg/m² on day 1, every 3 weeks). Patients achieving a complete, partial response or stable disease proceeded to a maintenance phase (up to 6 cycles). Patients with progressive/recurrent disease (PD) were treated with whole brain radiotherapy on an individual basis.

Results

Four patients presented complete response, six patients showed partial response and two patients presented progressive disease. The median progression-free survival (PFS) was 9.0 months [95 % confidence interval (CI) 2.0–45.3] and the median overall survival was 19.5 months (95 % CI 5.0–45.3). Adverse events included leukocytopenia, anemia, fatigue, rash and vomiting. No neurotoxicity or treatment-related death was observed. The estimated 1-year and 2-year survival rate was 66.7 and 41.7 %, respectively.

Conclusions

Our efficacy results demonstrate that the single-agent pemetrexed was feasible, active and well tolerated in elderly patients with PCNSL. Furthermore, this single-agent regimen results in higher response rates and less toxicity comparable with other chemotherapy or radiotherapy regimens. Prospectively, controlled studies are warranted to confirm such results.

     

Prospective trial on topotecan salvage therapy in primary CNS lymphoma.

BACKGROUND: Standard salvage therapy has not been established for recurrent primary central nervous system lymphoma (PCNSL). We report the final results of a prospective study on topotecan chemotherapy in relapsed or refractory PCNSL. PATIENTS AND METHODS: The study included 27 patients with a median age of 51 years and an ECOG performance status of 2. Fourteen patients were refractory to the last therapy, and 13 relapsed after a median period of 6.0 months. Pretreatment with up to four regimens included chemotherapy in 26 patients and whole brain irradiation in 14. A 30-min daily topotecan infusion of 1.5 mg/m(2) for 5 days was repeated every 3 weeks. RESULTS: The response rate was 33% with five complete (CR) and four partial remissions (PR). The median follow-up was 37.7 months. All complete responders had sustained remissions lasting for 9 to 28 months. The median event-free survival (EFS) was 2.0 months (9.1 months in responders), the overall survival (OAS) was 8.4 months. CTC grade 3-4 leukopenia occurred in 26% and thrombocytopenia in 11% of the patients. Eight of 12 patients alive without cerebral lymphoma > or = six months after topotecan exhibited deficits attributable to late neurotoxicity. CONCLUSION: Topotecan as monotherapy is active in relapsed and refractory PCNSL with tolerable toxicity.     

Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred?

Whole brain radiotherapy (WBRT) has been increasingly omitted as the first treatment of primary central nervous system lymphoma (PCNSL) because of neurotoxicity risks. However, neurotoxicity risks are lower in young (<60 years) patients; deferring WBRT may not be necessary and may compromise disease control. To investigate this question, we report a consecutive series of young (<60 years) PCNSL patients uniformly treated with a response-adjusted approach, with WBRT omitted in patients with chemosensitive disease. Treatment started with induction chemotherapy consisting of methotrexate (3 g/m(2)), CCNU, procarbazine, methylprednisolone and intrathecal methotrexate, cytarabine, and methylprednisolone. Patients achieving complete response (CR) received five additional chemotherapy cycles and no further treatment. Patients with less than CR were treated on an individual basis, typically with WBRT or high-dose chemotherapy (HDC) with stem cell rescue. Sixty-four patients were included (median age: 47; median KPS: 70). Median progression-free survival (PFS) was 12 months; median overall survival (OS) was 63 months (median follow-up: 108 months). Objective response after induction was 87% (CR: 54%; PR: 33%). To date, salvage WBRT has been given to a total of 27 patients and HDC to 29. Neurotoxicity developed in five patients (none in patients treated with chemotherapy only). Deferring WBRT in chemosensitive patients seems to compromise PFS but not OS. Neurotoxicity was reduced but not eliminated, as salvage WBRT was frequently required. HDC and WBRT were effective salvage treatments. As the objective of treatment in this population is a cure, withholding WBRT may not be the best strategy and deserves further investigation. Ongoing studies are investigating whether upfront treatment with HDC can replace WBRT in this setting.     

Salvage radiotherapy in patients with recurrent or refractory primary or secondary central nervous system lymphoma after methotrexate-based chemotherapy

BackgroundTo assess the efficacy of salvage radiation therapy (RT) in patients with recurrent/refractory primary or secondary central nervous system lymphoma (CNSL) after initial methotrexate (MTX)-based chemotherapy and to identify factors associated with treatment outcome.Patients and methodsWe reviewed 36 patients with primary or secondary CNSL who relapsed after MTX therapy and received salvage RT. Primary end points were radiographic response and overall survival (OS).ResultsAfter salvage RT, 18 patients (50%) achieved a complete radiographic response and 6 (17%) achieved a partial response, for an overall response rate of 67% [95% confidence interval (CI) 49% to 81%]. The median OS from start of salvage RT was 11.7 months (range: 0.6–94.7). Patients treated with less than five cycles of MTX before failure had a significantly shorter OS than patients who received five or more cycles (9.2 months versus not reached, P = 0.04). Patients with CNSL limited to brain only had a significantly longer OS than patients with disease in the brain and other central nervous system locations (16.5 versus 4.5 months, P = 0.01).ConclusionSalvage RT is effective for patients with recurrent/refractory primary or secondary CNSL after initial MTX therapy. Having received five or more cycles of MTX before failure and CNSL limited to the brain at relapse are associated with longer OS.     

Methotrexate re-challenge for recurrent primary central nervous system lymphoma

The prognosis of primary CNS lymphoma (PCNSL) recurring after methotrexate is poor (objective response rates [ORR] = 26–53 %; 1-year overall survival [OS] = 35–57 %). Salvage PCNSL chemotherapies have been based on the use of different agents to avoid cross-resistance; however, methotrexate is the most active agent in PCNSL, and methotrexate re-challenge may be an effective strategy for recurrent disease. We report our experience with methotrexate re-challenge in PCNSL. We reviewed 39 patients with histologically confirmed PCNSL who responded to methotrexate at initial diagnosis, experienced disease relapse and received methotrexate re-challenge. At the time of re-challenge, median age was 66 and median Karnofsky performance score (KPS) was 70. Median time from initial diagnosis was 26 m. Twenty-six patients were at first relapse and 13 at second or later relapse. At re-challenge, methotrexate was given in combination with other agents to 33 patients and as a single agent to six. The objective response rate was 85 %, with a complete response in 29 (75 %) patients, partial response in four (10 %) and disease progression in six (15 %). At median follow-up of 26 m, the median progression-free survival was 16 m; 1-year OS was 79 % (95 % CI 63–89) and median OS was 41 m. KPS was a prognostic factor for progression free survival (p = 0.04). In this population selected by previous methotrexate response, methotrexate re-challenge was a safe and effective strategy, indicating chemosensitivity was retained. Efficacy compared favorably to other salvage treatments suggesting methotrexate re-challenge should be considered in recurrent PCNSL patients who previously responded to methotrexate.     

Recurrent or refractory primary central nervous lymphoma: therapeutic considerations

Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes or spinal cord without evidence of systemic disease. Despite the high complete remission rate achieved with aggressive first-line therapy, 10–35% of PCNSL are treatment refractory and 35–60% of patients relapse. Standard therapy for recurrent or refractory disease has not yet been established, although retrospective data suggests improvement in survival with salvage therapy. The reported survival after relapse of PCNSL varies between 2 months and 24 months, with most series reporting an average of 4–12 months. The outcomes depend on whether treatment is instituted or not, suggesting a need for treatment guidelines for these patients. We review therapeutic approaches and their outcomes in recurrent or refractory PCNSL.     

R-FPD方案治疗初治原发中枢神经系统淋巴瘤的前瞻性研究

  目的   评估利妥昔单抗联合福莫司汀、培美曲塞、地塞米松方案（R-FPD）治疗原发中枢神经系统淋巴瘤（primary central nervous system lymphoma，PCNSL）的安全性、有效性和可行性，初步探索生物标志物在PCNSL治疗中的意义。   方法   本研究为前瞻性、单中心、单臂Ⅱ期临床试验。分析2018年7月至2019年7月郑州大学第一附属医院确诊的初治PCNSL患者。全组患者均接受R-FPD方案一线化疗。主要研究终点为客观缓解率（objective response rate，ORR），疾病控制率（disease control rate，DCR），无进展生存期（progression free survival，PFS），总生存期（overall survival，OS）。次要研究终点为不良反应（adverse reaction，ADR）。   结果   共12例患者纳入此研究，4个周期治疗后疗效评估为完全缓解（complete response，CR）6例，部分缓解（partial response，PR）2例，疾病稳定（stable disease，SD）1例，疾病进展（progressive disease，PD）3例。ORR为66.7%，DCR为75%。中位无进展生存期（median progression free survival，mPFS）为7个月（95% CI:4.4~9.6个月），中位总生存期（median OS，mOS）为10.5个月（95% CI:6.1~14.9个月）。R-FPD化疗方案的主要不良反应为血液学毒性，Ⅲ~Ⅳ级粒细胞和血小板减少分别为16.7%和25.0%。c-myc蛋白高表达（>40%）可能与预后无关。   结论   R-FPD对于初治的PCNSL患者是安全有效的方案。c-myc高表达与预后无显著相关性。      

Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma

BACKGROUND:

Despite initial treatment with high‐dose methotrexate‐based regimens, many patients with primary central nervous system lymphoma (PCNSL) relapse and die from their disease. No standard of care exists at progression or relapse, but chemotherapy and in some cases radiation are usually used. Pemetrexed is a multitargeted antifolate, similar to methotrexate, but with a broader spectrum of activity. Because methotrexate is an integral part of PCSNL treatment, the authors assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL.

METHODS:

Patients with relapsed/refractory PCNSL were enrolled in this trial. Treatment consisted of pemetrexed 900 mg/m² given every 3 weeks with low‐dose dexamethasone, folate, and B12 supplementation. Each cycle was 6 weeks, and follow‐up imaging was done before each new cycle. Treatment was continued until complete remission, progression, or toxicity.

RESULTS:

Eleven patients were treated, with a median age of 69.8 years and Karnofsky performance status of 70%; 10 of 11 patients had failed prior high‐dose methotrexate. The median number of pemetrexed cycles given was 5, with an associated overall response rate of 55% and disease control rate of 91%. The 6‐month progression‐free survival (PFS) was 45%, median PFS was 5.7 months, and median overall survival was 10.1 months. Toxicities were primarily hematologic and infectious.

CONCLUSIONS:

Pemetrexed has single‐agent activity in relapsed/refractory PCNSL. Toxicities were seen likely because of the higher than standard dose used. Further investigation of this agent or other multitargeted antifolates in PCNSL is warranted to determine optimal dose and efficacy in a more homogeneous population. Cancer 2012. © 2011 American Cancer Society.     

首次复发?难治原发性中枢神经系统淋巴瘤预后影响因素分析

  目的  分析复发/难治原发性中枢神经系统淋巴瘤（primary central nervous system lymphoma,PCNSL）患者临床特点并探讨其影响预后的因素,为临床诊疗提供依据。  方法  选取复旦大学附属华山医院2006年10月至2015年8月确诊的64例复发/难治PCNSL患者的病例资料、治疗方案、实验室辅助检查指标进行回顾性分析。采用Cox回归多因素分析。  结果  单因素和多因素分析结果显示,首次无疾病进展生存期（progression-free survival of first time,PFS1）≤1年、Karnofsky评分（Karnofsky performance score,KPS） < 70分为影响复发/难治PCNSL预后的独立危险因素。PFS1≥1年患者中位第二次无疾病进展生存期（median progression-free survival of second time,mPFS2）和中位第二次总生存时间（median overall survival of second time,mOS2）分别为19个月和21个月,而PFS1 < 1年患者mPFS2和mOS2分别为10个月和14个月。复发/难治时KPS评分≥70分患者与KPS评分 < 70分患者mPFS2分别为40个月和10个月,mOS2分别为43个月和12个月。另外,单因素分析首次复发/难治PCNSL患者选用含有大剂量甲氨蝶呤（high-dose methotrexate,HD-MTX）化疗方案的mPFS2为18个月,而选用不含HD-MTX化疗方案的mPFS2为10个月,差异具有统计学意义。多因素分析结果显示,挽救方案为影响患者PFS的相关因素;单因素分析结果显示,挽救方案含有HD-MTX与不含有HD-MTX组的mOS2分别为23个月和12个月,差异无统计学意义,考虑与样本量较小有关。  结论  PFS1≤1年、KPS评分 < 70分是影响复发/难治PCNSL预后的独立危险因素。首次复发/难治PCNSL患者挽救治疗继续给予HD-MTX为基础的化疗方案可能会提高患者的远期疗效。      

A phase II trial of PTK787/ZK 222584 in recurrent or progressive radiation and surgery refractory meningiomas

When surgery and radiation are no longer treatment options, salvage systemic therapy has been used for recurrent meningiomas with little compelling evidence to suggest effectiveness. Patients with surgery and radiation refractory recurrent meningiomas were treated with the oral multifunctional tyrosine kinase inhibitor PTK787/ZK 222584 (PTK787) at a dose of 500 mg twice a day. Each treatment cycle was 4 weeks with MRI done every 8 weeks. Twenty-five patients (14 men; 11 women) with a median age of 59 years and KPS of 80 were treated. Meningioma WHO Grade was I in 2 patients, II in 14 patients and III in 8 patients; 1 patient had a hemangiopericytoma. All patients had prior surgery, external beam radiation therapy or radiosurgery and 11 patients prior systemic chemotherapy. Median number of cycles of PTK 787 administered was 4 (range <1–22). Best response in the 22 evaluable patients was stable disease in 15 (68.2 %). Predominant PTK787 related toxicities included fatigue (60 %), hypertension (24 %) and elevated transaminases (24 %). Grade II patients had a progression free survival (PFS)-6 of 64.3 %, a median PFS of 6.5 months and an overall survival (OS) of 26.0 months; grade III patients had a PFS-6 of 37.5 %, median PFS of 3.6 months and OS 23 months. PTK787 was modestly toxic at the dose of 500 mg administered twice per day. Activity as determined by PFS-6 suggests that targeting PDGF/VEGF pathway warrants further investigation.     

Fotemustine,Teniposide and Dexamethasone in Treating Patients with CNS Lymphoma

Purpose: We developed and evaluated a regimen including fotemustine, teniposide and dexamethasone (FTD)for treating patients with central nervous system (CNS) lymphoma based on pharmacokinetic properties ofindividual agents and in combination. Patients and Methods: In a comparison study, 8 patients with primaryCNS lymphoma (PCNSL) and 8 with secondary CNS lymphoma (SCNSL) were treated with FTD (comprisingfotemustine 100 mg/m2, 1h infusion, day 1; teniposide 60 mg/m2, >0.5 h infusion, on day 2, 3, 4; dexamethasone 40mg, 1h infusion, on day 1, 2, 3, 4 and 5; and methotrexate 12 mg, cytosine arabinoside 50 mg plus dexamethasone5 mg intrathecally, on day 2 and 7). Cycles were repeated every 3 weeks. After response assessment, patientsreceived whole brain radiotherapy. Results: Of the 8 PCNSL patients, 4 (50%) achieved CR and 3 (38%) PR, anoverall response rate of 88%. Four patients (50%) were in continuing remission at the end of this study after amedian follow-up of 30 months (range 10 to 56 months). Of the 8 SCNSL patients the overall response rate was63% (CR+PR: 38%+25%). All responses were achievable with predictable toxicity mainly reflecting reversiblemyelosuppression. Conclusion: This study suggests that FTD could be an effective treatment for CNS lymphoma,and is worthy of further evaluation.     

Non-deep-seated primary CNS lymphoma: therapeutic responses and a molecular signature

The survival of patients with primary CNS lymphoma (PCNSL) has been improved by high-dose methotrexate (HD-MTX). Since the combination therapy of HD-MTX and whole-brain radiotherapy (WBRT) carries a significant risk for delayed neurotoxicity, it is important to know the therapeutic potential and prognostic factors for HD-MTX without WBRT. We retrospectively reviewed 46 consecutive patients with PCNSL treated with a HD-MTX (3.5 g/m²) and deferred WBRT. Patients who achieved complete response or partial response after three courses of HD-MTX were cautiously followed-up without additional treatment. Patients who had either stable disease, progressive disease, or disease relapse were offered salvage therapy. The median progression-free survival period was 10 months and the median overall survival period was 52 months, with a 5-year survival rate of 39 %. Nineteen patients (49 % of the evaluable patients) achieved a complete response at the initial response assessment. Involvement of deep structures of the brain (corpus callosum, basal ganglia and brainstem) was significantly associated with the worse progression-free survivals (p = 0.0058) and overall survivals (p = 0.0177). Gene expression profiling analysis by microarray was compared in eight patients between PCNSLs located in the deep structures of the brain and non-deep-seated tumors. The result showed that up-regulation of signal transduction-related genes and down-regulation of catalytic activity-related genes in the non-deep-seated PCNSL compared with the deep-seated tumors. The present study shows that PCNSL located in non-deep structures of the brain responds better to HD-MTX alone than those involved deep-structures.