Rituximab,methotrexate, procarbazine,vincristine and intensified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: a LOC network study

Primary CNS lymphoma (PCNSL) is chemosensitive to high-dose methotrexate-based chemotherapy. However, responses in the elderly are short-lasting and outcome is poor. Given that radiotherapy and intensive chemotherapy expose elderly to severe toxicities, alternative consolidation approaches need to be evaluated. In this multicenter study, we retrospectively analyzed consecutive patients with newly-diagnosed PCNSL, aged >60, treated with a (R)-MPV-AAA regimen. The regimen consisted of three 28-day cycles of methotrexate (3.5 g/m² D1, D15), procarbazine, vincristine, followed by three 28-day cycles of cytarabine consolidation (3 g/m² D1-2). Addition of rituximab (375 mg/m² D1) was optional. The results were compared with the historical MPV-A regimen. Ninety patients received the (R)-MPV-AAA regimen with (n?=?39) or without (n?=?51) rituximab. Median age was 68 and median KPS 60. 55% of patients achieved a complete response, 8% a partial response and 37% progressed. The median PFS was 10 months, the median OS 28.1 months. Toxicity was mainly hematological, with 54 and 51% of grade III-IV neutropenia and thrombopenia. The response rate was higher in patients receiving rituximab (77 vs. 53%; p?=?0.03), whereas no difference was observed in terms of PFS or OS. When comparing the results to the historical MPV-A, there was no difference in terms of response rate, PFS or OS, but a higher rate of hematotoxicity. This study suggests that extending cytarabine consolidation after methotrexate-based chemotherapy does not improve the MPV-A efficacy but increases toxicity in the elderly. The addition of rituximab may improve the response rate, but its impact on final outcome remains unclear.     

High-dose methotrexate for primary CNS lymphoma in the elderly

Primary central nervous system lymphoma (PCNSL) in the immunocompetent patient reaches a peak incidence in the sixth and seventh decades of life. This retrospective study reviewed the efficacy and tolerability of high-dose methotrexate (HDMTX) in an elderly patient population. Between May 1995 and September 1998, ten consecutive elderly patients with histologically proven PCNSL were treated with HDMTX. The median age was 72.5 years and eight patients (80%) were older than 70 years. HDMTX was well tolerated with no episodes of grade 4 toxicity nor febrile neutropenia. Toxicity included grade 3 nausea (1), grade 2 mucositis (2), and grade 2 asymptomatic elevation of liver transaminases (2). Grade 1 toxicity occurred in three patients with nausea, diarrhea, and mild reversible elevation in serum creatinine in one patient each. Six patients had a complete response and three patients achieved a partial response, giving an overall response rate of 90% (95% confidence interval, 56%-100%). The median overall survival for the cohort was 36 months (range 4-43 months). In summary, HDMTX is well tolerated in this elderly population with PCNSL and achieves response rates and median survival comparable with other chemotherapy or radiotherapy regimens.     

High-dose methotrexate for elderly patients with primary CNS lymphoma

The introduction of methotrexate (MTX)-based chemotherapy has improved median survival for patients with primary CNS lymphoma (PCNSL). Older age is a negative prognostic marker in patients with PCNSL and may increase the likelihood of MTX toxicity. We studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. We identified 31 patients at our institution diagnosed with PCNSL at age > or =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survival were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL.     

High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma

We conducted a prospective Phase II study of high-dose methotrexate (HD-MTX) and rituximab with deferred whole brain radiotherapy in patients with newly diagnosed B-cell primary central nervous system lymphoma with a primary objective of evaluating progression-free survival (PFS). Forty patients (25 men; 15 women), ages 18–93 years (median 61.5), were treated. All patients received biweekly HD-MTX/rituximab (8 g/m²/dose; 375 mg/m²/dose) for 4–6 cycles (induction) and following best radiographic response, with every 4 weeks HD-MTX (8 g/m²/dose) for 4 cycles (maintenance). Neurological and neuroradiographic evaluation were performed every 4 weeks during induction therapy and every 8 weeks during maintenance therapy. All patients were evaluable. A total of 303 cycles of HD-MTX (median 8 cycles; range 4–10) was administered. HD-MTX/rituximab-related toxicity included 16 grade 3 adverse events in 13 patients (32.5%). Following induction, 8 patients (20%) demonstrated progressive disease and discontinued therapy; 32 patients (80%) demonstrated a partial (8/40; 20%) or complete (24/40; 60%) radiographic response. At the conclusion of maintenance therapy (6–10 months of total therapy), 28 patients (70%) demonstrated either a partial (1/28) or complete (27/28) response. Overall, survival of these 28 patients ranged from 11 to 80 months (median 33.5). Survival in the entire cohort ranged from 6 to 80 months with an estimated median of 29 months. Overall, PFS ranged from 2 to 80 months (median 21.0). HD-MTX/rituximab and deferred radiotherapy demonstrated similar or better efficacy similar to other HD-MTX-only regimens and reduced time on therapy on average to 6 months.     

High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study

Background: To improve survival of elderly patients with primarycentral nervous system lymphoma (PCNSL), we conducted a phaseII study with high-dose methotrexate (MTX) combined with procarbazineand CCNU. To reduce neurotoxicity, whole-brain irradiation wasreserved for patients not responding to chemotherapy. Patients and methods: High-dose MTX was applied on days 1, 15,and 30, procarbazine on days 1–10, and CCNU on day 1.Study treatment comprised up to three 45-day cycles. There wasno lower limit of Karnofsky performance status (KPS). Results: Thirty patients with PCNSL (n = 29) or primary ocularlymphoma (n = 1) were included (median age 70 years, range 57–79years). The median initial KPS was 60% (range 30%–90%).Best documented response in 27 assessable patients were 12 of27 (44.4%) complete remissions, 7 of 27 (25.9%) partial remissions,and 8 of 27 (29.6%) disease progressions. Two patients diedof probable treatment-related causes. With a median follow-upof 78 months (range 34–105), the 5-year overall survivalis 33%. Eight of 30 patients (26.7%) are currently alive andwell, six without signs of leukoencephalopathy. Conclusion: The combination of high-dose MTX with procarbazineand CCNU is feasible and effective and results in a low rateof leukoencephalopathy. Comorbidity and toxicity remain of concernwhen treating PCNSL in elderly patients. Key words: CNS lymphoma, elderly, methotrexate, neurotoxicity, PCNSL Received for publication February 19, 2008. Revision received August 5, 2008. Accepted for publication August 7, 2008.     

Immunochemotherapy with rituximab, vincristine and 5-day cyclophosphamide for heavily pretreated follicular lymphoma

PURPOSE: Therapeutic options for relapsed or refractory follicular lymphoma include combination chemotherapy, immunotherapy and, for selected patients, autotransplant. Because of the different mechanisms of action and non-overlapping toxicities, combination of rituximab with chemotherapy is a rational approach. METHODS: 30 patients with follicular non-Hodgkin's lymphoma with advanced-stage disease were treated with four cycles of immunochemotherapy with rituximab 375 mg/m2 on day 1, vincristine 2 mg i.v. on day 2 and cyclophosphamide 400 mg/m2 i.v. from days 2 to 6, repeated at 3-week intervals. All patients had received multiple lines of therapy (median 3); 9 (30%) had relapses (2 after high-dose therapy with autologous transplant), and 21 (70%) were in relapse and refractory to salvage treatment (with an anthracycline-containing regimen in 19). RESULTS: Of 29 patients evaluable for response, 16 (55 %) obtained a complete response (CR) and 3 (10%) a partial response (PR), with an overall response rate of 65% (19/29); 10 patients (35%) achieved less than PR. The median event-free survival was 16.1 months for all patients, being 22.8 months for responders. After a median follow-up of 2 years from the start of therapy (range 6 months to 3.8 years), of 16 patients who achieved CR, 10 remain free of disease. CONCLUSION: The combination of rituximab with vincristine and 5-day cyclophosphamide is able to produce CR in patients with advanced follicular lymphoma, even in patients resistant to third-generation regimens. The regimen designed on the basis of pharmacokinetics of the chimeric antibody seemed important for the clinical efficacy of the combination.     

Prognostic impact of meningeal dissemination in primary CNS lymphoma (PCNSL): experience from the G-PCNSL-SG1 trial

BackgroundWe evaluated the frequency and prognostic impact of meningeal dissemination (MD) in immunocompetent adult patients with primary central nervous system lymphoma treated in a randomized phase III trial.Patients and methodsMD was evaluated at study entry and defined by lymphoma proof in the meningeal compartment detected by at least one of the following methods: cerebrospinal fluid (CSF) cytomorphology, detection of clonal B cells by IgH PCR in CSF or contrast enhancement of the leptomeninges on magnetic resonance imaging (MRI).ResultsData on MD were available in 415 patients, of those, MD was detected in 65 (15.7%): in 44/361 (12.2%) by CSF cytomorphology, in 16/152 (10.5%) by PCR and in 17/415 (4.1%) by MRI. Major patients' characteristics and therapy did not significantly differ between patients with MD (MD+) versus those without MD (MD-). There was a significant correlation of MD with CSF pleocytosis (>5/μl; P < 0.0001), but no correlation with CSF protein elevation (>45 mg/dl). Median progression-free survival was 6.7 months [95% confidence interval (CI) 0–14.5] in MD+ and 8.3 months (5.7–10.8) in MD- patients (P = 0.95); median overall survival was 21.5 months (95% CI 16.8–26.1) and 24.9 months (17.5–32.3), respectively (P = 0.98).ConclusionMD was detected infrequently and had no impact on outcome in this trial.     

Angiogenesis in primary central nervous system lymphoma (PCNSL)

Angiogenesis and angiogenic growth factors have a major role in the pathogenesis of malignancies. However, very little is known about the clinical and histopathological relevance of angiogenesis in primary central nervous system lymphoma (PCNSL). We investigated that expression of vascular endothelial growth factor (VEGF) of the lymphoma cells and microvessel density (MVD) were examined in 19 patients with PCNSL. Additionally, the presence of the blood–brain barrier (BBB) was examined using immunohistochemistry and the electron microscopy. MVD was significantly higher in nine cases with VEGF immunoreactivity (VEGF+) than in ten cases with negative immunoreactivity for VEGF (VEGF−) (P < 0.001). VEGF expression was significantly associated with a longer survival (P < 0.005). BBB markers were negative in angiogenic vessels of VEGF+. BBB markers were identified in vessels surrounding tumor cells and tight junctions were also preserved in the capillary endothelium surrounding tumor cells in VEGF−. Angiogenesis is associated with VEGF expression and an absent BBB in the vessels of PCNSL. The BBB may be preserved in lesions with lymphoma cell infiltration, especially in VEGF− PCNSL. VEGF may have a prognostic effect in PCNSL.     

Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly

Background Treatment for primary CNS lymphoma (PCNSL) in the elderly is associated with lower response rates and higher risks of acute and late delayed toxicity as compared to younger patients. Temozolomide has emerged as a new alternative treatment for PCNSL and constitutes an attractive option for the elderly because of its favorable toxicity profile. In this study we report outcomes of a consecutive series of PCNSL elderly patients initially treated with an innovative regimen combining methotrexate and temozolomide without radiotherapy or intra-thecal chemotherapy. Methods Histologically confirmed newly-diagnosed PCNSL patients older than 60 years were included. An induction chemotherapy was initially given (methotrexate 3 g /m² on days 1, 10, and 20, and temozolomide 100 mg/m² on days 1–5). Patients achieving a partial or complete response proceeded to a maintenance phase (up to 5 monthly cycles of methotrexate 3 g/m² on day 1, and temozolomide 100 mg/m² days 1–5). Non-responders were treated on an individual basis. Results Among the 23 included patients, a complete response was observed in 55%, and disease progressed in the other 45%. Median event-free survival was 8 months, and median overall survival was 35 months. Grades 3 or 4 toxicities included nephrotoxicity in three patients, and hematotoxicity in five; no neurotoxicity has been observed to date. One patient died while on treatment from complications of intestinal obstruction. Conclusion Our efficacy results are comparable to other reported regimens, with the advantages of a favorable toxicity profile, and absence of intra-thecal chemotherapy. Prospective, controlled studies are warranted to confirm such results.     

替莫唑胺联合利妥昔单抗对复发的老年原发中枢神经淋巴瘤的应用

Objective: 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). Methods: 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 ...     

利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果

目的 探讨利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果.方法 按照入院顺序将84例原发性中枢神经系统淋巴瘤患者分为对照组和观察组,每组42例,对照组接受大量甲氨蝶呤治疗,观察组患者接受利妥昔单抗联合大剂量甲氨蝶呤治疗.比较两组患者的临床疗效、不良反应、生存期和生活质量.结果 观察组患者的治疗总...     

Durable responses with the metronomic rituximab and thalidomide plus prednisone,etoposide, procarbazine,and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma

BACKGROUND:

Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT‐PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL).

METHODS:

RT‐PEPC included induction (Months 1‐3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells.

RESULTS:

Twenty‐five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52‐81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high‐risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1‐7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow‐up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression‐free survival was 10 months. Four CRs were ongoing (≥6 months, ≥31 months, ≥48 months, and ≥50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment.

CONCLUSIONS:

RT‐PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low‐intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients. Cancer 2010. © 2010 American Cancer Society.     

Efficacy and MRI of rituximab and methotrexate treatment in a nude rat model of CNS lymphoma

To determine the efficacy of methotrexate and/or rituximab in a CNS lymphoma model and to evaluate MRI modalities for monitoring efficacy, we inoculated female athymic nude rats (rnu/rnu) intracerebrally with human MC116 B-lymphoma cells. Between days 16 and 26, rats were randomized to receive intravenous (IV) treatment with (1) saline (controls, n = 15), (2) methotrexate 1,000 mg/m² (n = 6), (3) rituximab 375 mg/m² (n = 6), or (4) rituximab plus methotrexate (n = 6). T2/fluid-attenuated inversion recovery (FLAIR) and gadolinium contrast-enhanced T1 MRI sequences were performed prior to and 1 week after treatment. IV rituximab gave an objective tumor response in four of six animals (>50% reduction in tumor volume comparing pre- and posttreatment T2/FLAIR MRI) and resulted in stable disease (50%–125% of baseline) in another animal. The percent change in tumor volume on T2/FLAIR images was significantly different in the control versus rituximab group (p = 0.0051). IV methotrexate slowed tumor growth, compared to controls, but only one of six animals had an objective response. In untreated controls, tumor histological volumes correlated well with T2/FLAIR or contrast-enhanced T1 images (r = 0.877). In the treatment groups, T2/FLAIR correlation was good, but the gadolinium-enhanced T1 MRI was not significantly correlated with histology (r = 0.19). The MC116 CNS lymphoma model seems valuable for preclinical testing of efficacy and toxicity of treatment regimens. IV rituximab was highly effective, but methotrexate was only minimally effective. T2/FLAIR was superior to contrast-enhanced T1 for monitoring efficacy.     

Current status and future of relapsed primary central nervous system lymphoma (PCNSL)

The treatment of primary central nervous system lymphoma (PCNSL) has centered around high-dose methotrexate and radiotherapy (RT). Methotrexate administered intra-arterially (IA) with blood-brain barrier disruption (BBBD) and without RT, has been a highly effective treatment with a 5 year survival of 42% without cognitive loss. The purpose of this analysis is to determine responses for patients with relapsed PCNSL treated with second line IA carboplatin-based chemotherapy with BBBD. Between February 1991 and April 2000, 37 relapsed PCNSL patients, most who failed front line therapy with methotrexate based chemotherapy, were treated at Oregon Health & Science University (OHSU) and Hadassah Hebrew University Hospital (HHUH) with IA carboplatin-based chemotherapy with BBBD. Nine patients had prior RT. The mean age was 57.5 years, and all but 1 patient were treated within 8 months after relapse. The median time for survival from first IA carboplatin/BBBD treatment was 6.8 months;however, 7 out of 37 patients survived > or = 27 months. Nine patients had radiographic complete response (CR), 4 patients had radiographic partial response (PR), 12 had stable disease (SD), 10 had progressive disease (PD), and 2 were non-evaluable. The median time to failure for patients with CR and PR was 9.1 months. One long-term survivor is alive at 91.0 months from first carboplatin/BBBD treatment. In conclusion, we show that relapsed PCNSL has shown sensitivity to second line IA carboplatin-based chemotherapy with BBBD. We have developed a new protocol using i.v. rituximab prior to BBBD with IA carboplatin, i.v. cyclophosphamide and i.v. etoposide phosphate. The long-term program goal is to consolidate dose-intensive chemotherapy with monoclonal antibody directed radiation. Because patients with recurrent PCNSL commonly continue to relapse even after obtaining a complete response to enhanced chemotherapy treatment, patients w ho complete or fail the above carboplatin/BBBD treatment regimen will be offered consolidation with radioimmunotherapy using zevalin (Ibritumomab tiuxetan), IDEC-2B8 conjugated with yttrium-90 (90Y).     

High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma

BackgroundThe dose of high-dose methotrexate (HDMTX) in elderly patients often has to be reduced, resulting in a loss of treatment efficacy. We evaluated HDMTX-related toxicity with special regard to age distribution in patients with primary central nervous system lymphoma (PCNSL) in a phase IV multicenter trial.Patients and methodsOne hundred and fifty-four patients (median age 61 years; 89 patients >60 years old, 21 patients >70 years old) received 619 HDMTX cycles. Toxicity was evaluated prospectively using the WHO classification. Unless a reduced dose was required after calculating a decreased glomerular filtration rate (GFR), the patients received 4 g/m² HDMTX followed by leucovorin rescue.ResultsToxicity was generally mild with toxicities of WHO grade ≥3 usually <10%. The differences in the incidence and severity of toxicity were not statistically significant between patients >60 years and ≤60 years old. The same was true for therapy termination owing to MTX toxicity and for delayed serum MTX clearance. Dose reduction significantly differed between patients ≤60 years and those >60 years old (18% versus 44%; P = 0.001).ConclusionsHDMTX is a safe treatment for PCNSL patients regardless of age, with adherence to dose reduction determined by calculating the GFR before each treatment cycle.