Long-term survivors of a systemic and intraventricular chemotherapy with deferred radiotherapy in primary central nervous system lymphoma (PCNSL)

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 8557-8557
Author(s):  
U. Schlegel ◽  
A. Juergens ◽  
S. Rogowski ◽  
H. Schulz ◽  
H. Reichmann ◽  
...  
2016 ◽  
Vol 47 (2) ◽  
pp. 101-107 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Ken Morii ◽  
Masakazu Sano ◽  
Jumpei Homma ◽  
Naoki Yajima ◽  
...  

Neurosurgery ◽  
2000 ◽  
pp. 51-61 ◽  
Author(s):  
Leslie D. McAllister ◽  
Nancy D. Doolittle ◽  
Paul E. Guastadisegni ◽  
Dale F. Kraemer ◽  
Cynthia A. Lacy ◽  
...  

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 928-928
Author(s):  
Nancy D. Doolittle ◽  
Rochelle Fu ◽  
Prakash Ambady ◽  
Edward A Neuwelt

Abstract Recent reports propose high-dose (HD) methotrexate (MTX)-based cytoreduction followed by consolidation with HD chemotherapy (HDC) with or without autologous stem-cell transplantation (ASCT) as first-line treatment for primary central nervous system lymphoma (PCNSL). The main rationale is that HDC-ASCT may improve disease control by achieving higher therapeutic concentrations of cytotoxic chemotherapy in the CNS, thus circumventing the blood-brain barrier (BBB). We have employed an alternative approach to treat PCNSL patients effectively. This first-line treatment enhances delivery of standard dose (SD) MTX-based chemotherapy administered intra-arterially (i.a.) with osmotic BBB opening plus the anti-CD20 monoclonal antibody (mAb) rituximab, followed in complete responders by anti-CD20 mAb maintenance immunotherapy. The main features that distinguish our approach from HDC-ASCT consolidation are to utilize BBB properties to maximize delivery of SD chemotherapy to the CNS sanctuary, and maintenance immunotherapy to delay recurrence. A multi-center study of 149 PCNSL patients (2,079 i.a. BBB treatments) resulted in one death within 48 hrs after treatment, from pulmonary embolism. Prior to routine use of granulocyte colony stimulating factor, granulocytopenic fever occurred in 3% of BBB treatments (Angelov, J Clin Oncol 2009). This contrasts with HDC-ASCT consolidation which carries substantial morbidity and treatment-related mortality (6% to 9%) (Ferrari, Lancet Hemat 2016; Omuro, Blood 2015). Further, HDC-ASCT is used primarily in younger PCNSL patients (< 60-65 yrs) with good performance status and is not feasible in many PCNSL patients given the median age at diagnosis is 60-65 yrs. First-line enhanced BBB delivery of SD MTX-based chemotherapy in 149 patients provided an overall response rate (ORR) of 82% (58% CR rate) and median overall survival (OS) of 37 mo. In low risk patients (age < 60 yrs and KPS ≥ 70) median OS was approximately 14 yrs. Survivors in CR a minimum of 2 yrs after diagnosis (n = 24) were evaluated with standard neuropsychological tests. Median follow-up was 12 yrs (range 2 to 26 yrs) and results indicated long-term preserved or improved cognitive function (Doolittle, J Clin Oncol 2013). Recently we compared efficacy from two first-line MTX-based regimens: HD MTX (intravenous, 4gr/m2) (Thiel, Lancet Oncol 2010), and enhanced BBB delivery of MTX (i.a., 3.5gr/m2). After adjusting for patient characteristics, CR rate and progression free survival were higher in patients < 65 yrs treated with enhanced delivery of MTX (p < 0.001). When first-line rituximab was added to the i.a. enhanced delivery regimen in 24 patients (median age 64 yrs; median KPS 65), the ORR improved to 92% (75% CR) and OS to 61 mo. To prevent recurrence, Ney (Leuk Lymphoma 2009) treated a small group of patients in CR after standard PCNSL treatment, with maintenance rituximab. The addition of maintenance immunotherapy resulted in average disease control of 22 mo or longer. Consistent with the Ney report, we noted prolonged median CR duration of 38 mo (range: 10 to 85 mo) in a small subset treated with maintenance rituximab (n = 9). Increased survival was also seen in translational laboratory studies of a rodent model of intracerebrally implanted MC116 human B-cell lymphoma cells, using single agent rituximab, whether or not delivered with BBB disruption and whether or not MTX was included (Muldoon, Clin Cancer Res 2011). These results suggest that rituximab slowly leaked into main CNS tumor mass even in absence of BBB opening; and given the long half-life, was trapped by binding to CD20+ on tumor cells, attaining sufficient concentration for antitumor efficacy. Our goal is to maximize first-line enhanced BBB delivery of SD chemotherapy to enable less treatment-related morbidity and mortality than is associated with HDC-ASCT in PCNSL, and increase CR duration. Neurocognitive safety has been demonstrated in long-term survivors treated with BBB delivery. Based on the encouraging results from Ney et al, our pilot data using maintenance rituximab, and translational lab studies of mAb delivery to brain, a new randomized multi-center trial is underway to study the effect of maintenance obinutuzumab on CR duration, neurocognition and quality of life in PCNSL patients who achieve CR following first-line MTX-based chemotherapy (NCT02498951). A trial update will be presented during the ASH 2016 meeting. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1346-1346
Author(s):  
Carolyn J Owen ◽  
Andrew Daly ◽  
Neil Chua ◽  
Douglas A. Stewart

Abstract Abstract 1346 Background: Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin lymphoma. Outcomes for PCNSL are generally reported to be dismal and the standard of care for treatment remains unclear due to a lack of randomized studies. However, recent studies have demonstrated that intensive chemotherapy with autologous stem cell transplantation (ASCT) is effective as salvage therapy and provides encouraging results as a part of primary therapy. In Alberta, PCNSL is treated exclusively in 2 centres. As one centre adopted ASCT for PCNSL later, we were able to compare the outcomes for patients treated with a strategy including ASCT versus a radiotherapy (RT)-based treatment. We performed a retrospective analysis of the outcomes of all patients diagnosed with PCNSL in Alberta from 1998–2008 to determine the ‘real world’ outcomes for this disease. Methodology: Cases of PCNSL were obtained from the Alberta Cancer Board Cancer Registry. Charts were manually reviewed and data extracted on clinical characteristics, treatment, response, toxicities, relapse and survival. Results: Data was obtained for 95 patients (median age 61) with pathology-confirmed PCNSL of diffuse large B cell lymphoma (DLBCL)-type. Two additional cases with non-DLBCL pathology were excluded from analysis (2 cases with epidural follicular lymphoma and 1 case of marginal zone lymphoma). Eight additional patients were diagnosed with PCNSL by radiology, without pathological confirmation. These patients had a median age of 80 and were uniformly palliated without chemotherapy or RT and were excluded from evaluation. Nine (9.5%) patients were HIV+, of whom 4 were treated with radiotherapy (2 with resultant long-term survival) and 5 were palliated. Of the HIV- patients, 15 (17%) were treated with palliation alone. These patients had a median age of 70 and only 1 had an ECOG ≤ 1. Twenty-seven patients (34%) were treated with RT alone at a median of 4500cGy. These patients had a median age of 68 and 67% had an ECOG ≥2 at diagnosis. The mean overall survival (OS) for this group was 12 months, similar to previous reports and their 5 year OS was 15%. Forty-four patients (46%) were treated with curative intent with therapy including at least one cycle of high-dose methotrexate (HDM). These patients had a median age of 56 and 61% had an ECOG ≥2 at diagnosis. The complete remission (CR) rate, including unconfirmed CR (CRu) was 42%, 38% achieved a partial remission (PR) and 16% were refractory to HDM. Six (13%) received ≤ 3 cycles of HDM, with 2 (4%) early toxic deaths, 2 refractory disease and 2 discontinuations for toxicity. Sixteen (36%) were treated with HDM alone with 14 of these patients receiving ≥ 4 cycles of HDM. Eight patients (18%) were treated with a combination of HDM and RT of which 2 were due to early discontinuation of HDM for progressive disease (1) and toxicity (1). No survival difference was observed for patients treated with HDM alone compared to combined HDM and RT. The median OS for the HDM-treated patients not receiving ASCT as a part of initial therapy was 31 months. Patients <70yrs without major organ dysfunction were offered ASCT if they did not achieve a CR with HDM or later relapsed. All but 3 ASCTs were performed following thiotepa, busulfan and cyclophosphamide (TBC) conditioning. Long-term event-free survival post-ASCT was seen in 11 of 18 patients transplanted in first partial remission, 1 of 3 for patients transplanted for primary refractory/progressive disease, and 5 of 6 patients transplanted for relapsed disease. Three patients died early of transplant-related mortality (TRM). The 5 yr OS of all HIV- PCNSL patients, excluding those receiving only palliation was 37% while the 5 yr OS for patients with PCNSL who received an ASCT (at any time) was 66%. Patients ≤ 65, patients who received an ASCT at any time had a significantly improved survival (5 yr OS 70%) compared to those who did not (5 yr OS 20%). (p=0.009) Conclusion: ASCT with TBC conditioning is an effective therapy for PCNSL both as a part of primary therapy and for relapsed disease. However, TBC/ASCT is associated with high TRM so efforts should be made to optimize ASCT conditioning to reduce toxicity and make this effective treatment available to more PCNSL patients. Disclosures: No relevant conflicts of interest to declare.


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