AUTOLOGOUS STEM CELL TRANSPLANTATION with INTRAVENOUS BUSULFAN, CYCLOPHOSPHAMIDE, and ETOPOSIDE as First-LINE TREATMENT of PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA in a SINGLE CENTER.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1219-1219
Author(s):  
Dok Hyun Yoon ◽  
Dae Ro Choi ◽  
Byeong Seok Sohn ◽  
Shin Kim ◽  
Dae Ho Lee ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Induction Chemotherapy ◽  
Conditioning Regimen ◽  
Central Nervous System Lymphoma ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

Abstract Abstract 1219 Poster Board I-241 Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been evaluated in several trials and has shown feasibility as first-line treatment of primary central nervous system lymphoma (PCNSL). However, the best conditioning regimen is still to be identified and high-dose chemotherapy of busulfan, cyclophosphamide, and etoposide (BuCyE) has not been tried although the regimen was shown to be effective for leukemia and systemic non-Hodgkin's lymphoma. Methods Between May 2005 and November 2008, 12 consecutive patients of PCNSL with pathologic diagnosis of diffuse large-B cell lymphoma were treated with the intent of upfront ASCT at Asan Medical Center, Seoul, Korea. We retrospectively analyzed the results of these patients. The treatment included induction chemotherapy of high-dose methotrexate/cytarabine (Abrey et al., JCO 21:4151, 2003), followed by BuCyE chemotherapy consisting of iv busulfan (3.2mg/kg from day -7 to day -5), iv cyclophosphamide (50mg/kg from day -3 to day -2), and etoposide (200mg/m2 every 12 hours from day -5 to day -4), and ASCT. Whole brain radiotherapy (WBRT) was reserved for patients who failed to achieve complete response (CR) after ASCT. Results Median age was 50 years (range, 33-65) and 9 were male. The test of cerebrospinal fluid (CSF) cytology came out to be positive for 3 patients. Eight patients achieved CR and 4 gained partial response (PR) after induction chemotherapy. All 12 patients managed to complete ASCT. Following ASCT, additional 2 patients gained CR, resulting in total number of 10 patients (83.3%). Patients who failed to reach CR were further treated with WBRT and 2 more patients achieved CR. Median duration of first CR was 12.8 months (95% confidence interval [CI], 4.6-20.9) at a median follow-up of 23.8 months (range, 8.8-50.7). Relapse of disease occurred in 7 patients (58.3%) and 5 of them were given salvage treatment (Table 1). Two patients could regain CR and sustained remission for more than 2 years. Two patients had died of disease at the time of analysis. Median event-free survival (EFS) from the first day of induction chemotherapy was 15.0 months (95% CI, 8.3-21.8) and median overall survival (OS) was not reached. The 2-year OS probability was 78.8% and 2-year EFS was 25.7%. No patient experienced veno-occlusive disease or treatment-related mortality (TRM). Three patients among those who were treated with WBRT or intrathecal chemotherapy developed leukoencephalopathy. Conclusion BuCyE chemotherapy might be an option of conditioning regimen for ASCT considering high CR rate of 83.3% and favorable toxicity profile in the treatment of PCNSL. However, high relapse rate of 58.3% suggests that more optimization of induction and conditioning chemotherapy is still required. Disclosures No relevant conflicts of interest to declare.

High Efficiency of ICE (Ifosfamide-Carboplatin-Etoposide) in Relapse/Refractory Primary Central-Nervous System and Intra-Ocular Non Hodgkin Lymphoma, After First Line Treatment Containing High Doses of Methotrexate and Cytarabine. A Monocentric Retrospective Study From 2010 to 2012 On 17 Cases

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3664-3664 ◽  
Author(s):  
Sylvain Choquet ◽  
Damien roos Weil ◽  
Khe Hoang Xuan ◽  
Nathalie Cassoux ◽  
Helene Merle-Beral ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hodgkin Lymphoma ◽  
Salvage Chemotherapy ◽  
High Dose ◽  
Line Treatment ◽  
First Line ◽  
Non Hodgkin Lymphoma ◽  
High Doses ◽  
First Line Treatment

Abstract Abstract 3664 Background: Primary central nervous system lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL) are at very high risk of relapse after a first line treatment, and then carry a very poor prognosis. Autologous stem cell transplantation (ASCT) can offer prolonged responses but its results clearly depend on efficiency of salvage chemotherapy (Soussain, haemtologica, 2012). Since recent publications on first line treatment of PCNSL and PIOL recommend high dose methotrexate (Mtx) and cytarabine (AraC) (Ferreri, Lancet 2009), salvage chemotherapy must use other drugs with high level of penetration in the central nervous system (CNS). In this setting, ICE regimen, validated in systemic non Hodgkin lymphoma, seems to be appropriated but no data is published in PCNSL and PIOL. Methods: From june 2010 to may 2012, all relapse/refractory PCNSL and PIOL treated in first line by high doses of Mtx and AraC in the Pitie-Salpetriere Hospital, Paris, France, where treated by ICE regimen : ifosfamide (5g/m2 at day 2), carboplatine (AUC 5 at day 2) and etoposide (100mg/m2/d days 1 to 3). Doses where adapted on patient general status and ASCT proposed when possible. Results: Seventeen patients have been treated, 7 females and 10 males, median age 62 [28–84]. Four where refractory and 13 in relapse, with a mean progression free survival (PFS) of 368 days [85–1763], 4 had a second line, one a third before ICE. At moment of ICE treatment, localizations where 10 CNS, 2 CNS + PIOL, 3 PIOL and 2 meningitis. The mean number of cycles was 4 [1–6] and 4 patients needed a dose reduction. During treatment, grade 3/4 WHO toxicities where: 6 neutropenic fever (one death), 5 anemia, 9 neutropenia, 10 thrombopenia and one CNS complication (coma and hypersalivation). ASCT have been made in 6 patients (5 in CR, 1 in PR) and are pending in 3. Complete response (CR) have been obtained in 13 patients (76%), partial in 2. With a mean follow-up of 405 days, 6/15 patients in response relapsed (only one after ASCT), in a median of 81 days, 9 patients died (7 by progression, one during treatment and one in CR). Median Overall survival (OS) was 220 days for all patients but was not reached in case of ASCT. Conclusion: ICE regimen is very effective in relapse/refractory PCNSL and PIOL heavily treated by high dose Mtx and AraC. This efficacy can allow to perform ASCT in eligible patients, chemosensitivity being the most important factor influencing the OS and PFS after ASCT. ICE can represent a new standard in this setting. Disclosures: Leblond: Roche: Advisory Board Other, Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen-Cilag: Honoraria.

scholarly journals Primary Central Nervous System Lymphoma and the Blood-Brain Barrier

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 928-928
Author(s):  
Nancy D. Doolittle ◽  
Rochelle Fu ◽  
Prakash Ambady ◽  
Edward A Neuwelt
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Disease Control ◽  
Central Nervous System Lymphoma ◽  
Line Treatment ◽  
First Line ◽  
Anti Cd20 ◽  
Bbb Opening ◽  
First Line Treatment

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.

Bam Regimen Followed By High-Dose Therapy and Autologous Stem Cell Transplantation As First-Line Treatment Of Primary Central Nervous System Lymphoma: A Multicenter Study From Spanish Group GEL-TAMO

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4349-4349
Author(s):  
M López-Parra ◽  
A Martín ◽  
C Grande ◽  
S Bobillo ◽  
S M Rojas ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Preliminary Analysis ◽  
Central Nervous System Lymphoma ◽  
High Dose ◽  
Line Treatment ◽  
First Line ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Induction Regimen ◽  
First Line Treatment

Abstract Introduction Primary central nervous system lymphoma (PCNSL) is a rare malignancy with peculiar clinical and biologic features, aggressive course, and unsatisfactory outcome. To date, there is no standardized treatment of PCNSL. Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation, such as autologous stem-cell transplantation (ASCT). In the present study, we have evaluated the toxicity and efficacy of high-dose consolidation with ASCT after chemotherapy induction in patients with newly diagnosed PCNSL. Patients and Methods In 2008, the Spanish group GELTAMO developed a clinical protocol for first-line treatment of patients with PCNSL, consisting of an induction chemotherapy with 2 cycles of BAM (BCNU 100 mg/m2 day 1, Ara-C 3000 mg/m2 days 9, 25 and 41, and methotrexate 2000 mg/m2 days 8, 24 y 40). Patients who achieved at least partial response (PR) received an intensification with high-dose chemotherapy (BCNU 400 mg/m2 day -6, and thiotepa 5 mg/Kg days -5 and -4) followed by ASCT (day 0), whereas BAM refractory patients received WBRT (45 Gy), salvage therapy or palliative treatment. To date, 70 patients have been included in the protocol. We present the preliminary analysis of 57 patients (median age 55 years, range 29-74) treated between July 2008 and November 2012. Results BAM induction regimen was well tolerated, being the most common grade 3-4 toxicities: hematological (leucopenia in 32% of patients, thrombocytopenia in 15%), infectious (17%) and hepatic (5%). 33 out of 57 patients (58%) completed the 2 planned BAM cycles, achieving complete remission 19 patients (33,3%) and 8 (14%) PR. Reasons for not completing the 2 planned BAM courses were: lymphoma progression (n=21), and toxicity (n=3). 18 patients received WBRT, resulting in 5 and 9 patients achieving CR and PR, respectively. Regarding WBRT toxicity, 1 patient showed mild cognitive impairment, 3 leukoencephalopathy (2 mild, 1 severe), and 2 hydrocephalus. Finally, 24 patients (42%) underwent high-dose therapy and ASCT (18 after BAM and 6 after RT). Reasons for not performing the transplant were: progression of lymphoma (N=18), early death (N=2), comorbidities (N=3) or physician decision (N=10). After a median follow up of 22 months (4-49), 30 patients are alive (77% in CR), 26 patients have died (88% due to lymphoma progression, 8% due to infectious complications, and 4% due to other causes) and one patient have developed a secondary myelodysplastic syndrome (RAEB-2). Estimated 3-year progression-free survival and overall survival were 35% and 49%, respectively, for the whole series, and 65% and 85%, respectively, for transplanted patients. Conclusions This preliminary analysis shows that BAM induction regimen followed by high-dose therapy and ASCT shows an adequate toxicity profile and leads to prolonged remissions in approximately a third of patients with PCNSL. More than 50% of patients do not reach the transplant, mainly due to disease progression, but results after ASCT seem to be good. New induction regimens are needed in order to decrease the rate of early progression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Is It Time to Remove Radiotherapy in the Management of Primary Central Nervous System Lymphoma? Population-based Study, Pool-Analysis and Retrospective Study of Recurrence Pattern.

2021 ◽  
Author(s):  
Rongping Liu ◽  
Shasha Du ◽  
Yue Qin ◽  
Wan Zhang ◽  
Xuanzi Li ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Central Nervous System Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Pool Analysis ◽  
Subtotal Resection ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

Abstract BackgroundBefore the introduction of the chemotherapeutic agent methotrexate, radiotherapy (RT) and steroids have been the sole, first-line treatment of primary central nervous system lymphoma (PCNSL). With the application of methotrexate, the role of RT in the treatment of PCNSL has been challenged. MethodsWe performed observation analysis on 2,486 PCNSL patients between 1988 and 2016 from the Surveillance, Epidemiology and End Results (SEER) database. Propensity score matching (PSM) was employed to ensure well-balanced characteristics of two groups of patients who received RT and those who did not receive it. Two randomized controlled trials (RCTs) were pooled to further evaluate the role of consolidation whole-brain radiotherapy (WBRT) in PCNSL. To clarify whether WBRT is necessary for PCNSL, 27 relapsed patients who attained complete response (CR), partial response (PR) or stable disease (SD) during or after first-line treatment without WBRT for newly diagnosed PCNSL in our institution was retrospectively analyzed; the pattern and location of relapse was identified. ResultsAfter matching, there was no statistical difference on survival between the two groups. In patients did not received chemotherapy, RT significantly improved the survival of patients who undergone biopsy (All P < .0001) or subtotal resection (All P < .0001). In particular, RT helped improve survival for patients with other infectious and parasitic diseases including HIV (OIPDH). Pool-analysis shown the better progression free survival (PFS) of patients with WBRT arm compared with no WBRT arm in per-protocol (PP) population (HR 0.71, 95% CI 0.52 to 0.98). In the 27 relapse patients, 17 (63%) had new measurable enhancing lesions at relapse at a spatially distinct site, the remote recurrence after CR was 9/11 (82%), and after PR was 8/15 (53%). Single lesion occurred remote recurrence was 11/13 (85%), while multiple lesions were 7/14 (50%). We also established a novel prediction model with excellent performance to estimate the potential benefit from RT with respect to the end point of overall survival. ConclusionsRT is still an important method in the treatment of PCNSL, which cannot be removed. More precise studies should be carried out to perfect the treatment strategies of the disease.

scholarly journals Primary Central Nervous System Lymphoma in Elderly Patients: Management and Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3479
Author(s):  
Andrea Morales-Martinez ◽  
Fernando Lozano-Sanchez ◽  
Alberto Duran-Peña ◽  
Khe Hoang-Xuan ◽  
Caroline Houillier
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Elderly Patients ◽  
Treatment Strategies ◽  
Central Nervous System Lymphoma ◽  
High Dose Chemotherapy ◽  
Current Treatment ◽  
Cns Lymphoma ◽  
High Dose ◽  
Consolidation Phase

The management of elderly patients suffering from primary central nervous system (CNS) lymphoma, who represent a rapidly growing population, is challenging. Despite the advances made in PCNSL treatment, the prognosis in older patients remains unsatisfactory. The high risk of systemic and CNS toxicity induced by a high-dose chemotherapy regimen and radiation therapy, respectively, limits the use of consolidation phase treatments in elderly patients and contributes to the poor outcome of these patients. Here, we review the current treatment strategies and ongoing trials proposed for elderly PCNSL patients.

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