Therapy For Primary CNS Lymphoma Research Articles

QLTI-03. REAL-WORLD PARADIGM FOR TREATMENT OF PRIMARY CNS LYMPHOMA PATIENTS IN CLINICAL PRACTICE

Abstract Although high-dose methotrexate (HD-MTX) is the foundation of induction therapy for primary CNS lymphoma (PCNSL), a gold-standard regimen has yet to be established. A 10-case-based survey, to assess the practice patterns at key decision-points in adult PCNSL management outside of clinical trials, was distributed through IPCG, HOVON, and AAN Neuro-Oncology Section. Eighty-five responses were collected from North American (N=42), European (N=33), Asian (N=7), and other countries (N=3) from neurologist neurooncologists (N=35), hem-onc neurooncologists (N=24), hematologist-oncologists (N=18), neurosurgeons (N=5), radiation-oncologist (N=2), and hematopathologist (N=1). The most common first-line induction regimen was R-MP+/-V: rituximab, HD-MTX, procarbazine, +/-vincristine (N=28) followed by MATRix: HD-MTX, cytarabine, thiotepa, rituximab (N=23), then R-MT: rituximab, HD-MTX, temozolomide (N=19). For elderly patients, R-MP+/-V remained most common (N=32). The majority preferred to omit intra-CSF chemotherapy (N=50). The most preferred consolidation after complete response was high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT, N=57), or high-dose cytarabine (N=17) in elderly patients. In cases of partial response, the most common approach was still HDC-ASCT (N=24). For stable disease, participants would move to various salvage chemotherapy (N=33), continue additional induction (N=39), or to move to radiotherapy (N=10). If early progression was noted, the most preferred approach was non-methotrexate chemotherapy (N=31). For recurrences after previous complete response and HDC-ASCT consolidation, the majority preferred to try chemotherapy before moving to radiotherapy in scenarios < 1 year (N=64) or > 1 year from consolidation (N=68), and even if the performance status was poor (N=57). Close to half (N=34) participants felt there is a role for stereotactic radiosurgery in various clinical settings. This survey noted clear consensus to use multi-drug MD-MTX based chemotherapy, and common induction regimens, however, highlighted a great variety of treatment preferences after first-line therapy even amongst disease experts through clinical consortiums, suggesting likely wider range of treatments and disease response in larger community settings.

Real-World Experience with RTOG 0227 Induction for First Line Therapy of Primary CNS Lymphoma (PCNSL)

Introduction PCNSL is an aggressive and rare subtype of extranodal non-Hodgkin Lymphoma affecting the brain, spinal cord, cerebrospinal fluid (CSF), leptomeninges and/or vitreoretinal components. While there have been trials comparing outcomes of consolidation treatment with whole brain radiation therapy (WBRT) versus (vs) autologous hematopoietic cell transplantation (auto-HCT) following different induction regimens in PCNSL, the optimal induction regimen to pair with these forms of consolidation remains controversial. Our group adopted a modified version of the RTOG 0227 induction as our standard PCNSL induction in 2017. This regimen includes 5 cycles of Methotrexate (MTX) at 3.5 g/m 2 and Rituximab (R) at 375-500 mg/m 2, and Temozolomide (TMZ) on cycles 2 and 4. Based on the published phase 2 trial of 53 patients (pts), the regimen is significantly less toxic than more aggressive induction regimens such as MATRiX, especially in older pts or those with comorbidities. We evaluated our real-world outcomes in PCNSL pts treated with RTOG 0227 induction followed by consolidation with either WBRT/TMZ or auto-HCT, at a single academic university hospital. Methods We identified newly diagnosed PCNSL pts treated at a single academic university hospital between 2017 and 2023. Electronic medical records were retrospectively reviewed to collect data including demographics, clinicopathological features, treatment details, response rates, long-term follow up, disease recurrence, and survival. The IELSG prognostic index tool was used for risk assessment. All pts received induction regimen consisting of R (dose between 375- 500 mg/m 2) and 3.5 g/m 2 of MTX with leucovorin on weeks 1, 3, 5, 7 and 9 along with TMZ daily for 5 days on weeks 4 and 8, followed by consolidation with either WBRT/TMZ or auto-HCT. In WBRT cohort, maintenance TMZ was given at 200mg/m 2 daily for 5 days every 28 days, for total of 10 cycles, and dose was reduced if side effects developed. Objective response rate (ORR) and complete response rate (CRR) after induction chemotherapy were calculated. Overall survival (OS) and progression free survival (PFS) at 2 years were estimated with the Kaplan-Meir method (using GraphPad Prism 9.3.1) and compared between the WBRT and auto-HCT cohorts, using the log-rank test. Results A total of 29 PCNSL pts were included in the study. Patient and disease characteristics for the entire cohort, as well as pts treated with WBRT vs auto-HCT consolidation, are shown on the Table. On average (avg), pts received 4 cycles of MTX and 8 cycles of TMZ. Nine (31%) pts developed acute kidney injury and 1 (3.4%) developed transaminitis from MTX. The avg total cumulative TMZ dose was 5913 mg/m 2 and 8 (27.5%) pts required TMZ dose reduction. Treatment related mortality (TRM) following induction was 0%. Eight (27.5%) pts had complete response, 19 (65.5%) had partial response, 1 (3.5%) had stable disease and 1 (3.5%) had disease progression. ORR was 93.1% and CRR was 27.5%. Eighteen (62%) pts received WBRT/TMZ consolidation, while 11 (38%) received auto-HCT consolidation. Median dose of WBRT administered was 36 Gy (23.4 to 36 Gy). Thirteen (72.2%) pts received 36 Gy in 30 fractions (fx) of 1.2 Gy BID, 4 (22.2%) pts received 23.4 Gy in 13 fx of 1.8 Gy OD, and 1 (5.5%) pt received 30.6 Gy in 17 fx of 1.8 Gy OD. Most common conditioning regimen prior to auto-HCT was carmustine/thiotepa (BCNU/TT). With a median follow up of 36 months, 4 (22.2%) pts in WBRT cohort and 1 (9.1%) in auto-HCT cohort had disease recurrence. Two-year PFS was 83% overall, 81% for the WBRT pts and 87% for the auto-HCT pts, with a p value of 0.65 for log-rank comparison of PFS for the WBRT vs auto-HCT pts. Two-year OS was 96% for the entire cohort, 94% for the WBRT pts and 100% for the auto-HCT pts, with a p value of 0.27 for log-rank comparison of OS for the WBRT vs auto-HCT pts. Conclusion In this real-world cohort of PCNSL pts not treated as part of a clinical trial, we observed excellent outcomes using the modified RTOG 0227 induction regimen. PFS and OS at 2 yrs in our cohort exceeds those reported with any prospective clinical trial to date, and with zero TRM to date. This data indicates that the modified RTOG 0227 induction with either WBRT or auto-HCT consolidation represents a very tolerable and highly effective option for first line therapy of PCNSL, for both younger and older pts.

Carmustine in the Therapy of B-Cell Lymphomas

Aim. To analyze the efficacy and toxicity of different highdose chemotherapy protocols for the purpose of determining the optimal conditioning regimen with autologous hematopoietic stem cell transplantation (auto-HSCT). Materials & Methods. The present review provides the analysis of some comparative retrospective studies. The evidence-based analysis proceeded in two stages consisting of a search and then primary processing of available literature. The PubMed database was searched for publications for the period 2004-2020. Results. In relapsed and refractory non-Hodgkin’s lymphomas as well as in Hodgkin’s lymphoma, the literature analysis demonstrated satisfactory efficacy of carmustine as part of BEAM conditioning. With the use of the BEAM conditioning regimen with subsequent auto-HSCT, up to 50 % of complete remissions were achieved in patients with non-Hodgkin’s lymphomas and up to 70 % in patients with Hodgkin’s lymphoma. Comparative studies show that despite concerns about severe toxicity, the use of carmustine was not associated with an increase in the incidence of adverse events. Lung and liver toxicity proved to be comparable with that of being observed while using alternative programs of highdose chemotherapy and corresponded to 9 % and 6 % on LEAM and BEAM regimens, respectively. Besides, carmustine feasibility in primary diffuse large B-cell CNS lymphoma was considered and analyzed in the context of the lack of thiotepa. Conclusion. High efficacy of carmustine as part of BEAM conditioning with subsequent auto-HSCT was proved in extremely unfavorable patients with relapsed and refractory non-Hodgkin’s lymphomas and Hodgkin’s lymphoma with an acceptable toxicity profile. The study of carmustine in the therapy of primary CNS lymphoma seems to be аn important area of clinical studies aimed at developing rational treatment options.

High-dose therapy for primary CNS lymphoma

High-dose therapy for primary CNS lymphoma

Defining optimal initial therapy for primary CNS lymphoma

Defining optimal initial therapy for primary CNS lymphoma

Combination of Rituximab with Chemotherapy Improved Outcome of Newly Diagnosed Primary CNS Lymphoma: A Retrospective Study of 209 Unselected Patients Referred to a Single Institution

Introduction: Treatment of first-line therapy of primary CNS lymphoma (PCNSL) is based on high-dose methotrexate and cytarabine combination chemotherapy. Consolidation radiotherapy is mainly withdrawal for patients older than 60 years old regarding the excessive rate of neurological toxicity. Rituximab improved outcome of systemic diffuse large B-cell lymphoma but no data from randomized phase III trial is available to prove such outcome improvement for PCNSL. We introduced in daily practice intravenous rituximab in combination with chemotherapy for B-cell PCNSL in first-line therapy in 2004. The goal of this study is to determine whether such therapeutic modification improves PCNSL patient's outcome.Methods: Patients were from consecutive PCNSL cases (N=209) included in Leon Berard Cancer Centre registry (Lyon, France), from 1987 to 2011 (date of diagnosis). Median age of patients was 63 years (range, 26-87), 56% were male, 51% had a performance status (PS) >1, 63% had an involvement of deep structures of brain, 66% a high CSF protein level, 12% a meningeal involvement and 42% a high LDH level. Of the 171 available patients, 16% had 0-1, 60% had 2-3, and 24% had 4-5 adverse IELSG prognostic scores, respectively. Patients were all treated by chemotherapy, 92% and 63% of them by high-dose methotrexate and cytarabine containing chemotherapy, respectively followed by brain radiotherapy for 108 patients (58%). Intravenous rituximab was used in combination with chemotherapy in 61 patients (29%) between 2004 and 2011.Results: No difference in term of clinical characteristics (median age, PS, tumor site, CSF protein level, meningeal involvement, LDH level) was observed between patients treated with or without rituximab in combination with chemotherapy. With the median of 86.3 months (18.2-259), the median progression free survival (PFS) and overall survival (OS) for whole series were 17.3 months (95%CI, 10.7-25.9) and 35.6 months (95%CI, 22.7-50.0), respectively. The 3-year PFS were 55.5% (95%CI, 43-67) and 31.1% (95%CI, 24-39) for patients treated or not with rituximab, respectively (P=0.001). The 3-year OS were 73.6% (95%CI, 61-83) and 39.9% (95%CI, 32-48) for patients treated or not with rituximab, respectively (P<0.0001). A multivariate analysis was performed to test the impact of the addition of rituximab over clinical prognostic factors (age, PS, tumor site, CSF protein level, meningeal involvement, LDH level, IELSG score). Age>60 years (HR=1.74; 95%CI, 1.22-2.46; P=0.002), meningeal involvement (HR=2.33; 95%CI 1.42-3.85; P=0.0009) and used of rituximab (HR=0.50; 95%CI, 0.32-0.78; P=0.002) were identified as independent predictors of PFS. OS was significantly influenced by age>60 years (HR=1.94; 95%CI, 1.36-2.77; P=0.0002), PS (HR=1.76; 95%CI, 1.26-2.46; P=0.001), meningeal involvement (HR=2.17; 95%CI, 1.30-3.61; P=0.003) and used of rituximab (HR=0.39; 95%CI, 0.24-0.62; P=0.0001) in multivariate analysis. In a prognostic model integrating the IELSG score (0-1 vs. 2-3 vs. 4-5) (P=0.0002 for PFS and P<0.0001 for OS), used of rituximab was independently associated with the improvement of PFS (HR=0.60; 95%CI, 0.39-0.91; P=0.02) and OS (HR=0.44; 95%CI, 0.26-0.72; P=0.001). Disease free survival including patients who reached a complete response at the end of the first-line treatment was also improved by the used of rituximab (not reached versus 3.2 years, P=0.04). We also observed in this daily practice study, a reduction of the used of radiotherapy as first-line consolidation treatment (69% vs. 34%, P<0.001) before (1987-2003) and after (2004-2011) rituximab period.Conclusion: In this retrospective analysis, we showed that PCNSL patients treated with intravenous rituximab in combination with first-line chemotherapy had a better outcome. The frequency of consolidation radiotherapy was reduced for these patients treated at rituximab era. In multivariate analysis, CSF involvement was an independent adverse prognostic factor that inclines to improve meningeal explorations and propose new therapeutic options for CSF positive PCNSL patients. DisclosuresNo relevant conflicts of interest to declare.

Updated Results Confirm Favorable Outcome of Immunocompetent Patients with Primary CNS Lymphoma Treated By C5R Protocol in Combination with Intravenous Rituximab and Intrathecal Liposomal Cytarabine: A Multicentric Prospective Phase 2 Study of the Lymphoma Study Association (LYSA)

Background: The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favorable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years. In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and intrathecal (IT) liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL in the R-C5R protocol. We previously presented the results of the primary objective of the R-C5R protocol, showing an improvement of the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT from 33% in the LNHCP93 to 66% in the R-C5R protocol. We also showed no additional severe toxicities as compare to C5R with the addition of intravenous rituximab and IT liposomal cytarabine. We present here the updated results of the 53 patients included in this multicentric prospective phase 2 study from the lymphoma study association (LYSA) with a median follow-up 28 months (range, 1.08-75.04).Methods: This prospective study was designed for 18 to 60 years old immunocompetent patients with confirmed CD20 positive diffuse large B-cell lymphoma PCNSL. Fifty-three patients included between August 2007 and September 2011 received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2 and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients and then patients were followed every 4 months during the first 2 years and then every 6 months for the next 3 years. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test.Results: The median age of the 53 PCNSL patients was 55 years (range, 36-60), 57% were male, 42% had a performance status (PS)>1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Clinical characteristics according to the MSKCC score was as follows: 16 patients (32%) ≤50 years (class 1); 23 patients (46%) >50 years and KPS≥70 (class 2); 11 patients (22%) >50 years and KPS<70 (class 3). Of the 39 available patients, 38% had 0-1, 38% had 2, 21% had 3 and 3% had 4 adverse IELSG prognostic scores, respectively. Median MMSE score assessed for 42 patients at baseline was 26 (range, 3-30). Forty-five patients (85%) completed the fourth cycles of immune-CT and three patients (5.7%) died of acute toxicity. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 28 months, 20 patients progressed or relapsed (37.7%). The 3-year progression free survival (PFS) rate of whole cohort was 58% (95%CI, 42.5% to 71%). The 3-year PFS rates were 64.2%, 63.5% and 53% for patients with MSKCC class 1, 2 and 3, respectively (P=0.53); the 3-year PFS rates were 86% and 39% for patients with 0-1 and 2-4 adverse IELSG prognostic scores, respectively (P=0.02). The 3-year PFS rates were 66% and 80% for patients who received a reduced whole brain RT with a boost and patients treated with whole brain RT (P=0.25), respectively. At relapse or progression, 18 patients received a salvage treatment that allowed five CR/CRu. Five patients received a high-dose CT with autologous stem cell transplantation at relapse. The 3-year overall survival (OS) rate for whole cohort was 67% (95%CI, 48.3% to 80.1%). The median MMSE score was 29 (range, 23-30) for the 11 patients evaluated between 18 and 24 months after the beginning of treatment.Conclusions: With the addition of intravenous rituximab and IT liposomal cytarabine, R-C5R protocol provided promising outcome results with a 3-year PFS and OS of 58% and 67%, respectively. These results compared favorably with historical controls included in the LNHCP93 who presented a 3-year PFS and OS of 44% and 58%, respectively. IELSG score remained a strong prognostic factor for the patients treated with this schedule and could be helpful to stratify consolidation treatment after response to primary immunochemotherapy in particular patients with 2-4 IELSG score. DisclosuresGhesquieres:Mundipharma: Honoraria. Off Label Use: Liposomal cytarabine formulation had demonstrated better efficacy compared to standard cytarabine for the treatment of lymphomatous meningitis and is off label use in first line therapy of primary CNS lymphoma. Morschhauser:Mundipharma: Honoraria.

G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up.

8527 Background: The role of whole brain radiotherapy (WBRT) in first-line therapy of primary CNS lymphoma (PCNSL) has been increasingly questioned. This is the final report of the G-PCNSL-SG-1 tri...

Flying Solo: Chemotherapy Without Radiation for Primary CNS Lymphoma

Flying Solo: Chemotherapy Without Radiation for Primary CNS Lymphoma

A Multicentric Prospective Phase 2 Study of Intravenous Rituximab and Intrathecal Liposomal Cytarabine in Combination with C5R Protocol Followed by Brain Radiotherapy for Immunocompetent Patients with Primary CNS Lymphoma: A Lymphoma Study Association (LYSA) Trial

AbstractAbstract ▪796▪This icon denotes a clinically relevant abstract Background:The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favourable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years: the complete response (CR) rate was 33%, the 5-year progression-free survival (PFS) and overall survival (OS) rates were 31% and 42%, respectively with however 9% of toxic death. Rituximab improves outcome of systemic Diffuse Large B-Cell Lymphoma (DLBCL) but it is unclear if its addition is useful in PCNSL with DLBCL histology. Intrathecal (IT) liposomal cytarabine (Depocyt) which shows a long-CSF half-life and better efficacy compared to IT methotrexate and free cytarabine in lymphomatous meningitis is also an attractive treatment for PCNSL. Methods:In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and IT liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL. The primary objective of this study is the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT, according to International Primary CNS Lymphoma Collaborative Group response criteria. The number of patients was calculated in order to improve the 30% CR/CRu rate of LNHCP93 study up to 50%. The secondary objectives were side effect profile including acute and late neurological toxicities, PFS and OS. Patients received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients. A new response assessment was performed after RT. Patients were followed every 4 months for the first two years and then every 6 months. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test. Results:Fifty-three PCNSL patients with a confirmed diagnosis of CD20 positive DLBCL were included between August 2007 and September 2011: median age was 55 years (range, 36–60), 57% were male, 42% had a performance status >1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Median MMSE score assessed for 42 patients at baseline was 26 (range 3–30). After immuno-CT, 22 patients achieved a CR and 13 a CRu (CR + CRu, 66%), 7 a partial response (13%), 6 had a stable or progressive disease (11%) and 5 (10%) were not evaluated due to early death (n=2) or toxicities (n=3). For 45 patients who completed the fourth cycles, CR/CRu rate was 75.6%. Thirty-one patients (58%) presented at least one serious adverse event, mainly infections (25 patients, 47%). At least one red blood cell and platelet transfusions were given in 94% and 68% of patients, respectively and 57% of patients experienced a febrile neutropenia. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 22 months, 15 patients progressed or relapsed (28.3%) and 13 patients died (24.5%), 3 (5.7%) of them from acute toxicity. The 2-year PFS and OS rates are 67% (95%CI, 50.0% to 79.4%) and 82% (95%CI, 67.0% to 90.7%), respectively. Median MMSE score was 27 (range, 26–30) for the 7 patients evaluated between 12 and 18 months after the beginning of treatment. Conclusions:With the addition of intravenous rituximab and intrathecal liposomal cytarabine, C5R protocol provided higher CR/CRu rate and promising outcome results with a 2-year PFS of 67% as compared to historical controls. No additional severe toxicities were observed compared to C5R protocol and with short follow-up no neurocognitive decline was observed. Disclosures:Off Label Use: Depocyt (intrathecal liposomal cytarabine) is off-label used in first line therapy of Primary CNS Lymphoma but approval for treatment of lymphomatous meningitis. Morschhauser:Roche: Honoraria. Blay:Roche: Honoraria, Research Funding.

Neues in der Neuroonkologie

Die Standardtherapie des Glioblastoms für erwachsene Patienten ist operative Resektion, Bestrahlung und Temozolomid-Chemotherapie. Therapiestudien mit dem Ziel, dies zu verbessern, werden mit Substanzen durchgeführt, welche Neoangiogenese hemmen, und / oder intrazelluläre Signalübertragung als „small molecules” blockieren, oder auf anderem Wege in Prozesse eingreifen, die Zellproliferation, Migration und / oder Apoptose steuern. Zum Glioblastom des älteren Menschen wurden 2010 aus 2 großen europäischen Studien widersprüchliche Befunde zum Vergleich der Wirksamkeit einer postoperativen alleinigen Bestrahlung mit einer postoperativen alleinigen Chemotherapie vorgelegt, wobei die Unterschiede zwischen den Modalitäten jedoch marginal sind. Beim Rezidiv eines malignen Glioms kommen Re-Operation, Re-Bestrahlung und medikamentöse Therapien zum Einsatz. Zur Therapie des primären ZNS-Lymphoms ist bislang kein „Standard” definiert. Eine Chemotherapie unter Einschluss von Methotrexat (MTX) ist die Basis jeder erfolgreichen Primärtherapie; die Indikation für eine zusätzliche „konsolidierende” Strahlentherapie muss nach den Ergebnissen der größten Therapiestudie bei Primären ZNS-Lymphomen (G-PCNSL-SG1-Studie) bezweifelt werden. Danach besteht im randomisierten Vergleich einer kombinierten Methotrexat(MTX)-basierten Chemo- / Strahlentherapie mit einer alleinigen MTX-basierten Chemotherapie in der Primärbehandlung (und Bestrahlung erst im Rezidiv) kein Überlebensvorteil für eine der beiden Gruppen. Ermutigende Langzeittherapieergebnisse für Patienten bis zum 65. Lebensjahr konnten in einer einarmigen Phase-II-Studie mit einer kombinierten systemischen und intraventrikulären Chemotherapie ohne Bestrahlung erzielt werden: Bei guter Lebensqualität waren etwa die Hälfte der Patienten nach mehr als 8 Jahren noch am Leben.

Calculated versus measured creatinine clearance for dosing methotrexate in the treatment of primary central nervous system lymphoma

High-dose methotrexate (HDMTX) (>or=3 g/m2), the cornerstone of therapy for primary CNS lymphoma (PCNSL), is commonly dosed using a measured 24 h creatinine clearance (CrCl) every 2-4 weeks. Because these collections are cumbersome and at times unreliable, the use of a calculated CrCl was evaluated as a potential alternative. A retrospective analysis was performed on data from all 287 treatment cycles from the 25 patients with PCNSL who participated in a multi-center phase II clinical trial of HDMTX conducted by the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. The 25 patients had a median age of 61 years (range 32-75). Seventeen (68%) were men. The patients received a median of 14 (range 2-21) HDMTX treatments. For 256 of 287 treatments (89%), data were available to compare the measured and calculated (using the Cockcroft-Gault equation) CrCl. The average measured CrCl was 93 ml/min (95% CI, 89-96 ml/min), and the average calculated CrCl was 107 ml/min (95% CI, 102-112 ml/min). The Pearson correlation coefficient (r) was 0.49 (P<0.0001) between the measured and calculated CrCl. The average MTX dose determined using measured CrCl was 14.1 g (95% CI, 13.6-14.5 g), and the average MTX dose determined using calculated CrCl was 14.7 g (95% CI, 14.2-15.1 g). MTX doses based on measured and calculated CrCl were significantly correlated (r=0.72, P<0.0001). Of the 256 HDMTX treatments evaluated, 158 (62%) had reliable 48 h serum MTX levels documented. Forty-seven levels (30%) were within target range (0.3-1 micromol/l), 99 levels (62%) were below target range (<0.3 micromol/l), 12 levels (8%) were in the range associated with mild toxicity range (>1-3 micromol/l), and no levels were in the range associated with severe toxicity (>3 micromol/l). Of these 158 treatments, the use of a calculated rather than measured CrCl would have yielded an identical MTX dose for 48 treatments (30%), a higher MTX dose for 62 treatments (40%), and a lower MTX dose for 48 treatments (30%). This distribution was not significantly different among the subsets of below target, within target range, and above target MTX levels (P=0.87). In this cohort of patients with PCNSL, there is significant correlation between the calculated and measured CrCl. MTX doses determined using calculated and measured CrCl are not significantly different. For these patients, there is no clear association between the method of determining CrCl and serum MTX levels. As a result, calculated CrCl is a reasonable alternative to measured CrCl in this patient population and would avoid the inconvenience and potential inaccuracies associated with measured CrCl.

High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group

The optimum treatment of primary CNS lymphoma (PCNSL) is not yet determined. The objective of this study was to assess the safety and efficacy of initial methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) in patients with newly diagnosed PCNSL. Twenty-five patients received two courses of initial chemotherapy combining methotrexate, etoposide, carmustine and methylprednisolone, and one course of ifosfamide-cytarabine followed by peripheral stem cell collection. Seventeen responsive patients then received HDT using carmustine, etoposide, cytarabine and melphalan with autologous stem cell rescue. After ASCT for responding patients or after salvage therapy for non-responders, whole brain radiation therapy at a dose of 30 Gy was delivered. The objective response rate to the induction chemotherapy was 84%. Four of the 21 responding patients did not have ASCT because of toxicity or refusal. With a median follow-up time of 34 months, the projected event free survival rate is 46% at 4 years. Projected overall survival is 64% at 4 years. Sixteen patients are actually in continuous complete response. No evidence of late treatment-related toxicity was observed. This treatment approach appears feasible in newly diagnosed PCNSL with encouraging results.

Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide

The authors evaluated the efficacy of a combination of rituximab and temozolomide for recurrent or refractory primary CNS lymphoma (PCNSL). Fifteen patients with a median age of 69 years had a 53% objective response rate with acceptable toxicity. Median overall survival is 14 months and median progression free survival of responding patients is 7.7 months. This combination merits further study and provides a reasonable therapeutic alternative for older patients with progressive PCNSL.

Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide.

The authors evaluated the efficacy of a combination of rituximab and temozolomide for recurrent or refractory primary CNS lymphoma (PCNSL). Fifteen patients with a median age of 69 years had a 53% objective response rate with acceptable toxicity. Median overall survival is 14 months and median progression free survival of responding patients is 7.7 months. This combination merits further study and provides a reasonable therapeutic alternative for older patients with progressive PCNSL.

Glucocorticoid treatment of primary CNS lymphoma.

Glucocorticoid therapy may result in the rapid resolution of cerebral mass lesions in patients with primary CNS lymphoma. Since glucocorticoids will obscure the histological diagnosis of primary CNS lymphoma upon biopsy, steroids should be withheld if primary CNS lymphoma is a likely diagnosis by neuroradiological criteria. The lympholytic effect of glucocorticoids is mediated by cytoplasmic steroid receptors which are translocated to the nucleus and signal apoptosis. Glucocorticoid-induced apoptosis of lymphoid cells does not require wild-type p53 activity, seems not to depend on caspase activation, but is attenuated by the bcl-2 protooncogene product. Longterm glucocorticoid therapy of primary CNS lymphoma is not recommended because relapse is probably inevitable and because of the prominent side effects of long-term glucocorticoid treatment. Further, long-term glucocorticoid treatment is contraindicated in immunocompromised patients with primary CNS lymphoma.

Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy

Disease-free survival in primary CNS lymphoma has improved with the advent of methotrexate-based pre-irradiation chemotherapy. Prolonged response durations have been noted in six of eight patients refusing radiation therapy in two of our prior series. We have treated an additional 11 patients with methotrexate-based chemotherapy without subsequent planned irradiation. Some received maintenance chemotherapy. Most have had durable responses with little or no toxicity. Prolonged responses can be maintained without radiation therapy, thus avoiding potential long-term radiation toxicity.

Combined modality therapy for primary CNS lymphoma.

Primary CNS lymphoma (PCNSL), formerly rare, is being seen with increased frequency among apparently immunocompetent patients. Conventional treatment has consisted of whole-brain radiotherapy (RT) and corticosteroids, with a median survival of 15 to 18 months and a 3% to 4% 5-year survival. Chemotherapy has been useful in the treatment of recurrent PCNSL. In 1985 we began a treatment protocol using chemotherapy and cranial irradiation for the initial therapy of non-AIDS PCNSL. Thirty-one patients (group A) completed the combined modality regimen. All had placement of an Ommaya reservoir and received pre-RT systemic methotrexate, 1 g/m2, plus six doses of intra-Ommaya methotrexate at 12 mg per dose. A full course of cranial RT (4,000-cGy whole-brain RT plus a 1,440-cGy boost) was followed by two cycles of high-dose cytarabine (ara-C), with each course consisting of two doses of 3 g/m2 ara-C separated by 24 hours and infused over 3 hours. During this period, 16 additional patients (group R) were treated with RT alone, either because patients refused chemotherapy or RT was initiated before our consultation; all would have been eligible to participate in the protocol. Follow-up extended through April 1, 1991. Group A had a significantly prolonged time to recurrence (median, 41 months) compared with group R (median, 10 months; P = .003). Although median survival was doubled from 21.7 months for group R to 42.5 months for group A, this was not statistically significant because of small sample size. More importantly, group R patients received systemic chemotherapy for recurrent PCNSL, which improved survival. The addition of chemotherapy to cranial RT for initial treatment of PCNSL significantly improved disease-free survival and contributed to overall survival; all non-AIDS patients with newly diagnosed PCNSL should be considered for combined modality therapy.