Real-World Outcomes of Older Patients with Primary Central Nervous System Lymphoma (PCNSL): Methotrexate Dose Intensity and Combination with Cytarabine Correlate with Response and Survival
Edward PoyntonNicolás Martínez‐CalleAlia AlchawafShireen KassamMatthew HoranMark RaffertyPhillipa KelseyGemma ScottSarah BruceHannah BuckleyYeong Jer LimShelley A. JohnsL. NguRory McCullochDavid John LewisThankamma AjithkumarDominic CulliganClare RowntreeJosh WrightPam McKaySamih FouraliToby A. EyreJeffrey A. SmithWendy OsborneDeborah YallopKim LintonKate CwynarskiChristopher P. Fox
0
Citation
0
Reference
20
Related Paper
Cite
Background: Consolidation with high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) is a promising approach in the management of primary central nervous system lymphoma (PCNSL), although questions remain regarding the timing of its utilization and the optimal conditioning regimen. We reviewed our experience with HDC-ASCT using a CNS-directed conditioning regimen (TBC-based: thiotepa, busulfan, cyclophosphamide) for patients in first complete remission (CR1). Methods: Forty-four patients with PCNSL were transplanted in CR1 using TBC-based conditioning at Massachusetts General Hospital Cancer Center and Dana-Farber Cancer Institute/Brigham and Women's Hospital. All patients included had 3 6 months follow up after HDC-ASCT. Nine patients were treatedas part of a phase II clinical trial using TBC + high-dose rituximab. The conditioning regimen consisted of: thiotepa 250 mg/m2 on days −9, −8, and −7; busulfan 2.4-3.2 mg/kg on days −6, −5, and −4; cyclophosphamide 60 mg/kg on days −3 and −2. Rituximab 1000 mg/m2 was administered on days −9 and −2 for those on clinical trial. Results: There were 23 females and 21 males. All patients had CD20+ diffuse large B-cell histology. No cases were HIV-related. All patients included achieved a CR with induction therapy; the most common induction regimen (55%) was MT-R (methotrexate plus temozolomide and rituximab). All patients received high-dose IV methotrexate-based induction therapy, and 88% received IV rituximab. Thirty-five patients (80%) were mobilized with G-CSF following 1 cycle of consolidation with high-dose cytarabine. The median time from diagnosis to transplant was 6 months (range, 4-15). The median age at transplant was 59 years (range, 27-69). With a median follow up of 2.8 years (range, 6 months-7.8 years), the Kaplan-Meier (KM) estimates of 1-year and 3-year overall survival (OS) were 100% and 95%, respectively, and the KM estimates of 1-year and 3-year progression-free survival (PFS) were 95% and 89%, respectively (Figure 1). The 1-year and 3-year estimates of transplant-related mortality (TRM) were 0% and 2.9%, respectively. 25% of patients experienced clinically significant infectious complications within the first 100 days. Conclusions: HDC-ASCT with a CNS-directed conditioning regimen such as TBC should be strongly considered in selected patients with PCNSL in CR1, as this approach is associated with encouraging disease control and survival. We await the results of ongoing prospective randomized clinical trials to better clarify the role of HDC-ASCT in the management of PCNSL.
ThioTEPA
Autologous stem-cell transplantation
Regimen
Induction chemotherapy
Cite
Citations (0)
Cite
Citations (7)
6633 Background: Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin’s lymphoma arising within the brain in the absence of a systemic disease. High-dose methotrexate (MTX) followed by whole-brain irradiation therapy has consistently improved the length of survival in PCNSL, however, it is noteworthy that patients with an age >60 years and with renal dysfunction are precluded to high-dose systemic MTX.Previous studies have confirmed the activity of temozolomide and rituximab in the treatment of PCNSL. This association would be favourable for patients with impaired renal function. We report our experience with an immunochemotherapy regimen consisting of rituximab and temozolomide in patients with PCNSL. Methods: Between May 2003 and February 2004, 10 consecutive non- immunocompromised patients with PCNSL histologically documented CD20+ (6 males and 4 females) older than 60 years and with poor renal function were enrolled in this study, median Karnofsky status was 70%. Patients were scheduled to receive rituximab (375 mg/m2) on day 1 and temozolomide at a dose of 200 mg/m2 on days 1–5, repeated after 28 days for 8 cycles. A gadolinum-enhanced magnetic resonance image of the head was obtained after every two cycles of treatment. Results: After four cycles of rituximab and temozolomide, confirmed objective responses were observed in 6 patients (4 CR + 2 PR) resulting in a response rate of 60%, 4 patients had progression disease. Among the six responder patients after completion of planned therapy, the four patients, with a CR after 4 cycles, maintained a CR. One patient with PR achieved a CR. The median response duration was 7 months and the median survival time was 10 months. Three patients experienced grade 3 neutropenia and two patients experienced grade 3 thrombocytopenia. Conclusions: Initial results indicate that immunochemotherapy with rituximab and temozolomide is well tolerated and exhibited efficacy in these elderly patients. Treatment with rituximab followed by an alkylator such as temozolomide may offer synergic killing lymphoma cell without overlapping toxicities. No significant financial relationships to disclose.
Temozolomide
Regimen
Performance status
Cite
Citations (0)
Central nervous system (CNS) lymphoma may be isolated to the brain or leptomeninges in the absence of systemic disease (primary CNS lymphoma) or may occur as a neurologic complication of systemic lymphoma (secondary CNS lymphoma), usually in the form of leptomeningeal dissemination.
Leptomeninges
Cite
Citations (0)
Abstract Primary CNS lymphoma (PCNSL) is a rare diffuse large B-cell lymphoma originating within the central nervous system. The overall incidence of PCNSL is rising, particularly in the elderly population. Immunosuppression is a strong risk factor, but most patients with this tumor are apparently immunocompetent. Diagnosis of PCNSL can be challenging. Non-invasive or minimally invasive tests such as ophthalmological evaluation and spinal fluid analysis may be useful, but the majority of patients require tumor biopsy for definitive diagnosis. Our knowledge concerning optimum treatment of PCNSL is fragmentary due to paucity of adequately sized trials. Most patients are now initially treated with high-dose-methotrexate-based chemotherapy alone, as the addition of whole-brain radiotherapy at standard doses has not been shown to increase survival and does increase the risk of neurological toxicity. Ongoing trials are addressing issues such as the roles of reduced-dose radiotherapy, the addition of the CD20 antibody rituximab to chemotherapy, high-dose chemotherapy followed by autologous stem cell transplantation, and maintenance therapy in the primary management of PCNSL.
Immunosuppression
Cite
Citations (5)
We report two cases of primary CNS lymphoma (PCNSL) treated with high-dose methotrexate. Though standard adult treatment of PCNSL incorporates whole-brain radiotherapy, the literature suggests it may be possible to delay or avoid radiotherapy and the associated increased risk of neurologic sequelae in pediatric patients. Studies in adults indicate methotrexate therapy can be effective against PCNSL and has advantages over the current standard of treatment. Both patients have no evidence of disease 9 and 7 years after treatment, suggesting high-dose methotrexate may lead to disease control in pediatric patients with PCNSL while avoiding the effects of radiotherapy. Pediatr Blood Cancer. 2010;55:1227–1230. © 2010 Wiley-Liss, Inc.
Cite
Citations (17)
The International Extranodal Lymphoma Study Group-32 (IELSG32) randomized patients with primary central nervous system lymphoma (PCNSL) for induction treatment with methotrexate-cytarabine, methotrexate-cytarabine-rituximab, or methotrexate-cytarabine-thiotepa-rituximab (MATRix) and reported significantly improved complete remission with the MATRix regimen. This study assessed cost-effectiveness among these three induction strategies for PCNSL. A Markov model was developed based on the IELSG32 trial over a 20 year time horizon from the Canadian health care system perspective. Costs for induction, consolidation, inpatient treatment administration, follow-up, adverse events, relapsed disease, and palliative care were included. Methotrexate-cytarabine-rituximab was subject to extended dominance by the other two strategies. The MATRix regimen compared to methotrexate-cytarabine produced 3.05 quality-adjusted life year (QALY) gains at added costs of $75,513, resulting in an incremental cost-effectiveness ratio of $24,758/QALY gained. The MATRix regimen was the optimal strategy in the majority of simulations (98% probability at willingness-to-pay of $50,000/QALY gained) and results appeared robust across sensitivity analyses.
Regimen
ThioTEPA
Cite
Citations (4)
Tel aviv
Hematology
Pediatric Oncology
Blood cancer
Cite
Citations (0)
Despite recent advances in diagnosis and treatment, the prognosis of primary CNS lymphoma (PCNSL) and CNS relapse of systemic non-Hodgkin lymphoma remains poor, and the optimal treatment is yet to be defined. This review presents an overview of the current status of CNS lymphoma treatment. Treatment options include radiotherapy alone, intravenous conventional chemotherapy alone, intrathecal chemotherapy, high-dose chemotherapy with autologous stem cell transplantation, combined modality treatment (i.e., chemotherapy plus radiotherapy), immunotherapy, radioimmunotherapy and ocular radiation and/or chemotherapy for intraocular lymphoma. High-dose methotrexate remains an essential part of most first-line treatments for PCNSL and CNS relapse of systemic non-Hodgkin lymphoma. Treatment standardization is hampered by the rarity of the disease and the difficulty of conducting trials with a higher number of patients. However, a recently closed Phase III/IV trial will most likely define the role of adjuvant whole-brain radiation treatment in PCNSL. Future directions in the management of PCNSL and CNS relapse of systemic lymphoma may include treatment stratification according to patient age and clinical and biological prognostic factors.
Cite
Citations (13)
Primary central nervous system lymphoma (PCNSL) is a type of non-Hodgkin lymphoma limited to the central nervous system. It has a poor prognosis. Consensus has been reached on the treatment of newly diagnosed patients with high-dose methotrexate-based chemotherapy, but whether the addition of the monoclonal anti-CD20 antibody rituximab improves survival, as it does in systemic B-cell non-Hodgkin lymphoma, remains disputed. In this review, we reflect on the available evidence of the use of rituximab in PCNSL. Whether rituximab has any beneficial effect remains uncertain.
Cite
Citations (11)