scholarly journals Risk Prediction for Early Mortality in Patients with Newly Diagnosed Primary CNS Lymphoma

2019 ◽  
Vol 10 (17) ◽  
pp. 3958-3966 ◽  
Author(s):  
Chia-Hsin Lin ◽  
Ching-Fen Yang ◽  
Huai-Che Yang ◽  
Li-Yu Fay ◽  
Chiu-Mei Yeh ◽  
...  
Keyword(s):  
Risk Prediction ◽  
Primary Cns Lymphoma ◽  
Early Mortality ◽  
Cns Lymphoma ◽  
Newly Diagnosed

scholarly journals High-dose methotrexate-based regimens and post-remission consolidation for treatment of newly diagnosed primary CNS lymphoma: meta-analysis of clinical trials

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Junyao Yu ◽  
Huaping Du ◽  
Xueshi Ye ◽  
Lifei Zhang ◽  
Haowen Xiao
Keyword(s):  
Meta Analysis ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
Progression Free Survival ◽  
Complete Response ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Dose Methotrexate

AbstractWith the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL). This review focused on first-line induction and consolidation treatment of PCNSL and aimed to determine the optimal combination of HD-MTX and the long-term beneficial consolidation methods. A comprehensive literature search of MEDLINE identified 1407 studies, among which 31 studies met the inclusion criteria. The meta-analysis was performed by using Stata SE version 15. Forest plots were generated to report combined outcomes like the complete response rate (CRR), overall survival, and progression-free survival. We also conducted univariate regression analyses of the baseline characteristics to identify the source of heterogeneity. Pooled analysis showed a CRR of 41% across all HD-MTX-based regimens, and three- and four-drug regimens had better CRRs than HD-MTX monotherapy. In all combinations based on HD-MTX, the HD-MTX + procarbazine + vincristine (MPV) regimen showed pooled CRRs of 63% and 58% with and without rituximab, respectively, followed by the rituximab + HD-MTX + temozolomide regimen, which showed a pooled CRR of 60%. Pooled PFS and OS showed that post-remission consolidation with autologous stem cell transplantation (ASCT) was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Next, whole-brain radiation therapy (WBRT) + chemotherapy showed a pooled 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. In HD-MTX-based therapy of newly diagnosed PCNSL, MPV with or without rituximab can be chosen as the inductive regimen, and the rituximab + HD-MTX + temozolomide regimen is also a practical choice. Based on our study, high-dose chemotherapy supported by ASCT is an efficacious approach for consolidation. Consolidation with WBRT + chemotherapy can be another feasible approach.

BCL6 Expression and Treatment Delay Correlate with Adverse Outcome in Newly Diagnosed Primary CNS Lymphoma: Final Report of CALGB 50202 (Alliance)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 301-301
Author(s):  
James L. Rubenstein ◽  
Eric D. Hsi ◽  
Jeffrey L. Johnson ◽  
Sin-Ho Jung ◽  
Barbara Grant ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Progression Free Survival ◽  
Treatment Delay ◽  
Cns Lymphoma ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
Brain Irradiation ◽  
Bcl6 Expression ◽  
Ecog Ps

Abstract Abstract 301 Background: While whole brain radiotherapy (WBRT) has long been considered the standard consolidative therapy in primary CNS lymphoma (PCNSL), concerns regarding irreversible neurocognitive effects of brain irradiation have prompted development of dose-intensive induction and consolidative chemotherapeutic approaches, with the aim to eliminate brain irradiation. We present the updated results of the first Phase II multicenter trial, conducted by a major cooperative group within the United States, to evaluate an intensive chemotherapy-alone strategy in newly diagnosed patients with PCNSL. Methods: Induction chemotherapy consisted of methotrexate (MTX), temozolomide, rituximab (MT-R) with HD-MTX (8 gm/m2) administered every 2 weeks × 8, weekly rituximab × 6 and temozolomide (150 mg/m2) starting day +7 and continued monthly × 5. Patients who achieved a CR received intensive consolidation cytarabine 2 gm/m2 BID on days 1–4 with etoposide 40 mg/kg over 96 h (EA). Assessment of BCL6 and MYC expression by lymphoma cells was performed by immunohistochemical analysis of diagnostic specimens and scored (10% increments) by a pathologist who was blinded to clinical outcome. Results: 44 newly diagnosed, immunocompetent patients with PCNSL were treated at 12 CALGB centers between 2005 and 2009. Patient characteristics were as follows: median age was 61 yr (range 12–76), median ECOG PS was 1, 58% were IELSG risk group 2–3. 98% of tumors were large B-cell lymphoma. 66% of patients exhibited CR to induction MT-R. With median overall follow-up of 5.3 years, 21 out of 46 patients exhibited disease progression and 17 have died. There was one treatment-related death (sepsis) during consolidation. There has been no evidence for significant treatment-related neurotoxicity. The median progression-free survival (PFS) is 4.0 years and estimated PFS rates with 95% confidence limits at 1, 2, 3 and 4 years are 0.66 (0.50, 0.76), 0.59 (0.43, 0.72), 0.52 (0.36, 0.64) and 0.47 (0.32, 0.61). The probability of 2-year PFS for patients who completed the entire regimen is 0.69 (0.47, 0.94). The estimated overall survival (OS) rate with 95% confidence limits at 4 years is 0.65 (0.49,0.77). Remarkably, event-free survival (EFS) was similar in patients older and younger than 60 (p< 0.47). While ECOG PS>1 and high IELSG score showed a trend toward inferior EFS, the most significant clinical prognostic variable was treatment delay: those patients who started remission induction therapy more than 30 days after diagnosis exhibited shorter EFS than patients who received MT-R within a month (2-sided p-value = 0.05). There was no relationship between treatment delay and IELSG prognostic score. While high MYC expression (>50% lymphoma nuclei) was detected in 54% of cases, MYC was not prognostic. By contrast, high BCL6 expression (≥30% of lymphoma nuclei) was detected in 59% of cases and correlated as a continuous variable with inferior progression-free survival, event-free survival and overall survival. The 2-sided p-values for these models were p=0.045, p=0.019 and p=0.045 (log-rank test). Conclusions: CALGB 50202 (Alliance) demonstrates that induction MT-R followed by EA consolidation is feasible in the multicenter setting and yields rates of PFS and OS in newly diagnosed PCNSL patients that are at least comparable to combined modality treatment involving reduced dose whole brain irradiation. The MT-R-EA regimen is well-tolerated in patients age >60 and has similar efficacy in this population as in younger patients. Based upon these encouraging results, a successor, intergroup, randomized phase II trial, CALGB 51101 (Alliance) has been activated that compares dose-intensive consolidation (EA) with myeloablative chemotherapy and autologous stem cell transplant in this first randomized trial in PCNSL in which neither arm involves WBRT. Our observations regarding the association of treatment delay with adverse prognosis suggest that prompt initiation of therapy for PCNSL patients may translate into improved outcomes. In this first prospective analysis of molecular biomarkers in PCNSL in the setting of a clinical trial, high BCL6 expression was found to correlate with inferior outcome. This observation raises the possibility that in future studies BCL6 could be used as a biomarker in risk-adapted therapy and supports the investigation of BCL6 antagonists in the treatment of this disease. Supported by LLS and by NCI CA13908301. Disclosures: No relevant conflicts of interest to declare.

Combined immunochemotherapy with reduced dose whole brain radiotherapy (WBRT) for newly diagnosed patients with primary CNS lymphoma (PCNSL)

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 1518-1518
Author(s):  
F. G. El Kamar ◽  
L. M. Deangelis ◽  
J. Yahalom ◽  
D. D. Correa ◽  
B. W. Grant ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Cns Lymphoma ◽  
Newly Diagnosed ◽  
Whole Brain ◽  
Reduced Dose ◽  
Brain Radiotherapy

Combined immunochemotherapy with reduced dose whole brain radiotherapy (WBRT) for newly diagnosed patients with primary CNS lymphoma (PCNSL)

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 1518-1518
Author(s):  
F. G. El Kamar ◽  
L. M. Deangelis ◽  
J. Yahalom ◽  
D. D. Correa ◽  
B. W. Grant ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Cns Lymphoma ◽  
Newly Diagnosed ◽  
Whole Brain ◽  
Reduced Dose ◽  
Brain Radiotherapy

Rituximab, methotrexate (MTX), procarbazine, and vincristine (R-MPV) followed by consolidation high-dose chemotherapy (HDC) and autologous stem-cell transplant (ASCT) for newly diagnosed primary CNS lymphoma (PCNSL).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2008-2008 ◽  
Author(s):  
Antonio Marcilio Padula Omuro ◽  
Denise Correa ◽  
Craig Moskowitz ◽  
Matthew J. Matasar ◽  
Lisa Marie DeAngelis ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Primary Endpoint ◽  
Primary Cns Lymphoma ◽  
Unknown Etiology ◽  
Cns Lymphoma ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Induction Regimen

2008 Background: In our previous study in newly diagnosed PCNSL, induction chemotherapy with MTX and cytarabine followed by consolidation HDC (carmustine, etoposide, cytarabine, melphalan [BEAM]) with ASCT without radiotherapy resulted in only 50% of pts transplanted, reflecting low efficacy of induction chemotherapy, and short intent-to-treat (ITT) median PFS (=6m). In this phase II trial, we sought to optimize this strategy by utilizing a more effective induction regimen (R-MPV) and a more aggressive HDC regimen (Soussain et al). Methods: Pts received 5-7 cycles of R-MPV (MTX: 3.5g/m2) and if a partial or complete response was achieved, HDC with thiothepa, cyclophosphamide and busulfan was given, followed by ASCT and no radiotherapy. The primary endpoint was ITT 1 year event-free survival (promising: 75%, non-promising: 50%; 90% power, significance=0.05). Follow-up included comprehensive neuropsychological evaluation. Results: Accrual has been completed (N=32 pts, median age 57 [range 23-67], median KPS=80). Following R-MPV, 17 pts achieved a CR, 13 pts a PR and two pts progressed. A total of 25 (78%) pts were transplanted; the reasons for not receiving transplant were progressive disease (N=2), poor performance status/ physician’s decision (N= 2), mobilization failure (N=1) and consent withdrawn (N= 2). One pt who withdrew consent relapsed and received HDCASCT for salvage. Two (8%) pts died from early complications of ASCT (Stevens-Johnson: one, sepsis: one) and one pt experienced a fatal late colitis of unknown etiology. In the ITT population, the median EFS and OS have not been reached after a median follow-up of 22 months. The 1 year EFS was 78% (95%CI 58-90) and the 2y OS was 76% (95% CI 54-89). No pt has developed delayed neurotoxicity. Conclusions: R-MPV induction regimen resulted in improved response rates, allowing 78% of pts to receive HDC-ASCT. Although more toxic, this regimen resulted in excellent disease control and survival in the ITT population, far exceeding the efficacy of our previous transplant study. The primary endpoint was met, warranting further investigation.

Consolidation reduced dose whole brain radiotherapy (rdWBRT) following methotrexate, rituximab, procarbazine, vincristine, cytarabine (R-MPV-A) for newly diagnosed primary CNS lymphoma (PCNSL): Final results and long-term outcome.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2006-2006 ◽  
Author(s):  
Richard Charles Curry ◽  
Denise Correa ◽  
Jeffrey J. Raizer ◽  
Sean Aaron Grimm ◽  
Rose Lai ◽  
...  
Keyword(s):  
Verbal Memory ◽  
Primary Cns Lymphoma ◽  
Cognitive Outcomes ◽  
Cognitive Testing ◽  
Cns Lymphoma ◽  
Newly Diagnosed ◽  
Long Term Outcome ◽  
Early Results

2006 Background: After promising early results in the pilot phase (N= 30) reported by Shah 2007, we report on final results of a multicenter phase II study (N=52) in newly diagnosed PCNSL combining R-MPV-A and rdWBRT, expanded to address long-term disease control and cognitive outcomes in pts who actually received rdWBRT. Methods: Pts received 5 cycles of R-MPV (MTX dose: 3.5g/m2). Those with partial response (PR) received additional 2 cycles. Pts with a complete response (CR) after 5-7 cycles received rdWBRT (23.4 Gy), otherwise standard WBRT was offered (45 Gy). Consolidation cytarabine was given to all pts. Primary end-point was 2-y progression-free survival (PFS) in pts receiving rdWBRT (n=30 pts in CR required). Exploratory end-points included comprehensive neuropsychological testing, white matter changes (WMC) analysis (Fazekas scale) and apparent diffusion coefficient (ADC) on MRI. Results: Accrual was completed (N=52; 22 women); median (med) age= 60 (30-79); med KPS= 70 (50-100). In total, 31 (59%) pts were assessable for the primary endpoint (achieved a CR after induction and received rdWBRT). The 2-y PFS for this group was 78% (95% ci: 64%- 92%); med PFS= 7.7 y; the med OS was not reached (med follow-up= 6y); 3y-OS= 88% (ci 70-95); 5y-OS= 81% (ci 62-91). Cognitive testing showed improvement in executive function (P < 0.01) and verbal memory (P < 0.05) following induction chemotherapy; follow-up scores remained stable across the various domains. Minimal WMC developed in long term survivors: 36% of pts showed no change in Fazekas’ scores, 64% of pts developed scores 1 or 2 and no pt showed scores 3-6. The intent-to-treat (n=52) med PFS was 3.3y; med OS= 6.6 y. Differences in ADC values did not predict response (p=0.15), PFS (p=0.41) or OS (p=0.48). Conclusions: Consolidation rdWBRT is a highly effective and safe treatment for newly diagnosed PCNSL. Long term follow-up showed robust PFS and OS, comparable or superior to full dose WBRT, with excellent cognitive outcomes and no significant WMC over time. An RTOG randomized trial has been initiated comparing R-MPV-A with vs without rdWBRT.

scholarly journals ACTR-23. MAINTENANCE TREATMENT WITH IBRUTINIB FOLLOWING FIRST LINE METHOTREXATE-BASED IMMUNO-CHEMOTHERAPY IN ELDERLY PATIENTS WITH PRIMARY CNS LYMPHOMA (PCNSL). A PHASE 2 OPEN-LABEL STUDY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi17-vi18
Author(s):  
Osnat Bairey ◽  
Alexandra Benouaich-amiel ◽  
Shlomit Yust-Katz ◽  
Ronit Gurion ◽  
Tali Siegal
Keyword(s):  
Maintenance Treatment ◽  
Fungal Infections ◽  
Randomized Study ◽  
Primary Cns Lymphoma ◽  
Progression Free Survival ◽  
Cns Lymphoma ◽  
High Dose ◽  
Newly Diagnosed ◽  
First Line ◽  
Open Label

Abstract BACKGROUND Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment prolongs PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas. METHODS Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate–based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months. RESULTS Of the 16 patients screened for the study 2 were excluded due to relapse while on screening. 14 patients have been enrolled with a median age of 74 (61–80) years. The median interval between PCNSL diagnosis and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed. CONCLUSIONS Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-MTX based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.

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