Comparison of high dose methotrexate treatments in CNS lymphoma patients: The Henry Ford experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2028-2028
Author(s):  
Ranya Selim ◽  
Joyce Philip ◽  
Vijaya Donthireddy
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Phase Ii Trials ◽  
Entire Cohort ◽  
Dose Methotrexate ◽  
Increased Risk ◽  
Reference Phase

2028 Background: The main backbone of therapy for CNS lymphoma involves systemic treatment with high dose methotrexate (HDMTX)-based regimens,with radiotherapy reserved only for cases that fail systemic therapy due to the significant cognitive toxicity of radiation. Over the last decade, rituximab and subsequently temozolomide were added to HDMTX chemotherapy regimens. Methods: Patients diagnosed with CNS lymphoma between 2009 and 2015 were identified. A retrospective cohort study was conducted of patients who received HDMTX alone (Cohort A), HDMTX and rituximab (Cohort B) and HDMTX, rituximab and temozolomide (Cohort C). Data collected included treatment related adverse events along with OS and PFS. Results: 31 patients were diagnosed with CNS lymphoma. 11, 10 and 6 patients were in cohorts A, B and C respectively. Median PFS and OS for the entire cohort were 14 and 25 months respectively. Cohort results were compared to the respective reference trials published in the literature. Cohort A had a PFS of 11 months and OS of 12 months compared to 12.8 months and 22.8+ months in the reference Phase II trial. Cohort B had a median PFS of 25+ months and OS of 41 months compared to 21 months and 33.5 months in the reference trial. Cohort C had a 2-year PFS of 0.50 compared to 0.57 in the reference trial. 3 (9.6%), 5 (16.1%), and 2 (6.4%) patients developed renal dysfunction in cohorts A, B and C respectively. 4 (12.9), 2 (6.4%), and 0 patients developed leukopenia in cohorts A, B and C respectively. 3 (9.6), 2 (6.4%), and 1 (3.2%) patients developed anemia in cohorts A, B and C respectively. 1 (3.2%), 1 (3.2%) and 1 (3.2%) patient developed thrombocytopenia in cohorts A, B and C respectively. Conclusions: The addition of Rituximab to HDMTX treatment for the treatment of CNS lymphoma increased the PFS and OS compared to HDMTX alone and is in concordance with the reference phase II trials reported in the literature if not better. In addition, our data at HFH shows no increased risk of adverse events with combination therapies compared to HDMTX alone. The addition of Temozolomide to Rituximab and High Dose methotrexate treatment showed a median 2 year PFS of 0.50 which is comparable to published reports of a 2-year PFS of 0.59.

scholarly journals Single-Agent Ibrutinib in Recurrent/Refractory Central Nervous System Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 783-783 ◽  
Author(s):  
Christian Grommes ◽  
Alessandro Pastore ◽  
Igor Gavrilovic ◽  
Thomas Kaley ◽  
Craig Nolan ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Adverse Events ◽  
Clinical Response ◽  
Central Nervous System Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Methotrexate Chemotherapy

Abstract BACKGROUND: Primary Central Nervous System Lymphoma (PCNSL) is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Response rates (ORR) range between 30-60% with a PFS of 2-5 months. Ibrutinib has shown promising clinical response in Mantel cell lymphoma, CLL, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. METHODS: Eligible patients had r/r PCNSL or Secondary CNS Lymphoma (SCNSL), age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. RESULTS: Twenty patients were enrolled (3 at 560 mg; 17 at 840 mg). Median age was 69 (range 21-85); 12 were women. Median ECOG was 1 (0: 2, 1: 12, 2: 6). 65% had PCNSL and 35% SCNSL; 70% had recurrent disease. Eleven had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 6 both. Five grade 4 adverse events were observed in 4 patients (lymphopenia (2), sepsis (1), neutropenia (2)). Ten patients developed grade 3 toxicities, including lymphopenia in 3 patients, thrombocytopenia in 2, hyperglycemia in 2, lung infection in 2, neutropenia in 1, urinary tract infection in 1, colitis in 1, and fungal encephalitis in 1. The most common toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median follow-up of 193 days, 19/20 patients were evaluated for response: 8 CR, 7 PR, 1 SD and 3 PD; 75% (15/20) ORR. The median PFS is 7.29 months (95% CI: 3.80-15.43 months (longest: 15.3 months)). The mean Ibrutinib concentration in the CSF 2h post administration at day 1 and 29 is 1.75 ng/mL (3.97 nM) and 2.51 ng/mL (5.6 nM) which is above the IC50 (1nM) required in vitro to reduce growth of lymphoma cells.An additional treatment arm has been added to the trial which will evaluate adverse events of the combination of ibrutinib and high-dose methotrexate chemotherapy. Enrollment into the combination arm is ongoing and updates will be presented at the meeting. CONCLUSION: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Drug concentrations in CSF are higher at steady state (day 29) and meaningful CSF concentrations are reached. Clinical response was seen in 75% of CNS lymphoma patients. A combination arm will assess the adverse events of ibrutinib in combination with high-dose methotrexate chemotherapy. Disclosures No relevant conflicts of interest to declare.

Phase 1B of ibrutinib and high-dose methotrexate for recurrent/refractory CNS lymphoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7533-7533 ◽  
Author(s):  
Christian Grommes ◽  
Jacqueline Stone ◽  
Craig Nolan ◽  
Elina Tsyvkin ◽  
Julia Wolfe ◽  
...  
Keyword(s):  
Adverse Events ◽  
Systemic Disease ◽  
Single Agent ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Dose Methotrexate ◽  
Phase 1B

7533 Background: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). In this phase 1B trial, we investigate the toxicity of ibrutinib in combination with high-dose methotrexate (HD-MTX) in r/r PCNSL/SCNSL. Methods: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. HD-MTX was given at 3.5g/m2 every 2 weeks for a total of 8 doses. To minimize adverse events, ibrutinib was stopped on days of HD-MTX infusion and was restarted 5 days after MTX infusion or after completion of MTX-clearance, if clearance of MTX required more than 5 days. Ibrutinib was continued daily after completion of 8 doses of MTX. Results: Six patients have been enrolled; 3 received 560mg and 3 received 840mg ibrutinib in combination with HD-MTX. Median age was 62 (range 43-74); median ECOG 1 (0:2; 1:3; 2:1). Two had r/r PCNSL and 4 SCNSL. Three had brain disease, one isolated cerebrospinal fluid (CSF) involvement and two parenchymal and CSF involvement. Three patients had recurrent (2 PCNSL; 1 SCNSL), two refractory (both SCNSL), and one newly diagnosed disease (SCNSL). There were no grade 4 adverse events. Grade 3 events were observed in 5 patients (lymphopenia in 3, ALT elevation in 2, diarrhea in 1, electrolyte changes in 1, hypertension in 1). The most common adverse events were hypokalemia, low WBC, hyperglycemia, ALT and AST elevation. There was no dose reduction of methotrexate or ibrutinib in any patient. After a median follow-up of 130 days, all patients were evaluated for response after 4 doses of HD-MTX, with 4/6 (67%) showing a response: 2 CR, 2 PR, and 1 SD, 1 PD; both non-responders were refractory SCNSL. Ibrutinib concentrations were measured in plasma and CSF. Conclusions: Patients with CNS lymphoma tolerate the combination of HD-MTX and Ibrutinib (at 560 and 840mg) well. Continued enrollment into a combination arm that includes rituximab, methotrexate and ibrutinib is ongoing. Clinical trial information: NCT02315326.

scholarly journals RARE-13HYPERACUTE ADVERSE EVENTS OF HIGH-DOSE METHOTREXATE MONOTHERAPY IN PRIMARY CNS LYMPHOMA PATIENTS

2015 ◽  
Vol 17 (suppl 5) ◽  
pp. v203.3-v203
Author(s):  
Jae-Sung Park ◽  
Jae-Hyun Park ◽  
Sin-Soo Jeun ◽  
Yong-Kil Hong
Keyword(s):  
Adverse Events ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate

Chemotherapy in malignant pleural mesothelioma. A review.

1996 ◽  
Vol 14 (3) ◽  
pp. 1007-1017 ◽  
Author(s):  
S T Ong ◽  
N J Vogelzang
Keyword(s):  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Combination Chemotherapy ◽  
Response Rate ◽  
Single Agent ◽  
High Dose ◽  
Pleural Mesothelioma ◽  
High Dose Methotrexate ◽  
Phase Ii Trials ◽  
Dose Methotrexate

PURPOSE AND DESIGN We reviewed the published literature of clinical studies in malignant pleural mesothelioma, including phase II trials of the newer antifolates and plant derivatives, as well as older single-agent and combination chemotherapy trials. We excluded trials with less than 15 patients, although we have mentioned smaller trials in the text to make a specific point, as well as ones that show promise. We have also included confidence intervals when cited in the original reports, or calculated them when absent. RESULTS No drugs have consistently induced a response greater than 20%. Higher response rates have been reported with detorubicin, high-dose methotrexate, and edatrexate at 26%, 37%, and 25%, respectively, but these have yet to be confirmed. Agents that produce response rates in 10% to 20% of patients include doxorubicin, epirubicin, mitomycin, cyclophosphamide, ifosfamide, cisplatin, and carboplatin. Combination chemotherapy trials do not demonstrate a consistently greater response rate than single-agent trials. However, the combination of doxorubicin, cisplatin, bleomycin, and mitomycin demonstrated a response rate of 44% (95% confidence interval, 27% to 63%), but this remains unconfirmed. Intrapleural therapy using interferon gamma, particularly for small-volume disease, shows promise. CONCLUSION The successful treatment of unresectable pleural mesothelioma awaits the discovery of active drugs. Recent trials of high-dose methotrexate and other antifolates are encouraging. Newer agents, including suramin, should be evaluated in phase II trials. Off-protocol combination therapy cannot be recommended over single-agent therapy, but studies that use combinations of the newer agents should be conducted.

scholarly journals Is There an Indication for First Line Radiotherapy in Primary CNS Lymphoma?

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2580
Author(s):  
Clemens Seidel ◽  
Christine Viehweger ◽  
Rolf-Dieter Kortmann
Keyword(s):  
Stereotactic Radiotherapy ◽  
Residual Disease ◽  
Primary Cns Lymphoma ◽  
Current Evidence ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Phase Ii Trials ◽  
Reduced Dose ◽  
Dose Methotrexate

Background: Primary CNS Lymphoma is a rare and severe but potentially curable disease. In the last thirty years treatment has changed significantly. Survival times increased due to high-dose methotrexate-based chemotherapy. With intensive regimens involving autologous stem cell transplantation (ASCT), 4-year survival rates of more than 80% can be reached. However, this treatment regimen is not feasible in all patients, and is associated with some mortality. Methods: In this review, current evidence regarding the efficacy and toxicity of radiotherapy in PCNSL shall be summarized and discussed mainly based on data of controlled trials. Results: Being the first feasible treatment whole brain radiotherapy (WBRT) was initially used alone, and later as a consolidating treatment after high-dose methotrexate-based chemotherapy. More recently, concerns regarding activity and neurotoxicity of standard dose WBRT limited its use. On the contrary, latest evidence of some phase II trials suggests efficacy of consolidating WBRT is comparable to ASCT. After complete remission reduced dose WBRT appears as a feasible concept with decreased neurotoxicity. Evidence for use of local stereotactic radiotherapy is very limited. Conclusion: Radiotherapy has a role in the treatment of PCNSL patients not suitable to ASCT, e.g., as consolidating reduced dose WBRT after complete response. Local stereotactic radiotherapy for residual disease should be examined in future trials.

scholarly journals Treatment of HIV-associated primary CNS lymphoma with antiretroviral therapy, rituximab, and high-dose methotrexate

Blood ◽  
2020 ◽  
Vol 136 (19) ◽  
pp. 2229-2232
Author(s):  
Kathryn Lurain ◽  
Thomas S. Uldrick ◽  
Ramya Ramaswami ◽  
Mark N. Polizzotto ◽  
Priscila H. Goncalves ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate

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.

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