Outpatient administration of high-dose methotrexate for osteosarcoma treatment in Brazil

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10038-10038 ◽  
Author(s):  
C. R. Macedo ◽  
A. M. Cappellano ◽  
D. T. Noguchi ◽  
A. P. Martinho ◽  
C. G. Dias ◽  
...  
Keyword(s):  
Adverse Events ◽  
Patient Adherence ◽  
Elevated Serum ◽  
Serum Levels ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Serious Adverse Events ◽  
Early Introduction ◽  
Dose Methotrexate ◽  
Metronomic Treatment

10038 Background: We describe the experience with outpatient administration of high dose methotrexate (HDMTX) and leucovorin rescue for osteosarcoma treatment at Instituto de Oncologia Pediátrica. Methods: HDMTX (12g/m2) is administered as part of the Brazilian Osteosarcoma Treatment Group Protocol in an ambulatory basis. Daily MTX serum levels and fluid controls follows until the serum level is <0,2 μ/L. Families were oriented to measure urinary pH and volume, PO intake and to adjust leucovorin dose as needed. To achieve treatment adherence, a family education program was developed. Concomitantly to HD chemotherapy, low dose oral cyclophosphamide and MTX (metronomic treatment) were provided to metastatic (M) patients. This is a retrospective analysis of the HDMTX courses administered between 2006 and 2008. Results: Out of 341 HDMTX infusions, administered to 42 patients, 42.5% had abnormal serum levels at hour 24, 8.8% at hour 48 and 33.2% at hour 72. After required interventions, 2.9% (n = 8) had serum levels >0.2 μ/L at hour 72 leading to delayed excretion. Of these, 7 had also creatinine elevation and main adverse events were mucositis, reversible transaminasis elevation and one sepsis. In the overall analysis, other toxicities included mucositis grade II (20%), nefrotoxicity (5.6%) and neutropenia grades III and IV (25.4%). Serious adverse events of seizure, allergic reaction, and Steven Johnson's Syndrome lead to suspension of future HDMTX administration in 4 patients (01 metastatic). The main differences found between M and non-M patients were 16.8% versus 8.7% of leucopenia grade IV and 12.1% versus 6.6% of anemia grades III and IV. Conclusions: Similar to other authors’ experience, outpatient administration of HDMTX lead to elevated serum levels in 42.5% of the infusions, demonstrating the importance of a well trained staff and early introduction of supportive therapies to avoid associated toxicities. To a developing country, this approach helps lowering treatment costs and infection risks and increases patient adherence to treatment, with acceptable toxicities, even with the introduction of metronomic treatment. No significant financial relationships to disclose.

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.

A second administration of glucarpidase in a different cycle of high-dose methotrexate: Is it safe and effective in adults?

2020 ◽  
pp. 107815522094646 ◽  
Author(s):  
Amalia Domingo-González ◽  
Santiago Osorio ◽  
Elena Landete ◽  
Silvia Monsalvo ◽  
Jose L. Díez-Martín
Keyword(s):  
Renal Function ◽  
Case Report ◽  
Adverse Events ◽  
Kidney Injury ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
First Case ◽  
Methotrexate Concentration ◽  
Unknown Area

Introduction Methotrexate intoxication following high-dose methotrexate-induced acute kidney injury is a life-threatening complication. Glucarpidase can quickly reduce extracellular methotrexate to safe levels, but the effectiveness and safety of its use in different episodes of nephrotoxicity remain an unknown area. Case Report A 30-year-old male diagnosed with acute lymphoblastic T-cell lymphoma received methotrexate 5 g/m2 intravenous (IV) as part of the first consolidation cycle. On Consolidation 3, he restarted methotrexate at a dose of 3 g/m2 IV showing slow methotrexate elimination, associated myelosuppression, and hepatic toxicity. Glucarpidase was administered (total dose of 2000 International Units (IU)). No adverse events were observed, and his renal function returned to normal. One hundred and six days later, he was diagnosed with leptomeningeal and cerebellar relapse and treatment with methotrexate 3,5 g/m2 IV day 1 and cytosine arabinoside (Ara-C) 2 g/m2 IV twice per day days 1, 3, and 5 was started. At 36 h from methotrexate infusion, serum creatinine increased up to 1.89 mg/dL and methotrexate concentration was 100 µmol/L. Management and Outcome: Ara-C was suspended, and a second administration of glucarpidase (2000 IU) was dispensed. No adverse events were noticed, methotrexate levels decreased and renal function progressively improved, recovering completely three weeks later. Discussion The effectiveness and safety of the use of glucarpidase in different episodes of nephrotoxicity remain an unknown area, and the rate and consequences of antiglucarpidase antibody formation remain poorly understood. This case report is, to our knowledge, the first case of a second administration of glucarpidase in a different cycle of high-dose methotrexate in an adult patient.

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

Significant interaction between high-dose methotrexate and high-dose piperacillin-tazobactam causing reversible neurotoxicity and renal failure in an osteosarcoma patient

2020 ◽  
pp. 107815522095387 ◽  
Author(s):  
Irene Krämer ◽  
Jelena Rosentreter ◽  
Marius Fried ◽  
Michael Kühn
Keyword(s):  
Renal Failure ◽  
Significant Interaction ◽  
Rescue Therapy ◽  
Pharmacokinetic Interaction ◽  
Serum Levels ◽  
Calcium Folinate ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Medicinal Products ◽  
Dose Methotrexate

Introduction Pharmacokinetic interaction of high-dose methotrexate (MTX) and other concomitantly administered renally secreted medicinal products may lead to insufficient methotrexate serum level decrease and significant MTX toxicity. Case report We report the case of an 18-year-old male patient treated with high-dose MTX for an osteosarcoma and with high-dose piperacillin-tazobactam at the same time. MTX serum levels were severely elevated 24 hours after the MTX infusion and did not decrease in accordance with the specific calcium folinate rescue protocol. The patient experienced renal failure accompanied by neurological symptoms, most consistent with MTX-related renal and CNS toxicity. Management and outcome: After discontinuation of piperacillin-tazobactam, intensified calcium folinate rescue therapy, and IV hydration, the MTX serum levels decreased appropriately, and toxicity symptoms resolved. Discussion Severe MTX-related toxicity, caused by drug-drug interaction, suggests that the concomitant use of high-dose MTX and high-dose piperacillin-tazobactam should be avoided generally.

scholarly journals Pharmacokinetic analysis of high-dose methotrexate treatments in children with hematologic malignancies

2011 ◽  
Vol 152 (40) ◽  
pp. 1609-1617
Author(s):  
Katalin Csordás ◽  
Olivér Eipel ◽  
Márta Hegyi ◽  
Monika Csóka ◽  
Éva Pap ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Serum Levels ◽  
Hematologic Malignancies ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Serum Concentrations ◽  
Toxicity Evaluation ◽  
Dose Methotrexate

Monitoring the pharmacokinetic parameters of different anticancer drugs is necessary because they might have several side effects. Aim: Pharmacokinetic and toxicity evaluation of high-dose methotrexate treatments in children with acute lymphoblastic leukemia. Patients and methods: 43 children (28 boys, 15 girls, mean age: 7.03 years) in 147 cases were treated with 5 g/m2/24h MTX according to ALL-BFM 1995 and 2002 protocols. Methotrexate and 7-hydroxi-methotrexate levels were measured with high pressure liquid chromatography at 24, 36, 48 hours. Authors registered the development of hepatotoxicity, nephrotoxicity, grade III/IV oral mucositis. Results: Therapeutic methotrexate serum concentrations (30-100µmol/l) were achieved in 72.5% of the cases. Repeated treatments resulted similar serum levels. Hepatotoxicity and hypoproteinemia occurred in 17% and in 48.9% of the cases. There was significant correlation between serum 7-hydroxi-methotrexate and creatinine levels (p<0.05). Conclusion: 5 g/m2methotrexate resulted reliable therapeutic serum levels with mild and reversible toxicity. 7-hydroxi-methotexate measurements might be more useful than methotrexate levels to detect toxicity. Orv. Hetil., 2011, 152, 1609–1617.

Safety and Efficacy of Replacing Vindesine with Vincristine in R-ACVBP Protocol for the Treatment of High-Grade B Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 49-50
Author(s):  
Rola El Sayed ◽  
Haidar El Darsa ◽  
Jeries Kort ◽  
Farouk Al Chami ◽  
Charafeddine Maya ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Adverse Events ◽  
B Cell ◽  
High Dose ◽  
Inadequate Response ◽  
High Grade ◽  
High Dose Methotrexate ◽  
Safety And Efficacy ◽  
Dose Methotrexate

Background: Intensified immunochemotherapy with rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) has been shown to improve outcomes in younger adults with high-grade B-cell lymphomas (hg-BCL) when compared to standard therapy with R-CHOP (Cyclophosphamide-Adriamycin-Vincristine-Prednisone) (Recher C. Lancet 2011). Due to unavailability of vindesine at our institution, we primarily aimed at assessing the safety and efficacy of replacing vindesine with vincristine in a modified R-ACVBP protocol (mR-ACVBP). Secondary endpoints included progression-free survival (PFS), and overall survival (OS). Methods: This is a retrospective study performed at the American University of Beirut Medical Center (AUBMC), Lebanon, including all consecutive adult patients (pts) with newly diagnosed hg-BCL who received first-line mR-ACVBP from 10/2014 to 10/2019. mR-ACVBP protocol was similar to published original protocol with the exception of vindesine being replaced by vincristine 1.5 mg intravenously on days 1 and 5 of each cycle (initial protocol included vincristine 2 mg on days 1 and 5, later adjusted for toxicity). Pts were assessed for response after 4 cycles of mR-ACVBP. Responders continued with consolidation consisting of 2 cycles of high-dose methotrexate followed by 4 cycles of Rituximab-Ifosfamide-Etoposide then low-dose cytarabine x2. Pts with inadequate response on interim imaging were offered consolidative autologous stem cell transplantation (ASCT). Incomplete responders after 4 cycles (CR defined as delta SUVmax more than 70%) were shifted to salvage therapy including R-ICE (Rituximab, Ifosfamide, Cytarabine, Etoposide), or R-DHAP (Rituximab, Dexamethasone, Cytarabine, Cisplatin). Pts with age-adjusted IPI ≥ 2 could receive consolidative ASCT at the physician's discretion. Results: We identified 56 pts with hg-BCL, with a median age of 41 years [range: 21-67]. 64% of patients were males. 45 (80%) pts had advanced stage (III/IV), and 37 (66%) pts had an age-adjusted-IPI score &gt;1. Fifty-one pts were evaluable for response after 4 cycles by PET CT scan. The overall response rate was achieved in 46 (90%) pts; complete response (CR) in 41 (80%), partial response (PR) in 5 (10%), 2 of which considered to have inadequate response as per delta SUVmax. 12 (27%) pts received consolidative ASCT, 27 (61%) continued consolidation chemotherapy, and 5 (11%) pts received subsequent salvage treatment. The most common reported treatment emergent adverse events, encountered during induction mR-ACVBP, were anemia (n=51, 91%), followed by febrile neutropenia (n=36, 64%, grade 4 in 26 (46%) pts, of whom four required intensive care monitoring), thrombocytopenia (n=22, 39%), and mucositis (n=12, 21%). Peripheral neuropathy was encountered in 7 (12%) pts (grade 1, n=2, grade 2, n=4, grade 3, n =1). Two deaths were attributed to treatment due to febrile neutropenia and septic shock during first and third cycle of mR-ACVBP in patients who had an aaIPI of 3. After a median follow up of 17 months [range, 0.5-55], a total of 4/44 (9%) pts progressed, 3 while on treatment after high-dose methotrexate, 1 after therapy completion. The median PFS and OS were not reached. The 2-year PFS and OS were 86% and 87% respectively. At last follow up, 47 pts were alive (44 (94%) pts were in continuous CR, 1 (2%) pt in PR and 2 (4%) pts progressive disease), 6 pts died, and 3 were lost to follow up. Conclusion: The use of vincristine in mR-ACVBP instead of vindesine seems to be feasible, with acceptable manageable adverse events. Despite higher risk disease, survival rates seem to be comparable to published data of the original R-ACVBP protocol. Disclosures No relevant conflicts of interest to declare.

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