scholarly journals ABCC2(rs717620), and ABCC3 (rs4793665) affect high dose Methotrexate toxicity, and outcome in children with osteosarcoma

2020 ◽  
Author(s):  
Amr Yahia ◽  
Rania Labib ◽  
Sameh A. Abdelshafi3 ◽  
Asmaa Salama ◽  
Omneya Hassanain ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Plasma Concentrations ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Nucleotide Polymorphisms ◽  
Dose Methotrexate ◽  
Increased Risk ◽  
Patients At Risk ◽  
And Gender ◽  
Age Range

Objectives: Osteosarcoma (OS) is one of the aggressive bone tumors commonly diagnosed in adolescents and young adults. The study investigated the effect of 9 single nucleotide polymorphisms (SNPs) in 5 genes on methotrexate (MTX) plasma level and its impact on the patients’ clinical outcomes. Methods: One hundred and thirty-three patients with OS (68 boys and 65 girls with age range 4.00-17.86 years) were enrolled and treated with four weeks of high-dose methotrexate (HDMTX) as neo-adjuvant therapy in children’s cancer hospital (CCHE-57357). Blood samples were collected and genotyped for the studied SNPs (MTHFR rs1801133, SLCO1B1 rs11045879, rs4149081, rs2306283, ABCC3 rs4793665, rs4148412, rs733392 ABCG2 rs2231142, and ABCC2 rs717620 using Taqman® (RT-PCR) assay. Plasma concentrations of MTX were measured using the enzyme multiple immunoassay technique (EMIT®). The clinical outcomes included toxicities that were evaluated based on the common terminology criteria for adverse events - version 5 (CTCAEv5.0.), besides the studying of survival analysis and tumor necrosis (TN %). Results: Older patients experienced increased risk of delayed MTX elimination at 72-hour, OR=1.19 (95% CI=1.09-1.29, p=0.00059). The studied SNPs weren’t associated with MTX elimination. Patients with ABCC2 HW (Homozygous wild) genotype group showed a high statistically significant association with higher grade hyperbilirubinemia, OR= 2.05(95% CI=1.05-4.01, p=0.037). Moreover, the patients with ABCC3 (rs4793665) HV and HT (Homozygous variant and Heterozygous) genotypes had a significant association with severe nephrotoxicity, OR= 0.34(95% CI=1.6-0.72, p=0.005). Conclusions: ABCC2 (rs717620), ABCC3 (rs4793665) genotyping with age and gender could help in predicting patients at risk of toxicities due to HDMTX.

Using a Bedside Algorithm to Individually Dose High-dose Methotrexate for Patients at Risk for Toxicity

2017 ◽  
Vol 39 (1) ◽  
pp. 72-76 ◽  
Author(s):  
Jennifer H. Foster ◽  
Melanie. B. Bernhardt ◽  
Patrick A. Thompson ◽  
E. OʼBrian Smith ◽  
Eric S. Schafer
Keyword(s):  
At Risk ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Patients At Risk

Timing of high dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1,384 patients

Blood ◽  
2022 ◽  
Author(s):  
Matthew R. Wilson ◽  
Toby Andrew Eyre ◽  
Amy A Kirkwood ◽  
Nicole Wong Doo ◽  
Carole Soussain ◽  
...  
Keyword(s):  
High Risk ◽  
International Prognostic Index ◽  
Multivariable Analysis ◽  
B Cell Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Prophylaxis ◽  
Dose Methotrexate ◽  
Cns Relapse ◽  
Increased Risk

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n=749) or at the end (n=635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT; 5.7% vs 5.8%, p=0.98, 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n=1,253). In patients with high CNS international prognostic index (n=600), 3-year CNS relapse rate was 9.1% with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk versus i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

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 High dose methotrexate in the treatment of children with acute lymphoblastic leukemia

2007 ◽  
Vol 47 (1) ◽  
pp. 1 ◽  
Author(s):  
Johannes Bondan Lukito
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Plasma Concentrations ◽  
Risk Groups ◽  
Observation Time ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Minor Disease ◽  
State Concentration

Background It has been claimed that around 70% of childhoodacute lymphoblastic leukemia (ALL) can be cured. One of theimportant role is high dose methotrexate (HDMTX) administrationduring the consolidation therapy.Objective To determine the safety and effectiveness of HDMTXin children with ALL.Methods We reviewed patients with ALL in Pantai Indah KapukHospital, Jakarta during the period August 2000 through July 2005with observation time run through September 2006. Only patientswith normal kidney function were allowed to have HDMTX. Besidesgood hydration and alkalinization, patients were supported with goodhygiene (mouth, skin and anal area). MTX was given in loadingdose of 10% from the total dose in ½ hour and the rest 23½ hours for90%. Leucovorin rescue was started 12 hours after discontinuationof 24 hour MTX IV infusion. Leucovorin was given until the MTXconcentration reached 0.1 uM/L. Patients were stratified to low,intermediate and high risk groups; 2 gram/m 2 was given to low riskgroup and 5 gram/m2 to intermediate and high risk groups.Results There were 20 patients eligible for study. All methotrexatesteady-state plasma concentrations (MTX Cp ss ) were above 16 uM/L, and steady state concentration in CSF was always below 0.5 uM/L for 2 gram/m 2 and above 0.5 uM/L for 5 gram/m 2 doses. All 20cases went through the procedure with only mild side effects i. e,mild mucositis, anal furuncle and diarrhea, which recovered 2 weekslater. Only 1 high risk case with initial WBC 612X10 9 /L, succumbedafter he went through the HDMTX program smoothly and relapsedsubsequently during reinduction phase.Conclusion HDMTX can be given safely to ALL patients with normalkidney function with good supportive care. Five gram/m 2 HDMTXeffectively treat the minor disease and/or prevent CNS and testicularleukemia. This study has also given an impression that HDMTXmay increase event-free survival.

High-dose methotrexate: a critical reappraisal.

1987 ◽  
Vol 5 (12) ◽  
pp. 2017-2031 ◽  
Author(s):  
S P Ackland ◽  
R L Schilsky
Keyword(s):  
Clinical Investigation ◽  
Plasma Concentrations ◽  
Osteogenic Sarcoma ◽  
Clinical Situation ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Treatment Regimens ◽  
Dose Methotrexate ◽  
Metabolic Block ◽  
Childhood Acute Leukemia

High-dose methotrexate (HDMTX) with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology for more than a decade. Administration of HDMTX results in tumoricidal plasma concentrations of the drug without significant host toxicity, provided that plasma MTX levels are monitored and LV rescue is properly administered. The original premise of LV rescue was that the provision of reduced folate to normal cells would circumvent the metabolic block produced by MTX and allow resumption of DNA synthesis, although the presumed therapeutic selectivity of leucovorin has not yet been adequately explained. Despite a strong pharmacologic rationale and a vast clinical experience, HDMTX with leucovorin rescue has not been shown to be unequivocally superior to conventional doses of MTX in any clinical situation except, perhaps, for treatment of osteogenic sarcoma and childhood acute leukemia. While HDMTX is an important component of effective treatment regimens for these diseases, its precise contribution to the success of these regimens remains undefined. Although HDMTX can theoretically overcome all known mechanisms of MTX resistance, no data exist to suggest that this can be accomplished in the clinic. Thus, this well-known but poorly understood treatment regimen must remain a subject of clinical investigation rather than a part of routine clinical practice.

scholarly journals Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404)

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 874-883 ◽  
Author(s):  
Barbara L. Asselin ◽  
Meenakshi Devidas ◽  
Chenguang Wang ◽  
Jeanette Pullen ◽  
Michael J. Borowitz ◽  
...  
Keyword(s):  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Randomized Study ◽  
Lymphoblastic Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Oncology Group ◽  
Dose Methotrexate ◽  
Increased Risk ◽  
The Difference

Abstract The Pediatric Oncology Group (POG) phase 3 trial 9404 was designed to determine the effectiveness of high-dose methotrexate (HDM) when added to multi-agent chemotherapy based on the Dana-Farber backbone. Children with T-cell acute lymphoblastic leukemia (T-ALL) or advanced lymphoblastic lymphoma (T-NHL) were randomized at diagnosis to receive/not receive HDM (5 g/m2 as a 24-hour infusion) at weeks 4, 7, 10, and 13. Between 1996 and 2000, 436 patients were enrolled in the methotrexate randomization. Five-year and 10-year event-free survival (EFS) was 80.2% ± 2.8% and 78.1% ± 4.3% for HDM (n = 219) versus 73.6% ± 3.1% and 72.6% ± 5.0% for no HDM (n = 217; P = .17). For T-ALL, 5-year and 10-year EFS was significantly better with HDM (n = 148, 5 years: 79.5% ± 3.4%, 10 years: 77.3% ± 5.3%) versus no HDM (n = 151, 5 years: 67.5% ± 3.9%, 10 years: 66.0% ± 6.6%; P = .047). The difference in EFS between HDM and no HDM was not significant for T-NHL patients (n = 71, 5 years: 81.7% ± 4.9%, 10 years: 79.9% ± 7.5% vs n = 66, 5 years: 87.8% ± 4.2%, 10 years: 87.8% ± 6.4%; P = .38). The frequency of mucositis was significantly higher in patients treated with HDM (P = .003). The results support adding HDM to the treatment of children with T-ALL, but not with NHL, despite the increased risk of mucositis.

Increased Number of High Dose Methotrexate Cycles and the Addition of Rituximab Is Associated with Better Outcomes in a Large Primary CNSL Cohort

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4125-4125
Author(s):  
Prakirthi Yerram ◽  
Samantha Nicole Reiss ◽  
Lisa Modelevsky ◽  
Lauren Schaff ◽  
Anne Reiner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Outcomes ◽  
Multivariable Analysis ◽  
Standard Of Care ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Historical Cohort ◽  
Dose Methotrexate

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive primary brain tumor confined to the brain, eyes, and cerebrospinal fluid. Over the past few decades, prognosis for PCNSL has significantly improved due to the standard use of high dose methotrexate (MTX) containing treatment regimens. However, it remains unclear if the number of MTX doses and the addition of rituximab has an impact on clinical outcomes. The recent HOVON 105/ALLG NHL 24 study questioned the role of rituximab in the first line setting when combined with a MTX based polychemotherapy using only 4 doses of MTX and 6 doses of rituximab. Over the last 30 years, standard of care at Memorial Sloan Kettering Cancer Center (MSKCC) has evolved, allowing the comparison of patients receiving different numbers of MTX doses and those treated with and without rituximab. The purpose of this study was to describe clinical outcomes based on standard of care treatment changes. Methods: This single-center retrospective IRB approved study at MSKCC included patients with immunocompetent PCNSL, age ≥18 years and diagnosed between 1/1983-11/2017. Patients were identified through a departmental database and electronic medical record. The primary objective was to describe overall survival (OS) based on common prognostic markers such as age, KPS, MSKCC prognostic score class (RPA I- III), use of rituximab, and number of methotrexate cycles. Overall survival was calculated from the date of diagnosis to death or last follow-up using Kaplan-Meier methodology. When examining effect of MTX on OS, OS was calculated from date of last MTX cycle until death or last follow-up. Univariable and multivariable analysis for prognostic factors were analyzed using Cox proportional hazards regression. Results: Five hundred and forty-six patients with newly diagnosed PCNSL were identified. Median age at diagnosis was 62 (range 19 to 90), median KPS was 70 (range 10 to 100), and 282 (52%) were men. In total, 472 patients (86.4%) received high dose MTX. Of 460 with known number of MTX cycles, 95 (20.7%) received 1-4 cycles and 365 (79.3%) received ≥5 cycles (5 cycles: 189, 41.1%, 6 cycles: 24, 5.2%, 7 cycles: 74, 16.1%, 8+ cycles: 78, 17%). Rituximab was given to 231 (42.3%). Three hundred and ten (56.8%) patients, treated before 2006, had been reported previously (historic cohort) and 236 (43.2%) served as contemporary cohort. Median OS of the entire population was 4.7 years (95% CI: 3.8-5.7); 3.3 years (95% CI: 2.8-4.1) in the historic and 8.1 years (95% CI: 6.6-no upper limit) in the contemporary cohort. Five-year OS was 40.3% (95% CI: 35.1-46.2) for the historical cohort and 61.8% (95% CI: 55.0-69.5) for the contemporary cohort. Median OS in the contemporary cohort improved in all RPA classes in comparison to patients treated before 2006 (RPA I: not yet reached vs 9.2 years; RPA II: 7.6 years vs 3.5 years; RPA III 2.8 years vs 1.0 year) (Fig. 1). For the historical cohort compared to the contemporary cohort, five-year OS changed from 62.8% to 91.0% in RPA I, 42.0% to 63.0% in RPA II, and 16.3% to 36.9% in RPA III. Patients receiving ≥ 6 cycles of MTX had a better clinical outcome (median OS from last MTX cycle: 7.8 years versus 4.3 years; HR 0.68 (95% CI (0.51 - 0.91), p=0.0085) on multivariable analysis adjusted for age, KPS, sex, RPA classes Additionally, the stratification of rituximab further elucidated the association between MTX cycles and OS, such that in patients receiving rituximab, those treated with ≥ 6 cycles of MTX experienced longer median OS compared to patients receiving < 6 cycles of MTX (13.0 years vs 9.4 years, p=0.001). Furthermore, in patients receiving ≥ 6 cycles of MTX, there was a survival benefit seen in patients who received rituximab compared to those who did not receive rituximab (13.02 years vs 1.61 years, p<000.1) (Fig.2). Conclusions: Overall survival for newly diagnosed PCNSL has improved significantly over the last few decades regardless of age, KPS, RPA class. Patients seem to benefit with the addition of rituximab and when receiving 6 or more cycles of MTX. Disclosures Grommes: BTG: Consultancy; Kite: Consultancy; Squipps: Speakers Bureau.

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