Methotrexate In Adult Patients Research Articles

Development of a novel nomogram for predicting delayed methotrexate excretion following high-dose methotrexate in adult patients with hematologic malignancies.

High-dose methotrexate (HDMTX) is integral in treating hematologic malignancies but carries risks of severe toxicities due to prolonged MTX exposure. However, knowledge of delayed MTX excretion is primarily derived from pediatric and adolescent cohorts, with the reported predictors being presented as rough dichotomous values. This study aimed to identify risk factors for delayed MTX excretion exclusively in adult patients with hematologic malignancies and develop a more applicable predictive nomogram based on continuous clinical and laboratory variables. 517 HDMTX cycles in 194 patients were retrospectively analyzed. Delayed MTX excretion was defined as either MTX concentration ≥ 1.0 µmol/L at 48h or ≥ 0.1 µmol/L at 72h after HDMTX initiation. Multivariate logistic regression analysis was used to construct the nomogram internally validated with the bootstrap method. Delayed MTX excretion was observed in 24.0% of cycles. Six significant predictors were identified: relapsed/refractory disease (Odds ratio [OR] 2.03), fewer HDMTX cycles (OR 0.771), treatment intent (OR 2.13), lower albumin (OR 0.563) and creatinine clearance levels (OR 0.993), and increased γ-glutamyl transpeptidase levels (OR 1.004, all P < 0.05). These were incorporated into a web-based nomogram as continuous variables with good prediction accuracy (area under the curve, 0.73) and without significant overfitting. Delayed MTX excretion increased risks of developing acute kidney injury, even solely at the 72h timepoint (OR 2.57, P = 0.025), without providing any benefit of clinical outcomes. This study comprehensively characterized MTX elimination failure following HDMTX in adult patients and could pave the way for individualized risk prediction.

External Evaluation of Population Pharmacokinetic Models for High-Dose Methotrexate in Adult Patients with Hematological Tumors.

Currently, numerous population pharmacokinetic (popPK) models for methotrexate (MTX) have been published for estimating PK parameters and variability. However, it is unclear whether the accuracy of these models is sufficient for clinical application. The aim of this study is to evaluate published models and assess their predictive performance according to the standards of scientific research. A total of 237 samples from 74 adult patients who underwent high-dose MTX (HDMTX) treatment at Shanghai Changzheng Hospital were collected. The software package NONMEM was used to perform an external evaluation for each model, including prediction-based diagnosis, simulation-based diagnosis, and Bayesian forecasting. The simulation-based diagnosis includes normalized prediction distribution error (NPDE) and visual predictive check (VPC). Following screening, 7 candidate models suitable for external validation were identified for comparison. However, none of these models exhibited excellent predictive performance. Bayesian simulation results indicated that the prediction precision and accuracy of all models significantly improved when incorporating prior concentration information. The published popPK models for MTX exhibit significant differences in their predictive performance, and none of the models were able to accurately predict MTX concentrations in our data set. Therefore, before adopting any model in clinical practice, extensive evaluation should be conducted.

Oral methotrexate at doses 15-25mg/week is non-inferior to parenteral regarding efficacy and safety in the treatment of rheumatoid arthritis: a systematic review and meta-analysis.

The most optimal route of methotrexate (MTX) administration for the treatment of rheumatoid arthritis (RA) has not yet been established. Our aim was to compare the efficacy, safety, and bioavailability profiles of oral MTX with parenteral MTX in adult patients with RA. PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, and ClinicalKey were searched for published randomized trials through December 30, 2021. Random-effects models were used to assess pooled odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (95% CIs). This review was registered in PROSPERO (number CRD42022297810). Of 705 identified trials, 6 met the criteria and were included in our meta-analysis (644 subjects). Compared to parenteral MTX, oral MTX yielded no significant differences in response rates of 20% (OR: 0.68; 95% CI: 0.40-1.75), 50% (OR: 0.75; 95% CI: 0.44-1.28), and 70% (OR: 0.75; 95% CI: 0.51-1.09) improvement according to American College of Rheumatology criteria (ACR20/50/70 response), and no increased relative risk of any adverse event (OR: 1.20; 95% CI: 0.49-2.93). Furthermore, parenteral MTX showed a significant advantage in the value of AUC0-t (MD: - 536.36; 95% CI: - 1054.22 to - 18.50), but not in Cmax (MD: - 12.86; 95% CI: - 84.30 to 58.58) and Tmax (MD: - 0.31; 95% CI: - 0.70 to 0.08) compared with oral MTX. Oral MTX at doses of 15-25mg/week in active RA is not inferior to parenteral regarding efficacy and safety. This supports the initial therapy with oral MTX.

Routine use of low-dose glucarpidase following high-dose methotrexate in adult patients with CNS lymphoma: an open-label, multi-center phase I study

BackgroundHigh-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL).MethodsEight CNSL patients received HD-MTX 3 or 6 g/m2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles.ResultsFifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy.ConclusionsThis study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS.Clinical trial registrationNCT03684980 (Registration date 26/09/2018).

Efficacy and safety of tofacitinib modified-release 11 mg once daily plus methotrexate in adult patients with rheumatoid arthritis: 24-week open-label phase results from a phase 3b/4 methotrexate withdrawal non-inferiority study (ORAL Shift)

ObjectivesTo report the efficacy, safety and patient-reported outcome measures (PROs) of tofacitinib modified-release 11 mg once daily plus methotrexate in patients with rheumatoid arthritis (RA) from the open-label phase of...

A Phase II Study Evaluating the Efficacy of Rituximab in the Management of Patients with Relapsed or Refractory TTP

Background: As many as 30-50% of patients diagnosed with Thrombotic Thrombocytopenic Purpura (TTP) either relapse or become refractory to therapeutic plasma exchange (TPE). There remains a pressing need to evaluate novel treatments for these patients. Rituximab is a chimeric anti-CD20 monoclonal antibody that has demonstrated efficacy potentially by eliminating active B-lymphocytes and production of ADAMTS 13 inhibitor considered central to the pathogenesis of TTP.Intervention: We conducted a prospective multi-center phase II open-label trial in Canadian hospital-based apheresis units to evaluate the efficacy of rituximab in the management of adult patients with relapsed or refractory TTP. Functional and antigenic ADAMTS13 enzyme, inhibitor levels and anti-CD 20 were measured at initiation, 8, 12, 24 and 52-weeks as well as routine hematologic parameters, complete remission, rate of relapse, overall mortality and adverse events. Rituximab was administered intravenously once weekly for a total of 4 doses at 375 mg/m2 in eligible consenting patients.Results: Twenty refractory and 20 relapsing TTP patients were enrolled (N=40). A complete response (CR) was defined by a platelet count >150 x 109/L, an LDH <1.5 times the upper limit of normal, absence of progressive neurologic symptoms and no further need for TPE. At week 8, 77% of refractory patients and 90% of relapsed patients were in CR. At week 52, 15/20 refractory patients (3 deaths, 1 lost to follow-up) and 18/20 of relapsed patients (1 withdrew, 1 lost to follow-up) were alive and in CR. Of the 40 patients enrolled a total of 3 patients died; all in the refractory arm: two with functional ADAMTS13 <10% and detectable inhibitor. Two deaths were related to fungal infection (week 2) and active TTP (week 8). A third death was attributed to thrombotic complications at week 29. All refractory patients with normal ADAMTS13 enzyme at baseline had a complete response at week 8 and remained in remission for the remainder of follow-up (52 weeks). Despite being in complete hematological and clinical remission, relapsing TTP patients still had a positive inhibitor at 24 (50% of patients) and 52 weeks (10% of patients). All patients had < 3% CD 20+ B-lymphocytes at 8 and 12 weeks post rituximab. Median platelet counts in the refractory group recovered more slowly than in the relapsing TTP patients. By week 8 refractory TTP patients received a median of 26 plasma exchanges and relapsed patients received a median of 11(P<0.001).Conclusion: At the conclusion of this study the overall mortality rate was 8%, 15% (95% CI: 5% to 36%) for the refractory group and 0% (95% CI: 0% to 16%) for the relapsed group. Nine refractory patients were dialysis-dependent at baseline and only 2 had a serum creatinine >250 µmol/L and remained on dialysis at week 52. These patients had normal ADAMTS13 enzyme measurements throughout the time period of the study. Results of this study indicate that TPE and rituximab is an effective combination in patients with relapsed or refractory TTP. DisclosuresFoley:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Hoffman-LaRoche: Consultancy, Honoraria, Research Funding; Jansen: Consultancy, Honoraria; Alexion: Consultancy, Honoraria. Off Label Use: Rituxan is a CD20-directed cytolytic antibody indicated for the treatment of patients with: -Non-Hodgkin’s Lymphoma (NHL) (1.1) -Chronic Lymphocytic Leukemia (CLL) (1.2) - Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies (1.3) . Arnold:GSK: Honoraria, Research Funding; Hoffman-LaRoche: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Honoraria, Research Funding. Clark:Alexion: Honoraria; CSN: Honoraria; ASN: Honoraria; Octapharm: Honoraria; Danone Research: Honoraria.

THU0093 Clinical, radiographic, and immunogenic effects after 1 year of tocilizumab (TCZ)-based treatment strategy with and without methotrexate (MTX) in RA: The act-ray study

Background24-week data from ACT-RAY comparing an add-on strategy (TCZ+MTX) with a switch strategy (TCZ+placebo [PBO]) in MTX-IR patients have been previously reported, demonstrating relevant clinical and radiographic benefit without a...

A retrospective safety analysis of adult patients treated with high-dose methotrexate for osteosarcoma in Stockholm, Sweden.

10083 Background: Patients with osteosarcoma are routinely treated with pre- and post-operative chemotherapy that includes high-dose methotrexate. The treatment is associated with a risk of severe renal and hepatic toxicity. Methods: All patients with osteosarcoma that had received at least one cycle of high-dose methotrexate at the adult oncology department, Karolinska University Hospital were retrospectively identified. Treatment toxicity, including hematologic, renal, hepatic toxicity, infections and oral mucositis were registered and graded according to CTCAE v 4.0. A possible relationship between methotrexate blood concentration and toxicity was investigated. Results: Sixteen eligible patients that had received a total of 103 cycles of high-dose methotrexate were identified. Ten patients experienced a severe hepatic toxicity, (Grade 3, n=5 and Grade 4, n=5). Grade 3 renal toxicity was seen in one patient and although reversible, it led to treatment interruption. Reversible, grade 2 elavation of serum creatinine occured in 5 cases. Four grade 3 infections were seen in 2 patients and 8 patients had at least one occurrence of Grade 3 oral mucositis. Thrombocytopenia was a common event (Grade 3, n=5 and Grade 4, n=2) but no severe bleeding complications were observed. One patient died as a result of multi-organ failure two days after methotrexate administration. Methotrexate blood concentration at 24 hours from administration could predict for renal toxicity (p&lt;0.005, by chi-square test), but not for other toxicity. Conclusions: High-dose methotrexate in adult patients with osteosarcoma was frequently associated with severe, however reversible toxicity.

Intensive Induction Chemotherapy without Methotrexate in Adult Patients with Localized Osteosarcoma: Results of the Institut Gustave-Roussy Phase II Trial

To improve outcomes in localized osteosarcoma and to reduce the duration of preoperative chemotherapy, we conducted a phase ii trial assessing the efficacy of an intensive protracted regimen without methotrexate (api-ai regimen) in adolescent and adult patients with newly diagnosed disease. Induction chemotherapy consisted of 2 cycles (4 courses) of doxorubicin 60 mg/m(2) (days 1 and 15), cisplatin 100 mg/m(2) (day 1), and ifosfamide 5 g/m(2) (days 2 and 15). The primary endpoint was good histologic response [ghr (≤5% identifiable tumour cells)]. From March 1993 to March 2000, 32 patients [median age: 21 years (range: 15-49 years)] were administered 126 induction courses. The median time between chemotherapy courses was 15 days (range: 12-32 days). All but 3 patients underwent conservative surgery. Toxicity was mainly hematologic, with febrile neutropenia occurring in 35% of patients and grades 3-4 thrombocytopenia in 35%. The ghr rate was 47%. The median follow-up was 64 months (range: 30-115 months). The 5-year event-free and overall survivals were 65% [95% confidence interval (ci): 48%-79%] and 69% (95% ci: 50%-83%) respectively. Two secondary hematologic malignancies occurred: 1 acute myelocytic leukemia (M5) in a poor responder with concomitant relapse, and 1 myelodysplastic syndrome in a patient achieving ghr. Despite hematologic toxicity, the results observed with the api-ai regimen compare favourably with those observed during previous induction chemotherapy containing methotrexate in adult patients and the pediatric population treated at our institution. These promising results have to be validated by an ongoing national multicentre trial coordinated by the French Sarcoma Group.

High dose methotrexate in adult patients with osteosarcoma: Clinical and pharmacokinetic results

High dose methotrexate (HDMTX) with folinic acid rescue is widely used to treat osteosarcoma, which predominantly afflicts children; the study investigated HDMTX pharmacokinetics (pk) in adult subjects in neoadjuvant/adjuvant settings. Twenty five patients with advanced osteosarcoma (11 females – 14 males, median age 26.0 years) were treated by 12 g/m2 HDMTX 4 hour iv infusion (64 total courses, range 1 – 7 courses). Pk was determined by non-compartmental analysis and population pk modeling. Median (range) bioavailability pk parameters were: Cmax (maximum MTX concentration) 1149.5 µM (692 – 2 200), AUCtot (total area under curve) 6 955.1 µmol*h/l (3 477 – 12 681). Cmax>1 000 µM gave increased histological responses (p < 0.05). Six covariates (height-weight-hemoglobin-AST-ALT-creatinine) were found to influence MTX volume of distribution (V) and elimination rate constant (Kel). Toxicity was mild: only two reversible G4 events were observed, related to AUCtot >12 000 µmol*h/l (p < 0.001). HDMTX pk and interpatient variability in adults are comparable to those in children. No correlation between Cmax/AUCtot and subject age/sex was found, even in the population pk model. The excretion mechanism is not affected by sex/age differences. HDMTX can safely be administered to adults: as in younger patients, a good clinical response can be predicted by Cmax, while severe toxicity depends on highest AUCtot values.

Intensive induction chemotherapy (CT) without methotrexate (MTX) in adult patients with localized osteosarcoma (LO): Updated results of the Institut Gustave Roussy phase II trial

9020 Background: High dose MTX in adult patients (pts) with LO is highly toxic. We have designed in 1995 an intensive protracted regimen without MTX (API-AI regimen) in LO Methods:. Preliminary results were reported at ASCO 2001. The 3-yr event-free survival (EFS) compared favorably with those obtained with HDMTX CT regimen in pediatric population (Le Cesne, ECCO 11). Briefly good responders (≥95% necrosis) (GR) received 2 other API courses (c) and poor responders (PR) a salvage regimen of etoposide and ifosfamide. Results: from March 1993 to March 2000, 32 adult pts with LO (male/female : 19/13) with a median age of 21 yrs, [range 15–49], were included in the study. 126 c (API-AI) of CT were administered (median 3,94 c/pt, range 3 to 5). The planned protocol was given in 75% of pts, 16% received only 3 c for hematologic toxicity (T), and 10% received 5 c due to delay surgery. The median delay between each c of CT was 15 days (range 12–32). All pts received the fixed dose. All but 3 pts had a limb sparing surgery performed 10.3 weeks (median) after the first CT c (range 8–15). T was mainly haematological with febrile neutropenia, grade 4 neutropenia and thrombocytopenia observed in 34%, 69% and 35% of pts respectively. There were no renal and cardiac T. There were 15 GR (47%) and 17 PR (53%). The median follow-up was now 64 months [30–115]. The 5-yr EFS and overall survival (OS) were 65% [48–79%] and 69% [50–83%]. Two pts developed hemopathy: 1 AML5 in a PR with concomitant relapse and 1 MDS in a GR. Until december 2003, two pts with GR exhibited a distant relapse and one died from secondary hemopathy. The 5-yr EFS and OS for pts with GR were 79% [54–93%] and 85% [59–96%]. Eight of the pts with PR experienced relapse. The 5-yr EFS and OS for pts with PR were 52% [30–74%] and 56% [32–77%]. Conclusions: despite the haematological T, these results compare favorably with those observed with previous induction CT containing MTX in adult pts treated in our institution (Le Cesne, ASCO 98). These promising results had to be corroborated by an ongoing national multicenter coordinated by the French Sarcoma Group. No significant financial relationships to disclose.