High-dose Methotrexate Infusion Research Articles

Involvement of the ABCB1 C3435T Variant but Not the MTHFR C677T or MTHFR A1298C Variant in High-Dose Methotrexate-Induced Toxicity in Pediatric Acute Lymphoblastic Leukemia Patients in China.

It remains unclear whether the MTHFR C677T, MTHFR A1298C and ABCB1 C3435T genetic variants are associated with methotrexate (MTX) elimination delay and high-dose MTX (HD-MTX) toxicities in the treatment of pediatric acute lymphoblastic leukemia (ALL). The aim of our study was to analyze the potential predictive role of MTHFR C677T, MTHFR A1298C and ABCB1 C3435T in toxicities and the relationship between these variants and MTX elimination delay during HD-MTX therapy in pediatric ALL patients. We conducted a retrospective study on ALL patients receiving HD-MTX treatment with available MTHFR C677T, MTHFR A1298C and ABCB1 C3435T genotype and 44-h plasma MTX levels. Logistic regression analyses and chi-square tests were used to assess the relationship between the variants and HD-MTX toxicities and MTX elimination delay. Genotype frequencies were in Hardy-Weinberg equilibrium. MTX elimination delay did not significantly differ between MTHFR C677T and MTHFR A1298C or ABCB1 C3435T. Leukopenia (P=0.028), neutropenia (P=0.034) and oral mucositis (P=0.023) were 6.444-fold, 4.978-fold and 9.643-fold increased, respectively, in ABCB1 C3435T homozygous genotype (TT) patients compared to wild-type (CC) patients. No significant association was found between the toxicities investigated and MTHFR C677T or MTHFR A1298C. This study showed that the ABCB1 C3435T homozygous allele genotype (TT) is associated with increased MTX-related toxicities (leukopenia, neutropenia and oral mucositis). These results may help to distinguish pediatric ALL patients with a relatively high risk of MTX-related toxicities before HD-MTX infusion and optimize MTX treatment.

Acute Kidney Injury in Methotrexate treated Leukemia

Background: The study was performed to know the incidence of acute kidney injury within 48 hours following High dose Methotrexate administration in children with high-risk B cell Acute Lymphoblastic Leukemia along with its risk factors and toxicities. Most studies have been conducted in adults and have included non-Hodgkin lymphoma along with leukemia. There is a paucity of data regarding the burden of Acute kidney injury with Methotrexate use in the pediatric age group with B cell Acute Lymphoblastic Leukemia. Methods: It was a prospective observational study conducted at the pediatric ward of All India Institute of Medical Sciences, New Delhi between 2019 September to 2021 June. Children between 1 to 18 years with high-risk B lineage Acute Lymphoblastic Leukemia planned for high-dose Methotrexate at 3gm/m² were enrolled. The measurement of serum creatinine was done at baseline, 24 and 42 hours while serum methotrexate at 24 and 42 hours, adverse reactions were assessed till day 14 of methotrexate administration. Results: The incidence of Acute Kidney Injury and severe Acute Kidney Injury (stages 2 and 3) at 42 hours of High dose Methotrexate infusion was 24.3% and 12.8% respectively. Low serum albumin was associated with an increased risk of Acute Kidney Injury (p=0.004). Transaminitis and thrombocytopenia were common toxicities. Conclusions: Acute Kidney Injury is common following High dose Methotrexate administration in B cell Acute Leukemic Leukemia. Low serum albumin level increases renal toxicity following methotrexate infusion. The measures to prevent renal toxicity should be instituted promptly in high-risk groups.

Development of a Novel Nomogram for Predicting Delayed Methotrexate Excretion in Adult Patients with Hematologic Malignancies

Introduction: High-dose methotrexate (HD-MTX) is an essential regimen for the treatment or prevention of central nervous system disease in hematologic malignancies. However, delayed MTX excretion is a major contributor to increased MTX toxicity and limits its use in populations such as younger individuals with good kidney function. Given the variable degrees of older age and poor renal function, there is a need to focus on developing a more precise predictive tool for delayed MTX excretion rather than avoiding HD-MTX treatment in all patients considered relatively high-risk. The aim of this study is to identify risk factors for delayed MTX excretion in adult patients with hematologic diseases and establish an applicable model for clinical practice. Methods: We performed a retrospective analysis of consecutive patients with acute leukemia or malignant lymphoma who received HD-MTX therapy at Kameda Medical Center between 2011 and 2023. Standard supportive care, such as adequate hydration, urine alkalinization (pH >7.0), and leucovorin rescue, was performed according to our institutional protocol. Delayed MTX excretion was defined as plasma MTX levels ≥ 1 μmol/L at 48 h or ≥ 0.1 μmol/L 72 h after HD-MTX infusion. Univariate and multivariate analyses using logistic regression were performed to identify risk factors for delayed MTX excretion. Variables to create a nomogram was selected using a backward stepwise selection method. The internal validation of the nomogram was conducted using the bootstrap method (1000 bootstrap resample). Results: A total of 216 patients were treated with 579 cycles (median 2, range 1-14) of HD-MTX-containing chemotherapy. The median age was 66 years (range 15-84), with male predominance (58.3%). Most patients (82.9%) had an underlying malignant lymphoma, and most cycles were administered at diagnosis (81%) and for prophylactic intent (76.4%). The delayed MTX excretion occurred 129 in 579 cycles (22.2%); 39 (30.2%) at 48 hours and 107 (82.9%) at 72 hours after MTX infusion, and 17 (13.2%) at both time points. On univariate analysis, neither the dose of MTX nor the dosing formula (3 hours drip or 24-hour continuous infusion) was a significant risk factor for MTX elimination failure. By contrast, older age (Odds ratio [OR] 1.022, 95% confidence interval [CI] 1.006-1.039, P =0.009), male sex (OR 1.6 [1.05-2.42], P =0.027), levels of albumin (OR 0.44 [0.302-0.639], P <0.001), creatinine clearance (Ccr) (OR 0.99 [0.985-0.998]), gamma-glutamyl transpeptidase (γ-GTP) (OR 1.004 [1.001-1.007], P =0.005), and corrected calcium (cCa) (OR 2.746 [1.646-4.651], P <0.001) significantly associated with MTX clearance. Using backward stepwise selection, sex, albumin, Ccr, γ-GTP, and cCa were selected as continuous variables to create a nomogram (Figure 1). The nomogram showed the area under the curve of 0.69 (95%CI 0.64-0.74) in predicting delayed MTX excretion (Figure 2) without significant overfitting (optimism =0.091). Finally, we evaluated the impact of MTX elimination failure on clinical outcomes. As expected, delayed MTX excretion was highly associated with the development of any grade acute kidney injury (OR 30.9 [10.6-90.1], P <0.001). Patients who experienced a delay in MTX clearance had significantly worse survival after receiving HD-MTX than those without (5-year survival rate 38% vs. 64.5%, P <0.001). This negative effect remained significant (hazard ratio 1.73 [1.08-2.78], P =0.02) after adjusting age and disease status on multivariate analysis. Conclusions: To our knowledge, this is the first study to construct an easy-to-use nomogram based on routinely measured biochemical data and gender predicting the risk of delayed MTX excretion. Further studies are needed to validate this model and integrate the dynamic factors such as urine output and alkalinization.

Access to Methotrexate Monitoring in Latin America: A Multicountry Survey of Supportive Care Capacity

High-dose methotrexate (HDMTX) is used to treat a broad spectrum of cancers. Methotrexate (MTX) monitoring and adequate supportive care are critical for safe drug administration; however, MTX level timing is not always possible in low- and middle-income countries. The aim of this study was to evaluate HDMTX supportive care capacity and MTX monitoring practices in Latin America (LATAM) to identify gaps and opportunities for improvement. A multicenter survey was conducted among LATAM pediatric oncologists. Twenty healthcare providers from 20 institutions answered the online questionnaire. HDMTX was used to treat acute lymphoblastic leukemia (ALL; 100%), non-Hodgkin lymphoma (84.2%), diffuse large B-cell lymphoma (47.4%), osteosarcoma (78.9%), and medulloblastoma (31.6%). Delays in starting HDMTX infusion were related to bed shortages (47.4%) and MTX shortages (21.1%). MTX monitoring was performed at an in-hospital laboratory in 52%, at an external/nearby laboratory in 31.6%, and was not available in 10.5%. Median interval between sampling and obtaining MTX levels was ≤ 2 h in 45% and ≥ 6 h in 30%, related to laboratory location. Sites without access to MTX monitoring reduced the MTX dose for patients with high-risk ALL or did not include MTX in the treatment of patients with osteosarcoma. Respondents reported that implementation of point-of-care testing of MTX levels is feasible. In LATAM, highly variable supportive care capacity may affect the safe administration of MTX doses. Improving accessibility of MTX monitoring and the speed of obtaining results should be prioritized to allow delivery of full doses of MTX required by the current protocols.

A-126 Evaluation of NMR-based GFR Estimation in Dosing of High-dose Methotrexate

Abstract Background The cytotoxic agent methotrexate (MTX) is mainly used in oncology and rheumatology. MTX is 80%–90% excreted unchanged in the urine, thus, impaired renal excretion because of kidney disease leads to accumulation and prolonged exposure, with a consequent increased risk of myelosuppressive and other toxic adverse effects. Direct kidney damage from MTX crystal precipitation and tubular injury may also occur. Therefore, precise and accurate measurement of renal function prior to MTX administration is of paramount importance to determine accurate dosing and to minimize such adverse risks. Commonly used estimated glomerular filtration rate (eGFR) equations perform poorly in patients with cachexia and at later stages of life—the typical oncology patient. Here we evaluate the feasibility of applying the recently introduced nuclear magnetic resonance (NMR)-based GFR equation (GFRNMR) using creatinine, cystatin C, myo-inositol, and valine, in oncology patients receiving high-dose MTX. Methods A series of residual sera from patients scheduled to receive high-dose MTX infusion for oncological indications were collected from two sites: n = 52 sera from the University Hospital Regensburg (Regensburg, Germany), at four time points (t0h, t24h, t42h, and t48h), and n = 10 cross-sectionally from the Mayo Clinic (MN). Standard drug-monitoring trough levels were used as a reference. Serum was prepared and NMR-measured in five replicates for all samples. GFRNMR was compared with the current standard GFR equations: i) CKD-EPI2021Cr (creatinine) and ii) CKD-EPI2021CrCys (creatinine and cystatin-C). Coefficient of determination for linear regression, kappa coefficient for categorical regression and bootstrapped confidence intervals were calculated. Results MTX was shown not to increase the GFRNMR failure rate or affect the intra-assay precision of GFRNMR. When monitoring eGFR during high-dose MTX treatment, MTX affected GFR according to the RIFLE criteria for AKI in 13 cycles in 9 patients; 1/13 were classified as ‘risk’ (creatinine increased 1.5-fold) and 1/13 were classified as ‘injury’ (creatinine increased 2.0-fold). Using MTX clearance as a surrogate for measured GFR, GFRNMR was shown to reflect the MTX plasma clearance constant k more accurately (using a fitting function c = c0*e−kt) with r = 0.758 (95% CI 0.36–0.92, P = 0.004) compared to CKD-EPI2021Cr (r = 0.401, 95%CI −0.19–0.78, P = 0.176) and CKD-EPI2021CrCyc (r = 0.632, 95% CI 0.12–0.88). Conclusion The robustness of GFRNMR test results is not affected by HD-MTX treatment. Compared to standard eGFR equations, GFRNMR is more closely associated with MTX renal clearance rates and may therefore be a novel method to improve the accuracy of MTX dosing in the future.

Early clinical indicators of acute kidney injury caused by administering high-dose methotrexate therapy to juvenile pigs.

Early identification of compromised renal clearance caused by high-dose methotrexate (HDMTX) is essential for initiating timely interventions that can reduce acute kidney injury and MTX-induced systemic toxicity. We induced acute kidney injury (AKI) by infusing 42 juvenile pigs with 4 g/kg (80 g/m2) of MTX over 4 hours without high-volume alkalinizing hydration therapy. Concentrations of serum creatinine and MTX were measured at 15 time points up to 148 hours, with 10 samples collected during the first 24 hours after the start of the HDMTX infusion. During the first 28 hours, 81% of the pigs had increases in the concentrations of serum creatinine in one or more samples indicative of AKI (i.e., > 0.3g/dL increase). A rate of plasma MTX clearance of less than 90% during the initial 4 hours after the HDMTX infusion and a total serum creatinine increase at 6 and 8 hours after starting the infusion greater than 0.3 g/dL were predictive of AKI at 28 hours (p < 0.05 and p < 0.001, respectively). At conclusion of the infusion, pigs with a creatinine concentration more than 0.3 g/dL higher than baseline or serum MTX greater than 5,000 μmol/L had an increased risk of severe AKI. Our findings suggest that serum samples collected at conclusion and shortly after HDMTX infusion can be used to predict impending AKI. The pig model can be used to identify biological, environmental, and iatrogenic risk factors for HDMTX-induced AKI and to evaluate interventions to preserve renal functions, minimize acute kidney injury, and reduce systemic toxicity.

Assessing the Safety of Discharging Patients Receiving High-Dose Methotrexate with Levels Greater Than 0.1 Umol/L

Introduction: High-dose methotrexate (HD-MTX) remains a backbone therapy in a number of malignancies and is defined as a dose of greater than 500 mg/m2. HD-MTX requires supportive measures to minimize toxicity, particularly nephrotoxicity. MTX levels are followed to ensure adequate clearance of drug. Historically, patients were discharged with a MTX level of ≤0.05 umol/L. However, many single-center studies have shown that liberalizing the discharge level to <0.1 umol/L is safe and allows earlier hospital discharge. At NYU Langone Health (NYULH), many patients with stable renal function are discharged with a level of >0.1 umol/L, with supportive medications including oral leucovorin with or without sodium bicarbonate. The aim of our study is to confirm the safety of discharging patients with a MTX level of >0.1 umol/L. Methods/Results: This was a single center, retrospective, institutional-review board approved study of all adult patients who received HD-MTX in the inpatient setting, between January 1, 2017 and February 20, 2021. The primary endpoint was the incidence of renal injury post discharge from the HD-MTX admission. Outcomes were analyzed among three MTX level categories at discharge (>0.2 umol/L, 0.1-0.2 umol/L, <0.1 umol/L). If patients received more than one cycle of HD-MTX, each cycle was reported as an individual event. Baseline characteristics were reported based on the first infusion of each unique individual. Baseline renal insufficiency was defined as a creatinine clearance (CrCl) of less than 30 mL/min. Renal injury was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0). The first outpatient serum creatinine (SCr) documented in the patient chart post HD-MTX hospitalization was utilized to analyze renal injury. The study included 108 patients who received a total of 336 HD-MTX infusions. The primary indication for HD-MTX was central nervous system prophylaxis for diffuse large b-cell lymphoma or acute lymphoblastic leukemia. The most common HD-MTX doses were between 1,001-3,500 mg/m2 compared to 500-1,000mg/m2 and >3,500mg/m2 (p=0.0006). Four patients (4%) had baseline renal insufficiency. Of the 336 infusions, 49 (15%) infusions were categorized into MTX discharge level >0.2 umol/L, 145 (43%) into MTX 0.1-0.2 umol/L, and 142 (42%) into MTX <0.1 umol/L. Within the discharge category >0.2 umol/L, the median level was 0.28 umol/L (IQR, 0.22 - 0.37). The highest level was 1.04 umol/L at discharge. Patients were more likely to be discharged with oral leucovorin if they were discharged with a MTX level >0.1 umol/L (p<0.001). Similarly, patients were more frequently prescribed oral sodium bicarbonate if discharged with a MTX level >0.2 umol/L (p<0.001). There were 28 (8%) renal injury events, with no significant difference in renal injury occurring among the three MTX discharge level ranges. The renal injury events were primarily Grade 1. The median LOS in our study was statistically longer in the MTX <0.1 umol/L category (4 days, IQR 3-12) compared to the MTX 0.1-0.2 umol/L and >0.2 umol/L categories, 3 days (IQR 3-4) and 3.4 days, (IQR 3-4), respectively (p=0.023). There were 14 readmissions post HD-MTX hospitalization discharge. Two patients were admitted on two separate encounters after HD-MTX administration, leaving 12 unique patients. The primary reason for readmission was for myelosuppression, although all of these patients received other cytotoxic chemotherapy as part of the hyper-CVAD regimen. Two readmissions were after a MTX discharge level of >0.2 umol/L and 6 readmissions for both MTX discharge level of 0.1- 0.2 umol/L and <0.1 umol/L. Conclusion: Our study demonstrates that it is safe to discharge patients with a MTX level of >0.1 umol/L, with no difference in renal injury, and supporting shortened length of stay. Our data also suggest that it is safe to discharge a patient with a MTX level up to 0.4 umol/L, as our upper 75th quartile range was 0.37 umol/L, acknowledging supportive medications are prescribed. Limitations of this study include the retrospective nature of the study and heterogenous population. The length of stay data are confounded by other factors as well including multiday chemotherapy regimens, infections, and newly diagnosed malignancies. Our plan is to create an institutional protocol to outline the supportive care to support an early discharge of patients receiving HD-MTX. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hypoalbuminemia and not undernutrition predicts high-dose methotrexate-induced nephrotoxicity in children with acute lymphoblastic leukemia in resource-constrained centers.

The standard practice to mitigate high-dose methotrexate (HD-MTX)-induced nephrotoxicity (HMN) in acute lymphoblastic leukemia (ALL) is to monitor levels until serum MTX falls below a predefined threshold. It is not feasible in most resource-constrained centers. Literature on the various factors affecting HMN in these centers is limited, retrospective, and heterogeneous. Though hypoalbuminemia has been postulated as a risk factor for HMN, the relationship of undernutrition with HMN has not been studied. This prospective observational study consecutively enrolled children<12 years old with ALL receiving HD-MTX. Children with preexisting renal disease and exposed to nephrotoxic drugs two weeks preceding HD-MTX infusion were excluded. HD-MTX was administered over 24 hours (BFM-2009 protocol) with 12 hours of prehydration. Solitary MTX levels at 36 hours (MTX36) were outsourced, and 6-8 doses of leucovorin were given six-hourly. Hydration was continued till last dose of leucovorin. Various factors affecting HMN (rise in creatinine to 1.5 times baseline) were recorded: age, sex, type of ALL, risk group of ALL, first dose of MTX, dose of MTX, undernourishment, serum protein, and albumin along with C-reactive protein and MTX36 levels. Forty-four children who received 150 HD-MTX cycles were analyzed. HMN was seen in 14% of cycles. On univariate analysis, undernourishment, MTX36 levels, hypoproteinemia, and hypoalbuminemia were significantly associated with HMN. On multivariate analysis, hypoalbuminemia and MTX36 levels significantly predicted the development of HMN with odds ratios of 4.71 and 1.45. Hypoalbuminemia and solitary serum MTX levels predict HMN in centers where serial MTX level monitoring is not feasible.

Is hypoalbuminemia a risk factor for high-dose methotrexate toxicity in children with acute lymphoblastic leukemia?

BackgroundRepeated high-dose methotrexate (HDMTX) is a critical component of contemporary childhood acute lymphoblastic leukemia (ALL) treatment regimens. Serum albumin is considered a carrier of methotrexate (MTX) in the blood. Hypoalbuminemia is not a rare finding in children with leukemia. This study aimed to investigate the relationship between pre-infusion serum albumin and possible HDMTX toxicities.MethodsThirty Egyptian children with ALL were consecutively enrolled in the study between May 2018 and July 2020. They were prospectively followed up while receiving HDMTX during the consolidation phase of the TOTAL study XV protocol. HDMTX was administered intravenously as a 24-h infusion every 2 weeks. Doses of 2.5 g/m2 were used for low-risk patients and 5 g/m2 for standard/high-risk patients. The Common Terminology Criteria for Adverse Events (V.4.03) was used to report the observed toxicities after HDMTX cycles. Plasma MTX levels were estimated at 24 h (MTX24) from the beginning of HDMTX infusion in the first consolidation cycle. Serum albumin level was determined before HDMTX administration, and pre-infusion hypoalbuminemia was defined when serum albumin was <3.5 g/dL.ResultsThe patients’ age ranged from 2.3 to 13.3 years at diagnosis, and most of them had B cell ALL (86.7%). Overall, 120 HDMTX cycles were analyzed, equally distributed between low and standard/high risk. Grade 3–4 anemia, grades 3–4 thrombocytopenia, febrile neutropenia, and oral mucositis were significantly more frequent in HDMTX cycles with pre-infusion hypoalbuminemia than those with normal pre-infusion albumin (p=0.003, p=0.007, p=0.006, and p=0.001, respectively). In addition, pre-infusion hypoalbuminemia was significantly associated with additional hospitalization due to HDMTX toxicity (p=0.031). Most HDMTX toxicities were comparable irrespective of the MTX dose. Oral mucositis was more frequently encountered in the 2.5 g/m2 than the 5 g/m2 HDMTX cycles (46.7 vs. 26.7%, p=0.023). A significantly longer hospitalization (due to HDMTX toxicity) was observed in the 5 g/m2 HDMTX cycles (median= 7 days vs. 4 days, p=0.012).ConclusionsSerum albumin levels should be checked before starting HDMTX cycles, especially in resource-limited settings where malnutrition is common, and serum MTX monitoring may not be available. Optimizing serum albumin levels before HDMTX may help decrease the possibility of HDMTX toxicities.

Can high-dose methotrexate be safely administered to outpatients?

34 Background: High-dose methotrexate (HD-MTX) is administered as prophylaxis for central nervous system (CNS) relapse in Diffuse Large B Cell Lymphoma (DLBCL). It is traditionally administered in an inpatient setting due to its complex supportive care regimen. We developed an outpatient protocol and evaluated the safety of this approach. Methods: In 2019 a multidisciplinary team at Kingston Health Sciences Centre developed an outpatient HD-MTX protocol for CNS prophylaxis in DLBCL. Select eligible patients received their HD-MTX infusion in the day unit and returned daily for bloodwork and monitoring. Leucovorin and continuous intravenous hydration were administered via ambulatory infusion pumps. A single centre retrospective cohort analysis was conducted on all patients who received outpatient HD-MTX. These patients were compared to a historical control group who underwent inpatient HD-MTX and who would have met outpatient eligibility criteria. To evaluate the safety of the outpatient protocol we compared the risk of significant toxicity, defined as an elevation in serum creatinine or oral mucositis of grade III or higher, or development of febrile neutropenia. We also evaluated the time to MTX serum clearance, patient admissions and delays of subsequent chemotherapy cycles. Results: From June 2017 to March 2021, 6 outpatients undergoing 14 HD-MTX cycles and 13 inpatients undergoing 28 cycles were evaluated. Significant toxicity occurred in one outpatient cycle compared to five inpatient cycles (7.1% vs 17.9%, p = 0.79). Average time to MTX clearance was 4.1 days for outpatients and 3.5 days for inpatients (p = 0.013). Only one outpatient was admitted to hospital, resulting in an average length of hospital stay of 0.5 days for outpatients compared to 4.96 days for inpatients. There was no significant difference in the need to delay a subsequent cycle of chemotherapy. Conclusions: Outpatient administration of HD-MTX can be administered safely and effectively as CNS prophylaxis in select patients with DLBCL.[Table: see text]

High dose methotrexate containing regimen in pediatric non-metastatic extremity osteosarcoma patients: experience from a tertiary cancer center in India

Methotrexate containing chemotherapy is less commonly used for treatment of osteosarcoma in resource limited settings. We present our experience with the administration of high dose methotrexate (HDMTX) containing chemotherapy over a period of three years. Children between 1 and 14 years of age with newly diagnosed nonmetastatic extremity osteosarcoma, registered in Pediatric Oncology Department of a tertiary care cancer center in South India between 1st January 2016 and 31st December 2018 and receiving MAP chemotherapy were included. Patients in this study received HDMTX at 12 g/m2. Twenty two patients were included. After neoadjuvant chemotherapy, 20 patients underwent surgery (limb salvage surgery in 16, amputation in 4). The median time from initiation of chemotherapy to surgery was 97.5 days. Eighteen of 22 patients (81.8%) completed planned chemotherapy in our cohort, one patient was lost to follow up after progression and three patients required change of chemotherapy due to toxicities. Of a total of 227 cycles of HDMTX infusions in 22 patients, delayed clearance occurred in 22 cycles (9.7%). Major toxicities were myelosuppression (30 episodes in 17 patients), blood stream infections (24 episodes in 15 patients) and mucositis (15 episodes in 10 patients). Hearing loss was documented in 7 patients. There was no treatment related mortality. Chemotherapy was completed in a median duration of 38.5 weeks. Administration of high dose methotrexate containing chemotherapy is feasible in pediatric patients with osteosarcoma, even in resource limited settings, if there are facilities for hydration, determination of methotrexate levels and good supportive care.

Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

PurposeLow doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity.MethodsWe reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected.ResultsRapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given.ConclusionA pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

A single assessment of methotrexate levels at 42 hours permits safe administration and early discharge in children with lymphoblastic lymphoma and leukemia receiving high-dose methotrexate

High-dose methotrexate (HDMTX) is an important component of treatment in pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Optimal rescue therapy is essential for the safe administration of HDMTX. A cost-effective strategy that does not compromise safety is necessary for low- and middle-income countries. Consecutive admissions for HDMTX in children with ALL and LL over 12 months were analyzed. The dose of HDMTX was 3 g/m2 in B-ALL and B-LL and 5 g/m2 in T-ALL and T-LL. A methotrexate level was measured at 42 hours of starting HDMTX infusion (T42-MTX). Three doses of folinic acid at T42, T48, and T54 and alkalinized hydration till T54 were administered if T42-MTX <1 µM. A total of 282 cycles of HDMTX that were administered in 71 patients were analyzed. T42-MTX was <1 µM in 266 (94.3%) cycles. T42-MTX was ≥1 µM in 12% and 3% of cycles of HDMTX administered at a dose of 5 g/m2 and 3 g/m2, respectively (p = .074). The median duration of hospitalization for HDM was three days and did not differ with the dose of HDMTX administered (p = .427). Mucositis, delayed recovery of blood counts, and hospitalization for reversible toxicity occurred after 21 (7.4%), 28 (9.9%), and 19 (6.7%) cycles of HDMTX, respectively. Mucositis was greater following the administration of 5 g/m2 of HDMTX. A single T42-MTX measurement permits the safe administration of HDMTX and an expedited discharge from the hospital within three days in more than 90% of children with ALL/LL.

A pharmacologically-based approach to high dose methotrexate administration to investigate nephrotoxicity and acute kidney injury biomarkers in children and adolescents with newly diagnosed osteosarcoma.

High dose methotrexate (HDMTX) acute kidney injury (AKI) results in prolonged hospitalization and treatment delays. Using a pharmacologically-based approach, HDMTX was administered with standard combination therapy to patients with osteosarcoma; nephrotoxicity was assessed. Patients were randomized by cycle to 4h or 12h HDMTX (12g/m2) infusions administered with hydration, alkalization and leucovorin rescue. Urinalysis, AKI biomarkers, and estimated glomerular filtration rate using serum creatinine or cystatin C (GFRCr or GFRcysC) were obtained. Serum and urine methotrexate concentrations [MTX] were measured. Patients (n = 12), median (range) age 12.4 (5.7-19.2) years were enrolled; 73 MTX infusions were analyzed. Median (95% Confidence Interval) serum and urine [MTX] were 1309 (1190, 1400) µM and 16.4 (14.7, 19.4)mM at the end of 4h infusion and 557 (493, 586)µM and 11.1 (9.9, 21.1)mM at the end of 12h infusion. Time to serum [MTX] < 0.1µM was 83 (80.7, 90.7)h and 87 (82.8, 92.4)h for 4 and 12h infusions. GFRCr was highly variable, increased after cisplatin, and exceeded 150ml/min/1.73m2. GFRcysC was less variable and decreased at the end of therapy. AKI biomarkers were elevated indicating acute tubular dysfunction, however, did not differ between 4 and 12h infusions. Radiographic and histological response were similar for patients receiving 4h or 12h infusions; the median percent tumor necrosis was > 95%. Reducing peak serum and urine MTX concentration by prolonging the infusion duration did not alter risk of acute kidney injury. GFRcysC was decreased at the end of therapy. Proteinuria and elevations in AKI biomarkers indicate that direct tubular damage contributes to HDMTX nephrotoxicity. NCT01848457.

Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.

Development and Validation of UHPLC-MS/MS Assay for Therapeutic Drug Monitoring of High-dose Methotrexate in Children with Acute Lymphoblastic Leukemia.

PurposePrecise and timely detection of methotrexate (MTX) concentration played a key role in high-dose MTX individualization therapy in acute lymphoblastic leukemia (ALL) children to avoid serious adverse effects or nonresponse. This report described a sensibility and validation of ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for therapeutic drug monitoring (TDM) of methotrexate concentration in children’s plasma.MethodsOne-step protein precipitation of samples was accomplished by adding 200 μL of acetonitrile to 100 μL of plasma sample. The separation of plasma samples was carried out on a ZORBAX Eclipse Plus C18 Rapid Resolution HD column with gradient elution using a mobile phase constituted of acetonitrile and 1% formic acid. The detection was executed by electrospray ionization (ESI) of triple quadrupole tandem mass spectrometer (TQMS) in the multiple reaction monitoring (MRM) mode with the transitions m/z 455.2 → 307.9 for methotrexate and m/z 458.2 → 311.2 for IS, separately. Linear concentration range of the calibration curve was 44–11,000 nmol/L and 44 nmol/L was the lower limit of quantification.ResultsThe methotrexate elution time was at 1.577 min, and the overall running time was only 3.3 min. The intra- and interday precision for all the analysis results was within 11.24%, and mean recoveries rate of methotrexate exceeded 87.98%.ConclusionThe described and fully validated UHPLC-MS/MS method was successfully applied in clinical TDM after infusion of high-dose methotrexate 1–5 g/m2 to 41 childpatients.

Clinical outcomes of newly diagnosed primary CNS lymphoma treated with ibrutinib-based combination therapy: A real-world experience of off-label ibrutinib use.

Ibrutinib‐based combination therapy with high‐dose methotrexate (HD‐MTX) has recently shown clinical activity against relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL). Herein, we report our real‐world experience of treating 11 newly diagnosed PCNSL patients with the ibrutinib/MTX combination. HD‐MTX was given at 3.5 g/m2 every 2‐week for eight doses. Ibrutinib was held upon HD‐MTX infusion until clearance and was administered daily post‐induction until disease progression, intolerable toxicity, or death. Nine out of 11 patients completed the induction phase and received ibrutinib as maintenance therapy. An objective response rate (ORR) of 82% (9/11) was observed including complete response (64%) and partial response (18%). The median progression‐free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The ibrutinib/MTX combination was well tolerated in these treatment‐naïve PCNSL patients with an acceptable safety profile. Moreover, the longitudinal analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) revealed that CSF ctDNA detection was closely associated with tumor response, and sustained tumor responses correlated with the clearance of ctDNA from the CSF. In sum, our data not only demonstrated the clinical benefit of the ibrutinib and HD‐MTX combination regimen in treating newly diagnosed PCNSL patients in a real‐world setting, but also highlighted the significance of liquid biopsy including CSF ctDNA in tracing tumor burden and assessing treatment response.

Protocol concordance and impact of protocol deviations on selected outcomes in delivery of high-dose methotrexate in acute lymphoblastic leukemia in Sri Lanka.

17 Background: In Sri Lanka, children with acute lymphoblastic leukemia are treated on the UKALL 2011 protocol, which includes high-dose methotrexate (HDMTX) in high risk patients. Safe delivery of HDMTX is challenging in low resource settings, where deviation from accepted guidelines can occur frequently and result in toxicity, subsequent treatment delays, and in extreme cases, death. The goal of this study was to compare current practices to the treatment and supportive care details described in the protocol to identify the incidence and impact of guideline-discordant care to deliver HDMTX more safely children with cancer in Sri Lanka. Methods: We reviewed medical records to assess guideline concordance in 4 critical aspects of HDMTX delivery: 2 consecutive alkaline urine pH readings in the 2-hour period before starting HDMTX, 24-hour duration of MTX infusion (as opposed to early stop), the first dose of folinic acid administered later than 36 hours from start of HDMTX infusion (no inappropriately early rescue), and the administration of at least 3 folinic acid doses per course (appropriate duration of rescue). We analyzed how each deviation influenced AKI (creatinine increase of 0.3 mg/dL or more), infection, and treatment delays (defined as recovery delayed 7 days or longer from the 14 days expected between courses of HDMTX). Results: We analyzed 309 HDMTX courses in 91 patients younger than 20 years, including 105 girls (34%). In 83 courses (27%) alkaline urine was not documented prior to the start of MTX. Infusion time was less than 24 hours in 239 courses (77%), most of which finished 20-21 hours. In 37 courses (12%), the first folinic acid dose was given inappropriately early, and in 25 courses (8%) less than 3 doses of folinic acid were given. There were 2 episodes of AKI, 43 infections, 11 treatment delays and one death. None of the 4 guideline deviations were significantly associated with AKI or treatment delays. Patient sex was also not associated with any difference in guideline discordance or outcome (p&gt;0.1 in all cases). Conclusions: Significant deviations from HDMTX administration guidelines were common, especially early completion of infusion. However, outcomes were not impacted so quality standards may require adjustment to focus only on extreme deviations likely to impact patient outcomes.

Do intravenous fluid substitutions influence methotrexate clearance? An unanticipated impact of an intravenous sodium bicarbonate drug shortage.

National drug shortages of essential medications for childhood cancer have increasingly posed a challenge in the treatment of patients. The efficacy of standardized supportive care practices to avoid treatment-related toxicities may be limited during these drug shortages. High-dose methotrexate (HDMTX) plays a critical role in modern treatment protocols for acute lymphoblastic leukemia and requires stringent supportive care measures to mitigate toxicity. As the result of a national intravenous (IV) sodium bicarbonate shortage, institutional standard HDMTX supportive care guidelines had to be modified. We describe the unanticipated consequences on HDMTX clearance. We performed a retrospective chart review assessing the impact of alternative compositions of IV fluids on the mean 24-h methotrexate levels (Cpss ) of 25 patients receiving 76 total HDMTX infusions at Texas Children's Hospital Cancer Center from March to October 2017. During the sodium bicarbonate drug shortage, all patients received IV hydration consisting of either dextrose 5%, 0.45% normal saline (D5 ½ NS-Group A) or dextrose 5%, 0.2% normal saline (D5 ¼ NS-Group B). Patients receiving a higher total sodium dose demonstrated significantly lower Cpss (25.36 ± 16.6 μMol) compared to patients receiving less sodium (53.9 ± 37.9 μMol; P<.001). Our report shows that in the setting of IV sodium bicarbonate shortage, the composition of hydration IV fluids may affect methotrexate clearance. Patient who received a higher sodium load had a lower 24-h methotrexate level. This demonstrates the potential for unanticipated outcomes resulting from national drug shortages.

High-Dose Methotrexate in Pediatric Acute Lymphoblastic Leukemia: Predictors of Delayed Clearance and the Effect of Increased Hydration Rate on Methotrexate Clearance.

ObjectivesHigh-dose methotrexate (HDMTX) is an important chemotherapeutic agent in the treatment of many cancers. Identification of the predictors of poor clearance during HDMTX infusions could advance the introduction of improved supportive care to prevent toxicities and reduce hospital length of stay. The purpose of this study was to identify relationships between patient physical characteristics and HDMTX clearance in the treatment of pediatric acute lymphoblastic leukemia (ALL). At our hospital, patients who have delayed methotrexate (MTX) clearance during a cycle of HDMTX receive an increased rate of hydration with subsequent cycles. This increase in hydration rate was examined for its potential to mitigate predictors of poor clearance and to prevent nephrotoxicity.MethodsThis study retrospectively examined the treatment records of 87 pediatric patients diagnosed with ALL who were treated on or according to Children’s Oncology Group (COG) protocols AALL0232, AALL0434, AALL1131, and AALL1231. Each patient received four cycles of HDMTX (5 g/m2 over 24 hours) at two-week intervals. Patients received either 125 ml/m2/hour (standard) or 200 ml/m2/hour (delayed clearance protocol) hydration before, with, and after each infusion. MTX levels taken at 24-, 42-, and 48-hour time points were used as an indirect measure of drug clearance. Two-tailed inference for ordinary least squares regression and both heteroskedastic and paired two-tailed t-tests were performed to identify physical characteristics associated with delayed MTX clearance and the effects of hydration rate on MTX clearance, respectively.ResultsPatient age and body surface area (BSA) were found to have statistically significant (p<0.05) positive associations with the serum MTX levels at 24, 42, and 48 hours in cycle 1. Age and BSA were significant only at the 24-hour time point in cycles 2 and 4. Weight alone was not associated with delayed MTX clearance. For patients who had delayed MTX clearance once and thus received the delayed clearance protocol in subsequent cycles, increasing the hydration rate from 125 to 200 ml/m2/hour was associated with a statistically significant decrease in average MTX levels as well as serum creatinine levels at the 24-, 42-, and 48-hour time points. Once patients with delayed clearance received the 200 ml/m2/hour rate of hydration, the history of prior poor clearance lost its predictive value for serum MTX levels and delayed clearance.ConclusionsThese results suggest that patient age and BSA are significant predictors of MTX clearance if all patients receive the same rate of hydration. Age and BSA affect the distribution phase of MTX kinetics, with downstream effects in the elimination phase. Increased hydration mitigates the effects of these physical characteristics on the elimination phase kinetics by improving renal elimination of MTX, causing a loss of significance of age and BSA as predictors of MTX levels in subsequent cycles at the 42- and 48-hour time points, but with less effect at 24 hours. Thus, hyperhydration regimens prior to cycle 1 of HDMTX could be considered for patients presenting with risk factors of advanced age or high BSA to avoid delayed clearance.