High-dose Methotrexate Therapy Research Articles

Clinical feasibility of a label-free SERS assay for therapeutic drug monitoring of methotrexate

We present a therapeutic drug monitoring (TDM) feasibility study using a label-free surface-enhanced Raman spectroscopy (SERS)-based assay for quantifying methotrexate (MTX) from samples collected from children with acute lymphoblastic leukemia undergoing high-dose MTX therapy. We show that, when combined with an appropriate sample preparation (solid phase extraction) and multivariate data analysis (partial least squares regression), the SERS assay demonstrated a good correlation with a reference chromatographic method (r = 0.889, p < 0.005). We also found that the SERS-based approach underestimated MTX concentration, with a 10% bias calculated, but both methods showed similar variability (RSD of 8.4% for HPLC and 11.6% for SERS). The presented results are strong evidence that SERS can be used for TDM of MTX, and this work brings us one step closer to implementing a SERS-based assay in clinics.

Phase 2 study of glucarpidase in patients with delayed methotrexate elimination after high-dose methotrexate therapy.

High-dose methotrexate therapy (HD-MTX) is a standard treatment for various malignant tumors, but approximately 1-10% of patients experience delayed MTX elimination (DME) that can induce organ damage. Glucarpidase can hydrolyze MTX and thereby lower the level of active MTX in the blood. A multicenter, open-label, phase II investigator-initiated trial (CPG2-PII study) was conducted to evaluate glucarpidase rescue therapy in Japanese patients who showed DME after HD-MTX treatment. To confirm the robustness of this therapy, further corporate-sponsored clinical trial (OP-07-001 study) was conducted. The primary endpoint in the CPG2-PII study was to evaluate the proportion of patients of the percentage clinical important reduction (CIR) as an indicator of MTX concentration, which can be managed with leucovorin and supportive care. The primary endpoint of the OP-07-001 study was to evaluate the decreasing rate of plasma MTX concentration at 20min after glucarpidase administration from the baseline for four patients. Glucarpidase was administered at a dose of 50 U/kg for 15 and 4 patients, respectively in the two studies, and safety was analyzed for each of them. The rate of CIR was 76.9% (95% confidence interval, 46.2-95.0%) in the CPG2-PII study. The median reduction rate of plasma MTX was 98.83% in the OP-07-001 study. Hypersensitivity, blood bilirubin increased, and headache for each patient were the only study drug-related events. Glucarpidase showed an effect of reducing plasma MTX concentration in Japanese patients with DME as that observed in a previous US study, confirming its favorable safety and tolerability.

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.

Factors influencing delayed high-dose methotrexate excretion and its correlation with adverse reactions after treatment in children with malignant hematological tumors.

High-dose methotrexate (HDMTX) is crucial in treating pediatric malignant hematological tumors. However, its use is often complicated by delayed excretion and associated adverse reactions, which can significantly affect treatment outcomes and patient safety. Identifying risk factors is essential for safer, more effective therapy. This study aimed to investigate the influencing factors for delayed excretion and their correlation with adverse reactions in children with malignant hematological tumors after receiving HDMTX chemotherapy. From April to October 2021, the clinical information of children who had undergone HDMTX chemotherapy and had their blood tested for drug concentration was gathered by the Department of Hematology and Oncology at Shanghai Children's Medical Center. Via univariate and multivariate logistic regression, the factors affecting the delayed excretion of HDMTX were examined, and the relationship between delayed excretion and unfavorable effects in children was determined. This study included 99 patients comprising 199 courses of HDMTX. The occurrence rate of HDMTX delayed excretion was 20.1%. Age ≥9 years and a 24-hour methotrexate (MTX) concentration of 64 µmol/L were independent risk factors for delayed MTX excretion according to multivariate logistic regression analysis (P<0.05). Negative side effects, such as fever, infection, mucositis, gastrointestinal response, and decreased platelet count in children with delayed excretion were statistically significant when compared to those of children with normal excretion. White blood cell reduction, hemoglobin levels below 65 g/L, MTX excretion delay, and concomitant etoposide treatment were all independent risk factors for infection in children. To estimate the risk of delayed MTX excretion during HDMTX therapy, patient laboratory data should be scrutinized, especially for patients ≥9 years or those with a 24-hour MTX concentration of greater than 64 µmol/L.

Acetazolamide for acute kidney injury in patients undergoing high dose methotrexate therapy: a systematic review and meta-analysis.

Urine alkalization is one of the standard treatments to prevent acute kidney injury in patients receiving high-dose methotrexate. Carbonic anhydrase inhibitors are promising adjuvants/substitutes with advantages such as faster urine alkalization time and prevention of fluid overload. However, there is limited and contradictoryevidence on its efficacy and safety. We aimed to compare the efficacy and safety of carbonic anhydrase inhibitors to standard treatments in adult patients receiving high-dose methotrexate. The protocol was registered at PROSPERO (CRD42022352802) in August 2021. We evaluated the use of carbonic anhydrase inhibitors in combination with standard treatment compared to standard treatment alone. We excluded articles irrelevant to the efficacy and safety of acetazolamide in patients receiving high dose methotrexate and/or did not provide sufficient data regarding doses, recruitment criteria, and follow-up period. Two authors performed the data extraction independently. Among 198 articles retrieved, six observational studies met all eligibility criteria. Four studies with five datasets (totaling 558 patients/cycles) had enough data to be included in the meta-analysis. We independently report the results from the two remaining studies. The results did not show a significant difference between acetazolamide versus standard treatment in acute kidney injury (AKI) rate (OR = 0.79, 95% CI 0.48-1.29, P = 0.34, I2 = 0%). Regarding the time to urine pH goal, there was no significant time difference between the two groups (Mean Difference = 0.07, 95% CI - 1.9 to 2.04, P = 0.95, I2 = 25%). Furthermore, our meta-analysis showed that acetazolamide did not reduce length of stay (Mean Difference = 0.75, 95% CI -0.8 to 2.31, P = 0.34, I2 = 0%). In one study, the only reported side effect of acetazolamide was hypokalemia (nearly 50% in the acetazolamide group). This systematic review showed no significant difference between acetazolamide and standard care treatment regarding urine alkalinization time and AKI rate in adult patients receiving high dose methotrexate. We suggest performing a large blinded, randomized, controlled trial to evaluate the potential benefits of this low-cost medication.

Influence of Hypoalbuminemia on Methotrexate Clearance in Children Receiving High Dose Methotrexate Therapy

Aim: Methotrexate, a structural counterpart of folic acid, is well recognized as a very efficacious pharmaceutical agent utilized in the treatment of several pediatric oncological conditions. A high-dose methotrexate is employed as a therapeutic intervention for a diverse range of malignant conditions including leukemia, lymphomas, and osteosarcoma. Hypoalbuminemia also decreases the methotrexate clearance leading to increased toxicity. Objective: To determine the frequency of side effects among patients receiving high dose methotrexate therapy based on baseline albumin levels. Study Design: A quasi-experimental trial was conducted at the Pakistan Institute of Medical Sciences, Islamabad, from January 1, 2023, to July 31, 2023. A total of thirty-four children receiving HDMTX were enrolled in the study. Albumin level, grade of liver toxicity, renal function tests, gastrointestinal and neurological toxicity, and mucositis were noted. Length of stay and methotrexate level at 24 hours were also noted. All the information was recorded in proforma.

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 &amp;gt;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 &amp;lt;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 &amp;lt;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 &amp;lt;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 &amp;lt;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.

The effect of the plasma methotrexate concentration during high-dose methotrexate therapy in childhood acute lymphoblastic leukemia

Two hundred and thirty-one acute lymphoblastic leukemia (ALL) children with 1376 high-dose methotrexate (HD-MTX) courses (3–5 g/m2) were enrolled to analyze the influence of the plasma MTX concentration (C MTX) in ALL. The 24-h target peak C MTX (C 24h) was set at 33 μmol/l for low-risk (LR) and 65 μmol/l for intermediate/high-risk (IR/HR) groups. The median C 24h was 42.0 μmol/l and 69.7 μmol/l for LR and IR/HR groups, respectively. MTX excretion delay was observed in 14.6% of courses, which was more frequent in IR/HR groups (56.9% vs. LR group 40.2%, p = .014) and T-ALL patients (82.6% vs. B-ALL 47.1%, p = .001). MTX-related toxicities were more common in courses with MTX excretion delay. However, survival between the patients who failed to reach the target C 24h or not, with or without MTX excretion delay, was comparable. These findings suggest that, owing to the effectiveness of risk stratification chemotherapy, C MTX does not exert an independent influence on the prognosis of childhood ALL.

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.

A pooled subgroup analysis of glucarpidase treatment in 86 pediatric, adolescent, and young adult patients receiving high-dose methotrexate therapy in open-label trials.

Delayed methotrexate elimination can occur in patients undergoing high-dose methotrexate cancer treatment. Effectiveness of glucarpidase for rapidly reducing methotrexate concentrations was shown in compassionate-use trials in patients aged 0-84years. We performed post hoc analyses of infants (≥28days to <2years), children (≥2 to <12years), adolescents (≥12 to <15years), and young adults (≥15 to <25years) from four multicenter, open-label, single-arm, glucarpidase compassionate-use trials. Patients had toxic methotrexate levels due to delayed methotrexate elimination and/or renal dysfunction, and received glucarpidase (50U/kg). The primary endpoint was clinically important reduction (CIR) in plasma methotrexate (methotrexate ≤1μmol/L at all post-glucarpidase measurements) based on high-performance liquid chromatography. Among 86 patients included in efficacy analyses, CIR was achieved by zero of one infant (0.0%), five of 16 children (31.3%), seven of 24 adolescents (29.2%), and 26/45 young adults (57.8%). Median methotrexate reduction was 98.7% or higher in each group 15minutes post-glucarpidase. Patients with pre-glucarpidase methotrexate less than 50μmol/L (35/42, 83.3%) were more likely to achieve CIR than those with methotrexate 50μmol/L or higher (1/37, 2.7%). The most common treatment-related adverse event was paresthesia, occurring in three adolescents (4.5%) and six young adults (5.2%). No other treatment-related adverse event occurred in 5% or higher of any age group. After accounting for pre-glucarpidase methotrexate levels, glucarpidase efficacy at inducing CIR in pediatric/young adult patients was consistent, with efficacy observed in the overall study population (i.e., patients aged 0-84), and no unexpected safety findings were observed. These findings demonstrate glucarpidase (50U/kg) is an effective and well-tolerated dose for pediatric, adolescent, and young adult patients.

High dose methotrexate (MTX) treatment: Value of post treatment MTX level monitoring and risk factors for acute kidney injury.

e19539 Background: High-dose methotrexate therapy is an effective treatment for primary central nervous system (CNS) lymphoma and other tumors. Methotrexate (MTX) is an antimetabolite which penetrates blood brain barrier when administered intravenously at high doses. Defective or delayed clearance of MTX may lead to toxicities, especially acute kidney injury (AKI) in 2-13% of patients. We developed a protocol to mitigate side effects by checking MTX levels every 24 hours, administering leucovorin or glucarpidase rescue, and hydration with urine alkalization. This study examines the risk factors for developing AKI after high dose MTX administration. Methods: Patients who began treatment with high dose methotrexate in 2020 and 2021 were eligible. We collected data on demographics, diagnosis, methotrexate levels, laboratory levels at baseline and after treatment, toxicities, interventions and outcomes. Results: 26 patients were included, who received 112 cycles of treatments (median 3.5, range 1-10). Median age was 62 years (range 25-83) and 57% were male. 20 patients experienced elevated MTX levels. Among the 112 cycles, MTX levels were elevated at 24h, 48h and 72h in 22 (19.6%), 16 (14.3%), and 45 (40.2%) of the cycles respectively, which trigged an increase in the rescue leucovorin dose and hydration dose in 26 (23.2%) and 16 (14.3%) cycles, respectively. AKI was recorded in 20 cycles (17.9%), with 17 (85%) being grade 1 (ULN – 1.5 x ULN), and 3 (2.7%) being grade 2 (1.5-3x ULN). In 20 cycles with AKI, 9 (45%) had grade 1 elevated creatinine level pretreatment; 8 (88.9%) of them remained grade1 without increase &gt; 0.2. The development of AKI occurred in all MTX dose levels, without a difference in frequency. 57% of cycles with elevated 24h MTX level, and 13% of cycles with delayed clearance &gt; 4 days, were associated with AKI. 75% of cycles with AKI had delayed clearance (avg 7 days). Two patients required glucarpidase rescue treatment, based on elevated 24-36 h MTX level and grade 1-2 AKI; one of these patients permanently discontinued MTX. Conclusions: Among 26 patients who received a total of 112 cycles of high dose MTX treatment, 11 developed AKI in 20 cycles, mostly grade 1 with spontaneous recovery. MTX level elevation at 24 hours predicted the development of AKI. Elevated baseline creatinine or MTX dose range is not a risk factor for AKI.

FEASIBILITY AND SAFETY OF HIGH‐DOSE METHOTREXATE INTERCALATED WITH R‐CHOP IN DIFFUSE LARGE B‐CELL LYMPHOMA: A SINGLE‐CENTER EXPERIENCE

Background: Central nervous system (CNS) relapse still represents an often-fatal event in diffuse large B cell lymphoma (DLBCL). Efforts to prevent it aimed to identify higher risk patients and to administer adequate prophylaxis. In this setting, unmet needs such as the type of prophylaxis (high-dose methotrexate, HD-MTX vs. triple intrathecal therapy) and its timing are still under debate. Hereby, we report our experience of DLBCL patients undergoing CNS prophylaxis with systemic HD-MTX intercalated with systemic chemotherapy. Methods: We retrospectively collected data of DLBCL patients receiving CNS prophylaxis with at least 1 cycle of HD-MTX from 2017 to 2022. The administration of HD-MTX was based on CNS-IPI and on lymphoma histology/clinical presentation in those cases who may not tolerate more intensified chemo-immunotherapy regimens. We performed a Kaplan-Meier analysis to estimate overall survival. Results: Twenty-one patients received HD-MTX. The mean age at diagnosis was 62 years (range 33–77), with 66% of patients over 60 years. The median Cumulative Illness Rating Scale (CIRS) was 8 (range 4–13). At presentation, 76% of patients had advance stage disease (III-IV) with more than 1 extranodal localization in 15 cases. Median IPI and CNS-IPI were 3 (range 0–5) and 3 (range 0–5), respectively. According to immunohistochemistry, a non-germinal center phenotype was shown in 24% and 52% patients had double-expressor profile. Patients received R-CHOP (71%) or R-COMP (29%) associated with variable HD-MTX dose, adjusted on age and comorbidities. At a mean delay of 2 days after R-CHOP, a median number of 3 HD-MTX cycles were administered at a mean dosage of 2 g/mq (range 1–3). Regarding safety, 19% of patients experienced acute renal injury (ARI), among them 2 in patients over 60 years and only one grade 3 ARI. We observed a complete response (CR) in 67% of patients, up to 79% if considering over 60 years. Particularly patients over 60 years were more likely to achieve CR (p = 0.052), even in those who delayed R-CHOP. At a mean follow-up of 24 months, 82% of patients over 60 years patients are alive (Figure 1). A substantial difference in overall survival was seen in patients reaching CR than others (100% vs. 33%) (p = 0.001). Six patients relapsed at a median time of 3 months, among them 4 died from lymphoma. Conclusions: Our report confirms the feasibility of HD-MTX in the treatment of DLBCL patients with high-risk features and high comorbidity burden. Patients over 60 years showed higher rate of complete remission without significant toxicity, independently on chemotherapy delay suggesting a good balance between response and toxicity with MRCHOP/COMP in this setting. Further studies with longer follow-up are needed to draw more definitive conclusions, especially in frail patients such as elderly. Keywords: aggressive B-cell non-Hodgkin lymphoma, chemotherapy No conflicts of interests pertinent to the abstract.

Risk factors for acute kidney injury after high-dose methotrexate therapy: a single-center study and narrative review.

To assess the risk factors associated with high-dose methotrexate (HDMTX) (≥ 1g/m2) treatment-induced acute kidney injury (AKI). Patients who received HDMTX from July 2014 to August 2019 in one medical center were enrolled. The patients' demographic, laboratory, and medication data were collected and compared between groups with or without AKI. Risk factors of HDMTX-induced AKI were explored using univariate and multivariate logistic regression analyses. Additionally, we searched and summarized previous studies to identify key correlates of AKI in a narrative review. We enrolled 59 patients who had received 200 HDMTX courses. The incidence of HDMTX-induced nephrotoxicity was 9.5%. Multivariate logistic regression revealed that male sex (odds ratio [OR], 4.20; P = .037), and angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) (OR, 5.18; P = .016) were significantly associated with AKI. Diuretics with urinary acidification, such as loop diuretics, were also a key factor in AKI (OR, 4.91; P = .018). Furthermore, a forest plot identified 21 predictors from nine additional cohort studies showing correlations with the development of AKI. Male sex, ACEIs/ARBs, and diuretics with urinary acidification are associated with AKI. Furthermore, laboratory data should be monitored to assess AKI risk before HDMTX therapy, especially in elderly patients with obesity, diabetes, or acute lymphoblastic leukemia.

Correlation between methylation level of the SLC19A1 promoter region and methotrexate metabolism in adult acute lymphoblastic leukemia.

Aims: To analyze the methylation level in the promoter region of SLC19A1 in adult acute lymphoblastic leukemia (ALL) patients, and explore the relationship between methotrexate (MTX) drug metabolism and SLC19A1 methylation. Methods: The methylation levels of the SLC19A1 promoter region in 52 adult ALL patients who received high-dose MTX chemotherapy were retrospectively analyzed in combination with clinical indicators and plasma MTX concentration. Results: Methylation levels of 17 CpG units were differently correlated with clinical parameters of ALL patients including gender, age, immunophenotype and Philadelphia chromosome status. Patients with delayed MTX drug excretion had higher methylation levels in the SLC19A1 promoter region. Conclusion: The methylation may affect the MTX plasma level and adverse reactions, which may predict patients at risk of adverse reactions after high-dose MTX therapy.

Primary pituitary lymphoma successfully treated with Bruton’s tyrosine kinase inhibitor monotherapy: case report

Introduction: Primary pituitary lymphoma (PPL) is a rare disease characterized by lymphoma confined to the sella or parasellar region without systemic involvement. The clinical symptoms of PPL may include headache, hypopituitarism, visual field disturbance and visual impairment. To date, there is no established standard treatment for this condition. Here, we present a case of successful treatment with a Bruton’s tyrosine kinase (BTK) inhibitor. Case report: A 78-years-old man with a history of severe left renal insufficiency caused by retroperitoneal fibrosis, and sequential right nephrostomy, underwent brain magnetic resonance imaging (MRI) due to the altered hormonal status. An enlarged pituitary stalk was noted and led to a diagnosis of lymphocytic hypopituitarism. Six months later, visual field disturbance and visual acuity deterioration developed, and an MRI revealed a neoplastic lesion and further enlargement of the stalk and the pituitary itself, with an obvious optic nerve compression. Expedited transsphenoidal partial resection was performed to relieve the compression. Pathohystology led to the diagnosis of the large B-cell lymphoma of the germinal center origin. Because of the patient’s poor renal function, high-dose methotrexate therapy was not an option; rather, the patient was treated with a BTK inhibitor - tirabrutinib. Symptoms improved within a week, and a follow-up MRI confirmed a marked reduction of the pituitary lesion. Conclusion: BTK inhibitors may be considered as a first-line treatment option for PPL, especially in patients with contraindications for other treatment protocols.

Usefulness of leadless pacemaker implantation to continue chemotherapy for Burkitt's lymphoma without device infection despite repeated systemic infections.

Usefulness of leadless pacemaker implantation to continue chemotherapy for Burkitt's lymphoma without device infection despite repeated systemic infections.

プロテオーム解析とゲノム薬理学を応用した薬剤性中枢神経障害の病態解明

Neurocognitive complications such as leukoencephalopathy after high-dose intravenous methotrexate therapy （HD‒MTX） are important for childhood cancer survivors, because these neurocognitive complications affect the quality of life of patients. We identified Protein A in cerebrospinal fluid （CSF） as an MTX-related neurotoxicity-associated protein by proteomics analysis. In a series of CSF samples obtained during MTX-containing chemotherapy of 17 pediatric patients with hematological malignancy, Protein A was elevated at onset and just before onset of neurocognitive complications associated with HD‒MTX or intrathecal MTX therapy in the patients. The concentration of MTX in CSF was higher in the 5 g/m2 HD‒MTX group than the 2 g/m2 HD‒MTX group. We will evaluate the significance of Protein A in CSF as a biomarker for leukoencephalopathy in a larger cohort. We will also study the association between Protein A and MTX in CSF and leukoencephalopathy by pharmacogenetic approach.

Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy.

Glucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation. In this study, a CPG2 population pharmacokinetics (popPK) analysis in healthy volunteers (phase 1 study) and a popPK-pharmacodynamics (popPK-PD) analysis in patients (phase 2 study, n = 15) who received 50 U/kg of CPG2 rescue for delayed MTX excretion were conducted. In the phase 2 study, the first CPG2 treatment at a dose of 50 U/kg was intravenously administered for 5min within 12h after the first confirmation of delayed MTX excretion. The second dose of CPG2, with a plasma MTX concentration >1 μmol/L, was administered to the patient more than 46h after the start of CPG2 administration. The population mean PK parameters (95% CI) of MTX, obtained from the final model post hoc, were estimated as follows: CLrMTX = 2.424 L/h (95% CI: 1.755-3.093), VcMTX = 12.6 L (95% CI: 10.8-14.3), VpMTX = 2.15 L (95% CI: 1.60-2.70), and α = 8.131 x 105 (4.864 x 105-11.398 x 105). The final model, including covariates, was CLrMTX (L/h): 3.248 x Body Weight/Serum creatinine/60 (CV 33.5%), VcMTX (L): 0.386 x Body Weight/body surface area (CV 29.1%), VpMTX (L):3.052 x Body Weight/60 (CV 90.6%), and α (L/h): 6.545 x 105 (CV 79.8%). These results suggest that the pre-CPG2 dose and 24h after CPG2 dosing were the most important sampling points in the Bayesian estimation of plasma MTX concentration prediction at 48h. These CPG2-MTX popPK analysis and Bayesian estimation of rebound in plasma MTX concentrations are clinically important to estimate >1.0 μmol/L 48h after the first CPG2 dosing. https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2363, identifier JMA-IIA00078 and https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2782, identifier JMA-IIA00097.

Long-term outcomes of combined intravitreal methotrexate and systemic high-dose methotrexate therapy in vitreoretinal lymphoma.

The optimal treatment for vitreoretinal lymphoma (VRL) remains a challenge, as central nervous system (CNS) relapse occurs frequently, leading to the worst impact on survival. We previously proposed combined intravitreal methotrexate and systemic high-dose methotrexate therapy for this disease. This study aimed to report the long-term outcomes of patients with VRL using this combination treatment. We conducted a retrospective cohort study on patients with VRL at a tertiary referral center between 2003 and 2018. Thirty-two patients were included, of whom 23 had primary VRL (PVRL) and nine had concurrent intraocular and CNS diseases. The treatment was well tolerated. Twenty-six (81.3%) patients achieved complete response (CR). After a median follow-up time of 103.5 months, the 5-year survival rate was 73.3%, whereas the 5-year progression-free survival (PFS) rate was 29.9%. Twenty-four (75%) patients relapsed, including 12 with isolated intraocular relapses at first relapse and a total of 17 with CNS/systemic relapses. The development of CNS/systemic relapse negatively affected survival, but intraocular relapse did not. The median CNS/systemic PFS was 69.5 months, but the risk of CNS/systemic relapse increased steadily with a cumulative incidence rate at 2, 5, and 10 years being 22.6%, 44.2%, and 65%, respectively. Multivariate analysis identified concurrent CNS disease at diagnosis as the only poor-risk factor for CNS/systemic relapse. This study confirms good efficacy and acceptable toxicities of the combination approach. However, incorporation of further intensive consolidation strategies into the treatment protocol to effectively prevent subsequent CNS/systemic relapse deserves to be considered.

Risk assessment and prophylactic treatment strategies for central nervous system relapse of diffuse large B-cell lymphoma

Rituximab treatment significantly improved the outcomes of diffuse large B-cell lymphoma (DLBCL). A central nervous system (CNS) relapse remains a serious and fatal event for patients with DLBCL; therefore, the clinical question of the optimal treatment regimen for reducing the risk of CNS relapse remains unknown. The CNS-International Prognostic Index was identified as a predictive model for CNS relapse. No factors can completely predict CNS relapse although several reports regarding high-risk factors for CNS relapse have been reported. In practice, intrathecal methotrexate (MTX) and high-dose MTX therapy have been used for CNS prophylaxis. Unfortunately, evidence of the optimal therapy for CNS prophylaxis in patients with DLBCL remains lacking. This study aimed to review CNS relapse assessment and discuss study results with clinical impacts on CNS prophylaxis treatment strategies in DLBCL.