Courses Of High-dose Methotrexate Research Articles

Frontline combination of dasatinib and low-intensity chemotherapy in adults with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia

ABSTRACT Background Studies on dasatinib-based low-intensity induction regimens and post-remission strategies are limited in China. Therefore, we conducted a single-center phase 2 trial in newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) to establish the efficacy and safety of this treatment approach. Research design and methods Patients received one month of dasatinib plus low-intensity chemotherapy and two months of dasatinib monotherapy for induction, followed by a single course of high-dose methotrexate for consolidation. Subsequently, they underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) or tyrosine kinase inhibitor (TKI)-based treatment for maintenance therapy between October 2015 and August 2022. Results Twenty-two patients were enrolled. Median age was 45 years (range, 20–71). The rates of major and complete molecular responses in the third month were 18.2% and 40.9% respectively. With a median follow-up of 15 months (range, 5–89), the estimated 3-year disease-free survival (DFS) and overall survival (OS) were 52.4% and 73.2%, respectively. The TKI-based cohort had a significantly poorer DFS (p = 0.014) and OS (p = 0.008) than the allo-HSCT cohort. Conclusions Our results suggest that dasatinib-based low-intensity chemotherapy is safe and effective as an induction strategy in the Chinese population. Allo-HSCT plays a crucial role in the long-term outcomes of patients with Ph+ ALL. Clinical trial registration The trial was registered at ClinicalTrials.gov as NCT02690922.

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.

Assessment of Outcomes of Consolidation Therapy By Number of Cycles of Blinatumomab Received in Newly Diagnosed Measurable Residual Disease Negative Patients with B-Lineage Acute Lymphoblastic Leukemia: In the ECOG-ACRIN E1910 Randomized Phase III National Clinical Trials Network Trial

Introduction: ECOG ACRIN E1910 is a randomized phase III trial that showed that adults with newly diagnosed BCR::ABL1 negative acute lymphoblastic leukemia (ALL) who become MRD negative (&amp;lt;0.01%) after induction chemo who receive blinatumomab with conventional chemotherapy (chemo) have improved survival compared with those who received chemo only (Litzow et al, Blood (2022) 140: Supplement 2, LBA-1). However, not all pts were able to receive all four planned cycles of blinatumomab in consolidation. In this report we assessed outcomes of pts in the blinatumomab arm of the trial who received all 4 cycles of blinatumomab compared to those who received 1-2 cycles. Methods: Patient between the ages of 30 and 70 with newly diagnosed BCR::ABL1 negative B-lineage ALL were enrolled and initially received 2.5 months of combination induction chemo utilizing a BFM-like regimen adapted from the E2993/UKALLXII clinical trial, with pegaspargase (after induction only for patients &amp;gt;=55 years of age) and addition of rituximab for CD20 positive patients. After remission induction (step 1) pts in morphologic complete remission (CR/CRi) received an intensification course of high dose methotrexate with pegaspargase for CNS prophylaxis (step 2). At the conclusion of step 2, remission and MRD status were determined centrally by 6-color flow cytometry with MRD negativity defined as &amp;lt;0.01%. In the primary analysis subset, MRD negative patients were randomized to receive an additional 4cycles of consolidation chemo or 2 cycles of blinatumomab at 28 mcg/day (flat dose) for 28 days each cycle followed by 3 cycles of consolidation chemo, another 4-week cycle of blinatumomab (3rd cycle of blinatumomab) followed by an additional cycle of chemo and then a 4th cycle of blinatumomab (step 3). Following completion of consolidation chemo +/- blinatumomab, pts were given 2.5 years of POMP maintenance therapy timed from the start of the intensification cycle (step 4). Estimates of OS were calculated using the Kaplan-Meier method. Comparison of OS between treatment arms were conducted using the stratified log-rank test and Cox proportional-hazards model with age, CD20 status, rituximab use, and whether pts intend to receive HSCT or not as stratification factors. As the number of cycles needed to optimize outcome has not been studied, an unplanned landmark analysis was used to compare OS of pts in the blinatumomab arm who received all 4 cycles o those who received 1-2 cycles. Time 0 was chosen as 9 months post step 3 randomization (the time that patients were supposed to complete 4 cycles of blina). Four pts who received blinatumomab but died within 9 months post step 3 randomization were therefore excluded from this analysis. Results: The study was activated on December 17, 2013 and closed to enrollment on October 15, 2019. 772 pts were screened for the trial and 488 were enrolled on step 1 induction therapy. The median age of the pts was 51 years (range 30-70). 224 MRD negative pts were randomized, 112 pts to each arm. In the blinatumomab arm 12 pts received 1 cycle (11%), 32 pts received 2 cycles (29%), 4 pts received 3 cycles (4%) and 63 pts received 4 cycles (57%). The OS of pts who received 1-2 cycles of blinatumomab was compared to control (Figure 1) The difference was not significant (hazard ratio 0.62, 95% CI 0.28 to 1.34, p=0.22). Fig 2 compares the survival of those who received 1-2 cycles to those who received 4 cycles ( (HR: 0.39, 95% CI 0.12 to 1.16, p=0.076). Conclusion: The addition of blinatumomab to consolidation chemotherapy resulted in a significantly better overall survival compared to chemotherapy alone in pts with newly diagnosed B-lineage ALL who were MRD negative after intensification. This represents a new standard of care for pts aged 30-70 years with BCR::ABL1 negative ALL. The optimal dose and number of cycles is however unknown. In this unplanned subgroup analysis we demonstrate that a survival benefit can only be confirmed in patients who receive the intended 4 cycles of blinatumomab during consolidation. Further studies will be needed to determine if fewer cycles can provide a similar benefit.

Higher incidence of delayed methotrexate clearance in pediatric acute lymphoblastic leukemia patients treated with imatinib

BackgroundPediatric patients with Philadelphia chromosome positive (Ph+) or ABL-class fusion positive acute lymphoblastic leukemia (ALL) are currently treated with the tyrosine kinase inhibitor (TKI) imatinib added to a chemotherapy backbone that also contains several courses of high-dose methotrexate (HDMTX). A limited number of case studies suggested delayed MTX clearance in patients concomitantly using HDMTX and imatinib. MethodsMTX clearance and serum creatinine in 24 newly diagnosed Ph+/ABL-class fusion positive pediatric ALL patients treated with imatinib (imatinib group) were compared with 281 randomly selected age-matched Ph-negative pediatric ALL patients treated without TKI (control group), receiving in total 61 and 897 HDMTX courses, respectively. ResultsMild to severe delayed MTX clearance (MTX level at T48 hours>0.4 µM) was more frequently found in the imatinib group than in the control group in all courses (55.7% vs 41.1% p = 0.036). After the first HDMTX course, 12.5% (n = 3) of the imatinib group presented with a severe delayed MTX clearance (T48 > 5 µM) versus 2.3% in the control group (p = 0.039). In two (8.3%) of these patients in the imatinib group, this was accompanied by increased creatinine, therefore meeting the criteria for Delayed MTX Elimination (DME). In the control group 12/281 (4.3%) patients presented with DME. Glucarpidase was administered in 2 (8.3%) vs 4 (1.4%) patients in the imatinib group and control group, respectively. ConclusionImatinib increased the risk of delayed MTX clearance in newly diagnosed pediatric Ph+ chromosome or ABL-class fusion positive ALL patients. We therefore recommend stringent supportive care measures and for patients with severe delayed MTX clearance resulting in severe toxicities temporary discontinuation of imatinib or a lower dose of MTX during the next HDMTX courses.

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.

High-Dose Methotrexate-Related Toxicity in Children with Acute Lymphoblastic Leukemia

Introduction: High-dose methotrexate (HD-MTX) is a key component in treatment of acute lymphoblastic leukemia (ALL) but associates with several toxicities. In addition to myelosuppression and emesis, HD-MTX has specific adverse effects such as oral mucositis, nephrotoxicity, hepatotoxicity, dermatitis, and methotrexate-related stroke like syndrome. Toxicity during prior courses of HD-MTX, delayed MTX elimination and pre-existing nephropathy are associated with toxicity, but information on other risk factors is scarce. Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol included an intensive consolidation with HD-MTX for non-high risk patients. We aimed to describe the incidence of and risk factors for HD-MTX induced toxicity during consolidation therapy. Method: This is a retrospective study, including patients aged 2-<18 years with ALL, treated according to the non-high risk arm of the NOPHO ALL2008 protocol in Stockholm and Uppsala, Sweden, during 2008-2019. Data on toxicities during the consolidation was collected after the three HD-MTX courses (5 g/m2) during consolidation. Concomitant chemotherapeutic agents were pegylated asparaginase, vincristine and oral mercaptopurine. The registered toxicities included hematological toxicity (transfusions and/or neutropenia), infections or mucositis requiring hospitalization, administration of intravenous antibiotics or parenteral nutrition, liver toxicity, dermatitis, increased creatinine and CNS toxicity (definitions in Table). Clinical variables included age, immunophenotype, renal ultrasound at diagnosis, blood cell count and creatinine at diagnosis and at start of HD-MTX, BMI standard deviation scores (BMI-SDS), and weight change during induction. Results: The study cohort comprised 143 patients with 426 high-dose HD-MTX courses in total. The median age at diagnosis was 5.1 years (IQR 5.09). Toxicity was common, especially after the first HD-MTX course (Figure). Every fifth patient was hospitalized due to mucositis after the first HD-MTX and 79% of those needed parenteral nutrition. Infections were frequent; 49.7% were admitted to in-patient care with infection after the first HD-MTX, of whom all but one (70/71) were treated with intravenous antibiotics and 15% had a positive blood culture. Hematological toxicity, whilst most frequent after the first HD-MTX, was common after all three HD-MTX courses. A significantly higher risk of recurrent toxicity after the first HD-MTX was found for mucositis (Odds ratio (OR) 5.4; 95% confidence interval (CI) 1.1- 26.1; p=0.034), dermatitis (OR 32.8; 95% CI 5.5-197; p=<0.001), delayed nephrotoxicity (OR 59.0; 95% CI 11.2-307; p=<0.001). Liver toxicity and acute nephrotoxicity were not associated with an increased risk of recurrence after subsequent HD-MTX courses. When risk factors were analyzed separately for the first HD-MTX course, mucositis was more frequent in patients with weight loss (> 5%) during induction (p=0.007). The median BMI-SDS at diagnosis was also lower in patients with mucositis than those without (p=0.081). High MTX concentration (MTX >1 µM at hour 42) at first HD-MTX was associated with an increased need of thrombocyte- (p=0.021) and erythrocyte transfusion (p=0.041). Mildly (42-hour plasma MTX ≥1.0-3.9 µM), moderately (42-hour plasma MTX ≥4.0-9.9 µM) or severely delayed (42-hour plasma MTX ≥10 µM) elimination was seen in 38.0% (moderate; 5.6%; severe; 1.4%), 17.6% (moderate 2.1%) and 19.9% (moderate; 1.4%; severe; 0.7%) after first, second and third HD-MTX courses, respectively. Higher MTX concentration and slower clearance to non-toxic levels was associated with acute and delayed nephrotoxicity after the first HD-MTX (p=0.001). Conclusion: Our study demonstrated that severe toxicities that warrant hospitalization are very common, especially after the first HD-MTX. Low BMI at diagnosis and weight loss during induction was related to higher risk for mucositis and high MTX concentration and delayed excretion predicted nephrotoxicity after the first HD-MTX. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing.

High-dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity. Anonymized, de-identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non-profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite. A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three-compartment model adequately fitted the data. Time-dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose-normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence. We developed a population pharmacometric model that considers weight, albumin and time-dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.

Methotrexate(MTX) Induced Leukoencephalopathy(LE) and Relation of Vitamin B12, Folate and / or Homocysteine Levels with MTX Toxicity: A Prospective Study

▪Background: MTX-induced neurotoxicity is often associated with leukoencephalopathy, and the diagnostic radiological feature in magnetic resonance imaging (MRI) is white matter hyper intensities. The clinical significance of these white matter changes is unknown. The risk factors of MTX-induced acute leukoencephalopathy are not well established. Few authors have suggested increased homocysteine or alteration of Central Nervous System (CNS) folate, vitamin b12 homeostasis may be associated with CNS toxicity. It is a usual clinical practice to withhold methotrexate during further duration of chemotherapy after an episode of leukoencephalopathy but the risk of neurotoxicity must be weighed against the risk of relapse of leukemia. Moreover, there is limited data on continued treatment with High-dose methotrexate (HD-MTX) or Intrathecal Methotrexate (IT-MTX) or Oral-MTX in patients who developed leukoencephalopathy.Objective: The study aims to 1) identify the risk and prevalence of leukoencephalopathy in patients of Acute Lymphoblastic Leukemia (ALL) receiving intrathecal or high dose or oral methotrexate therapy through sequential MRI Brain study. 2) Safety of re-administration of methotrexate in patients with documented toxic leukoencephalopathy 3) The relationship of serum homocysteine, vitamin b12 and folate levels with methotrexate induced leukoencephalopathyMethods: Our study enrolled 34 newly diagnosed pediatric ALL / Lymphoblastic Lymphoma (LBL) patients (age ≤18 years) between June 2019 & June 2020. Induction chemotherapy was initiated as per modified ALL IC BFM 2002 protocol after obtaining informed consent. Apart from the Hematological investigations, Bone Marrow Aspiration and Biopsy, Flow Cytometry/Immunohistochemistry (IHC), Cytogenetics, Molecular study were done. All the patients underwent MRI Brain and Serum homocysteine, Vitamin B12, Folate level measurement (sequentially as per protocol at 4 different time points). 1st time point - AT DIAGNOSIS, i.e. before starting methotrexate, 2nd time point - POST CONSOLIDATION, 3rd time point - POST EXTRACOMPARTMENT THERAPY, 4th time point - IN MAINTENANCE, thus analyzing leukoencephalopathy secondary to different modes of administration of methotrexate therapy. At all-time points serum folate, vitamin b12 or homocysteine level were done before administering methotrexate and any association with development of leukoencephalopathy was analyzed.Results: We identified Leukoencephalopathy secondary to methotrexate in 6.03% (7/116) on MRI brain in 5 of 33 (15.15%) patients of which 1 (3.03%) had symptomatic LE and 4 (12.12%) were clinically asymptomatic. All our LE patients were in the age group more than or equal to 10 years. We found no increase in the incidence of leukoencephalopathy secondary to methotrexate: leucovorin ratio, also there was no difference in the incidence with respect to mode of administration of MTX (IT/HD/ORAL), even there was no increase in incidence after 4 courses of high dose methotrexate. MRI at baseline was not a predictor of development of leukoencephalopathy. 3 out of 5 patients with LE had abnormal b12/folate/homocysteine with corresponding abnormal MRI Brain at pre-specified time point. Also 4 patients with abnormal b12/folate/homocysteine levels had intractable cytopenias while on chemotherapy and more after HD MTX therapy which got corrected after supplementation with vitamin b12 and folic acid.Conclusion: MTX-induced clinical leukoencephalopathy is transient, and most patients can be re-challenged with subsequent MTX without recurrence of acute or subacute symptoms. MRI at baseline was not a predictor of development of leukoencephalopathy. More multi institutional prospective studies of large number of patients are needed to study the incidence of MTX-induced leukoencephalopathy and its relation with folic acid, vitamin b12 and homocysteine level. DisclosuresNo relevant conflicts of interest to declare.

Efficacy and safety of humanized CD19 CAR-T as a salvage therapy for recurrent CNSL of B-ALL following murine CD19 CAR-T cell therapy.

The present study aimed to compare the differences between the humanized CD19 chimeric antigen receptor (CAR)-T cell therapy and the murine CD19 CAR-T therapy in recurrent B-acute lymphoblastic leukemia (B-ALL). A 62-year-old male patient who had B-ALL (BCR/ABL+) for 4 years was diagnosed with relapsed central nervous system leukemia (CNSL). After several courses of high dose methotrexate combined with intrathecal chemotherapy, the patient received murine CD19 CAR-T therapy and achieved complete response (CR). The patient was diagnosed with relapsed CNSL again 15 months after his murine CD19 CAR-T therapy, and was therefore enrolled in the humanized CD19 CAR-T therapy. Subsequently, the present study aimed to compare murine and humanized CD19 CAR-T cells against Nalm-6 cells in vitro and in mice. The patient initially achieved CR from his murine CD19 CAR-T therapy with Grade 1 cytokine-release syndrome (CRS) and Grade 1 CAR-T cell-related encephalopathy syndrome (CRES). The patient then achieved CR again from his humanized CD19 CAR-T therapy with Grade 1 CRS and Grade 2 CRES. Peak levels of CD19 CAR-T cells were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy 7 days after infusion in the peripheral blood, in bone marrow and in cerebrospinal fluid (CSF). The cytokine levels were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy in the peripheral blood and in CSF. The cytotoxicity to Nalm-6 cells was higher in humanized CD19 CAR-T cells than that in murine CD19 CAR-T cells in vitro. In Nalm-6 BALB/c mice, the median survival time of mice in the murine CD19 CAR-T group was 35 days, while it was 43 days in the humanized CD19 CAR-T group. In conclusion, humanized CD19 CAR-T cell therapy had a better curative effect than that of murine CD19 CAR-T therapy, and may be used as a salvage treatment for recurrent B-ALL after treatment with murine CD19 CAR-T therapy.

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.

Risk factors for delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia and lymphoma.

High-dose methotrexate (HD-MTX) therapy is widely used in patients with acute lymphoblastic leukemia (ALL) and lymphoma. However, some patients experience delayed MTX elimination, which requires treatment suspension or dose reduction to avoid organ damage. This single-center retrospective analysis reviewed the clinical data of 88 children with ALL or non-Hodgkin lymphoma who received a total of 269 courses of HD-MTX therapy between April 2008 and April 2019. HD-MTX was defined as MTX administration at 2.0, 3.0, or 5.0g/m2 over a 24-h period, and delayed MTX elimination was defined as a serum MTX concentration ≥ 1.0µmol/L at 48h after the start of HD-MTX. Clinical factors were compared between courses with and without delayed MTX elimination. MTX elimination was delayed in 21 of the 269 courses (7.8%). Multivariate analysis showed that first HD-MTX course (OR 4.04), lower urine volume per BSA on the first day of HD-MTX administration (< 2,675mL/m2, OR 5.10), higher total bilirubin (> 0.5mg/dL, OR 5.11), lower eGFR (< 136mL/min/1.73m2, OR 3.90), higher dose of MTX(> 3.0g/m2, OR 10.8), and lower urine volume per BSA on the next day of starting HD-MTX (< 2,107mL/m2, OR 3.43) were independent risk factors for delayed MTX elimination.

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.

The evaluation of red blood cell folate and methotrexate levels during protocol M in childhood acute lymphoblastic leukemia

BackgroundAfter High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients. Leucovorin and MTX are structural analogues, possibly competing for cellular transport and intracellular metabolism. We hypothesize that Leucovorin accumulates during consecutive courses, which might result in a lower MTX uptake.MethodsWe prospectively measured red blood cell (RBC) folate and MTX levels during four HD-MTX and Leucovorin courses in 43 patients treated according the DCOG ALL-11 protocol with 2-weekly HD-MTX (5 g/m2/dose) and Leucovorin (15 mg/m2/dose) using LC-MS/MS. We estimated a linear mixed model to assess the relationship between these variables over time.ResultsBoth RBC MTX-PG and folate levels increased significantly during protocol M. MTX-PG2–5 levels increased most substantially after the first two HD-MTX courses (until median 113.0 nmol/L, IQR 76.8–165.2) after which levels plateaued during the 3d and 4th course (until median 141.3 nmol/L, IQR 100.2–190.2). In parallel, folate levels increased most substantially after the first two HD-MTX courses (until median 401.6 nmol/L, IQR 163.3–594.2) after which levels plateaued during the 3d and 4th course (until median 411.5 nmol/L, IQR 240.3–665.6). The ratio folate/MTX-PG decreased significantly over time, which was mostly due to the relatively higher increase (delta) of MTX-PG.ConclusionThese results suggest that the increase in RBC folate levels does not seem to have a large effect on RBC MTX levels. Future studies, assessing competition of Leucovorin and MTX on other cellular mechanisms which might negatively affect treatment efficacy, are necessary.

Effect of SLCO1B1 Polymorphisms on High-Dose Methotrexate Clearance in Children and Young Adults With Leukemia and Lymphoblastic Lymphoma.

High‐dose (HD) methotrexate (MTX) is a critical component of treatment for hematologic malignancies in children and young adults. Therapeutic drug monitoring is necessary due to substantial interindividual variation in MTX clearance. Common function‐altering polymorphisms in SLCO1B1 (encodes OATP1B1, which transports MTX) may contribute to clearance variability. We performed pharmacokinetic modeling using data for 106 children and young adults treated with HD MTX for hematologic malignancies; of 396 total courses of HD MTX, 360 consisted of 5 g/m2 over 24 hours. We evaluated the contribution of clinical covariates and SLCO1B1 genotype (388A>G and 521T>C) to MTX clearance variability. Of the clinical covariates studied, patient weight improved the pharmacokinetic model most significantly (P < 0.001). The addition of the SLCO1B1 variants individually further improved the model (P < 0.05 for each). An interaction between these variants was suggested when both were included (P = 0.017). SLCO1B1 genotype should be considered in efforts to personalize HD MTX dosing.

ALL-406: Comparison of Safe Delivery of 2 and 5 g/m2 of High-Dose Methotrexate to Children with Acute Lymphoblastic Leukemia in Sri Lanka without Availability of Methotrexate Levels

<h3>Context</h3> In many low- and middle-income countries (LMICs), there are barriers to delivery of chemotherapy based on international protocols. For higher-risk Acute Lymphoblastic Leukemia (ALL) in children and adolescents, most protocols mandate four courses of high-dose methotrexate (HDMTX) at 5 g/m². However, because of the risk of toxicity, many patients in LMICs receive lower doses. <h3>Design</h3> We retrospectively reviewed management and outcomes of patients treated for ALL using HDMTX (2 or 5 g/m²) as a 24-hour infusion to determine whether the higher dose had unacceptable toxicity. <h3>Setting</h3> At the National Cancer Institute Sri Lanka, delivery of HDMTX is challenging due to shortage of nurses, large numbers of patients, crowded conditions, and inability to measure methotrexate levels. Our team disagrees about the optimal dose of HDMTX, with some physicians using 2 and others 5 g/m². <h3>Patients</h3> Ninety-three consecutive patients with ALL treated on protocols containing HDMTX. <h3>Intervention</h3> Two doses of HDMTX were used, based on clinician preference. Each clinician used a uniform strategy for all her/his patients; toxicity risk was not used to determine the dose. <h3>Main outcome measures</h3> We compared methotrexate toxicities, including acute kidney injury, mucositis, infections, hemorrhage, hospital length-of-stay and delay of subsequent treatment cycles. Patient outcomes were also assessed, but with the short follow-up time, no difference in survival would be expected unless toxicities were extreme. <h3>Results</h3> Toxicities were uncommon in all patients (age 3 months to 19 years) who received 330 courses of HDMTX (103 courses of 2 g/m² and 227 courses of 5 g/m²). There was one death in the 5 g/m² arm due to severe mucositis. Mucositis in 5 g/m² was 6/227 (2.6%) and in 2 g/m² was 1/103 (0.97%) (p=0.34). Two courses were complicated by acute kidney injury (1 in each group, p=1.0), and infections occurred in 32/227 (14.1%) higherdose courses versus 8/103 (7.7%) lower-dose courses (p=0.1). Length of stay was 4.8 days in both groups (p=0.88). <h3>Conclusions</h3> HDMTX up to 5 g/m² can be safely delivered, even in a limited-resource setting and no access to methotrexate levels. One death with severe mucositis suggests that monitoring methotrexate levels could improve safety even more.

Re-challenge with High Dose Methotrexate vs. Reduced Dose After Methotrexate Toxicity in Pediatric Osteosarcoma:Case Report

Introduction: Methotrexate (MTX), a classic antifolate, is one of the most widely used and well-studied anticancer agents. High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is one of the standard therapies for osteosarcoma. High-dose methotrexate (HDMTX) can exert significant toxicity and requires complex pharmacokinetic monitoring and leucovorin rescue. The side effect profile of MTX varies markedly according to the dose. Regimens containing MTX are classified as high, intermediate, or low-dose. High-dose methotrexate (HD-MTX; 12 g/m2) is a part of the golden standard therapy for pediatric osteosarcoma (OS). Risk factors associated with MTX toxicity in children with OS are not well defined. Case Presentation: We report here a case of pediatric osteosarcoma with nephrotoxicity associated with delayed MTX excretion who was successfully managed using supportive measures that encouraged us to re-challenge with a full dose of MTX then we reduced the dose to 50% to attain the final critical decision about continuation or changing the regimen of treatment for the patient. Our patient developed moderate renal complications during therapy that improved with supportive care, so we challenged with more cycles of a high dose MTX, but the patient developed serious renal complications. A reduced dose of MTX with 50% was given successfully without any renal impairment. Conclusion: Methotrexate toxicity that might not occur during the initial courses of high-dose MTX is not a predictive of the tolerability of further courses and re-challenging with HDMTX is risky, but reduced dose methotrexate is a good option rather than changing the regimen, with good tolerability and rapid clearance of HDMTX. HDMTX-induced renal impairment occurs in a low percentage of patients with osteosarcoma and can be managed successfully by maximum supportive care. MTX clearance can be affected by gender and age.

Effect of access to care on outcomes of rural and elderly patients with primary central nervous system lymphoma.

e14008 Background: Primary central nervous system lymphoma (PCNSL) can often be cured, especially in younger patients, but requires intense chemotherapy with high-dose methotrexate (HDMTX) and rituximab to optimize outcomes. Toxicities can lead to dose reduction or omission that may increase relapse risk, or lead clinicians to select less effective regimens that do not contain HDMTX. Methods: Anonymized, de-identified data of patients from 110 community oncology practices of the Guardian Research Network (GRN, www.GuardianResearch.org ) was analyzed to determine treatments, toxicities, and outcomes of adults with PCNSL. All data from the medical record is available from GRN (diagnoses, demographics, labs, medicines, toxicities, radiology, pathology, procedures, and encounters), so each patient’s journey can be fully characterized. Results: Of 533805 adults with cancer, 49 were treated for PCNSL with HDMTX-containing regimens (n = 35), other chemotherapy regimens (n = 3), or radiation therapy (RT) alone (n = 11). HDMTX patients received HDMTX only in 8 cases, HDMTX plus rituximab in 23 cases, addition of RT in 11 cases, and HDMTX with other chemotherapy but no rituximab in 3 cases. Survival at 5 years was 53% (standard error [SE] 8.6%) for patients treated with HDMTX versus 33% (SE 13%) for those treated with other therapies. Of those treated with HDMTX, survival was 0% for patients who experienced early toxicity that required cessation of HDMTX prior to receiving 3 doses and having response evaluated versus 62% (SE 9.1%) for patients who received 3 or more courses of HDMTX (p &lt; 0.001). In a multivariable Cox proportional hazards model including completion of at least 3 doses of HDMTX, age, race, and sex, only lack of HDMTX toxicity was associated with survival (hazard ratio 0.22, 95% confidence interval 0.07 to 0.70, p = 0.01). Conclusions: Use of HDMTX and prevention of toxicity improves outcomes for PCNSL patients treated in the community.

Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis

AbstractSurvival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.

Concurrent Imatinib Dosing With High-dose Methotrexate Leads to Acute Kidney Injury and Delayed Methotrexate Clearance in Pediatric Patients With Philadelphia Chromosome-positive B-Cell Acute Lymphoblastic Leukemia.

Imatinib, a tyrosine kinase inhibitor has improved survival in pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. There are no formal drug interactions listed between methotrexate and tyrosine kinase inhibitors. Four pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia had delayed methotrexate clearance during their first cycle of high-dose methotrexate while receiving imatinib, resulting in acute kidney injury. For subsequent high-dose methotrexate cycles, imatinib was withheld resulting in decreased acute kidney injury, shorter time to methotrexate clearance, less toxicity, and shorter hospitalizations. For pediatric patients with acute lymphoblastic leukemia receiving imatinib, we recommend escalated supportive care measures including increased hyperhydration and leucovoruin frequency. For patients with toxicities secondary to delayed clearance or need for glucarpidase, we recommend holding imatinib with subsequent high-dose methotrexate courses.

Current diagnostic and therapeutic standards in aggressive B-celllymphomas

In this review, we focus on new advances regarding diagnostic and therapeutic standards of aggressive B-cell lymphomas. This includes the introduction of the so-called "cell of origin" classification which differentiates diffuse large B-cell lymphomas (DLBCL) into the ABC and GCB subtypes and became part of the revised WHO classification of 2017. While 6-8 cycles of R-CHOP remain the standard of first-line treatment in DLBCL, for young patients up to 60years of age with an international prognostic index (IPI) of 0 the treatment can be shortened to 4 cycles of R-CHOP plus 2 cycles of rituximab.With regard to the prophylaxis of CNS relapse, the so-called CNS-IPI helps to identify patients with high risk of relapse in the CNS even if data from randomized clinical trials is sparse. For those patients, 2 courses of high-dose methotrexate in addition to first-line treatment seem advisable.For patients with relapse or refractory disease, salvage treatment followed by autologous or allogeneic transplantation remains the standard. After failure of 2 lines of treatment, 2 different CAR-T-cell products are licensed offering a potentially curative treatment options even for patients not eligible for transplantation strategies. New treatment modalities as antibody-drug conjugates and bispecific antibodies show promising results in clinical studies and will presumably broaden the spectrum of treatment options for patients with DLBCL.